1

                 DEPARTMENT OF HEALTH AND HUMAN SERVICES

                       FOOD AND DRUG ADMINISTRATION

                 CENTER FOR DRUG EVALUATION AND RESEARCH

                GASTROINTESTINAL DRUGS ADVISORY COMMITTEE 

                      NDA 21-200, Zelmac (tegaserod)

                   Novartis Pharmaceuticals Corporation

                          Monday, June 26, 2000

                                8:30 a.m.

                        Marriott Washington Center
                        9751 Washington Boulevard
                          Gaithersburg, Maryland

                                                                  2

                               PARTICIPANTS

       Stephen Hanauer, M.D., Chairperson
       Thomas H. Perez, M.P.H., Executive Secretary

       MEMBERS

                 Loren Laine, M.D.
                 George D. Ferry, M.D.
                 Christina M. Surawicz, M.D.
                 Joanne A.P. Wison, M.D.
                 Joel Richter, M.D.
                 M. Michael Wolfe, M.D.

       INVITED CONSULTANTS AND GUEST EXPERTS

                 Richard Buyalos, M.D.
                 Richard J. Hammes, R.Ph.
                 Samuel Smith, M.D.

       FDA 

                 Lilia Talarico, M.D.
                 Sonia Castillo, Ph.D.
                 Hugo Gallo-Torres, M.D., Ph.D.
                 Florence Houn, M.D.
                 Raymond Joseph, M.D.
                 Robert O'Neill, Ph.D.

                                                                  3

                             C O N T E N T S

                                                               Page

       Call to Order, Introduction: Stephen Hanauer, M.D.       4

       Meeting Statement: Thomas H. Perez, M.P.H.               4

       Opening Comments: Lilia Talarico                         5

       Novartis Pharmaceuticals Corporation Presentation

            Introduction: Mathias Hukkelhoven, Ph.D.            6

            Irritable Bowel Syndrome: Arnold Wald, M.D.        11

            5-HT4 Receptor Activation: Michael Camilleri, M.D. 18

            Efficacy of Tegaserod: Martin Lefkowitz, M.D.      27

            Preclinical Findings: Philip Bentley, Ph.D.        95

            Review of Data on Ovarian Cysts: Bruce Carr, M.D. 101

            Safety of Tegaserod: Martin Lefkowitz, M.D.       109

            Closing Remarks: Sidney Cohen, M.D.               118

       FDA Presentation 

            Statistical Reviewer: Sonia Castillo, Ph.D.       130

            Medical Reviewer: Raymond Joseph, M.D., FACP,     142

       Open Public Hearing: Ms. Nancy Norton                  167

       Responses from Novartis                                176

       Discussion and Questions                               214

                                                                  4

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

   2                   Call to Order, Introduction

   3             DR. HANAUER:  I would like to call this meeting to

   4   order.  I am Steve Hanauer, Chair of the FDA GI Advisory

   5   Panel.

   6             To begin this meeting, Thomas Perez is going to

   7   give some opening remarks.

   8                        Meeting Statement

   9             MR. PEREZ:  Good morning.  The following

  10   announcement addresses the issues of conflict of interest

  11   with regard to this meeting and is made part of the record

  12   to preclude even the appearance of such at this meeting.

  13             The following announcement addresses the issue of

  14   conflict of interest with regard to this meeting and is made

  15   a part of the record to preclude even the appearance of such

  16   at this meeting.

  17             Based on the submitted agenda and information

  18   provided by the participants, the Agency has determined that

  19   all reported interest in firms regulated by the Center for

  20   Drug Evaluation and Research present no potential for a

  21   conflict of interest at this meeting with the following

  22   exceptions.

  23             In accordance with 18 U.S.C. 208(b), full waivers

  24   has been granted to Dr. Michael Wolfe and Dr. George Ferry.

  25             Copies of these waiver statements may be obtained

                                                                  5

   1   by submitting a written request to the FDA's Freedom of

   2   Information Office located in Room 12A-30 of the Parklawn

   3   Building.

   4             In the event that the discussions involve any

   5   other products or firms not already on the agenda for which

   6   an FDA participant has a financial interest, the

   7   participants are aware of the need to exclude themselves

   8   from such involvement, and their exclusion will be noted for

   9   the record.

  10             With respect to all other participants, we ask in

  11   the interest of fairness that they address any current or

  12   previous financial involvements with any firm whose products

  13   they may wish to comment upon.

  14             In addition, I have been informed by Novartis,

  15   they have asked us to bring to your attention that their

  16   handout was inadvertently printed with a stamp of

  17   "Confidential" on it.  They wish to make it clear that it is

  18   a public document and completely releasable.

  19             DR. HANAUER:  Thank you.

  20             To begin the meeting, I believe Dr. Lilia Talarico

  21   wishes to provide some opening comments.

  22                         Opening Comments

  23             DR. TALARICO:  Good morning.  My name is Lilia

  24   Talarico.  I am the director of the Division of GI and

  25   Coagulation Drug products.  I wanted to welcome you all to

                                                                  6

   1   this advisory committee and before we open the meeting, I

   2   would like to make a couple of comments.

   3             Two members of the GI Advisory Committee, Dr.

   4   Laine and Dr. Hanauer, will leave us because they have

   5   completed their tenure as members of the committee, and we

   6   wanted to take this opportunity to express our gratitude and

   7   thanks for the help that they have provided.

   8             Our thanks go particularly to Dr. Hanauer on whom

   9   we have called on several occasions without problem, and he

  10   has always been very helpful with his immense scientific

  11   knowledge and clinical expertise.

  12             In way of our appreciation and for their

  13   contribution, and with our thanks, we want to provide them

  14   with a little token.

  15             [Presentation of awards to Dr. Laine and Dr.

  16   Hanauer.]

  17             DR. TALARICO:  Thank you very much from all of us.

  18             [Applause.]

  19             DR. HANAUER:  We are going to go right ahead into

  20   the presentation by Novartis.  Dr. Mathias Hukkelhoven will

  21   introduce the group.

  22        Novartis Pharmaceuticals Corporation Presentation

  23                           Introduction

  24                    Mathias Hukkelhoven, Ph.D.

  25             DR. HUKKELHOVEN:  Thank you.

                                                                  7

   1             Dr. Hanauer, Dr. Houn, Dr. Talarico, members of

   2   the FDA Advisory Committee, FDA, and guests:  Good morning.

   3             My name is Matt Hukkelhoven.  I am vice president

   4   of Regulatory Affairs for Novartis Pharmaceuticals

   5   Corporation.  On behalf of Novartis, I would like to thank

   6   you for the opportunity this morning to present and review

   7   tegaserod, also known by its trade name Zelmac.

   8             [Slide.]

   9             Zelmac has been developed to treat multiple

  10   symptoms of irritable bowel syndrome.  Specifically, we are

  11   seeking FDA approval of Zelmac for the following indication.

  12             [Slide.]

  13             Zelmac, or tegaserod, is indicated for the

  14   treatment of irritable bowel syndrome (IBS) in patients who

  15   identify abdominal pain or discomfort and constipation as

  16   their predominant symptoms.

  17             [Slide.]

  18             Before discussing tegaserod, I would like to

  19   review briefly some aspects of irritable bowel disease.  IBS

  20   is a common functional gastrointestinal disorder

  21   characterized by chronic or recurrent abdominal pain or

  22   discomfort, bloating, and altered bowel habits in terms of

  23   both frequency of bowel movements and stool consistency.

  24             The disorder has a broad range of severity ranging

  25   from mild symptoms to severe and intractable symptoms. 

                                                                  8

   1   Although the pathophysiology of IBS is not fully understood,

   2   symptoms appear to be due to disturbances in GI motility and

   3   enhanced visceral sensitivity.

   4             IBS is highly prevalent in the general population

   5   and associated with significant disability and health care

   6   costs.  Prevalence estimates indicate that IBS affects 14 to

   7   24 percent of women and 5 to 19 percent of men.

   8             [Slide.]

   9             The most common subdivision of IBS is based on

  10   altered bowel habits with classification into diarrhea-

  11   predominant IBS, alternating IBS, and constipation-

  12   predominant IBS.

  13             The arrows indicate that this is really a spectrum

  14   of symptoms rather than three very separate distinctions.

  15             In our clinical studies, we enrolled patients who

  16   identified abdominal pain or discomfort and constipation as

  17   their predominant symptoms.  It is important to note that

  18   Zelmac is the first drug developed for constipation-

  19   predominant IBS.

  20             [Slide.]

  21             Tegaserod is a new chemical entity which has the

  22   following pharmacologic profile.  Tegaserod is a potent and

  23   selective 5-HT4 receptor partial agonist.  It modulates

  24   normal and impaired motility throughout the gastrointestinal

  25   tract.

                                                                  9

   1             It modulates intestinal chloride/water secretion,

   2   it inhibits visceral sensation upon colorectal distension,

   3   and tegaserod lacks cardiovascular, renal, respiratory,

   4   central nervous system, and endocrine effects.

   5             [Slide.]

   6             With regard to the clinical development of this

   7   drug, it is important to realize that at the time of the

   8   design of the Phase III program, there were no established

   9   clinical guidelines and no medical consensus in the field

  10   regarding appropriate outcome measures in IBS.

  11             Because of this lack of reference guidelines,

  12   Novartis conferred with medical experts and had several

  13   interactions with FDA regarding the most appropriate outcome

  14   measures for the three tegaserod phase III studies.

  15             In addition, we had a specific consultation with

  16   FDA's GI Division on the outcome measures following the

  17   analysis of the first phase III study.  That is study B351. 

  18   The results of this consultation, i.e., modified outcome

  19   measures were subsequently applied to the other two Phase

  20   III studies, studies B301 and B307, in a fully prospective

  21   way and prior to unblinding of these studies.

  22             [Slide.]

  23             The totality of the data both in terms of primary

  24   outcome measures and secondary endpoints drawn from over

  25   4,000 subjects of whom more than 3,000 IBS patients were

                                                                 10

   1   enrolled in tegaserod clinical studies support the following

   2   clinical profile for tegaserod.

   3             Tegaserod given as 12 mg/day (6 mg BID) is

   4   effective in relieving abdominal pain or discomfort,

   5   bloating, and constipation in patients who identify

   6   abdominal pain or discomfort and constipation as their

   7   predominant symptoms.

   8             The cumulative safety experience further indicates

   9   that tegaserod is safe and well tolerated.

  10             [Slide.]

  11             This morning we would like to present to you

  12   detailed data on the role of tegaserod in constipation-

  13   predominant IBS.

  14             First, Dr. Arnold Wald, Professor of Medicine at

  15   the University of Pittsburgh Medical Center, will present an

  16   overview of the disorder IBS.

  17             Then, Dr. Michael Camilleri will discuss the 5-HT4

  18   receptor physiology and the pharmacodynamic effects of

  19   tegaserod.  Dr. Camilleri is Professor of Medicine and

  20   Physiology at the Mayo Clinic.

  21             Subsequently, Dr. Martin Lefkowitz, who has been

  22   involved in the clinical development of tegaserod at

  23   Novartis, will review the efficacy and safety data of

  24   tegaserod.

  25             Dr. Philip Bentley, from Novartis Preclinical

                                                                 11

   1   Safety Department, will then discuss preclinical findings

   2   with tegaserod.

   3             Subsequently, Dr. Bruce Carr will review the data

   4   on ovarian cysts.  Dr. Carr is Professor and Director of the

   5   Division of Reproductive Endocrinology of the Department of

   6   Obstetrics and Gynecology at the University of Texas in

   7   Dallas.

   8             Finally, Dr. Sidney Cohen, Chairman of the

   9   Department of Medicine of Temple University in Philadelphia,

  10   will present the conclusions of these presentations to the

  11   members of this advisory committee.

  12             I would now like to turn the podium over to Dr.

  13   Arnold Wald for an overview of the disorder irritable bowel

  14   syndrome.

  15             DR. HANAUER:  Just before Dr. Wald starts, I would

  16   mention that the sponsor has asked that we hold questions

  17   until the end of their complete presentation.  So, we will

  18   try, unless there is something burning, to hold it until the

  19   end, which is going to take just about an hour and a half

  20   total.

  21                     Irritable Bowel Syndrome

  22                        Arnold Wald, M.D.

  23             [Slide.]

  24             DR. WALD:  Dr. Hanauer, members of the Advisory

  25   Committee, ladies and gentlemen:  as Dr. Hukkelhoven has

                                                                 12

   1   mentioned, irritable bowel syndrome is a chronic functional

   2   disorder which is characterized primarily by altered bowel

   3   habits and is associated with lower abdominal pain and

   4   discomfort and bloating.

   5             Like all the other functional bowel disorders, it

   6   is characterized by having no biologic disease marker.  Of

   7   course, the hallmark of the syndrome is that the symptoms,

   8   which are generally nonspecific, are not explained by

   9   structural or biochemical abnormalities.

  10             [Slide.]

  11             From a clinical standpoint, there are a variety of

  12   subgroups which are based primarily upon bowel habits.  We

  13   think of these as constipation-predominant, as diarrhea-

  14   predominant, and those patients who have alternating

  15   constipation and diarrhea.

  16             I would emphasize the word "predominant" in that

  17   these symptoms are not exclusive, but they do provide the

  18   major bowel habit which characterizes each of the subgroups.

  19             [Slide.]

  20             The subgroup that we wish to focus on today is

  21   that of the constipation-predominant patients with irritable

  22   bowel syndrome.  Now, this is a disorder which has often

  23   been diagnosed by nonspecific terms and by excluding organic

  24   diseases and therefore the imprecision has characterized

  25   both its clinical activity, as well as the clinical research

                                                                 13

   1   which has been done on it.

   2             In an effort to be more precise, a number of

   3   criteria have been advocated to define irritable bowel

   4   syndrome, particularly for clinical research and

   5   epidemiological purposes.

   6             [Slide.]

   7             One of these criteria which is now in widespread

   8   use is the so-called Rome criteria, and I have listed the

   9   Rome II criteria which were published in 1999 and in book

  10   form this year.

  11             According to these criteria, patients with

  12   irritable bowel syndrome should have at least 12 weeks or

  13   more, which need not be consecutive during the preceding 12

  14   months, of abdominal discomfort or pain that has at least

  15   two out of the following three features:

  16             There should be relief of that discomfort or pain

  17   by defecation.  The onset of discomfort should be associated

  18   with a change in the frequency of stool or with a change in

  19   the form or the appearance of stool.

  20             Rome II differs significantly from Rome I

  21   criteria, the original criteria, and that Rome II requires

  22   that two of these features be present whereas Rome I

  23   criteria required that only one of the three be present.

  24             The study that you will hear today uses the Rome I

  25   criteria in the patients who were entered into it, of those

                                                                 14

   1   patients, 90 percent would fulfill the criteria of both Rome

   2   I and Rome II.

   3             [Slide.]

   4             Now, from an epidemiologic standpoint, irritable

   5   bowel syndrome is quite common in the U.S. population. 

   6   Population surveys have estimated that between 15 and 20

   7   percent of the population will exhibit symptoms which are

   8   consistent with this disorder.

   9             Fortunately perhaps only 20 percent of such

  10   patients seek medical attention.  The vast majority of these

  11   patients are seen by primary care physicians.  Perhaps 20 to

  12   25 percent will be seen by specialists, mainly

  13   gastroenterologists, because of severe disease and other

  14   related concerns.

  15             On the other hand, 25 to 50 percent of all

  16   outpatient referrals to gastroenterologists are patients who

  17   have IBS or related disorders.  Importantly, 70 percent or

  18   more of these patients, whether non-consulters or patients

  19   who are seeing physicians, are women, and these are

  20   reflected in most studies and are reflected in the studies

  21   that will be presented today.

  22             [Slide.]

  23             Now, the prevalence of these disorders, IBS

  24   compares with other disorders, such as GI disorders and non-

  25   GI disorders, shown here.  Dyspepsia is defined as greater

                                                                 15

   1   than one episode per week, 8 percent of the population will

   2   exhibit this.  Seven percent of the adult population will

   3   experience GE reflux symptoms on a daily basis.  Four

   4   percent have asthma.  Three percent have diabetes.

   5             So, IBS is quite prevalent and is a potentially

   6   significant disorder in our adult population.

   7             [Slide.]

   8             Now, it is important to emphasize that the concept

   9   of irritable bowel syndrome is not one which causes

  10   increased mortality or shortens life span, but it has a

  11   significant effect on patient well-being, and well-being

  12   really is affected by the two most prominent symptoms which

  13   characterize this disorder.  On the one hand, abdominal

  14   pain, on the other hand, altered bowel habits.

  15             This will vary from patient to patient, but it is

  16   important to emphasize that it's the totality of the

  17   symptoms which are important in defining clinical success,

  18   that one cannot look at one or the other in isolation, but

  19   one should look at both in a given patient, and we hope to

  20   convince you of this today.

  21             [Slide.]

  22             Now, the medical costs associated with irritable

  23   bowel syndrome are considerable.  In 1992 dollars, it was

  24   estimated that $8 billion were spent annually on irritable

  25   bowel syndrome patients in terms of direct medical costs.

                                                                 16

   1             It has been shown that there are increased

   2   physician visits by IBS patients for both GI and non-GI

   3   complaints, and that IBS patients incur 74 percent more

   4   health care costs than do non-IBS sufferers.  This is a

   5   significant medical issue.

   6             [Slide.]

   7             But in addition, what is not shown by such data is

   8   the impact of IBS on work and other economic factors.  In a

   9   study recently published, it was found that 30 percent of

  10   patients with IBS had missed work during the previous 30

  11   days that they were asked, and this averaged 1.7 days per

  12   patient for IBS symptoms.

  13             Forty-six percent of the survey population

  14   reported that they reduced the days that they worked, and

  15   the average for this was three days because of IBS symptoms. 

  16   Sixteen percent of those queried said that sometime during

  17   their careers that they had turned down promotions or

  18   advancement because of their IBS symptoms, 9 percent

  19   indicated that they had changed jobs for their health

  20   reasons, and 8 percent had changed their work schedules to

  21   accommodate their disabilities, a significant economic

  22   impact for patients with a disorder which does not decrease

  23   mortality or shorten life span.

  24             [Slide.]

  25             The pathophysiology of irritable bowel syndrome is

                                                                 17

   1   rather complex, and it has been labeled a biopsychosocial

   2   disorder because there are both biologic and psychosocial

   3   factors that are at work.

   4             From a biologic standpoint, there is good

   5   supporting data that suggest that altered GI motor activity

   6   and altered visceral sensations or visceral hyperalgesia

   7   play important roles in the pathogenesis of symptoms.

   8             Psychosocial issues do not produce the symptoms,

   9   but behavioral, cognitive, and emotional factors may

  10   influence the perception of the patient of their symptoms

  11   and their health-seeking behavior.  Both need to be

  12   incorporated into the holistic management of these

  13   individuals.

  14             [Slide.]

  15             It is not surprising that in such a disorder, that

  16   multiple medications have traditionally been used to treat

  17   IBS.  I have listed some of the more prominent ones -

  18   anticholinergic agents, tricyclic antidepressants, selective

  19   serotonin re-uptake inhibitors, antidiarrheals, bulking

  20   agents, laxatives, and finally alosetron.

  21             I would emphasize for the first six that there is

  22   no supporting data that suggest efficacy for any one or a

  23   combination of these agents for the treatment of IBS or the

  24   diarrhea-predominant or constipation-predominant.

  25             As this committee knows, the committee recommended

                                                                 18

   1   the approval of alosetron for women only who had diarrhea-

   2   predominant irritable bowel syndrome earlier this year based

   3   on the data at hand.

   4             We are not dealing with diarrhea-predominant IBS. 

   5   The subgroup that we are looking at today are those who have

   6   constipation-predominant IBS.

   7             [Slide.]

   8             What we propose perhaps is a new treatment

   9   paradigm for constipation-predominant irritable bowel

  10   syndrome shown here.  Looking at brain gut interactions, we

  11   see that there are altered motility and altered sensation.

  12             Dr. Michael Camilleri will present the physiologic

  13   and pharmacologic data that suggests that 5-HT4 agonists

  14   alter both GI motility and also alter visceral sensations.

  15             We believe that based upon the benefits of the

  16   drug shown, and the safety profile, that this drug that we

  17   are presenting today fulfills the paradigm and is indicated

  18   for the treatment of patients with constipation-predominant

  19   irritable bowel syndrome.

  20             Thank you for your attention, and I would like to

  21   introduce Dr. Michael Camilleri, who will make the next

  22   presentation.

  23                    5-HT4 Receptor Activation

  24                     Michael Camilleri, M.D.

  25             DR. CAMILLERI:  Thank you, Dr. Wald.  Good

                                                                 19

   1   morning, Dr. Hanauer, members, and guests.

   2             [Slide.]

   3             It is my pleasure today to review with you some of

   4   the aspects of the 5-HT4 receptor physiology and

   5   pharmacodynamic effects of tegaserod.  My talk will consist

   6   of two parts.  I will review first the physiological role of

   7   serotonin and its type-4 receptors in GI functions, and

   8   secondly, review the effects of this partial 5-HT4 receptor

   9   agonist, its pharmacodynamic effects on the GI tract.

  10             [Slide.]

  11             As we all know, serotonin is a biogenic amine

  12   which is located predominantly in the gastrointestinal

  13   tract.  In fact, 90 percent of this serotonin in the

  14   gastrointestinal tract is in the lining of the intestine, in

  15   the enterochromaffin cells, and 10 percent is located in

  16   neurons.

  17             [Slide.]

  18             There are four main 5-HT receptor subtypes which

  19   have been identified in the human gastrointestinal tract. 

  20   There are designated  5-HT1 to 5-HT4.  Indeed, the diverse

  21   effects of serotonin are due to the different receptor

  22   subtypes that are activated in the mucosa, serosa, or the

  23   muscular layers, or indeed in the afferent functions.

  24             5-HT3 and 5-HT4 receptors are involved in multiple

  25   GI functions including motor, sensory, and secretory

                                                                 20

   1   functions.  These receptors are located on neurons,

   2   enterochromaffin cells, enterocytes, and smooth muscle

   3   cells.

   4             [Slide.]

   5             In this cartoon, we have depicted the potential

   6   role of serotonin in intrinsic signaling pathways in the

   7   gastrointestinal tract.  Note here at the bottom the mucosal

   8   aspect and the top the serosa of the intestine.

   9             Note also that in response to local stimulation

  10   either by chemical or mechanical stimuli, the

  11   enterochromaffin cells act as transducers, releasing 5-HT to

  12   activate receptors on the intrinsic primary afferent neuron.

  13             Data which we will present later indicate that the

  14   5-HT4 receptor is located on this intrinsic primary afferent

  15   neuron, and this is essential for the establishing of the

  16   peristaltic reflex which involves an excitation above, and

  17   an inhibition below, the area of local activation of the

  18   mucosa.

  19             There are also 5-HT4 receptors located

  20   strategically on intrinsic cholinergic neurons and excited

  21   motor neurons, as well as cholinergic neurons that activate

  22   the inhibitory responses.  These receptors located in the

  23   myenteric plexus are accessed also via the circulation, such

  24   that circulating 5-HT or a circulating systemically

  25   administered 5-HT4 agonist would be anticipated also to have

                                                                 21

   1   an effect on these important receptors in the myenteric

   2   plexus.

   3             [Slide.]

   4             5-HT is also involved in extrinsic signaling

   5   pathways.  The most important for today's discussion

   6   pertains to the role of 5-HT receptors in afferent, visceral

   7   afferent functioning.  Visceral afferents arise in the

   8   mucosa or in response to stretch of tension receptors in the

   9   circular muscle there and activate these visceral afferent

  10   fibers that send a message of sensation to the brain.

  11             We will show you evidence that this 5-HT4 agonist,

  12   tegaserod, inhibits these visceral afferent pathways to

  13   reduce activation and sensation perception in the brain.

  14             [Slide.]

  15             I now want to review for you the pharmacodynamic

  16   effects of tegaserod on motility.  Tegaserod is a

  17   representative of a new chemical class of compounds, the

  18   aminoguanidine indoles, which are designed to act

  19   specifically at 5-HT4 receptors in the gastrointestinal

  20   tract.

  21             [Slide.]

  22             Its pharmacological profile is as follows.  It is

  23   a partial agonist, which displays high affinity for human 5-

  24   HT4 receptors with the affinity constant in the nanomolar

  25   range.  It mimics the action of 5-HT and potently

                                                                 22

   1   stimulating that intrinsic primary afferent neuron that is

   2   so important for the activation of the peristaltic reflex.

   3             Tegaserod has negligible affinity for 5-HT3

   4   receptors, and therefore is devoid of relevant 5-HT3

   5   antagonism.

   6             [Slide.]

   7             This is a model of the peristaltic reflex, and as

   8   mentioned previously, tegaserod mimics the effects of

   9   endogenously released 5-HT to activate this 5-HT4 receptor

  10   on the intrinsic primary afferent neuron.  This then results

  11   in an ascending excitation, which results in contraction and

  12   descending inhibition, which results in relaxation,

  13   facilitating the passage of the bolus down in an aborad

  14   direction.

  15             In response to the activation of this intrinsic

  16   primary afferent neuron, data which you will see on the next

  17   slide indicates that the excited retransmitter, substance P,

  18   is released, and the inhibitory transmitter VIP is released. 

  19   Therefore, it has been demonstrated that the mechanisms for

  20   this peristaltic reflex that are classically described have

  21   been activated in response to 5-HT agonist tegaserod.

  22             [Slide.]

  23             This slide also demonstrates the effect is

  24   selectively inhibited by a 5-HT4 antagonist.  Note here that

  25   in several species, there is activation of the excited

                                                                 23

   1   retransmitter substance P, as well as the inhibitory

   2   transmitter VIP.  These are crucially involved in that

   3   peristaltic reflex and that are inhibited only and

   4   selectively by the 5-HT4 antagonist, not a 5-HT3 antagonist.

   5             [Slide.]

   6             Tegaserod induces propulsion in the guinea pig

   7   colon, and it does this in a dose-dependent manner.

   8             [Slide.]

   9             Tegaserod has also been demonstrated in vivo to

  10   activate important peristaltic functions in the intestine. 

  11   Propulsive activity has been demonstrated in this in vivo

  12   canine study, and the propulsive activity is shown in the

  13   jejunum, the ileum, as well as these prolonged contractions

  14   in the colon that are involved in aborad transits of content

  15   through the colon.

  16             [Slide.]

  17             Simultaneous studies were performed using a radio

  18   tracer instilled into the colon of the dog, as shown in this

  19   cartoon here.  In response to tegaserod in a dose-dependent

  20   manner, there is increased aborad movement of the content

  21   into the more distal regions of the colon following the

  22   intravenous injection of tegaserod.

  23             [Slide.]

  24             In human studies, it has been demonstrated that

  25   tegaserod accelerates gastric emptying.  This is achieved

                                                                 24

   1   both with intravenous tegaserod, as well as with oral

   2   tegaserod, suggesting that there may be a local effect from

   3   the absorption of the tegaserod, but also probably a

   4   systemic effect, which we believe likely activates those 5-

   5   HT4 receptors on the cholinergic neurons in the myenteric

   6   plexus.

   7             Similarly, tegaserod also accelerates small bowel

   8   transit.  Shown here is a reduction in small bowel transit

   9   time relative to control.

  10             [Slide.]

  11             In patients with constipation-predominant

  12   irritable bowel syndrome, it has been demonstrated that

  13   tegaserod accelerates oral-cecal transit.  This is measured

  14   radioscintigraphically, and is quantitated as the colonic

  15   filling at six hours, a validated endpoint that has been

  16   previously demonstrated to correlate very significantly with

  17   the oral-cecal transit time.

  18             Notice that tegaserod accelerates or increases the

  19   proportion of isotope reaching the colon at six hours,

  20   whereas, placebo does not do so.

  21             [Slide.]

  22             In the same studies, it was also demonstrated that

  23   tegaserod accelerates colonic transit in the patients who

  24   received the tegaserod.  You can see the increase in the

  25   geometric center, the location of isotope in the colon is

                                                                 25

   1   further onward toward the stool following treatment versus

   2   baseline.

   3             [Slide.]

   4             In summary, tegaserod mimics the physiological

   5   response to serotonin released from the enterochromaffin

   6   cells, triggering the peristaltic reflex, and it also

   7   promotes motility throughout the gastrointestinal tract in

   8   animals and humans.

   9             [Slide.]

  10             Next, I would like to discuss the data on visceral

  11   sensitivity effects of tegaserod.

  12             There are several models in small animals to

  13   assess visceral sensitivity effects of medications.  The two

  14   models which are used in the current portfolio are the

  15   single afferent fiber recordings following distension of the

  16   colon in the experimental animal and a pseudo-affective

  17   measurement, which is a robust endpoint, the development of

  18   abdominal contractions in response to colorectal distension.

  19             [Slide.]

  20             Let me remind you of the methodology here. 

  21   Distension apparatus is placed into the colorectum or the

  22   lower bowel of the cat, and a single afferent fiber in the

  23   dorsal root of S2, the appropriate dermatome for the segment

  24   of the colon, is then assessed.

  25             The firing frequency increases with the increased

                                                                 26

   1   pressure of distension of the balloon within the colorectum

   2   of the cat.  Notice here, it has about 50 mm of mercury,

   3   here is a submaximal increase in the firing rate in these

   4   visceral afferents.  Therefore, this distension stimulus is

   5   used as a means to assess the dose-related effects of

   6   tegaserod in the subsequent slide.

   7             [Slide.]

   8             Here, you can see that in response to this

   9   standardized stimulus of 50 mm of mercury distension, the

  10   firing rate in that S2 afferent is then measured relative to

  11   the vehicle control.  As you increase the dose of tegaserod,

  12   you will see a reduction dose relatedly in the firing rate

  13   of those visceral afferents in response to rectal

  14   distension.

  15             Importantly, it has been demonstrated that this

  16   effect is inhibited by a 5-HT4 antagonist, suggesting that

  17   5-HT4 receptors are indeed important in the visceral

  18   afferent sensitivity of the lower bowel of the cat.

  19             [Slide.]

  20             In a separate series of experiments looking at a

  21   pseudo-affective endpoint, which is demonstrated by the

  22   abdominal contractions developed in awake rats following

  23   colorectal distension, it has been demonstrated that

  24   tegaserod reduces the number of abdominal contractions for

  25   five minutes in response to that rectal distension.

                                                                 27

   1             [Slide.]

   2             To summarize the sensory effects of tegaserod

   3   during colorectal distension, tegaserod reduces visceral

   4   afferent firing in cats via stimulation of 5-HT4 receptors. 

   5   Tegaserod also inhibits visceral discomfort and pain in

   6   rats, as demonstrated by the experiment looking at abdominal

   7   contractions, a validated pseudo-affective endpoint for

   8   pain.

   9             [Slide.]

  10             In summary, Dr. Hanauer, ladies and gentlemen,

  11   serotonin and its 5-HT4 receptors are involved in motor,

  12   secretory, and sensory processes in the gastrointestinal

  13   tract.

  14             Tegaserod, a partial 5-HT4 receptor agonist,

  15   stimulates GI motor functions, and inhibits visceral

  16   sensitivity.

  17             These data suggest to us that tegaserod may

  18   influence the sensory motor dysfunctions and symptoms of

  19   constipation-predominant irritable bowel syndrome.

  20             To discuss the safety and efficacy of tegaserod in

  21   constipation-predominant irritable bowel syndrome, I would

  22   like now to introduce Dr. Martin Lefkowitz for the core

  23   presentation.

  24                      Efficacy of Tegaserod

  25                    Martin P. Lefkowitz, M.D.

                                                                 28

   1             DR. LEFKOWITZ:  Good morning, members of the

   2   Advisory Committee, members of the Reviewing Division, Dr.

   3   Hanauer, ladies and gentlemen.  Thank you for the

   4   opportunity to review with you today the efficacy and safety

   5   of tegaserod in irritable bowel syndrome.

   6             I will begin the presentation with a review of the

   7   efficacy data followed by a presentation of the safety

   8   profile.

   9             [Slide.]

  10             The results that I will present today on efficacy

  11   and safety support the following:  the totality of the data

  12   provides convincing evidence of efficacy for tegaserod at a

  13   dose of 12 mg/day on a global relief measure and multiple

  14   secondary parameters of efficacy.  The drug is safe and well

  15   tolerated, and has a favorable benefit-to-risk profile in

  16   constipation-predominant irritable bowel syndrome, a

  17   disorder with no proven therapeutic options.

  18             [Slide.]

  19             The principal studies that form the core of our

  20   clinical program, and which I will review today, are shown

  21   here.  A large Phase II dose-ranging study, Study 251, was

  22   conducted, which evaluated doses of tegaserod ranging from 1

  23   to 24 mg/day of tegaserod in 547 patients drawn from the

  24   United States, Europe, and Canada.

  25             The Phase III program consisted of three large

                                                                 29

   1   well-controlled, placebo-controlled studies.  Study B351 and

   2   Study B301 used identical study designs.  Patients received

   3   placebo 4 mg/day, or 12 mg/day of tegaserod.  Study B351 was

   4   conducted primarily in the United States, and Study B301

   5   predominantly in Europe.

   6             The third Phase III study, Study B307, used a dose

   7   titration design in which patients received either placebo 4

   8   mg/day, or a dose titration regimen of 4 to 12 mg/day.  This

   9   study enrolled patients, about two-thirds from the United

  10   States and one-third from Europe.

  11             In addition, we performed a long-term 12-month

  12   safety study, Study 209, which also utilized a dose

  13   titration regimen of 4 to 12 mg/day of tegaserod, in 579

  14   patients from Europe, the United States, and Canada.

  15             Throughout the tegaserod clinical program, the

  16   drug was dosed twice a day.

  17             [Slide.]

  18             The efficacy presentation will proceed as follows. 

  19   In the interests of time, I will briefly review the Phase II

  20   data and present in more detail the Phase III design and

  21   endpoints, Phase III results, and then summarize the data.

  22             [Slide.]

  23             The study design of our Phase II dose-ranging

  24   study is shown here.  Patients underwent a four-week

  25   baseline treatment period during which they received no

                                                                 30

   1   placebo medication, and recorded their symptoms in a patient

   2   diary.

   3             Those patients eligible for randomization were

   4   randomized to placebo or 1 to 24 mg of tegaserod with

   5   approximately 100 patients per treatment arm, and received

   6   medication for 12 weeks.

   7             [Slide.]

   8             The results for the primacy efficacy variable in

   9   Study 251 was the subject global assessment of overall GI

  10   symptoms.  The results, response rate shown here for placebo

  11   in blue, followed by increasing doses of tegaserod.

  12             The placebo response rates were 31 percent with 1

  13   mg/day showing no evidence of efficacy.  The 4 to 24 mg/day

  14   doses all had higher response rates compared to placebo.  In

  15   our Phase III program, we chose to study both the 4 and 12

  16   mg/day doses, as the 24 mg/day dose offered no additional

  17   efficacy benefit.

  18             [Slide.]

  19             An important consideration for our Phase III

  20   program was the choice of the primary outcome measure.  At

  21   the time that the Phase III studies were initiated, and

  22   indeed the case today, there was no consensus in the primary

  23   outcome measure in trials of IBS.

  24             This relates both to the assessment variable to be

  25   used, that is, the symptom or symptoms to be measured, as

                                                                 31

   1   well as the measurement scale.  Both an overall measure that

   2   integrates the IBS symptoms, as well as a specific symptom

   3   measure, particularly abdominal discomfort and pain, have

   4   been advocated as primary outcome measures.

   5             Recently, the Rome II Consensus Committee on

   6   Treatment Trials has recommended that the primary outcome

   7   measure in treatment trials of IBS should be an overall

   8   integrative measure.  In our Phase III program, we elected

   9   to utilize two primary outcome measures - a global relief

  10   measure, the Subject Global Assessment of Relief, and a

  11   subject global assessment of abdominal discomfort and pain.

  12             Both ordinal and visual analog scales have been

  13   used to measure symptoms.  Recently, some concerns have been

  14   expressed regarding the difficulty of defining a responder

  15   on visual analog scales.

  16             [Slide.]

  17             There is agreement on a number of issues regarding

  18   designs of trials in IBS, in particular that the primary

  19   efficacy variable should be based on a responder approach,

  20   that is, a positive response definition should be defined

  21   and then responders compared across treatment groups.

  22             In addition, frequency of the primary outcome

  23   measures should be done at least once a week due to

  24   potential recall problems, and the scales should be self-

  25   administered by the patient.

                                                                 32

   1             In our Phase III program, our primary outcome

   2   measures were measured once a week, and they were performed

   3   by the patient in their diary.

   4             [Slide.]

   5             Shown here is the design of the first of our Phase

   6   III studies, Study B351.  Again, there was a four-week

   7   baseline.  Patients recorded their symptoms in their paper

   8   diary and received on placebo medication.

   9             Those patients eligible for randomization after

  10   the four-week baseline were randomized in a 1 to 1 to 1

  11   fashion to 4 mg/day, 12 mg/day, or placebo for 12 weeks

  12   during which they continued to record their symptoms in

  13   their diaries.

  14             Study B301 had an identical design.

  15             Study B307 used the dose titration regimen in

  16   which patients received 4 mg/day placebo or dose titration

  17   regimen where at one month non-responders were dose

  18   escalated to 12 mg, and responders remained on 4 mg/day.

  19             As was mentioned earlier, once the results of B351

  20   became known, and while B301 and B307 remained blinded, and

  21   in agreement with FDA, we modified the primary efficacy

  22   variables for Study 301 and 307.  The rationale for this

  23   modification will be discussed shortly.

  24             [Slide.]

  25             Inclusion criteria were similar for the three

                                                                 33

   1   studies.  Males and females greater than 18 years of age

   2   were included.  The lower age limit in Study 351 was 12

   3   years, but very few adolescents were enrolled.

   4             There was a requirement for an evaluation of the

   5   colon within the last five years, was dependent on age,

   6   consisted of either a colonoscopy, sigmoidoscopy, or barium

   7   enema.

   8             As Dr. Wald mentioned, at the time of the Phase

   9   III program, the Rome I criteria was used, and as he

  10   mentioned, 90 percent of these patients did also fulfill

  11   Rome II.  Rome I criteria, shown here, patients were

  12   required to have continuous or recurrent discomfort or pain

  13   in the lower abdomen in the last three months.

  14             In addition, they had to fulfill one of the three,

  15   of having the discomfort either relieved by a bowel

  16   movement, associated with the change in frequency of the

  17   bowel movements, or associated with a change of consistency

  18   of the stools.

  19             In addition, to make a diagnosis of constipation-

  20   predominant IBS, the patient needed to fulfill two of the

  21   following three constipation symptoms at least 25 percent of

  22   the time.  That is, less than three bowel movements a week,

  23   hard or lumpy stools, or straining.

  24             Thus, the diagnosis of IBS and eligibility for the

  25   study mirrored clinical practice in that it was based on the

                                                                 34

   1   patient history following exclusion of other causes of the

   2   symptoms.

   3             [Slide.]

   4             The major exclusion criteria are shown here. 

   5   Patients who had diarrhea associated with their IBS at least

   6   25 percent of the time were excluded.  Patients with other

   7   relevant GI conditions, such as inflammatory bowel disease,

   8   were excluded.

   9             Concurrent use of narcotics and motility agents

  10   were prohibited.  Laxative was not allowed except as

  11   required as rescue medication, which was defined as at least

  12   four days with no bowel movements and associated with

  13   abdominal discomfort.

  14             In addition, for patients who are on bulking

  15   agents for at least one month prior to the study, they were

  16   to continue their bulking agents throughout the 16 weeks of

  17   the study.

  18             [Slide.]

  19             Following the four weeks of baseline, for

  20   randomizations, patients were required to have had at least

  21   a score of 35 mm on a 100-mm visual analog scale.  This

  22   requirement was to ensure a diagnosis of irritable bowel

  23   syndrome.  However, there was no upper limit required cutoff

  24   for pain severity, such that patients with more severe

  25   degrees of pain were allowed to be enrolled.

                                                                 35

   1             There was no specific stool consistency mean score

   2   required for enrollment, so that again, eligibility for

   3   randomization was also largely based on the clinical history

   4   of abdominal discomfort and pain and constipation.

   5             An attempt was made to enroll a wide spectrum of

   6   patients into the study that would likely receive the drug

   7   in clinical practice.

   8             [Slide.]

   9             One of the two primary efficacy variables used in

  10   Study B351 was a global relief measure, the Subject Global

  11   Assessment of Relief.  Patients answered the following

  12   questions or responded to the following questions in their

  13   paper diary once a week.

  14             Please consider how you felt this past week in

  15   regard to your IBS, in particularly your overall well-being,

  16   and symptoms of abdominal discomfort, pain, and altered

  17   bowel habit.

  18             Compared to the way you usually felt before

  19   entering the study, how would you rate your relief symptoms

  20   during the past week:  completely, considerably, somewhat

  21   relieved, unchanged, or worse.

  22             A positive response was defined as at least 50

  23   percent of the week, complete or considerable relief at

  24   study endpoint.

  25             [Slide.]

                                                                 36

   1             The second primary efficacy variable was the

   2   Subject Global Assessment of abdominal discomfort and pain. 

   3   This utilized a visual analog scale, a 100 mm visual analog

   4   scale with variable descriptors.

   5             Patients were instructed to place a vertical line

   6   on the scale in response to the question, how much of a

   7   problem was your abdominal discomfort or pain over the last

   8   week.  A positive response here was defined as greater than

   9   a 40 percent reduction and at least a 20 mm absolute

  10   reduction from baseline at study endpoint.

  11             The stool definition of response was utilized,

  12   such that patients who came here into the study at the lower

  13   end would still have a significant reduction of their

  14   abdominal discomfort of at least 20 mm.

  15             [Slide.]

  16             Statistical methodology for the primary efficacy

  17   variables are shown here, study endpoint being defined as

  18   the last four available weekly scores.  In the great

  19   majority of the patients in this study, this corresponded to

  20   their last four weekly scores.

  21             Treatment comparisons were by the Mantel-Haenszel 

  22   test stratified by center, and a multiple comparison

  23   procedure was used to ensure that the overall two-sides type

  24   1 error rate was less than an alpha of 0.05.

  25             [Slide.]

                                                                 37

   1             In addition, for the primary analysis at study

   2   endpoint, specific adjustment criteria were applied. 

   3   Specifically, if a patient had no post-randomization subject

   4   global assessments, they were considered a non-responder. 

   5   This applied mainly to patients who dropped out of the study

   6   very early, within the first week.

   7             In addition, however, patients with less than 28

   8   days of treatment were also considered non-responders for

   9   the primary analysis.  At the request of FDA to account for

  10   the potential confounding influence of laxative intake, use

  11   of laxatives was also included as one of the adjustment

  12   rules, such that if a patient used laxatives more than five

  13   days overall in the study or any use in the last four weeks,

  14   that is, at study endpoint, they were also considered a non-

  15   responder regardless of how they may have answered their

  16   subject global assessments.

  17             [Slide.]

  18             The secondary efficacy assessments are shown here. 

  19   In addition to the two weekly assessments, the SGA of relief

  20   and SGA of abdominal discomfort, the third weekly assessment

  21   was a subject global assessment of bowel habits, which used

  22   the same visual analog scale and definition of response that

  23   you saw earlier.

  24             In addition, four questions are asked of the

  25   patients on a daily basis - the intensity of abdominal

                                                                 38

   1   discomfort and pain, and the intensity of bloating was rated

   2   on a six-point scale from zero being none to 5 being very

   3   severe.  Days of significant abdominal was defined as days

   4   with mild or more pain.  In addition, patients recorded the

   5   number of bowel movements on a daily basis, and rated their

   6   stool consistency on a seven-point scale, from 1 being water

   7   to 7 being very hard.

   8             Endpoint for the daily diary measures were the

   9   last 28 days in the study.  Thus, the bowel habits were

  10   evaluated both by the weekly subject global assessment and

  11   recording of bowel movements and stool consistency, and

  12   abdominal pain was evaluated with the weekly subject global

  13   assessment of abdominal pain the daily recording of the

  14   intensity of abdominal pain in the diary.

  15             [Slide.]

  16             Patient disposition across the three studies are

  17   shown here with approximately 1,100 to 1,160 patients

  18   enrolled across the three studies with a discontinuation

  19   rate during baseline of 21 to 27 percent.  The most common

  20   reason for discontinuation during baseline was an inability

  21   or unwillingness to fill out the patient diary.

  22             Please note the discontinuation rate of 21 to 27

  23   percent was less than the reported greater than 50 percent

  24   discontinuation rates in recent trials of IBS during the

  25   baseline.

                                                                 39

   1             Study B351 randomized 799 patients; 301, 881

   2   patients; and 307, 845 patients.  Seventy-nine to 85 percent

   3   of patients completed the study with a corresponding

   4   discontinuation rate during the double blind of 15 to 21

   5   percent.  The discontinuation rate in the placebo group and

   6   the 12 mg/day groups were similar, and approximately 5

   7   percent higher in the 4 mg/day group.

   8             [Slide.]

   9             Patient demographics are shown here for the three

  10   studies with a mean age across the studies of 43 to 46.  The

  11   study was predominantly female with approximately 85 percent

  12   of women in the studies.  It was largely Caucasian. 

  13   Importantly, patients had a fairly long duration of IBS of

  14   13 to 14 years.  Use of bulking agents ranged from 11 to 18

  15   percent, and patients recorded their fiber intake as being

  16   approximately 10 grams a day.

  17             Thus, the three studies generally had similar

  18   demographics with the exception of a high Caucasian

  19   population here in Study 301, and less use of bulking agents

  20   here in 301.  In addition, the treatment groups within the

  21   individual study were well balanced.

  22             [Slide.]

  23             Baseline demographics for the three studies showed

  24   that the visual analog scale and the discomfort/pain and the

  25   bowel habit ranged from 60 to 64, corresponding to greater

                                                                 40

   1   than moderate pain on the scale.

   2             Days with significant discomfort and pain, and

   3   days with significant bloating, again, days with mild or

   4   more pain was approximately 85 percent.  The number of bowel

   5   movements ranged from 5.4 to 6.2 per week.  Days without

   6   bowel movements were 41 to 46 percent; with hard stools,

   7   approximately 30 percent.

   8             The stool consistency score was 4.7, generally

   9   corresponding to somewhat hard on the scale.  Again, the

  10   treatment groups were well balanced within the studies for

  11   these baseline characteristics.

  12             [Slide.]

  13             I will now proceed to review the efficacy results

  14   as follows.  The efficacy results of 351 will be shown,

  15   followed by the modification of the primary efficacy

  16   variable and the rationale for the modifications in Study

  17   301 and 307, and the results of 301, 307, and a

  18   summarization of those results.

  19             [Slide.]

  20             For clarity of presentation, shown here

  21   schematically, is how the subject global assessment will be

  22   presented.  Endpoint, which was the primary analysis, is

  23   shown here for patients who complete the study, the last

  24   four available SGA scores.  Patients who drop out would have

  25   their endpoint their last four weeks in the study.

                                                                 41

   1             As was mentioned, adjustment rules as shown here,

   2   patients without any SGAs, less than 28 days of treatment,

   3   or laxative use as defined earlier, would be defined as a

   4   non-responder for the endpoint analysis.

   5             However, given that irritable bowel syndrome is a

   6   disorder of varying severity that waxes and wanes, it is

   7   also important to present the longitudinal time course

   8   effect of the drug, so we will present results at month 1,

   9   month 2, month 3, as well as the actual weekly responses

  10   that patients recorded in their daily diary.

  11             [Slide.]

  12             Shown on this slide are the results for the

  13   primary efficacy variables for study 31, the SGA or relief

  14   on the left, and the SGA of abdominal discomfort here on the

  15   right, placebo in blue, 4 mg in red, and the yellow being 12

  16   mg/day.  As you can see, response rates were higher in the

  17   tegaserod groups than placebo, but these results were not

  18   statistically significant.

  19             We did not, however, that response rates overall,

  20   and particularly in the placebo groups of 19 and 22 percent,

  21   were lower than what we had seen in Phase II, which were

  22   about 30 percent, lower than what has been reported recently

  23   in the literature, 40 percent or more, suggesting that the

  24   definitions used in 351 established a high hurdle for

  25   response and potentially may have made detection of a drug

                                                                 42

   1   effect, or was not sensitive to detect a significant drug

   2   effect.

   3             [Slide.]

   4             Shown here are the weekly results with the SGA of

   5   relief for patients who responded complete or considerable

   6   relief on a weekly basis in their daily diary.  As you can

   7   see, for the 12 mg/day group here in yellow, the percentage

   8   of people responding complete or considerable relief was

   9   higher than placebo throughout the study with the 4 mg/day

  10   group having a more variable response.

  11             [Slide.]

  12             The results for the weekly subject global

  13   assessment of abdominal discomfort and pain are shown here,

  14   again with the 12 mg group tending to have higher response

  15   rates throughout the study, with the more variable response

  16   seen for the 4 mg/day group.

  17             [Slide.]

  18             The results for the third weekly subject global

  19   assessment, the subject global assessment of bowel habit are

  20   shown here, again with similarly higher response rates in

  21   the tegaserod group, but not statistically significant,

  22   again with a low placebo response rate.

  23             When one looks at the weekly scores, again, there

  24   is a tendency for the tegaserod 12 mg/day group to have

  25   higher response rates.

                                                                 43

   1             [Slide.]

   2             Now, in contrast to the results for the weekly

   3   subject global assessments, when one looks at the daily

   4   dairy variables in Study 351, one consistently shows a

   5   favorable significant effect for the tegaserod groups

   6   compared to placebo.

   7             Shown here on the left, this is for abdominal

   8   discomfort and pain as recorded in the daily diary.  Shown

   9   here on the left is the reduction in days of significant

  10   pain in the daily diary or reduction in days with at least

  11   mild pain at study endpoint, the last 28 days in the study. 

  12   Thus, patients on tegaserod, the 4 and 12 mg groups, had

  13   significant reductions compared to placebo at study

  14   endpoint.

  15             Shown on the right are the actual pain scores from

  16   which this data is derived and which patients recorded in

  17   their diary.  As you can see, during the four-week baseline

  18   period, patients recorded a score of approximately 3,

  19   corresponding to moderate pain.

  20             During the course of the study, beginning at week

  21   1, for the 12 mg/day group, pain scores were significantly

  22   lower throughout the course of the study, again with an

  23   intermediate result for the 4 mg/day group.

  24             [Slide.]

  25             Results on abdominal bloating are shown here in a

                                                                 44

   1   corresponding fashion, again showing an improvement or a

   2   reduction in the days of significant bloating shown here for

   3   the tegaserod groups compared to placebo, which was

   4   significant for the 12 mg/day group.

   5             One looks at the weekly score.  Again, the rating

   6   of approximately moderate during baseline for the 12 mg

   7   group showing an effect here a month 1, and then again

   8   towards the end of the study, during month 3.

   9             [Slide.]

  10             The last two questions in the daily diary are

  11   related to the recording of bowel movements and stool

  12   consistency, bowel movements shown on the left, stool

  13   consistency on the right, and one can see an early dose-

  14   dependent increase in the number of bowel movements, that

  15   then for the two groups were similar and stayed generally

  16   different from placebo for the remainder of the study.

  17             The results for stool consistency mirrored these

  18   effects with an early dose-dependent decrease, and then

  19   similar effects for the two studies, and a persistent effect

  20   throughout the remainder of the study.

  21             Of note, this early dose-dependent increase in

  22   bowel movements and stool consistency translates into an

  23   early transient diarrhea that is seen with the drug and

  24   which I will review during the safety profile.

  25             [Slide.]

                                                                 45

   1             To summarize Study 351, although response rates

   2   were higher for tegaserod compared to placebo, these results

   3   were not statistically significant for the primary efficacy

   4   variables.  Noted, however, with the low placebo response

   5   rates suggesting a high hurdle for response.

   6             In contrast, for the daily diary variables,

   7   significant treatment differences with tegaserod were seen. 

   8   Thus, a consistent pattern of improvement for tegaserod

   9   across the primary and secondary variables were evident.

  10             It was this combination of findings with higher or

  11   trends towards the higher rates for the weekly subject

  12   global assessment with significant differences in the daily

  13   diary variables that suggested that the response definition

  14   used in this study may have been too stringent to allow for

  15   the detection of a treatment effect.

  16             Accordingly, we consulted with medical experts in

  17   the field, as well as with FDA, and considered an

  18   alternative definition of response.

  19             [Slide.]

  20             Compared to the response definition here, used in

  21   Study B351, a component was added to the response definition

  22   to include patients with a persistent positive relief as

  23   defined as patients who had at least somewhat relief as

  24   complete considerable or somewhat relief for 100 percent of

  25   the time at study endpoint.

                                                                 46

   1             It was felt clinically meaningful to include

   2   patients who had a persistent positive response, such that

   3   the response definition now captured those patients who had

   4   a significant magnitude of response from the 50 percent

   5   complete or considerable part of the definition, as well as

   6   those who had a persistent positive response from the 100

   7   percent at least somewhat part of the definition.

   8             [Slide.]

   9             Further, we performed associations, as shown at

  10   this slide, which supported the clinical relevance of this

  11   modified definition.

  12             Now, importantly, I need to be very clear here. 

  13   We are not looking at differences between tegaserod and

  14   placebo, but rather what you are looking at is on patients

  15   who rated their response as a positive response, how they

  16   recorded their other symptoms of irritable bowel syndrome

  17   compared to patients who were non-responders to this

  18   modified definition of response.

  19             Thus, if one looks at abdominal pain in various

  20   ways, these are using the VAS score, visual analog score,

  21   days with significant pain, daily pain score, different ways

  22   of looking at bloating or different ways of looking at bowel

  23   habit, one can see that patients with a positive response

  24   had a clinically meaningful and statistically significant

  25   response of approximately 35 to 45 percent improvement

                                                                 47

   1   compared to patients with non-responders, thus indicating

   2   that this modified definition of response appeared to be a

   3   clinically relevant definition of response.

   4             Further, since somewhat relief was now

   5   incorporated into the response definition, we also evaluated

   6   how patients perceived their specific response on the SGA

   7   scale.

   8             [Slide.]

   9             Shown here are the responses for the last study

  10   week for patients who reported complete, considerable,

  11   somewhat, unchanged, or worse.  As expected, patients who

  12   recorded complete relief had very substantial reductions in

  13   their symptoms of approximately 70 percent.

  14             Patients who recorded unchanged or worse had

  15   either small decreases or improvements in their symptoms or

  16   actual worsening of their symptoms.  Patients who recorded

  17   somewhat relief perceived somewhat as a positive response

  18   with improvement in all their symptoms and compared to the

  19   unchanged and worse of approximately 15 to 25 percent

  20   improvements on most of these secondary efficacy variables,

  21   thus justifying the use of somewhat relief, especially when

  22   used as a persistent response as part of the modified

  23   response definition.

  24             [Slide.]

  25             Accordingly, for Study 301 and 307, this modified

                                                                 48

   1   response definition was adopted as the primary efficacy

   2   variable, again 50 percent complete or considerable relief,

   3   100 percent somewhat relief.  The subject global assessment

   4   of abdominal discomfort or pain was retained as a secondary

   5   efficacy variable, thus, in 301 and 307, the SGA of relief

   6   was a single primary efficacy variable.

   7             [Slide.]

   8             We then retrospectively analyzed the data in SGA

   9   of relief according to this new, modified definition of

  10   response, and as expected, all response rates increased, now

  11   with the 33 percent placebo response, now also showing a

  12   dose response for the tegaserod groups with a 12 percent

  13   difference in response rates between tegaserod 12 mg/day and

  14   placebo.

  15             [Slide.]

  16             I will now go on to present the results of 301. 

  17   As a reminder, the study design of 351 and 301 was

  18   identical, 351 being conducted primarily in the United

  19   States and 301 in Europe.

  20             [Slide.]

  21             Shown here are the results for the primary

  22   efficacy variable, the SGA of relief at study endpoint.  The

  23   results of the tegaserod group showed statistically higher

  24   response rates compared to placebo of approximately 9

  25   percent and 8 percent.

                                                                 49

   1             [Slide.]

   2             Now, as mentioned previously, laxative use was

   3   used as one of the adjustment factors for the primary

   4   analysis.  This was done to try to control for the

   5   confounding influence that laxative may have for the primary

   6   analysis.

   7             The criteria used was patients with greater than

   8   five days of laxatives or any day within the last 28 days

   9   were considered as non-responders.  Approximately one-third

  10   of the patients in the trials used laxative for one day,

  11   one-third for two to four days, and one day for greater than

  12   five days.

  13             Laxative use was generally well balanced within

  14   the groups.  In Study 301 in particular, 27 to 28 percent of

  15   patients in the different treatment groups used laxatives. 

  16   As expected, response rates when laxative adjustment was not

  17   applied were all greater than when it was applied here in

  18   the primary analysis.

  19             Now, as you can see, response rates in the placebo

  20   and 4 mg/day groups were decreased by approximately 4

  21   percent, however, were decreased by 7 percent in the 12

  22   mg/day group.  Thus, when not applying the laxative

  23   adjustment, the laxative non-adjusted response rate showed a

  24   difference for the 4 mg/day group of 10 percent compared to

  25   12 percent in the 12 mg/day group.

                                                                 50

   1             For comparative purpose on this slide and the next

   2   several slides are presented the results for 351.  Again, in

   3   351, laxative use was generally well balanced between the

   4   group, actually slightly higher in the placebo group.  The

   5   laxative adjustment in this study affected all groups to a

   6   similar extent.

   7             Note that the difference in the 12 mg/day and the

   8   placebo group in Study 351 was 12 percent, the exact

   9   difference as seen for the 301 study.

  10             [Slide.]

  11             Shown here are the monthly results in Study 301 of

  12   the subject global assessment of relief.  At month 1, month

  13   2, and month 3, the results of the 12 mg/day group showed

  14   higher response rate that was significantly different from

  15   placebo.  For the 4 mg/day group, the response rates were

  16   significantly different at month 1 and at month 3.

  17             When looking at 351, these higher response rates

  18   that were significant in the 12 mg/day group at month 1 and

  19   month 3 with higher response rate at all months.  The

  20   results for Study 301 and 351 were therefore quite

  21   consistent.

  22             [Slide.]

  23             Shown on this slide are the weekly responses of

  24   the patient on the subject global assessment of relief. 

  25   These are patients who responded complete, considerable, or

                                                                 51

   1   somewhat relief.

   2             Here, at week 1, both groups had higher response

   3   rate compared to placebo, that then persisted for the

   4   remainder of the study.

   5             Results for 351, shown here, again showed an early

   6   response at week 1, that for the 12 mg/day group again

   7   persisted throughout the study, with more variable results

   8   in the 4 mg/day group.

   9             [Slide.]

  10             I will now go on to present the secondary efficacy

  11   variables in Study 301, the subject global assessment of

  12   abdominal discomfort and pain shown here at study endpoint

  13   and shown here for the weekly results.

  14             At study endpoint, response rates were higher in

  15   the tegaserod group and significantly higher for the 12

  16   mg/day group.  The weekly results showed that the 12 mg/day

  17   group again had consistently higher response rates compared

  18   to placebo, the 4 mg/day group again with intermediate

  19   results.

  20             [Slide.]

  21             The results for the SGA of bowel habits showed

  22   higher response rate in tegaserod groups, but these were not

  23   significant.  One looks at the weekly values, one again sees

  24   higher response rates throughout the study with the

  25   tegaserod groups.

                                                                 52

   1             [Slide.]

   2             Now, for the daily diary variables, the days of

   3   significant pain for tegaserod was reduced compared to

   4   placebo although this reduction was not statistically

   5   significant.  When one looks the pain score, one can see for

   6   both groups significant reductions in pain score and lower

   7   pain scores throughout the study.

   8             [Slide.]

   9             Significant days of bloating were also reduced at

  10   endpoint, but these were not significant with bloating

  11   scores also tending to be lower with tegaserod patients

  12   compared to placebo.

  13             [Slide.]

  14             The number of bowel movements and stool

  15   consistency was similar to what you saw in 351, with an

  16   early dose-dependent increase and then a persistence of

  17   effect for both groups throughout the study, similar results

  18   on stool consistency.

  19             [Slide.]

  20             Thus, in Study 301, there was clear evidence of

  21   efficacy, with a significant difference for the primary

  22   efficacy variable, the subject global assessment of relief,

  23   and consistent positive findings on the secondary efficacy

  24   variables.

  25             [Slide.]

                                                                 53

   1             Study 307, as mentioned before, used a dose

   2   titration regimen.  Patients were randomized to 4 mg/day,

   3   placebo or dose titration regimen, following one month,

   4   patients who were non-responders were dose titrated to 12

   5   mg/day, patients who were responders remained on 4 mg/day. 

   6   Approximately two-thirds of the patient were dose titrated

   7   and one-third remained on 4 mg/day.

   8             For the 4 mg/day group and the placebo groups,

   9   patients underwent mock titration.  Patient received two

  10   tablets twice a day throughout the study.

  11             [Slide.]

  12             Shown here are the results for the subject global

  13   assessment of relief, both the adjusted and values not

  14   adjusted for laxative, this being the primary analysis, and

  15   although the response rates at endpoint were higher for the

  16   dose titration groups, here in green, compared to placebo,

  17   these results were not significant.

  18             Shown here are the monthly results at month 1,

  19   month 2, and month 3.  The tegaserod groups at month 1 and

  20   month 2, the dose titration groups had higher response rates

  21   that were significant from placebo, but at endpoint, the

  22   response rates were similar.

  23             To point out a discrepancy in the results here, at

  24   month 1, remember that the dose titration group at month 1

  25   were also receiving 4 mg/day.  The reason for the

                                                                 54

   1   discrepancy in results is not clear.

   2             [Slide.]

   3             Shown on this slide are the weekly results for

   4   patients on the SGA of relief, the dose titration group,

   5   again, early higher response rates in the dose titration

   6   group.  If one looks at the placebo group, one can see a

   7   significant increase in placebo response rates here at week

   8   4.  It then persisted for the remainder of the study with no

   9   significant differences seen at study endpoint.

  10             The reason for this increase in placebo response,

  11   which occurred at the time of dose titration here at week 4,

  12   may have been related to heightened expectation, may have

  13   been due to random variability.

  14             [Slide.]

  15             The results for the subject global assessment of

  16   abdominal discomfort and pain are shown here, with response

  17   rates at study endpoint being lower in the tegaserod groups

  18   compare to placebo.

  19             If one looks at the weekly results, one again sees

  20   an early effect of the drug here on abdominal pain for the

  21   dose titration group.  Interesting, at week 4, all response

  22   rates were similar, and this time, following dose titration,

  23   there was a significant increase in the response rates in

  24   the dose titration group with no differences here seen at

  25   study endpoint.

                                                                 55

   1             [Slide.]

   2             The results of the subject global assessment of

   3   bowel habit were similar.  At endpoint, response rates were

   4   similar with no differences, again, with an early effect

   5   seen in the dose titration group that did not persist at

   6   study endpoint.

   7             [Slide.]

   8             Shown here are the results for the bowel movements

   9   and stool consistency, this time again showing early effect

  10   that more tended to persist for the remainder of the study

  11   for bowel movements and here for stool consistency.

  12             [Slide.]

  13             In summary, then, for Study 301, favorable effects

  14   for tegaserod at months 1 and 2 with mixed results seen at

  15   endpoint.  The results were not statistically significant

  16   for the primary efficacy variable endpoint.  These results

  17   may have been related to the trial design.

  18             [Slide.]

  19             Now, to put this data across the three studies in

  20   perspective, on the next several slides I will present the

  21   results in a slide-by-slide presentation.

  22             [Slide.]

  23             Shown here are the results you have seen earlier

  24   on an individual study basis for at least somewhat relief,

  25   this time showing the results for the 12 mg/day group in 351

                                                                 56

   1   and 301, and the dose titration group in 307 compared to

   2   placebo.

   3             For 351 and 301, for both studies, despite

   4   differences in placebo rates, the difference from placebo

   5   for both these groups were similar in the two studies, again

   6   showing the consistency of results between the two studies,

   7   and as you just saw for the 307 study, these early results

   8   did not persist at study endpoint.

   9             [Slide.]

  10             Shown here are the results for

  11   complete/considerable relief on the SGA of relief.  Again,

  12   351 and 301, consistent results with higher response rates

  13   seen in 351 and 301, that interestingly in 307, persisted

  14   out to about week 9 and 10, but then not at study endpoint.

  15             [Slide.]

  16             Now, this is a rather busy slide where we show the

  17   efficacy variables, both primary and secondary efficacy

  18   variables across the studies at study endpoint.

  19             Now, at the SGA of relief in Study 351 is the one

  20   efficacy variable shown here, which was a retrospective

  21   analysis.  All these other efficacy variables were defined

  22   prospectively and administered similarly in the two studies.

  23             P-values are shown that were less than 0.05. 

  24   These pluses indicated that there was a favorable effect for

  25   tegaserod, but the results were not less than 0.05, these

                                                                 57

   1   negative results indicating that there was a negative effect

   2   with tegaserod, again with the results being not

   3   significant.

   4             If you first focus on 351 and 301, one can see the

   5   consistency of the finding with either statistically

   6   significant effects in favor of tegaserod or favorable

   7   effects that did not reach statistical significance.

   8             In 351, for the 12 mg/day group, the diary

   9   variables achieved significance, whereas, the subject global

  10   assessments had trends in favor of tegaserod, which is

  11   mentioned for 301, a combination of favorable findings.

  12             In Study 307, although some of the bowel habit

  13   criteria had significant results, in general, the results at

  14   endpoint presented a mixed picture.

  15             [Slide.]

  16             To gain more insight into the strength of the

  17   evidence across the three studies, we performed several

  18   additional post-hoc analyses.

  19             [Slide.]

  20             To examine the data for a positive drug effect

  21   across the three studies, we performed a pooled analysis. 

  22   This pooled analysis was done applying the prespecified

  23   primary efficacy variables.

  24             Despite differences in study design between Study

  25   307 and Studies 351 and 301, we believe that this pooling of

                                                                 58

   1   studies is justified when using the prespecified efficacy

   2   variables and in an effort to evaluate whether a drug effect

   3   is present looking across the three studies.

   4             Thus, in this analysis in 351, both the original

   5   SGA of relief and the SGA of abdominal discomfort was used,

   6   and in 301 and 307, the SGA of relief was used.  The 4

   7   mg/day groups were pooled across the studies, and the high-

   8   dose groups, the 12 mg/day and dose titration groups, pooled

   9   across the study.

  10             The analyses were performed at study endpoint,

  11   that is, the last four available SGAs, as well as in a

  12   longitudinal analysis, using response rates at month 1,

  13   month 2, and month 3.

  14             As you can see for the high-dose groups, using

  15   either the endpoint analysis or in the longitudinal

  16   analyses, strongly significant results in favor of tegaserod

  17   were seen, suggesting strongly that a drug effect is seen

  18   when integrating the results across the three studies.

  19             [Slide.]

  20             In an analysis that was presented to this advisory

  21   committee in November for the approval of another drug in

  22   IBS, alosetron, the primary analysis that was used there,

  23   using the approach, we looked at the number of months with a

  24   positive relief throughout the study.

  25             Thus, patients who had three months of a positive

                                                                 59

   1   relief were given a score of 3; two months, a score of 2;

   2   one month, a score of 1, and no relief, a score of zero, and

   3   then these scores were compared.

   4             Shown here are when this analysis was applied to

   5   the tegaserod data.  For 351, for the original SGA of

   6   relief, the results were not statistically significant due

   7   to the multiple testing, however, this is consistent with

   8   the high hurdle of the response.

   9             However, when look at 301 and 307, for the high-

  10   dose groups, when looking across the three months of the

  11   study, one sees a significant effect in favor of tegaserod.

  12             [Slide.]

  13             Now, further, we then simply did not use a

  14   responder approach here.  We simply compared the percent of

  15   weeks in the three studies that patients had at least

  16   somewhat relief, were 351, 301, and 307.

  17             As you can see for the high-dose groups in each

  18   study, the results had higher rates and were significantly

  19   different in favor of tegaserod.  Similar significant

  20   results are seen for complete considerable relief, although

  21   the differences from placebo were less.

  22             [Slide.]

  23             We then also finally looked at the impact of

  24   gender on the results, as shown here.  As you will recall,

  25   85 percent of the patients enrolled into the study were

                                                                 60

   1   women.  We did look at baseline differences, and male

   2   patients tended to have less constipation than the women in

   3   the study.

   4             Shown here are the results at month 1 and then at

   5   endpoint, and as expected for the women being the

   6   predominant population, the results were consistent with the

   7   overall results, showing significant results here at month

   8   1, as well as at endpoint in a dose-dependent fashion.

   9             For the males in the study, at month 1, higher

  10   response rates were seen, whereas, at endpoint, the response

  11   rates were similar when looking across the three studies.

  12             Given the small number of men in the study, it is

  13   difficult to draw any reliable conclusion concerning the

  14   evidence of efficacy in men.  It should be noted that there

  15   was variability, as you see here, over time, as well as

  16   between studies in the male population.

  17             [Slide.]

  18             Shown on this slide are the results at study

  19   endpoint specifically using the placebo-subtracted approach

  20   where we subtract the placebo response rates from the

  21   tegaserod response rates, and looked at the therapeutic gain

  22   for 351, 301, and 307.

  23             For the male patients in 301, the results were in

  24   a negative direction as it was in 301, and in a positive

  25   direction here on 307.

                                                                 61

   1             For the women in the study, in 351 and 301, the

   2   treatment difference for the tegaserod groups were 14.2 and

   3   11.4 percent.  Again, given the small numbers of males in

   4   the study, and the variability seen over the course of the

   5   study, no reliable conclusions can be drawn, but certainly

   6   no evidence efficacy here at study endpoint.

   7             [Slide.]

   8             In conclusion then, or in summary, for Study 301,

   9   we showed clear evidence of efficacy with significant

  10   treatment differences for the SGA of relief, consistent

  11   positive findings on the secondary efficacy variables.

  12             For Study 351, although not statistically

  13   significant on the prespecified primary efficacy endpoints,

  14   the overall results are strongly supportive of efficacy,

  15   with daily diary variables showing statistically significant

  16   results in favor of tegaserod and positive trends for all

  17   SGA assessments.

  18             [Slide.]

  19             When looking at the results across 301 and 351,

  20   the B351 results were largely replicated in Study 301, with

  21   results being highly consistent between the two studies.

  22             In addition, consistent results were seen between

  23   the weekly SGA assessments and the daily diary variables. 

  24   Tegaserod at a dose of 12 mg had the most consistent effect

  25   across the efficacy variables and over time.

                                                                 62

   1             In Study 301, favorable effects were seen at month

   2   1 and month 2, with mixed results at endpoint, and no

   3   statistically significant results for the primary efficacy

   4   variable.

   5             [Slide.]

   6             In addition, the additional analyses including the

   7   pooled analysis, number of months with positive relief, or

   8   percent weeks with relief, or reinforce the findings of a

   9   positive treatment effect.

  10             The overall positive treatment effect was

  11   primarily due to the efficacy of women, for men, no evidence

  12   of efficacy was seen, possibly due to the small numbers.

  13             Overall, the totality of the data across the

  14   multiple efficacy variables, including the global relief

  15   measure and secondary symptom variables, provides convincing

  16   evidence that tegaserod is effective in the treatment of

  17   constipation-predominant IBS.

  18             DR. HANAUER:  Thank you, Dr. Lefkowitz.

  19             I am taking a chairman's prerogative and change my

  20   mind.  Rather than going through the entire presentation by

  21   the sponsor, what I would like to do is stop at this point

  22   and allow the panel to discuss any questions that they might

  23   for Dr. Wald or for Dr. Camilleri or Dr. Lefkowitz, since

  24   obviously, a series of studies have had complicated changes

  25   in their design and analysis and methods.

                                                                 63

   1             Dr. Laine.

   2             DR. LAINE:  I just had a couple or three maybe

   3   statistical questions.

   4             First of all, can you share with us what, when you

   5   first designed these studies, were your baseline

   6   assumptions?  You know, usually, you say we expect our

   7   primary endpoint to be positive and X percent in control and

   8   Y percent, and this is the difference that we are looking

   9   for.

  10             Can you tell us what those were when you designed

  11   your endpoint and perhaps when you changed your endpoint?

  12             DR. LEFKOWITZ:  The sizing of the study was sized

  13   on 15 percent treatment difference with the placebo response

  14   rate being 30 percent.  When we changed our endpoint, the

  15   studies were all fully enrolled and it really didn't come

  16   into consideration, the changing in the endpoint were more

  17   related to the --

  18             DR. LAINE:  The 15 percent was your?

  19             DR. LEFKOWITZ:  The 15 percent was what the

  20   studies were sized on, yes.

  21             DR. LAINE:  And also in your analysis when you are

  22   showing the daily --

  23             DR. HANAUER:  Was that 15 or 50?

  24             DR. LEFKOWITZ:  15.

  25             DR. HANAUER:  15.

                                                                 64

   1             DR. LAINE:  An absolute difference was 15 percent?

   2             DR. LEFKOWITZ:  Right, assuming a placebo response

   3   rate to 30 percent is what the sizing was based on, yes.

   4             DR. LAINE:  Up to 45 basically.

   5             DR. LEFKOWITZ:  Correct.

   6             DR. LAINE:  Also, when you are presenting the

   7   daily diary weekly scores, are you presenting each day, in

   8   other words, what I am looking for is how many data points

   9   are there, is it like seven days?  We have lots of data

  10   points there.

  11             DR. LEFKOWITZ:  Right, each weekly is based on the

  12   mean of the seven days of that week, yes.

  13             DR. LAINE:  So there are seven data points for

  14   each patient per week?

  15             DR. LEFKOWITZ:  Correct.

  16             DR. LAINE:  So, we have a lot more data points

  17   than, for instance, the overall end of thing.

  18             Finally, the pooled analysis, was that just kind

  19   of combining all the numbers together, or was there actually

  20   a weighted statistical, you know, quote "meta-analysis" to

  21   combine them, or you just kind of add all the numbers

  22   together?

  23             DR. LEFKOWITZ:  I think it would probably best if

  24   perhaps Dr. Fisher would respond to how the pooling was

  25   done.  He could probably give you a more definitive answer.

                                                                 65

   1             DR. FISHER:  I am Lloyd Fisher, biostatistician,

   2   from the University of Washington, and a paid consultant for

   3   Novartis on this project.

   4             I am glad you asked this question because it will

   5   come up again in the FDA presentation, and I think it is

   6   quite important in this context.

   7             I will first answer the direct question, and then

   8   if I might add a few other comments.  The studies were

   9   adjusted for the comparison basically within study.  All the

  10   data was not thrown in without regard to doing it within

  11   study, which is more in the meta-analytic tradition.

  12             Your task, of course, as well as the Agency and

  13   the sponsor's, is to assess whether or not there is

  14   substantial evidence of efficacy according to the

  15   regulations, and the assessment must integrate in some way,

  16   either formally or informally, the entire development

  17   program.

  18             I would like to think we have advanced a little

  19   beyond the primitive tribe that can only count to two, and I

  20   would suggest that pooling in one sense is always done.  Let

  21   me give you an example to illustrate it in the opposite

  22   direction.

  23             If you saw a development program that had six

  24   clinical trials, two of which were statistically

  25   significantly positive, and the other four went in the other

                                                                 66

   1   direction with fairly strong trends, let's say, p-values

   2   between 0.05 and 0.10, any rational reviewer would assess

   3   the totality of the data, and assuming the trials all had

   4   the same size, and so on and so forth, would put it together

   5   and you would end up saying no, this is not adequate for

   6   approval.

   7             So, I would submit that one way or another,

   8   pooling is done formally or informally, and now certainly if

   9   we had had three studies, all of which were statistically

  10   significantly positive on the primary endpoint, the pooling

  11   wouldn't have been presented, but part of the reason it is

  12   not presented is because everybody knows what it would show,

  13   I mean so there was no need for it.

  14             But that doesn't mean to me it isn't there in the

  15   back of your mind.  The pooling as done here has

  16   statistically correct properties.  You will notice that your

  17   document on page 66, and the slide that Dr. Lefkowitz

  18   presented, used the prespecified primary endpoints for each

  19   of the studies, in other words, the p-values you saw did not

  20   use the new retrospective endpoint which undoubtedly is

  21   biased in a favorable direction, because, after all, they

  22   looked at their database to see what went wrong and come up

  23   with a good endpoint.

  24             But the numbers you saw were not biased, they used

  25   the endpoint.  Clearly, if you are going to do a pooling or

                                                                 67

   1   meta-analytic type approach, you should use all the data,

   2   you shouldn't just select positive studies or negative

   3   studies, but in general, that is compelling reasons to

   4   exclude things, you want to use all the data.

   5             In the data you saw, the p-value was 0.0028, and

   6   if you used a longitudinal approach, which of course has

   7   more statistical power, but was not used by the sponsor, the

   8   p-values were, as you can see for the high dose, 0.0001.  I

   9   personally find this fairly compelling evidence, you may

  10   not, and we will hear your discussions shortly.

  11             You are also, of course, perfectly free, and it

  12   may be that you personally, when you try to integrate a

  13   clinical development program, don't like to go to an

  14   analytic approach, but like to do it informally, but one way

  15   or another, it always has to be done.

  16             The Agency presents a number of possible

  17   criticisms on pages 10 to 12 of their review.  I think there

  18   are good responses to each point.  I know that Dr. Castillo

  19   is going to speak about some of these, and so, although I

  20   would be happy to talk to anybody on the panel about any of

  21   this right now, it might be better to wait until the FDA has

  22   had their say.

  23             DR. HANAUER:  I agree, but did that answer your

  24   question?

  25             DR. LAINE:  Kind of.  Did you test for statistical

                                                                 68

   1   heterogeneity?  In three studies it looked similar, but in

   2   combining them?

   3             DR. FISHER:  The p-value for an interaction or

   4   heterogeneity was 0.58, so there is really no evidence.

   5             DR. LAINE:  So, the answer was there was a formal

   6   analysis, and not just adding up the numbers together.

   7             DR. FISHER:  Correct.

   8             DR. HANAUER:  Dr. Wolfe.

   9             DR. WOLFE:  You have properly broken down the data

  10   into responses with males and females.  There is also large

  11   differences between Americans and non-Americans.

  12             Have you broken those data down to look at

  13   response, have you broken down the analysis to look at

  14   response at Americans versus those in Europe and other

  15   countries?

  16             DR. FISHER:  I am not the best person to speak to

  17   that.

  18             DR. LEFKOWITZ:  We looked at several things,

  19   first, whether, as far as we can determine, whether the

  20   disorder seemed to be different between Europe and the U.S.,

  21   and we did that based on looking at the demographics and the

  22   baseline variables, which I can show you in Slide QA65 to

  23   begin with.

  24             [Slide.]

  25             As you can see here, we looked at 351, which was

                                                                 69

   1   97 percent U.S., 100 percent North America, and then we

   2   broke out the European patients in 301.  As you can see

   3   demographically, with a high Caucasian rate and a low use of

   4   bulking agents, but other than that, very similar

   5   demographics.

   6             [Slide.]

   7             On the next slide, QA66, when we looked at the

   8   baseline variables, again, very similar across the studies. 

   9   We did break out the results in 301, and we looked at

  10   response rates specifically on QA75 in this study by region.

  11             Shown here are the results overall.  Shown here

  12   are the results in Europe.  Again, U.S. did not contribute a

  13   whole lot to the study, also, in the study, specifically

  14   with Turkey and South Africa.

  15             As you can see, response rates in Europe obviously

  16   were similar overall.  Response rates in U.S. also showed

  17   effects in favor of tegaserod.  Actually, in Turkey, we

  18   really had this very high placebo response rate. 

  19   Demographics and baseline characteristics, in fact, Turkey

  20   were different than what I just showed you in Europe and the

  21   U.S. in several things, and in South Africa, sort of mixed

  22   results.  Again, very small numbers here in South Africa.

  23             So, as best we can determine -- what we also did,

  24   for example, the associations that I showed you earlier, the

  25   patients, the scale difference, how they responded to the

                                                                 70

   1   scale, the associations in 351 and 301, in Europe versus the

   2   U.S., was also very similar, so they seemed to understand

   3   the scale similarly, as well.

   4             DR. HANAUER:  Go ahead.

   5             DR. HOUN:  I am wondering if Dr. O'Neill could

   6   comment on the meta-analytic tradition at FDA and looking at

   7   the total database versus pooled analysis.

   8             DR. O'NEILL:  Well, before that, I have a couple

   9   questions just in terms of -- just replay for me how these

  10   trials were powered, sample size-wise, originally, because

  11   as I understand it, a couple things happened.  One, the size

  12   were up-sized, and the trials were up-sized dramatically. 

  13   The endpoint was restated.

  14             Was the up-sizing done on the basis of the

  15   original or the restated endpoint?  And how were these

  16   trials monitored?  I would suspect that monitoring

  17   multinational, multi-regional studies might be kind of

  18   difficult.  How was that done?

  19             DR. LEFKOWITZ:  Let me try to remember the first

  20   point being the general sizing, increase in sample size.  If

  21   you go to Slide 012, the original size was originally based

  22   on one primary efficacy variable.  An amendment was made to

  23   the protocol, which added the second primary efficacy

  24   variable, the subject global assessment of relief.

  25             At the time that these studies were initiated,

                                                                 71

   1   there was a lack of consensus both in the medical community,

   2   as well as at the Agency, whether the primary variable

   3   should be pain or should be an overall relief measure.

   4             Accordingly, we then added the second primary

   5   efficacy variable, and because of the multiple testing, the

   6   sample size was then increased accordingly to maintain the

   7   same power of the study.

   8             DR. O'NEILL:  That was added prior to or during

   9   the trial?

  10             DR. LEFKOWITZ:  Prior to the beginning of the

  11   study, prior to the start of the study, yes.

  12             What then happened here, these were the actual

  13   enrollment into the study.  Please note, however, that Study

  14   301 and 307 were fully enrolled, before 351 were completed. 

  15   So, there was no -- the over-enrollment was clearly not due

  16   to looking for any -- driven by anything other than the fact

  17   that we had over-enrollment into the baseline phase, and we

  18   allowed all patients who signed informed consent to be

  19   randomized.

  20             So, this is how the enrollment went to the study.

  21             DR. O'NEILL:  So, there was over-enrollment.

  22             DR. LEFKOWITZ:  There was over-enrollment, yes,

  23   and again the point being the enrollment in both 301 and

  24   307, they were fully enrolled before 351 ever completed.

  25             DR. O'NEILL:  And originally, you said this was

                                                                 72

   1   powered for an absolute 15 percent difference in response

   2   rates or something along those lines?

   3             DR. LEFKOWITZ:  That was the size that we powered

   4   the studies for, yes.

   5             DR. O'NEILL:  In absolute difference in response

   6   rates based upon the original?

   7             DR. LEFKOWITZ:  Correct, based on an assumption of

   8   the 30 percent placebo response we saw --

   9             DR. O'NEILL:  Okay.  I am just curious.  What was

  10   the effect size in the meta-analysis?

  11             DR. LEFKOWITZ:  The effect size in the meta-

  12   analysis across the three studies was 6 to 7 percent.

  13             DR. O'NEILL:  What?

  14             DR. LEFKOWITZ:  Six to 7 percent.

  15             DR. O'NEILL:  Six to 7 percent?

  16             DR. LEFKOWITZ:  Right.

  17             DR. O'NEILL:  About half of what you anticipated. 

  18   I mean these are big studies, 800, 900 subjects for a trial,

  19   that's big-time studies.

  20             DR. LEFKOWITZ:  Yes.  I think, however, what we

  21   were doing in the pooled analysis was trying to integrate

  22   the results of the three studies.

  23             DR. O'NEILL:  I understand.

  24             DR. LEFKOWITZ:  Including Study 307, which clearly

  25   had a different result from the other two studies at study

                                                                 73

   1   endpoint, so we wanted to see, even taking that study into

   2   account, whether we would see a treatment effect.

   3             Certainly if the issue is magnitude of effect, I

   4   understand that certainly an important issue in the benefit-

   5   risk profile of the study.  I would submit, however, that

   6   the intent to treat analysis that was used generally, and

   7   used in the study, is necessarily a conservative analysis

   8   that is there to look for evidence of efficacy.

   9             I think if you are really wanting to look at

  10   magnitude effect, I think the real question to answer is

  11   what is the magnitude of effect that patients can be

  12   expected to get the drug in clinical practice, that is,

  13   patients who will remain on the drug, patients who may or

  14   may not use laxatives, and if you look in Study 351 and 301,

  15   either on a monthly basis, at month 1, month 2, and month 3,

  16   or at study endpoint, if you look at QA12, I think

  17   consistently you see a treatment difference of about 10 to

  18   15 percent.

  19             Again, it was not our intent in these studies to

  20   highly select a population, we enrolled a wide spectrum of

  21   patients into the study, and I think these results shown

  22   here adjusted, not laxative adjusted in 351, adjusted, not

  23   laxative adjusted in 301, I think in clinical practice, the

  24   type of benefit is this 10 to 15 percent, and if you go on

  25   to QA13, which is the monthly results, and again looking

                                                                 74

   1   across 351 and 301 monthly results except for month 2, one

   2   generally sees 10 to 15 percent response rate, and again,

   3   slightly higher if one is only looking at a female

   4   population.

   5             We do feel that a 10 to 15 percent treatment

   6   difference in clinical practice, in a difficult disease to

   7   treat, for which there is no good alternative therapy, and

   8   which I hope you will agree is a safe drug, is a clinical

   9   meaningful benefit for the patients.

  10             DR. HANAUER:  Do you have a one-week response rate

  11   versus placebo?

  12             DR. LEFKOWITZ:  You mean at week 1?

  13             DR. HANAUER:  At week 1, because it seems that the

  14   overall long-term kind of peters out a bit compared to the

  15   early response, and I am wondering if this is a drug that

  16   works early because of its laxative effect on the primary

  17   endpoint.

  18             DR. LEFKOWITZ:  The results at week 1 in

  19   particular are generally a bit higher, and are about roughly

  20   13 to 15 percent at week 1, but then they do tend to

  21   stabilize and remain persistent throughout the 12 weeks. 

  22   The last four weeks are no different than, for example, week

  23   3 to 6 or whatever.

  24             So, I think that it is true that at week 1, you

  25   see more of an effect, but then it does stay persistent

                                                                 75

   1   throughout the study.

   2             DR. O'NEILL:  I still want to get back to the

   3   meta-analysis, Dr. Houn had asked me to address that.

   4             So, these trials were only looked at once with

   5   regard to relative treatment effect, and that was at the

   6   completion of the trial, and the up-sizing of the trial had

   7   nothing to do with monitoring the trial in between.

   8             DR. LEFKOWITZ:  That is absolutely correct.  We

   9   did no exploratory analyses of the data, other analyses of

  10   the data, yes.

  11             DR. O'NEILL:  Generally, with regard to the meta-

  12   analysis issue, I think it is appropriate to look at all of

  13   the data collectively, but I think there is a sequence to

  14   how the data came about, and I think that also needs to be

  15   thought about.

  16             The first study might be considered, I guess, the

  17   study that define the endpoints for the further studies. 

  18   351 could be viewed as an exploratory study even though it

  19   was one of the identical design trials, but that was used to

  20   design the primary endpoints, I believe, for the other

  21   studies.

  22             So, I think in that sense there is a sequence to

  23   this, and meta-analyses, if you are going to do a meta-

  24   analyses, you should really prespecify it in advance with

  25   all the conditions in terms of how it might be used for an

                                                                 76

   1   inferential purpose.  That is not to say that isn't useful

   2   to get effect sizes in other things.  That is why I asked

   3   you what the overall effect size was, which was around 6 to

   4   7 percent.

   5             But the other studies also, the individual studies

   6   seemed to be, on their face, you gave them the best shot in

   7   terms of the primary endpoint, powering them, and when you

   8   put under studies that are not significant in with the

   9   others, you have to ask was it but for power I would have

  10   found an effect.

  11             I think that is what the issue is here.  The dose

  12   titration study, I believe in some ways might have been your

  13   optimal shot, because you optimized in the titration arm the

  14   ability to maximize the responder, and that study seems to

  15   be a little different in design even though that is being

  16   combined in the other two studies.

  17             So, I think there are some other questions with

  18   regard to dissecting the components of the meta-analysis

  19   that would like to talk about perhaps later on.

  20             DR. LEFKOWITZ:  If I could just make two points

  21   before letting Dr. Fisher respond.  Again, the pooled

  22   analysis is just one of several analyses we would ask the

  23   committee to consider, and we are asking the committee to

  24   consider the totality of evidence across the three studies.

  25             You know, in terms of the dose titration design,

                                                                 77

   1   it again was our intent to see if we could, in that study,

   2   see if predominants on 4 mg, we could optimize their

   3   response.  In retrospect, perhaps it wasn't the best design

   4   in a study, such as irritable bowel syndrome, where you have

   5   varying degrees of severity, a disease that waxes and wanes,

   6   so I am not -- again, in retrospect, I am not sure that in

   7   this particular disorder that would be the optimal design,

   8   and I would submit that 351 and 301 are the studies that

   9   more show the efficacy of the product.

  10             Dr. Fisher.

  11             DR. FISHER:  The primary meta-analysis, just to

  12   reiterate, in fact, both Gary Koch and I came in and sort of

  13   gave them the same advice, which was go with the original

  14   endpoints, which, of course, works against the -- you know

  15   that slide we had up there, the righthand one, used all the

  16   data, but nevertheless, for the 351, it used the original

  17   endpoints.

  18             So, number one, that works against the studies,

  19   and it is also conservative in the following sense.  I

  20   imagine later the clinicians will discuss what went on in

  21   307, but one of the striking things about it is this

  22   particular sponsor decided to use the last four weeks, but

  23   actually, they looked quite good for two months, and then

  24   due to chance, due to design, due to whatever, things sort

  25   of fall part in the last four weeks, but that was also

                                                                 78

   1   included in the meta-analysis.

   2             So, in that sense, what is done is conservative. 

   3   It is true there is sort of a mixture of apples and oranges

   4   because you have some studies with 12 mg and some with 4 to

   5   12, and I suggested the meta-analysis for primary evidence

   6   of efficacy.

   7             Once you bring up efficacy, if you are talking

   8   about the best way to estimate the effect you get with a

   9   particular dosing regimen or something, then, I think there

  10   are much subtler issues, and then a lot of the things

  11   actually that have been raised in the FDA document start to

  12   come into play, but the first task obviously is decide is

  13   there substantial evidence of efficacy, because if the

  14   answer to that is no, then, we can just all go home, we can

  15   ignore safety, too, for that matter.

  16             So, we did this to look at the overall program in

  17   a fairly conservative way, but trying to integrate all the

  18   data for primary evidence of efficacy.

  19             DR. LAINE:  Just real quickly, you did say this

  20   was a post-hoc analysis, this meta-analysis was post hoc, is

  21   that right, it was not prespecified?

  22             DR. FISHER:  Yes, we were trying to integrate the

  23   data across the three studies.

  24             DR. HANAUER:  Dr. Richter.

  25             DR. RICHTER:  Steve and Martin, I want to get back

                                                                 79

   1   to the drug is being proposed for people with constipation-

   2   predominant IBS, and what I am a little perplexed about is

   3   your inclusion criteria which has the Rome aspects to it,

   4   which again is based on a consensus of opinion rather than

   5   necessarily strong scientific data.

   6             I was involved in Rome I, and somewhat involved in

   7   Rome II, but there you talk about bowel movements on an

   8   average of less than three a week, and then I am kind of

   9   surprised that when you get over to the demographics of your

  10   actual patient population, they don't really fit in, that

  11   is, their average number of bowel movements a week is five

  12   or more, and they tend to have not that firm of a stool.

  13             I am perplexed there, and also the secondary issue

  14   I have is if you were to really stay with the Rome criteria

  15   of more severe constipation, have you had the opportunity to

  16   look at that subset, and those with more severe

  17   constipation, which you anticipate would have more pain, do

  18   they get a better response with your drug.

  19             DR. LEFKOWITZ:  I must admit we were initially I

  20   guess bit perplexed with the number of bowel movements per

  21   week, as well, which were about five to six.  If you look at

  22   median bowel movements, there are perhaps four and a half to

  23   five, still perhaps higher than what you might expect.

  24             However, you know, Rome criteria, which is 25

  25   percent of the time less than three bowel movements a week,

                                                                 80

   1   and again number of bowel movements is not the only or

   2   perhaps the best measure of constipation.

   3             In addition, patients could fulfill the other two

   4   of the three Rome criteria and get in.  However, when we did

   5   look and if you go to QA77, what patients actually did over

   6   the four weeks -- and if I could have QA77.

   7             [Slide.]

   8             This is when we looked over their four-week

   9   baseline, and you can see that fully two-thirds of the

  10   patients either fulfilled the less than three bowel

  11   movements a week 25 percent of the time, or the hard or very

  12   hard stool, so one or the other was fulfilled almost two-

  13   thirds of the time.

  14             There was also patients who did seem to have a

  15   diarrhea component of disease or perhaps an alternating

  16   component of the disease, and again our intent by not having

  17   strict stool consistency criteria, for example, would be to

  18   try to enroll patients who would likely get the drug in

  19   clinical practice, which is generally based on clinical

  20   history.

  21             So, we do think that it was a generally

  22   constipation-predominant population with clearly some

  23   alternators in the disease.  We actually did not look at

  24   people in terms of response rates who had a more severe

  25   constipation, we looked at people who had more of a

                                                                 81

   1   diarrheal component, either based on this group right here

   2   or based on a stool consistency less than 3.5.  Those people

   3   tended to do worse or did not have differences from placebo,

   4   whereas, people who either had stool consistency between so-

   5   called normal, between 3.5 and 4.5 or more than 4.5, both

   6   those groups of patients had response rates higher than

   7   placebo that were similar between them.

   8             DR. RICHTER:  Let me clarify the point then. 

   9   Then, for the ones with the more severe forms of

  10   constipation, when you did a post-hoc look at it, they

  11   seemed to respond as well as the ones with the milder form?

  12             DR. LEFKOWITZ:  Yes.  We looked at it, it was

  13   based on stool consistency, we broke it with less than 3.5,

  14   3.4 to 4.5, and then 4.5 being higher.

  15             If you give me one second, I will show you the

  16   results.  If you go to ESG125.

  17             [Slide.]

  18             Shown here, as you can see, about half the

  19   patients had stool consistency greater than 4.5.  This

  20   accounted for 11 percent of the population.  Again, these

  21   are pooled results across the three studies, so no treatment

  22   effect of less than 3.5, and a fairly similar treatment

  23   effect from looking across these patients here, intermediate

  24   stool consistency, and those with higher stool consistency.

  25             DR. HANAUER:  So, the more constipated, the less

                                                                 82

   1   of an effect?

   2             DR. LEFKOWITZ:  No, no, I am sorry, this is people

   3   with less constipation, less than 3.5 being the loose end of

   4   the scale, which is shown down here, 4.0 higher, 5.0 being

   5   somewhat hard.  So, 3.5, 4.5 in the middle, 3.5 being less

   6   constipated.

   7             DR. RICHTER:  This is stool consistency, right?

   8             DR. LEFKOWITZ:  This is stool consistency, yes.

   9             DR. RICHTER:  Did you look at it for stool number?

  10             DR. LEFKOWITZ:  We only looked it for greater than

  11   three bowel movements a week, and those patients tended to

  12   do less well than the rest of the population.  We didn't

  13   look at people on the lower end in terms of response rates.

  14             DR. HANAUER:  Constipation-predominant, why did

  15   you not look at the constipated patients?

  16             DR. LEFKOWITZ:  Well, I guess you are defining

  17   constipation strictly on bowel movements.  I guess we felt

  18   that that entire population fulfilled constipation-

  19   predominant IBS in terms of the diagnostic criteria.

  20             DR. HANAUER:  I am sure you had a group of experts

  21   telling you that having constipation up to 25 percent of the

  22   time was constipation-predominant.

  23             Maybe Dr. Wald, who we have talked about

  24   constipation before, is this really the group of patients

  25   that were enrolled in the study who clinicians considered

                                                                 83

   1   constipation-predominant?

   2             DR. WALD:  Well, I think that, strictly speaking,

   3   if you had constipation greater than 25 percent, but you had

   4   diarrhea 25 percent of the time or greater, you would be

   5   mixed.  If you had constipation greater than 25 percent, but

   6   in all other respects, in those non-constipated intervals,

   7   you had what we would call normal bowel habits, we would,

   8   yes, call that constipation-predominant irritable bowel.

   9             DR. HANAUER:  Is this group of patients the ones

  10   in your practice who you consider constipation-predominant?

  11             DR. WALD:  Yes, I think that would be a fair

  12   statement.  There are some that have occasional diarrhea,

  13   but that doesn't form the essence of their being, so to

  14   speak.  As I say, it's a predominant, it's a strictly

  15   speaking definitional issue.

  16             The issue with constipation and irritable bowel is

  17   I think the frequency of the deranged bowel habit versus

  18   what we would call the normal bowel habit, in the absence of

  19   diarrhea or significant diarrhea would then put them into

  20   this, plus, of course, the finding of pain, which

  21   distinguishes them basically from pure constipation or pure

  22   diarrhea.

  23             DR. HANAUER:  Dr. Wison.

  24             DR. WISON:  I just wanted to again clarify the

  25   definition of constipation because I think that from a

                                                                 84

   1   patient-driven diagnosis, the straining and consistency

   2   seems to predominate at least from some of the studies that

   3   we have reviewed more recently.  Therefore, the number is

   4   one of the problems that I think physicians have always face

   5   that doesn't necessarily define constipation, at least that

   6   is my understanding.

   7             So, from a patient-driven standpoint in studies in

   8   the elderly, and so forth, the character of the stool and

   9   the passage of the stool is more critical.  I don't know if

  10   that is a fair assessment to the experts there.

  11             DR. WALD:  I am sorry.  The microphone must be

  12   malfunctioning because I didn't catch your remarks at all

  13   except I could see you were looking at me, and I had a

  14   feeling you were talking to me.

  15             DR. WISON:  I was just going to say that the point

  16   that I thought Rome II, and so forth, was trying to focus on

  17   was the patient-driven definition of constipation as

  18   straining at stool and character of stool less than the

  19   number of stools.  So, that was one of the points that was

  20   being raised, you know, in a clinical arena with our

  21   evaluation of constipation-predominant symptomatology.

  22             DR. WALD:  I think that is absolutely correct, Dr.

  23   Wison.  The concept of frequency alone, if you use frequency

  24   alone as less than two, very few patients would be

  25   constipated, forget the irritable bowel issue.  So, it

                                                                 85

   1   becomes what they call a satisfactory bowel movement or one

   2   that is truly a complete bowel movement.

   3             So, frequency is one part of that, but it would be

   4   the frequency of a complete or satisfactory bowel movement.

   5             DR. HANAUER:  Dr. Surawicz.

   6             DR. SURAWICZ:  I have three questions, but I will

   7   ask them one at a time.

   8             What is your definition of a laxative in the group

   9   that you said laxative or you excluded that?

  10             DR. LEFKOWITZ:  If you are asking what particular

  11   laxative, anything --

  12             DR. SURAWICZ:  No, what I want to know is whether

  13   that includes fiber and bulk, are you considering that a

  14   laxative?

  15             DR. LEFKOWITZ:  No, bulking agents were not used

  16   as part of the adjustment criteria.  If people were on

  17   bulking agents, they continued bulking agents.  That was not

  18   used as part of the adjustment for laxatives.

  19             DR. SURAWICZ:  Okay.  You say that the low placebo

  20   rate was a high hurdle, and I know you tried to explain that

  21   later, but to me it seems like a low placebo rate would make

  22   it easier to show efficacy.

  23             DR. LEFKOWITZ:  I think whether or not a low

  24   placebo response helps to show efficacy really depends on he

  25   disorder and the variable being involved.  I don't think it

                                                                 86

   1   is necessarily true that low placebo response -- I mean if

   2   you take it to the extent, I don't think complete relief in

   3   irritable bowel, at least where we are right now, is a

   4   reasonable criteria.

   5             So, clearly, if we went to complete relief, you

   6   wouldn't expect it.  There is examples in, for example,

   7   hypertension, if your criteria was a blood pressure of 80,

   8   you know, again, that is a stringent, so I think it really

   9   depends on the particular variable or the particular

  10   disorder, whether low placebo response rates will make it

  11   easier or harder.

  12             I think the 30 percent that we saw when we changed

  13   is very much in line with I think more the recent trials and

  14   where one can detect treatment differences, not the 50 or 60

  15   percent perhaps that had been reported in some earlier

  16   trials, but also not the very stringent, and that was what

  17   our data supported, and that is what we believe.

  18             DR. SURAWICZ:  But why did you call the low

  19   placebo rate a high hurdle, because you said that several

  20   times?

  21             DR. LEFKOWITZ:  I was only meaning to refer

  22   complete, considerable relief being a difficult -- it is

  23   only in a sense complete is higher than considerable.

  24             DR. HANAUER:  The endpoint was the hurdle, not the

  25   placebo rate.

                                                                 87

   1             DR. LEFKOWITZ:  Yes.  The endpoint was the hurdle,

   2   that is correct.  That is correct.

   3             DR. HAUPTMAN:  Lawrence Hauptman, Novartis.

   4             Let me address that point about the low placebo

   5   rate possibly making it harder to find the difference.  We

   6   hypothesized 30 percent versus 45.  The 15 percent that we

   7   hypothesized was in part due to what we thought we would

   8   need to get in placebo, the 30 percent.

   9             The fact that the placebo rate turned out to be

  10   lower, say, 20 percent, had the difference been the same,

  11   had it still been 15 percent, you are right, it would have

  12   been easier to show a difference, but that may not be the

  13   case.  The lower placebo rate in the face of what we thought

  14   we would expect might mean we weren't measuring what we

  15   thought we were measuring, and then the 15 percent that we

  16   thought we would see actually wouldn't be relevant.

  17             Under that context of a stringent high hurdle, the

  18   difference in those terms could have been some number less

  19   than 15 percent, we have no idea.  If it had been, say, 7,

  20   8, or 9 percent, those same power calculations would have

  21   led to a smaller power, would have been harder to do it.

  22             Just take a ridiculous example where it is

  23   virtually impossible, you set it so high that not only does

  24   the placebo rate come down to virtually zero, but then any

  25   treatment effect would come down to virtually zero, the

                                                                 88

   1   same, and it would be almost impossible to find the

   2   treatment difference.  That is the context in which we

   3   expressed that.

   4             DR. SURAWICZ:  May I ask one last question about

   5   the placebo rate, and that is why does the placebo rate

   6   improve over time, and does that have any influence on your

   7   drug efficacy over time?  Are the same factors possibly

   8   involved?

   9             DR. LEFKOWITZ:  It is hard for me to explain why

  10   the placebo rate increases over time.  It was more so I

  11   think in 307 than the other studies, but the difference, as

  12   Dr. Hanauer said, well, at week 1, our difference was the

  13   greatest of any week.  When you go beyond week 1, the

  14   difference from placebo stays fairly constant over the

  15   course of the study.

  16             DR. HANAUER:  Dr. Smith, did you have a question?

  17             DR. SMITH:  Yes, I do.

  18             I would like to follow up on the placebo concept

  19   again.  In any clinical trial dealing with an entity that

  20   has a psychosocial component, you anticipate a strong

  21   placebo response that can last variably three to six months.

  22             But what I have a concern about is that the

  23   planners -- or have a question about -- is the people who

  24   planned and designed the study, knowing that there is a

  25   psychosocial overlay to irritable bowel syndrome, didn't

                                                                 89

   1   have a four-week washout period or pre-study period where

   2   all placebo responders are segregated out, and wouldn't that

   3   have made it easier to detect a true clinical difference,

   4   because in my second, if you want to use the word concern,

   5   is the statistical difference that you can document on

   6   slides versus the clinical difference.

   7             DR. LEFKOWITZ:  The issue of whether having a

   8   placebo run-in, then eliminating placebo responders was

   9   certainly one that we seriously considered in the design of

  10   the trial.

  11             It has been almost the uniform recommendation of

  12   those who give recommendations, such as Rome II, not to have

  13   a placebo run-in in the trial, for several reasons, one

  14   being that it may actually select out non-responders to the

  15   drug; two, being it may not be real world in a sense because

  16   the psychosomatic part of it is the real world, and

  17   therefore it should be included as part of the trial.

  18             I actually know of no recent studies that have

  19   done that.  We did seriously consider it, but based on the

  20   consensus in the field, which is the recommendation not to

  21   have a placebo run-in, eliminate placebo responders.

  22             DR. WOLFE:  My question or comment was almost

  23   exactly the same, that psychosocial-related diseases do have

  24   these kind of responses.  If you look at pain syndromes in

  25   general, placebo response rates seem to increase with time,

                                                                 90

   1   especially when you are giving the people the perception of

   2   getting more drug possibly.

   3             But getting back to the design, you are right, a

   4   run-in can cause the problem of bias, but did you look at

   5   the patients four weeks after the drug was stopped and see

   6   what happened to these people, the people on drug, was their

   7   sense of well-being that much less than those who were on

   8   placebo?

   9             The other thing is did you ever consider a cross-

  10   over design in which people could really then determine the

  11   effect and use themselves as their own control?

  12             DR. LEFKOWITZ:  Again, I agree.  You know, as you

  13   said, heightened expectations may certainly have been more

  14   of a factor in Study 307 as you mentioned.  In terms of a

  15   cross-over design, I think that is potentially fraught with

  16   some difficulties in terms of carryover effects and other

  17   things in this disorder.

  18             I am sorry -- oh, in terms of the month

  19   withdrawal, while we continued to collect safety information

  20   30 days after the study, we did not do a formal withdrawal. 

  21   I think unless one really does a double-blind type of

  22   withdrawal, I think there is a very likely expectation that

  23   everybody after the study -- I think it would be hard to

  24   tease out what is going on once the study ends in an open-

  25   label fashion.  We did not do a four-week formal withdrawal

                                                                 91

   1   period.

   2             DR. HANAUER:  I am going to give Dr. Laine the

   3   last question unless Dr. Ferry wants one, and then we are

   4   going to take a 15-minute.  We will do it Dr. Laine and then

   5   Dr. Ferry, and then a break.

   6             DR. LAINE:  I noticed in your indications that you

   7   were seeking, it made no reference to gender.  Clearly, you

   8   have a relatively small number of men.  There are gender

   9   differences in response to therapy in general, in this

  10   disease perhaps, and you showed no even suggestion I guess

  11   that made that benefit men.

  12             I was wondering why you were going for men and

  13   women, rather than just women, based on your data.

  14             DR. HANAUER:  I would like to come back to that

  15   because that is a summary type question rather than a

  16   methodology question.

  17             DR. LEFKOWITZ:  If I could just point out in

  18   response to that, if you do look over the study, the results

  19   are variable.  You do see some effect, however, endpoint you

  20   don't.  It is a variable response.  I fully agree with the

  21   small numbers that we clearly have not demonstrated evidence

  22   of efficacy, and we would look to the committee for their

  23   recommendations.

  24             DR. HANAUER:  Dr. Ferry.

  25             DR. FERRY:  My question was really sort of a

                                                                 92

   1   clarification.  You used the global assessment, and that

   2   sort of is the standard to try to come up with an answer for

   3   irritable bowel syndrome, but I mean a global assessment

   4   includes sort of a general category of well-being, it

   5   includes abdominal pain and discomfort and altered bowel

   6   habits.

   7             If I am looking at the data correctly, the pain

   8   and discomfort aspect of it, looked at separately, wasn't

   9   that significantly improved across the three studies.

  10             So, my real question is, I guess, are we looking

  11   at a drug that is basically altering bowel habits as its

  12   real efficacy or does it have something else on well-being

  13   other than bowel habits either centrally, and it seems like

  14   it is mostly altering bowel habits.  Is that --

  15             DR. LEFKOWITZ:  I think, number one, certainly in

  16   a disorder like irritable bowel, it is very difficult to

  17   tease out the effects on bowel habits compared to pain,

  18   whereas, the primary, when we modified it with the overall

  19   integrative assessment.

  20             However, if we can show QA41 --

  21             [Slide.]

  22             I do think we have shown a significant effect on

  23   pain.

  24             [Slide.]

  25             Shown here are pain scores on Study 301, baseline,

                                                                 93

   1   12 mg, versus placebo.  Shown here are the bowel movements. 

   2   When we try to tease it out, one thing that one sees is a

   3   continued decrease in pain, whereas, there is stabilization

   4   of bowel movements, but I think it is very hard to tease

   5   out.

   6             However, in terms of pain specifically, if you go

   7   to QA45 --

   8             [Slide.]

   9             These are the pain scores, again changed from

  10   baseline over the course of the study, and I think when one

  11   looks at the pain scores for the 12 mg group, there is a

  12   clear effect on pain scores, showing an effect of the drug

  13   on pain.

  14             When you look at the subject global assessments,

  15   they again were all consistently favorable for the drug.  We

  16   then also did try to tease out pain versus bowel movement,

  17   which again I think clinically is difficult, and is also

  18   difficult in the context of the study, but if you go to QA

  19   43 --

  20             [Slide.]

  21             We did do a correlation, and again this certainly

  22   doesn't fully answer it, but we correlated --

  23             DR. HANAUER:  On that last slide, if you go back

  24   to that -- could we go back to the last slide?

  25             DR. LEFKOWITZ:  That is QA45.

                                                                 94

   1             [Slide.]

   2             DR. HANAUER:  Now, the data that we are seeing

   3   here at 12 weeks, is that of the percentage of patients that

   4   are still in the study, or is this carried over, this data?

   5             DR. LEFKOWITZ:  No, these are patients who are

   6   still in the study, throughout the study.

   7             DR. HANAUER:  So, we don't have an overall

   8   proportion?

   9             DR. LEFKOWITZ:  No.  We do have it study endpoint,

  10   for example, days with significant pain reduction, which was

  11   significant in 351 and in a positive direction for 301.  If

  12   you just look at pain scores at endpoint, those are highly

  13   significant if you just look at pain scores at endpoint, but

  14   these results are shown for patients as they remained in the

  15   study.

  16             If you go to QA43 --

  17             [Slide.]

  18             What we did here was a correlation between the

  19   change in abdominal pain score, reduction in pain compared

  20   to the change in number of bowel movements.  As you can see,

  21   there is a lot of scatter here with fairly weak correlation

  22   between this rough measure of number of bowel movements and

  23   visual analog of pain.

  24             I think, however, it is difficult to separate out

  25   the two.

                                                                 95

   1             DR. HANAUER:  Okay.  Here is the rest of the

   2   agenda.  We are going to take a 15-minute break and

   3   reconvene at 10:45, and then we are going to complete your 

   4   adverse events and summary, and then try to get the FDA in

   5   before lunch.

   6             [Break.]

   7             DR. HANAUER:  Dr. Lefkowitz, do you want to

   8   introduce your next speaker?

   9             DR. LEFKOWITZ:  Prior to proceeding with the

  10   safety overview of tegaserod, the Agency has asked us to

  11   address two specific issues, finding of in the preclinical

  12   studies of carcinogenicity in mice and also an initial

  13   imbalance in the reporting of ovarian cysts.

  14             Dr. Bentley will present the results of the

  15   preclinical studies.

  16                       Preclinical Findings

  17                      Philip Bentley, Ph.D.

  18             DR. BENTLEY:  Dr. Hanauer, members of the

  19   committee, ladies and gentlemen:  I would like to briefly

  20   review the findings from the long-term toxicity studies.

  21             [Slide.]

  22             We performed carcinogenicity studies in rats and

  23   in mice.  In the rat study, there was no indication of an

  24   increased tumor incidence in any organ.  In the mouse study,

  25   there was a treatment-related increase in the incidence of

                                                                 96

   1   tumors in one organ, tumors in one site.

   2             [Slide.]

   3             If you look in details at the study, you can see

   4   that the incidence, in the small intestine, the incidence of

   5   adenocarcinomas was increase in the high-dose animals only,

   6   and that this increased incidence was associated with a

   7   mucosal hyperplasia which persisted during the treatment

   8   period.

   9             I would like to draw your attention to the doses

  10   used in this study.  The 600 mg/kg dose was exceptionally

  11   high.  The animals had a 70-fold higher systemic exposure to

  12   the drug than is seen in the clinic, or based on a body

  13   surface area, a 240-fold excess of the drug.

  14             In terms of current guidelines, actually, the 200

  15   mg/kg dose, the middle dose, is more representative of the

  16   type of maximum dose used with 34 times the human exposure.

  17             [Slide.]

  18             We concluded from this study that treatment with

  19   high doses, treatment of mice with high doses of tegaserod

  20   caused an increased incidence of small intestinal tumors,

  21   which was associated by a sustained hyperplasia in the

  22   intestinal mucosa.

  23             However, it is important to note that the high

  24   dose in these animals really exceeded what would be classed

  25   as the maximum tolerated dose for the animals when defined

                                                                 97

   1   in terms of a decrease in body weight gain.  This is shown

   2   on the next slide.

   3             [Slide.]

   4             This shows the weight gain of the animals

   5   throughout the two-year course of the study.  The top lines

   6   are the two control groups and the low-dose group.  The

   7   white line is the mid-dose group, and the blue line on the

   8   bottom shows the body weight curve for the high-dose group.

   9             It is apparent that the animals had a severe

  10   reduction in body weight gain.  In fact, the body weight

  11   gain was only 33 percent that of the control animals.

  12             The white line, the mid-dose group, is around 20

  13   percent, which again more clearly fulfills the criteria for

  14   a maximum tolerated dose.

  15             [Slide.]

  16             So, the tumors were only seen in a single organ at

  17   very, very high doses, which clearly exceeded the maximum

  18   tolerated dose.

  19             It is important to note that we have examined the

  20   mutagenicity of tegaserod in a variety of in vitro and in

  21   vivo tests.  Particularly important were the different

  22   endpoints used - mutagenicity, chromosomal endpoints, and

  23   test for chromosomal damage in the mouse strain which was

  24   used for the carcinogenicity study.

  25             All these mutagenicity tests were negative,

                                                                 98

   1   indicating that there is no mutagenic potential of the

   2   compound, which also indicates that the tumors must have

   3   arisen through non-genotoxic or epigenetic mechanisms.

   4             The importance of that is that if the mechanism is

   5   non-genotoxic, it generally has a clear dose dependence with

   6   clear no-effect levels.  So, you can clearly say at the

   7   doses it did not occur, there is a biological reason for it.

   8             [Slide.]

   9             The main driving force behind the tumors in this

  10   case is an induction of cell proliferation at the high doses

  11   by treatment of tegaserod.  This slide shows the results of

  12   a 13-week study in which the cell proliferation in the

  13   intestine was examined by the incorporation of

  14   bromodeoxyuridine, and histopathologically, we examined for

  15   hyperplasia.

  16             It is clear that there was at these doses an

  17   increased incidence of cell proliferation within the

  18   intestine associated with hyperplasia, but once treatment is

  19   discontinued, these effects reverse and are totally

  20   reversible, and after a four-week recovery period, that is,

  21   a four-week period with no treatment after the 13-week

  22   treatment period, there were no signs of hyperplasia or

  23   increased cell proliferation within the intestine.

  24             [Slide.]

  25             The conclusion then is that short-term treatment

                                                                 99

   1   of mice with high doses of tegaserod induces a reversible

   2   hyperplasia within the small intestine.  A longer term

   3   treatment, as witnessed by the carcinogenicity studies,

   4   results in a sustained hyperplasia, particularly at the high

   5   doses, and this hyperplasia can then result in

   6   carcinogenicity.

   7             [Slide.]

   8             If we look at the processes involved, we have a

   9   sort of scheme here, going through cell division to the

  10   induction of hyperplasia, to the induction of tumors, and it

  11   is important to note that for each of these steps here,

  12   there are clear no-effect levels, so there are no-effect

  13   levels for the compound which don't induce cell division,

  14   there is a no-effect level then between the induction of

  15   cell division and hyperplasia, and you can have doses of the

  16   compound which induce hyperplasia, but do not induce

  17   sustained hyperplasia and do not induce tumors.

  18             If we look at tegaserod, the no-effect level for

  19   the induction of sustained hyperplasia is 200 mg/kg.  The

  20   no-effect level for the induction of hyperplasia is around

  21   150 mg/kg, although this is not shown on that slide.

  22             So, if we look at these doses which are involved

  23   then, the no-effect level again would be 200 mg/kg, we

  24   considered the doses involved.  The high dose is 600 mg/kg

  25   was equivalent to 240-fold the human dose on the body

                                                                100

   1   surface area basis.  That is 70-fold the expected human

   2   exposure, but probably more important for a case like this,

   3   where we are looking at the effect directly in the intestine

   4   or the anticipated intestinal concentrations, in this case,

   5   we estimate that the exposure of these animals in the

   6   intestine itself, at the site of action, was 570-fold that

   7   estimated in the human situation.

   8             At the no-effect level, we had doses of around 80-

   9   fold the human dose on a body surface area basis, resulting

  10   in a 34-fold excess of exposure, and local concentrations

  11   around 190-fold higher than expected.

  12             I would like to point out again that this dose

  13   actually more correctly fulfills the criteria for a maximum

  14   tolerated dose than the higher dose, which clearly exceeded

  15   these criteria.

  16             [Slide.]

  17             Our conclusion therefore is that tegaserod therapy

  18   poses no carcinogenic risk for patients.  This is based on

  19   the fact that the compound is not mutagenic, that the tumor

  20   incidences were only seen at a single site, which is again

  21   an indication there is not a genotoxic mechanism involved.

  22             The mechanism involved is an induction is an

  23   induction of intestinal mucosa hyperplasia.  No such

  24   hyperplasia was seen in studies of one-year duration in dogs

  25   or in the rat toxicity studies even though the exposure

                                                                101

   1   levels of these animals were as high as those of the mice,

   2   so it suggests it was a species sensitivity in this case.

   3             The initial effects in the mouse were reversible. 

   4   There were no carcinogenic effects in the rat, and above

   5   all, the tumors were only seen at very high doses, and from

   6   the no-effect level for the tumors, there are very high

   7   safety margins.

   8             DR. HANAUER:  Does anyone on the committee have

   9   questions related to this?  Dr. Wolfe.

  10             DR. WOLFE:  Quick question.  Any work in isolated

  11   cell lines, any new  mechanism of action proposed why you

  12   may see some effects in mice?

  13             DR. BENTLEY:  We haven't worked in isolated cell

  14   lines, no.

  15             DR. HANAUER:  And it is only small bowel mucosa,

  16   have you looked at colonic or gastric mucosa?

  17             DR. BENTLEY:  We looked at all the intestine, it's

  18   only in the small bowel and only at the very high doses.

  19             DR. HANAUER:  Thank you.

  20                 Review of Data on Ovarian Cysts

  21                         Bruce Carr, M.D.

  22             [Slide.]

  23             DR. CARR:  Mr. Chairman and members:  I was asked

  24   by Novartis to (a) review the adverse events reported as

  25   ovarian cysts with the use of tegaserod; and (b) to

                                                                102

   1   determine if there is an increased association with the

   2   laparotomies due to gynecological and gastrointestinal

   3   indications in tegaserod.

   4             [Slide.]

   5             First, I will discuss the issue related to ovarian

   6   cysts.  In review, the ovary is a dynamic organ with

   7   follicular growth and development occurring continually, so

   8   that at any given time, ovarian follicles or corpora lutea,

   9   which are the remnants of the follicle, are present in the

  10   ovaries.

  11             Physicians and even gynecologists sometimes call

  12   ovarian follicles cysts, a term which may itself suggest a

  13   pathological condition, when, in fact, they are describing

  14   normal ovarian events and physiology.

  15             Ovarian cysts are usually defined as greater than

  16   4 cm and persist for a number of months, but the pathology

  17   and the treatment of ovarian cysts is not clearly

  18   understood.

  19             [Slide.]

  20             Now, this slide illustrates an ultrasound of an

  21   ovary and associated follicle, mature follicle.  If a

  22   patient experienced abdominal pain and the physician ordered

  23   an ultrasound, the diagnosis of a cyst would be provided

  24   back to the physician, and he or she may consider the cyst

  25   to be the cause of the pain.

                                                                103

   1             However, this ultrasound is an infertility patient

   2   of mine with a mature follicle one day prior to ovulation. 

   3   The day the patient ovulates, the cyst, the follicle will

   4   rupture, and the patient may develop short-term, acute pain

   5   known as Mittelschmerz, but this is a normal physiological

   6   event.

   7             Now, with this as background, we can proceed with

   8   the discussion of the cases of ovarian cysts.

   9             [Slide.]

  10             This slide illustrates my further analysis of nine

  11   adverse events, termed ovarian cysts, of which eight

  12   patients were being treated with tegaserod and one with

  13   placebo.

  14             I divided these into those where the diagnosis was

  15   not confirmed or confirmed.  In those cases that were not

  16   confirmed, the revised diagnosis, in fact, was a

  17   cystadenofibroma, which is in fact a benign ovarian tumor, a

  18   peritubal cyst, which is a cyst of the fallopian tube, which

  19   is probably a congenital defect of muellerian origins.  A

  20   third case had no cyst found at surgery, and only pelvic

  21   adhesions, and the fourth I considered not confirmed was a

  22   patient who had abdominal pain where the adverse report was,

  23   quote, "ruptured ovarian cyst," but there was no evidence to

  24   document this either by examination or imaging studies.

  25             In addition, there were five cases in which the

                                                                104

   1   ovarian cysts were confirmed.  Of these five, two in fact

   2   had history of prior ovarian cysts.  Two of these patients

   3   were both on tegaserod.

   4             One patient had prior ovarian cysts diagnosed, as

   5   well as adenomyosis and menorrhagia.  The other case had a

   6   case of ovarian cysts on the left and right ovaries removed

   7   approximately three to four months prior to surgery and at

   8   the time of recurrent surgery we will discuss a little bit

   9   later, also had appendicitis of the appendix.

  10             This leaves us with three cases of newly occurring

  11   ovarian cysts.  One was placebo, which she had a diagnosis

  12   of polycystic ovary, which is an ovary with very small

  13   follicles, possibly a genetic disease.

  14             An additional polycystic ovary was seen in a

  15   patient on tegaserod.  This was confirmed by CT scan. 

  16   Again, PCO is not a disorder associated with abdominal pain

  17   or development of large cysts.

  18             One patient had a cyst or follicle that was

  19   diagnosed by a gynecologist that arose during a cycle, that

  20   regressed in a subsequent cycle.

  21             [Slide.]

  22             This slide illustrates the Phase II, the Phase II

  23   and III combined, as well as uncontrolled, long-term studies

  24   in female patients with ovarian cysts.  Looking at the

  25   percent of patients in the combined Phase II/III studies,

                                                                105

   1   the percent patients with cysts was approximately the same

   2   in the placebo, as well as in the drug-treated group.

   3             In the uncontrolled, long-term studies, the

   4   percentage of patients with the cysts remains the same, but

   5   obviously, there was no placebo patients in this group, but

   6   this information is somewhat reassuring.

   7             [Slide.]

   8             Next, we evaluated the estimated ovarian cyst

   9   frequency in women aged less than 50 years, in the pooled

  10   Phase II/III and long-term studies.

  11             The data presented here is presented as the

  12   estimated frequency per 1,000 women years.  There is no

  13   significant difference between the groups.

  14             [Slide.]

  15             We also investigated the prevalence of ovarian

  16   disease or ovarian surgery at baseline.  In the patients

  17   with previous ovarian surgery, the prevalence was similar in

  18   the placebo- and tegaserod-treated patients.  In the

  19   patients with previous ovarian cysts at baseline, the

  20   prevalence was similar in the placebo and again drug

  21   treated-patients.

  22             [Slide.]

  23             In order to place these data in perspective, in a

  24   review of the literature, the prevalence of simple cysts and

  25   polycyst ovarian disease, which were detected by ultrasound

                                                                106

   1   in asymptomatic healthy populations, was evaluated.

   2             As seen in the postmenopausal patients, and in

   3   women aged 25 to 40 years, there was a similar prevalence of

   4   around 6 percent.  This number appeared to be double,

   5   however, in adolescent girls.

   6             [Slide.]

   7             With respect to the preclinical studies with

   8   tegaserod, there appears to be no treatment-related ovarian

   9   cysts in the rat toxicity studies up to six months, dog

  10   toxicity studies up to 12 months, mouse carcinogenicity

  11   study or after reevaluation of the rat carcinogenicity

  12   study.

  13             In addition, there was no histopathological

  14   evidence or hormonal perturbation in any of the studies.

  15             [Slide.]

  16             In summary, there is no evidence of a link between

  17   tegaserod and the development of ovarian pathology either by

  18   evaluating of the clinical studies, which I have just

  19   presented to you, or the preclinical/toxicology studies.

  20             [Slide.]

  21             Next, I will discuss the relationship between

  22   laparotomies in patients due to gynecological and

  23   gastrointestinal indications.

  24             [Slide.]

  25             I evaluated those women undergoing gynecological

                                                                107

   1   surgery as shown in yellow.  We can see that in patients

   2   where the ovarian cysts were not confirmed, that were on

   3   tegaserod, they had different etiologies and indications for

   4   laparotomies, which I had discussed previously - an ovarian

   5   tumor, a peritubal cyst, or pelvic adhesions, again,

   6   different etiologies.

   7             In the confirmed patients on tegaserod, two

   8   patients, which I had previously described, underwent

   9   surgery, again with different etiologies.

  10             The first patient had an indication for surgery

  11   that revolved around bleeding problems, a CT scan diagnosis

  12   of adenomyosis and ovarian cyst.

  13             The second case had a diagnosis of ovarian cyst

  14   and possible appendicitis, and was proven to have

  15   appendicitis at the time of surgery, and a cyst was merely

  16   drained.

  17             [Slide.]

  18             The next slide summarizes five patients undergoing

  19   laparotomy for gastrointestinal indications.  The first

  20   placebo patient had adverse event of appendicitis.  Second,

  21   had a perforated cecum.  The three patients on tegaserod had

  22   ileus, benign pancreatic cyst, and a small bowel

  23   obstruction, again different etiologies.

  24             [Slide.]

  25             The frequency of laparotomies by year in the NDA

                                                                108

   1   database was evaluated.  The frequencies per year appear to

   2   be similar in the Phase II and III studies with tegaserod

   3   and placebo, and in long-term therapy, placebo data is not

   4   available, but the frequency of laparotomies per year

   5   appears to be confirmatory of that observed in the Phase II

   6   and III studies.  Again, this is somewhat reassuring.

   7             [Slide.]

   8             In summary, regarding tegaserod and laparotomies,

   9   in the study population a variety of different gynecological

  10   and GI disorders led to the laparotomies.

  11             The frequency of laparotomies by exposure duration

  12   were similar for tegaserod- and placebo-treated patients.

  13             There appears to be no obvious causal relationship

  14   or signal that tegaserod affects the frequency of

  15   laparotomies.

  16             Thank you.

  17             DR. HANAUER:  Any questions from the committee

  18   regarding this?  Yes, Dr. Houn.

  19             DR. HOUN:  Just a question on 5-HT4 receptors. 

  20   Have there been studies to see if they are located other

  21   than in the GI tract?

  22             DR. CARR:  We specifically did a research review

  23   of this, of the literature, and could not find any reports

  24   of these receptors in ovarian tissue.

  25             DR. HOUN:  Have you conducted those studies?

                                                                109

   1             DR. CARR:  No, I conducted a review of the

   2   literature, and there have been no reports.

   3             DR. HOUN:  And this wasn't studied by the company?

   4             DR. CARR:  No.

   5                       Safety of Tegaserod

   6                      Martin Lefkowitz, M.D.

   7             [Slide.]

   8             DR. LEFKOWITZ:  I will now review the safety

   9   profile for tegaserod beginning with a review of the

  10   exposure, adverse events, laboratory evaluations, ECG, and

  11   overall summary.

  12             [Slide.]

  13             Over 3,500 healthy subjects or patients have been

  14   exposed to the drug at the time of the NDA submission, with

  15   a maximum daily dose up to 200 mg in healthy subjects.

  16             Over 1,800 IBS patients received the drug for at

  17   least 85 days, and 302 IBS patients for more than 335 days.

  18             [Slide.]

  19             Serious adverse event reporting through the

  20   tegaserod clinical program was low, pooling the control

  21   studies in Phase II and III reporting frequency of serious

  22   adverse events was similar, exactly balanced, of 1.8 percent

  23   in the placebo and tegaserod groups.

  24             Serious adverse events were reported in 4.1

  25   percent in the long-term studies consistent with the longer

                                                                110

   1   duration of the study.

   2             [Slide.]

   3             The reasons for discontinuation through the Phase

   4   III program is shown here, blue, placebo, red, 4 mg, here,

   5   the dose titration dose, and the 12 mg/day dose.

   6             For the titration, the 12 mg/day dose, over all

   7   discontinuations were similar and 5 percent higher in the 4

   8   mg/day dose.  Adverse event, discontinuations specifically

   9   due to adverse events was slightly increased in the

  10   tegaserod groups compared to placebo, but were overall low.

  11             Other reasons for discontinuation were low and

  12   generally similar between the groups.

  13             [Slide.]

  14             When we specifically look at reporting of any

  15   adverse events, that was balanced across the group with a

  16   slightly higher reporting of severe adverse events in the

  17   tegaserod group compared to placebo.

  18             As mentioned before, serious adverse events

  19   reporting was low in the program, and discontinuation rates

  20   due to adverse events, as you saw previously, also low.

  21             [Slide.]

  22             Reporting of adverse events greater than 5 percent

  23   in the Phase III program are shown here, the two most common

  24   adverse events being headache and abdominal pain, placebo

  25   here, with similar reporting frequency of headache and

                                                                111

   1   abdominal pain compared to tegaserod groups.

   2             The single adverse event that was reported with a

   3   higher frequency was diarrhea, which was reported at about

   4   two-fold higher, 5 percent in the placebo group, 11 to 12

   5   percent in the tegaserod group, without any dose

   6   relationship in the reporting of diarrhea.

   7             Reports of severe diarrhea was approximately one-

   8   third in the tegaserod and one-third on placebo, and was

   9   about 2 versus 4 percent.

  10             Other adverse events were all similarly reported

  11   between tegaserod and placebo.

  12             [Slide.]

  13             We then looked at the time to the first episode of

  14   diarrhea after day 1.  This is day 2 to 7, and then over the

  15   next three weeks, month 2, and then month 3.

  16             As you can see, most patients who had diarrhea

  17   early on in the study, this was generally due to the

  18   tegaserod with about half of the cases of tegaserod-induced

  19   diarrhea occurring within the first week, with then a

  20   slightly higher frequency of first episodes of diarrhea

  21   throughout the rest of the study.

  22             The majority of these cases of diarrhea were

  23   single episodes with a median duration of two days and a

  24   mean duration of seven days.

  25             [Slide.]

                                                                112

   1             Shown here are the adverse events leading to

   2   discontinuation.  Overall in the program about 1 to 2

   3   percent higher patients in the tegaserod group discontinued

   4   compared to placebo.

   5             Importantly, discontinuations due to abdominal

   6   pain was balanced between the groups.  Again, the single

   7   reason that patients discontinued more frequently in

   8   tegaserod was due to diarrhea, 0.4, compared to 1.6 percent

   9   due to drug.  So, although higher, a low discontinuation

  10   rate due to diarrhea.  In the entire program, 2.1 percent of

  11   patients discontinued due to diarrhea.  Discontinuation

  12   rates due to other reasons were low and similar in the

  13   treatment groups.

  14             [Slide.]

  15             We conducted a long-term safety study, a 12-month

  16   open label study, which utilized a dose titration design, of

  17   which 80 percent of the patients were dose titrated to 12

  18   mg/day.  579 patients enrolled, and 304 completed.

  19             [Slide.]

  20             The adverse events seen in the long-term safety

  21   study was very similar with what was seen in Phase III,

  22   again headache and abdominal pain being the two most common

  23   adverse events, and an adverse event rate of diarrhea being

  24   reported at 15 percent.

  25             [Slide.]

                                                                113

   1             Reasons for discontinuations due to adverse

   2   events, again was compatible with the Phase III program. 

   3   The discontinuation rates overall, 11 percent in the study,

   4   and those due to diarrhea, 4 percent over the 12-month

   5   study, and 3 percent due to abdominal pain and flatulence.

   6             [Slide.]

   7             We evaluated laboratories throughout the program. 

   8   In Phase III, clinically relevant laboratory abnormalities

   9   in hematology and biochemistry values were rare and with

  10   similar frequency for tegaserod- and placebo-treated groups.

  11             Liver chemistries, a 3-fold increase in ALT

  12   elevations was seen in 0.4 percent of tegaserod and 0.2

  13   percent of placebo patients, with 3-fold elevations in AST

  14   of 0.1 and 0.1 percent in the two groups.

  15             There were no simultaneous elevations in ALT/AST

  16   and bilirubin.  There were no serious adverse events of

  17   hepatitis or elevated LFTs.  The results in Phase II and

  18   long term were similar, showing no evidence of tegaserod-

  19   induced hepatotoxicity.

  20             [Slide.]

  21             We carefully evaluated the effects of tegaserod on

  22   the ECG both in preclinical studies, as well as in clinical

  23   studies.  We conducted a series of preclinical studies both

  24   in vitro and in vivo, that showed no effects on the QT

  25   interval and specifically no effects on the delayed

                                                                114

   1   rectifier current, which is the mechanism whereby cisapride

   2   is known to cause prolongation of the QT interval.

   3             In our clinical studies, we conducted well over or

   4   we analyzed well over 10,000 tracings in the patients, shown

   5   here in Phase III.  ECGs were recorded at baseline two hours

   6   after the first dose at a maximum concentration of the drug

   7   at month 1 and again two hours after dosing at month 3 or at

   8   study endpoint.

   9             In the long-term study, patients had ECGs

  10   periodically over the course of the study.

  11             All ECGs in Phase III and in the long-term study

  12   were centrally analyzed by an independent cardiologist with

  13   intervals evaluated by a SigmaScan technique, in which a

  14   jeweler's lamp is used to magnify the ECG tracing, and then

  15   the intervals are measured.

  16             The results of this analysis showed no effects on

  17   the ECG, specifically no effects on the QTc interval or

  18   other ECG intervals, and no difference in arrhythmias

  19   between tegaserod and placebo.

  20             [Slide.]

  21             In summary, tegaserod at a dose of 4 and 12 mg/day

  22   was well tolerated with a similar safety profile between the

  23   4 and 12 mg dose.

  24             Diarrhea was the single adverse event with the

  25   higher frequency than placebo, and an overall

                                                                115

   1   discontinuation rate of approximately 2 percent.

   2             No effects were seen on the ECG or on laboratory

   3   parameters.

   4             [Slide.]

   5             Our overall conclusion is that the totality of the

   6   data demonstrate that tegaserod is effective in the

   7   treatment of irritable bowel syndrome in patients who

   8   identify abdominal pain or discomfort and constipation as

   9   their predominant symptoms.

  10             Tegaserod at a dose of 12 mg/day improves the

  11   abdominal discomfort or pain, bloating, constipation seen in

  12   patients with irritable bowel syndrome.  The drug has a

  13   favorable safety profile, and we believe presents a

  14   favorable benefit-to-risk profile for patients with

  15   constipation-predominant IBS.

  16             At this point, should I take questions?

  17             DR. HANAUER:  Thank you.

  18             Are there any additional questions for the sponsor

  19   from the committee?  Dr. Laine.

  20             DR. LAINE:  Just while we are here I always

  21   forget, so I always ask the FDA officers this.  The ICH

  22   criteria for number of patients long-term follow up, can

  23   somebody remind me of those, you know, how many patients for

  24   like one year, how many patients for -- maybe after lunch

  25   you can tell me.

                                                                116

   1             DR. HOUN:  Dr. O'Neill or Dr. Castillo for the ICH

   2   statistical long-term exposure study -- 100 for 12 months

   3   and 3 to 6 months, it is between 300 and 600.  That is the

   4   recommendation.

   5             DR. LAINE:  Thank you.

   6             DR. HANAUER:  Anyone else on the committee?  Dr.

   7   Wolfe.

   8             DR. WOLFE:  Can I ask a preclinical question, a

   9   pharmacological question?

  10             DR. HANAUER:  Yes, you may.

  11             DR. WOLFE:  I think Mike Camilleri might be the

  12   best person to ask that to.

  13             This is a receptor agonist, and what is the

  14   signaling pathway?

  15             DR. CAMILLERI:  Yes.  Thank you.  The 5-HT4

  16   receptor is a G-protein related, 7 transmembrane domain

  17   receptor.

  18             DR. WOLFE:  Those receptors are notoriously prone

  19   to desensitization.

  20             DR. CAMILLERI:  That is an excellent point, Dr.

  21   Wolfe.  One of the advantages of this particular compound is

  22   that it is a partial agonist, which notoriously are less

  23   sensitive to desensitization although, of course, there

  24   could conceivably be some.

  25             DR. WOLFE:  What about up-regulation of receptor

                                                                117

   1   synthesis?

   2             DR. CAMILLERI:  I may have to ask my colleague,

   3   Dr. Pfannkuche, about up-regulation of receptor synthesis.

   4             DR. PFANNKUCHE:  Hans Pfannkuche, Novartis.

   5             Maybe we can show a slide QA160, which very nicely

   6   explains what Dr. Camilleri already alluded to.

   7             [Slide.]

   8             With respect to desensitization, it is clear that

   9   it has been shown very often that with a partial agonist

  10   there is less desensitization tendency.

  11             With respect to up-regulation, there are some

  12   hints based on findings with atrial tissue that during

  13   chronic treatment with beta blockade, that there might be

  14   kind of a higher response rate with respect to 5-HT4

  15   receptors, which are only located on atrial tissue, but this

  16   is rather preclinical findings.

  17             DR. WOLFE:  As a follow up to that question, in

  18   the animal studies, was there any tachyphylaxis observed?

  19             DR. PFANNKUCHE:  We did some subchronic studies on

  20   motility, of course, and we had a very slight tendency with

  21   respect to tachyphylaxis.

  22             DR. HANAUER:  Okay.

  23             DR. LEFKOWITZ:  It is now my pleasure to introduce

  24   Dr. Sidney Cohen for concluding remarks.

  25             DR. HANAUER:  One more question.  Yes, Dr. Hammes.

                                                                118

   1             DR. HAMMES:  I am curious.  There seems to be no

   2   dose response to the diarrhea effect.  Is there any

   3   speculation on why?

   4             DR. LEFKOWITZ:  Although we did observe on those

   5   graphs a dose response in terms of bowel movements and stool

   6   consistency, those were the reports.  I personally can't

   7   speculate on why, but it was 11 to 12 percent in 4 mg and 12

   8   mg/day groups, and, in fact, dropouts overall were less in

   9   the 12 mg/day group than the 4 mg/day group.

  10             It is still my pleasure to introduce Dr. Cohen.

  11                         Closing Remarks

  12                        Sidney Cohen, M.D.

  13             DR. COHEN:  Mr. Chairman, members of the Advisory

  14   Panel:  I would like now to summarize and highlight some of

  15   the important features of today's presentations.

  16             [Slide.]

  17             First, let me remind everybody that irritable

  18   bowel still remains a very difficult to diagnose and to

  19   treat condition.  There are no measurable serological or

  20   gastrointestinal motility markers of irritable bowel

  21   syndrome despite investigators looking over many years.

  22             Therefore, we must rely on clinical syndrome, and

  23   it is a compilation of symptoms.  Despite the discussions of

  24   the Rome criteria, I must remind you that you still come

  25   down to two important clinical symptoms - abdominal pain and

                                                                119

   1   change in bowel habit, and those are the symptoms that bring

   2   the patient to see the physician, and those are the symptoms

   3   that we will look for, for relief

   4             Irritable bowel syndrome treatment is empiric;

   5   there are no proven efficacious therapies for patients with

   6   abdominal pain, bloating, and constipation as their

   7   predominant symptoms.  So, this is the background upon which

   8   today's presentation is given.

   9             [Slide.]

  10             Tegaserod is a unique pharmacological agent, and I

  11   want to highlight some of the points that Dr. Camilleri

  12   raised, that tegaserod addresses the clinical components in

  13   irritable bowel syndrome, the abdominal pain, bloating, and

  14   constipation.

  15             It does this by stimulating the peristaltic

  16   reflect, augmenting aboral propulsion, and diminishes

  17   visceral sensitivity, reducing pain.

  18             The peristaltic reflex is the physiological basis

  19   of motor function in the gut.  The reflex was described by

  20   Bayliss and Stalling at the turn of the century, and

  21   describes how the gut relaxes distally and contracts

  22   proximally.

  23             Tegaserod stimulates and augments this response,

  24   so it physiologically enhances movement through the

  25   gastrointestinal tract in the small intestine and colon.

                                                                120

   1             Dr. Camilleri showed very nicely that tegaserod

   2   reduces the firing, the action potential firing of spinal

   3   afferent nerves, so it is a visceral analgesic in a disorder

   4   where you have increased visceral sensation or visceral

   5   hypersensitivity.

   6             [Slide.]

   7             The clinical trials that were presented recruited

   8   a largely unrestricted population of patients with irritable

   9   bowel who identified abdominal pain or discomfort and

  10   constipation as their predominant symptoms.

  11             These patients are reflective of patients seen in

  12   common clinical practice, and my review of this material

  13   clearly indicates, pertaining to the question raised

  14   earlier, that this is a constipation-predominant group.  It

  15   fulfills the criteria.

  16             [Slide.]

  17             Now, the primary efficacy variable was the global

  18   relief  of symptoms, but as a clinician, as a clinical

  19   investigator, I remind you that specific symptoms of

  20   irritable bowel syndrome is what brings the patient to see

  21   the physician, it is what causes the patient to lose time

  22   from work, and this is abdominal pain with associated

  23   bloating and the constipation with its stool frequency and

  24   stool consistency changes.

  25             [Slide.]

                                                                121

   1             I took the opportunity, therefore, to look at

   2   those specific symptoms.  In the study, they are secondary

   3   efficacy variables, but for a clinician, they are very

   4   clinically relevant and important.

   5             What I did here was compile for Study 301 the

   6   individual symptoms, by week, removing the 4 mg dose,

   7   looking at placebo versus the 12 mg dose.  The data is very

   8   impressive.

   9             If you look at the pain score, by week, 11 of 12

  10   weeks, consistently the patient had less pain.  In addition,

  11   the patient had more bowel movements, as you can see here,

  12   so the two main features of this condition, pain and

  13   constipation, were affected in a positive way.  The symptoms

  14   were relieved in 11 out of 12 weeks.

  15             Additionally, the patients had less bloating by

  16   score over the weeks, and had improved stool consistency.

  17             So, to me, as a clinician, these are very

  18   important data, highlighting the clinical symptoms that

  19   bring the patient to see the physician.

  20             [Slide.]

  21             When you look at the 351 study, the major

  22   supporting study, again, you see very similar findings,

  23   looking at pain, improvement in bowel function, bloating,

  24   and stool consistency.  Week after week, the patient has

  25   improvement in all of these clinical parameters, the

                                                                122

   1   secondary efficacy variables of the study, but the primary

   2   parameters that a patient witnesses and a physician sees in

   3   clinical practice.

   4             [Slide.]

   5             The 307 study was more difficult to evaluate.  It

   6   was a dose escalation study, but I highlight here that

   7   looking at the individual symptoms, pain, constipation,

   8   bloating, and stool consistency, for many of the weeks you

   9   see clinical improvement.  Taken together with the other

  10   studies, you see clear trending and you see clear

  11   improvement in these secondary efficacy parameters, the

  12   clinical symptoms of IBS.

  13             [Slide.]

  14             Now, this is the overall global relief, and

  15   looking at the three efficacy parameters - complete,

  16   considerable, and somewhat relief, and again I would like to

  17   highlight, by week, and you can see over the 12-week period,

  18   you see clinical improvement, the overall relief of symptoms

  19   in patients with irritable bowel for the 351, 301, and you

  20   see some improvement in the 307 study, but then with dose

  21   escalation, you see this rise in placebo response, making

  22   this a more difficult study to interpret.

  23             I would emphasize here one of the questions

  24   raised, this is an appropriate placebo response for a

  25   clinical GI disorder where you are measuring symptom scores.

                                                                123

   1             [Slide.]

   2             When you look at the very high hurdle of complete

   3   or considerable relief, you see a much lower placebo

   4   response, and I think very much more difficult to achieve

   5   clinical efficacy, which is complete or considerable relief,

   6   but yet with some of the overall relief you still see points

   7   over the weeks of clinical improvement.

   8             [Slide.]

   9             So, in summary, Mr. Chairman, I would say that

  10   tegaserod at a dose of 12 mg, 6 mg BID, has been

  11   demonstrated to be effective in the treatment of abdominal

  12   pain, bloating, and constipation in irritable bowel

  13   syndrome.  This effect is more dramatic in women.

  14             Tegaserod is safe and well tolerated.  Diarrhea is

  15   the only drug-related side effect, it is self-limited, and

  16   infrequently led to discontinuation of the drug.

  17             [Slide.]

  18             The overall conclusions here indicate that you

  19   have an agent with a unique pharmacological action that

  20   addresses the clinical components of constipation-

  21   predominant irritable bowel.  The drug enhances the

  22   peristaltic reflex and decreases visceral sensitivity,

  23   leading to decreasing constipation and reduction in pain.

  24             When you look at the studies by clinical symptoms,

  25   individual symptoms, you see a positive and significant

                                                                124

   1   clinical effect in reducing abdominal pain, bloating,

   2   constipation, and stool consistency, the hallmark symptoms

   3   of irritable bowel syndrome.

   4             When you look at global relief, you see that it is

   5   effective in providing overall or global relief of the

   6   symptoms of irritable bowel.

   7             [Slide.]

   8             My final bottom line is that in a clinical

   9   syndrome in which there has been no proven treatment,

  10   effective treatment, tegaserod is a strong first step in the

  11   management of constipation-predominant irritable bowel

  12   syndrome.  This effect is most dramatic and most prominent

  13   in females.

  14             Thank you.

  15             I will now turn the podium to Dr. Lefkowitz for

  16   questions.

  17             DR. HANAUER:  Dr. Laine.

  18             DR. LAINE:  I was wondering if you could back to

  19   one of Dr. Cohen's slides, which is 351 with the four

  20   different graphs on it, and I would actually just ask Dr.

  21   Cohen -- it was like CO 4 or 5 or one of those -- but I

  22   guess it comes up to, as an example of that one, if we look

  23   at the pain score where there are significant differences,

  24   but as I remember, that is a 6-point pain score, is that

  25   correct?

                                                                125

   1             DR. LEFKOWITZ:  Yes, that is correct.

   2             DR. LAINE:  As I look at that, we are seeing again

   3   the point I made earlier, you have 800 and some patients or 

   4   you have many patients with many data points, which may be

   5   giving this statistical significance because you have so

   6   many data points, but I would ask Dr. Cohen, as a clinician,

   7   does a 0.1 change on a 6-point scale really mean anything

   8   clinically to him.

   9             DR. COHEN:  I think this is a very difficult

  10   question to answer.  As a clinician, if a patient can tell

  11   you week after week that they have less pain and improved

  12   bowel function, I think you have to take that as being

  13   clinically significant, and my conclusion is that this drug

  14   is moderately effective in reducing those symptoms.

  15             DR. LAINE:  I was wondering if the sponsor has

  16   information, you know, typically, you can look at perhaps

  17   the minimum discriminating difference, if you will, that a

  18   patient can actually distinguish, is there evidence that a

  19   0.1 or 0.2 change, or 0.3 change on a scale of 6 is a

  20   clinically relevant interaction, something that a patient

  21   can -- I forget the right wording -- but is distinguishable

  22   by a patient, let's say?

  23             DR. LEFKOWITZ:  No, clearly, we don't have that

  24   information.  I think the scores are used to show that the

  25   drug is having an effect on pain and bloating.  We also

                                                                126

   1   looked at abdominal pain in different ways.  For example, we

   2   looked at the subject global assessment of abdominal

   3   discomfort and pain, where we did show consistent

   4   differences for the tegaserod groups compared to placebo.

   5             We looked at days with significant pain.  We also

   6   saw significant differences, so we tried to translate these

   7   pain scores into some patients' perceptions.

   8             DR. LAINE:  And not that you would have for

   9   secondary endpoints, but did you predefine any things that

  10   you felt were going to be clinically significant in changes

  11   in pain scores or the other scores, because, as you know,

  12   there are actually times when you have enough data points

  13   where something can meet your clinical equivalence criteria,

  14   but still be statistically significantly different, so I was

  15   just trying to separate those two out.

  16             DR. LEFKOWITZ:  Yes.  No, again, these pain and

  17   bloating scores I think, as Dr. Cohen said, is difficult to

  18   interpret clinically.  I think they do show that the drug is

  19   having an effect on pain, and I guess I would look to the

  20   subject global assessments as an indication of the patient's

  21   perception of response.

  22             DR. HANAUER:  And there was a correlation between

  23   the global assessment and the degree of improvement on the

  24   visual analog scales?

  25             DR. LEFKOWITZ:  I am sorry?

                                                                127

   1             DR. HANAUER:  You have them graded as somewhat

   2   relief, considerable relief.

   3             DR. LEFKOWITZ:  Oh, from the SGA of relief to the

   4   subject global, yes, the measures were highly correlated,

   5   yes.

   6             DR. RICHTER:  Martin, was there any attempt to

   7   look at quality of life in these issues because again you

   8   are getting to the aspects of pain which is very subjective,

   9   difficult to assess.

  10             Is that contemplated by your group if you haven't

  11   already done it?

  12             DR. LEFKOWITZ:  As you recall, at least, number

  13   one, for our global relief endpoint, we did include trying

  14   to capture at least an element of that.  The question both

  15   related to abdominal discomfort or pain, altered bowel

  16   habit, and overall well-being, so it was captured as part of

  17   that.

  18             We did administer quality of life scales in this

  19   study as a tertiary variable.  The scale used was not, and

  20   has not, been validated in controlled clinical trials for

  21   responsiveness.  We saw, on that scale, significant

  22   increases on both placebo and on drug that were not

  23   different between the groups.

  24             DR. HANAUER:  Dr. Buyalos.

  25             DR. BUYALOS:  Yes, a couple questions.  Number

                                                                128

   1   one, since the benefit was demonstrated in women, and most

   2   of these women were on reproductive age, and a lot of women,

   3   the luteal phase of their cycle after ovulation frequently

   4   will have gastrointestinal symptoms, such as diarrhea or

   5   constipation, was that examined separately?

   6             The next question I have is the impact of

   7   hydration and exercise.  A lot of these patients were

   8   consenting to be studied, were they specifically instructed

   9   not to change their exercise or hydration patterns?

  10             DR. LEFKOWITZ:  Yes, patients were instructed to

  11   continue on their usual diet and exercise patterns.

  12             I am sorry, I forgot the first question.

  13             DR. BUYALOS:  The impact of being in the luteal

  14   phase of their menstrual cycle.

  15             DR. LEFKOWITZ:  Yes.  We did not collect

  16   information during the study on menstrual cycle.  The

  17   incidence of dysmenorrhea was very low and balanced between

  18   the two groups.

  19             DR. HANAUER:  Dr. Talarico.

  20             DR. TALARICO:  The last slide before your summary,

  21   the complete and considerable disease responders, I have

  22   difficulty understanding the placebo curve.

  23             Slide 10, I think.

  24             DR. LEFKOWITZ:  In Dr. Cohen's talk?

  25             DR. TALARICO:  Yes.

                                                                129

   1             DR. LEFKOWITZ:  CO10.  I think clearly in 307, we

   2   have difficulty understanding the continued increase in the

   3   responder rate.

   4             DR. TALARICO:  Yes. I can understand the low

   5   starting, the rate of responder, since these are the two

   6   most rigid criteria of response, but I have difficulty

   7   understanding how they can, how the response can escalate

   8   with the placebo at such a rate.

   9             DR. LEFKOWITZ:  I guess perhaps over here, one is

  10   seeing some sort of --

  11             DR. TALARICO:  I would have started, I would

  12   plateau it at the system point.

  13             DR. LEFKOWITZ:  I am sorry?  These are the placebo

  14   rates that we observed in the study.  I don't know what I

  15   could say beyond that.  Again, I think if you look at the

  16   entire relief score, the SGA of relief, one doesn't get this

  17   very high placebo response rate.  These are fairly low

  18   rates, and I think they are more impacted by perhaps small

  19   changes in small numbers of patients.

  20             If you look, for example, at percent somewhat

  21   relief, that is quite flat, if you go to the previous slide.

  22             DR. TALARICO:  Oh, yes, this, I can understand

  23   this one, but the one before, even though the numbers are --

  24   it's the pattern that is very difficult for me.

  25             DR. LEFKOWITZ:  I certainly agree the pattern in

                                                                130

   1   307 is difficult for us to understand.

   2             DR. TALARICO:  Thank you.

   3             DR. HANAUER:  Okay.  Let's move on to the Agency's

   4   review.

   5             DR. TALARICO:  We have made a slight change in our

   6   agenda.  Since all the preclinical issues have been

   7   addressed by the sponsor, we will omit our preclinical

   8   presentation and go right to the first one, which is the

   9   statistical, followed by the medical presentation.

  10                         FDA Presentation

  11                       Statistical Reviewer

  12                      Sonia Castillo, Ph.D.

  13             DR. CASTILLO:  Good morning, Committee, and ladies

  14   and gentlemen.  I am Sonia Castillo, and I was the

  15   statistical reviewer for this product.

  16             [Slide.]

  17             Here is a list of the topics I will present today,

  18   so let's begin with a little bit of background.  I would

  19   like to thank the sponsor for presenting such a great

  20   presentation.  It makes my job a lot easier.

  21             We are going to zip through the first couple of

  22   pages here.

  23             [Slide.]

  24             Here, we have a listing of all the three clinical

  25   trials studied for this product.  I just want to note again

                                                                131

   1   that in Studies 301 and 351, we had 4 mg/day group, 12

   2   mg/day group, the placebo, and in 307, we had 4 mg/day and a

   3   4 to 12 mg/dose titration group and placebo.  Also, in Study

   4   307, after four weeks on treatment, all patients were either

   5   titrated or mock titrated depending if they responded to

   6   treatment or not.

   7             [Slide.]

   8             Here is a little bit of background again.  As the

   9   sponsor has mentioned, Study 351 was completed and analyzed

  10   first.  The results of the protocol-specified analyses were

  11   not significant.

  12             This led to a change in the definition of a

  13   responder to treatment.  When this change was subsequently

  14   applied in a post-hoc analysis, the data gave significant

  15   results and led to protocol amendments for Studies 301 and

  16   307 although they were still blinded.

  17             Therefore, we have two studies in which the

  18   analysis presented is prospective.  Those are 301 and 307,

  19   and one in which it is post-hoc, which is 351.

  20             [Slide.]

  21             The original protocol for all three studies had

  22   one primary efficacy variable, and that was the subject

  23   global assessment of abdominal pain and discomfort.  It

  24   called for an enrollment of 591 intent-to-treat patients.

  25             [Slide.]

                                                                132

   1             Here is what the variable looked like.  You heard

   2   the question before.  Patients on a weekly basis were asked,

   3   "How much of a problem was your abdominal discomfort/pain

   4   over the last week?"

   5             What they did is they put a slash somewhere on

   6   this 100 mm VAS, or visual analog scale, as to how they

   7   felt.  The definition for responder to this variable was

   8   greater than or equal to 20 mm and greater than or equal to

   9   40 percent reduction in the mean visual analog scale at

  10   study endpoint, which was defined as the last four weeks on

  11   treatment compared to the baseline value.

  12             DR. HANAUER:  If you would go back to the last

  13   one, because this is somewhat unclear I think to everybody. 

  14   There were four assessments in the last month, right, this

  15   was a weekly VAS score.

  16             DR. CASTILLO:  Weekly VAS score.

  17             DR. HANAUER:  So, is the one that counted the

  18   absolute, the fourth of the third month?  You only counted

  19   the 12?  Do you understand what I am saying?  If this is

  20   done weekly, and you are looking at the endpoint for the

  21   last four weeks, were they looking at the endpoint of the

  22   absolute last determination?

  23             DR. CASTILLO:  No, the four last weeks.

  24             DR. HANAUER:  Averaged?  The four last weeks were

  25   averaged.

                                                                133

   1             DR. CASTILLO:  No, you took -- yes, average, the

   2   four last weeks compared to the baseline value, yes.

   3             DR. HANAUER:  Thank you.

   4             [Slide.]

   5             An amendment was submitted prior to the start of

   6   all the studies.  In this amendment, the subject global

   7   assessment of relief was added as a second primary efficacy

   8   variable.

   9             Now, the sponsor added the second efficacy

  10   variable because they considered both the subject global

  11   assessment of relief and the subject global assessment of

  12   abdominal discomfort/pain as clinically relevant outcome

  13   variables of irritable bowel syndrome, but the sponsor did

  14   not know whether either was more important than the other. 

  15   This amendment also called for enrollment of 693 intent-to-

  16   treat patients.

  17             [Slide.]

  18             As you have seen before, here is the subject

  19   global assessment of relief.  The questions that patients

  20   answered every week in terms of how they felt their overall

  21   well-being, symptoms of abdominal discomfort and pain, and

  22   altered bowel habits, and they had to choose from the five

  23   answers down there, listed in yellow, completely relieved,

  24   considerably relieved, somewhat relieved, unchanged, or

  25   worse.

                                                                134

   1             [Slide.]

   2             Definition of responder for this variable was a

   3   patient who fulfilled the following four criteria.  You had

   4   to have complete or considerable relief at least 50 percent

   5   of the time at study endpoint, and that was the last four

   6   weeks on treatment.

   7             In addition, this definition took into account the

   8   number of days with laxative use, which had to be less than

   9   five, less than or equal to five, and no laxative use during

  10   the last 28 days of treatment.  Duration of exposure to

  11   study medication be at least 28 days, and had to have at

  12   least one post-baseline subject global assessment of relief.

  13             Just recall that laxative use is allowed for

  14   purposes or rescue during the entire study period, and in

  15   addition, bulking agent use was permitted during the entire

  16   study.

  17             [Slide.]

  18             As I mentioned before, after the post-hoc analysis

  19   of Study 351, another amendment was submitted prior to

  20   breaking the blind Studies 301 and 307.

  21             In this amendment, the definition for responder

  22   for SGA of relief was modified.  At first, it was just this

  23   component, complete or considerable relief at least 50

  24   percent of the time at study endpoint.

  25             An addition component was added, which was

                                                                135

   1   complete or considerable or somewhat relief 100 percent of

   2   the time at study endpoint.

   3             The Division considered this change clinically

   4   meaningful.  In addition, the subject global assessment of

   5   relief became the only primary efficacy variable, so we went

   6   from two to one, and the subject global assessment of

   7   abdominal discomfort/pain was changed from a primary to a

   8   secondary efficacy variable.

   9             The Agency would appreciate the committee's view

  10   on changing the subject global assessment of abdominal

  11   discomfort/pain from a primary to a secondary efficacy

  12   variable, since it was considered a clinically relevant

  13   outcome.

  14             I am going to present the results for both the

  15   subject global assessment of relief and the subject global

  16   assessment of abdominal discomfort and pain.

  17             [Slide.]

  18             This table seems a little busy, but I will

  19   simplify it here.  On the left here we have results for the

  20   primary efficacy analysis when using the original definition

  21   of responder, and on the right is when we have the new

  22   definition just to see what happens to the responder rates.

  23             As you can see, adding the extra category of

  24   somewhat relieved across the last four weeks of study, for

  25   example, in Study 301, the responder rate for the 4 mg group

                                                                136

   1   went from 28 percent to 39, the 12 mg went from 27 percent

   2   to 38, and placebo, 20 percent to 30 percent.

   3             So, the effect was you increased the responder

   4   rates.

   5             Using the original definition of responder, you

   6   see that none of the treatment differences were

   7   statistically significant in all studies.

   8             In Study 301 -- we are going to focus now on the

   9   new definition of responder to SGA of relief -- in Study

  10   301, both the 4 mg and 12 mg showed statistically

  11   significant results, a treatment difference of 9 percent or

  12   about 1 additional responder for every 11 patients treated,

  13   a treatment effect of about 8 percent of the 12 mg group, or

  14   about 1 additional responder for every 12 patients treated.

  15             In Study 307, neither of the treatments were

  16   statistically significant, and for Study 351, recall that

  17   for the protocol-specified analyses -- I have blocked them

  18   off right here -- none of the results were statistically

  19   significant.

  20             In the post-hoc analysis, we get statistical

  21   significance for the 12 mg group, and that was 12 percent or

  22   about 1 additional responder for every 8 patients treated.

  23             [Slide.]

  24             Here is a quick overview of the subject global

  25   assessment of abdominal discomfort/pain.  In all studies,

                                                                137

   1   across all studies, there was not a statistically

   2   significant difference seen, and, in fact, in Study 307, the

   3   treatment difference was negative, which means that the

   4   active treatment was numerically worse than placebo.

   5             [Slide.]

   6             So, what we can conclude from these analyses are

   7   as follows.  For the subject global assessment of relief, a

   8   statistically significant treatment effect was demonstrated

   9   in Study 301 for the 4 mg and 12 mg doses and supported in a

  10   post-hoc analysis of Study 351 for the 12 mg dose, but not

  11   replicated in Study 307.

  12             For the subject global assessment of pain, a

  13   statistically significant treatment effect was not

  14   demonstrated across all three studies.

  15             This gives two questions that we would like the

  16   committee to consider.  One is why is efficacy not shown in

  17   Study 307 for either dose, and which, if any dose, is

  18   effective.

  19             [Slide.]

  20             By regulation, the Agency investigates efficacy by

  21   gender.  Here are the results that we get.  On the lefthand

  22   side, we have the results for males.  As you can see, in all

  23   studies, none of the treatment differences were

  24   statistically significant, and they were either close to

  25   zero or negative.  For those that are negative, those are

                                                                138

   1   the ones in yellow here, that just shows you that the active

   2   treatment was worse than placebo, numerically worse than

   3   placebo.

   4             We will go over to female patients here.  Study

   5   301, we had a significant difference for both the 12 mg and

   6   the 4 mg dose groups, 10 percent for the 4 mg, which is

   7   about a additional responder for every 10 patients treated,

   8   for the 12 mg, about 11 percent response rate or a treatment

   9   difference which is 1 additional responder for every 9

  10   patients treated.

  11             In Study 307, again, we see no statistically

  12   significant results.  For Study 351, these analyses --

  13   recall these are the post-hoc analyses -- we get a

  14   statistically significant result only for the 12 mg group,

  15   which is about 15 percent or 1 additional responder for

  16   every 7 patients treated.

  17             [Slide.]

  18             From these analyses, we can conclude that the

  19   treatment effect results are mixed in female patients, that

  20   efficacy in male patients is not clear, and that clinically,

  21   the results for female and male patients may indicate a

  22   difference in the pathophysiology of constipation-

  23   predominant irritable bowel syndrome between the genders.

  24             [Slide.]

  25             I just want to briefly make the statement, and Dr.

                                                                139

   1   Joseph will further address this issue, that changing the

   2   subject global assessment of abdominal discomfort/pain from

   3   a primary to a second efficacy variable is of clinical

   4   concern because pain is an important clinical component of

   5   irritable bowel syndrome.

   6             Also, its assessment via the subject global

   7   assessment of discomfort/pain, which was at one point in

   8   time a primary efficacy variable and then became a

   9   secondary, did no show statistical significance across the

  10   three studies.

  11             [Slide.]

  12             I am going to talk about taking into account

  13   laxative use in the analyses.  The sponsor presents

  14   additional analyses -- and these additional analyses are all

  15   analyses done by week and by month that were not subject

  16   global assessment type of analyses -- that do not take

  17   laxative use into account when defining a responder for

  18   subject global assessment of relief and subject global

  19   assessment of abdominal discomfort/pain.

  20             The Division does not agree that laxative use can

  21   be ignored, because the protocol-specified definition of

  22   responder takes laxative use into account, and laxative use

  23   is taken into account because it affects bowel habit in

  24   abdominal discomfort.

  25             So, consequently, these additional analyses are

                                                                140

   1   not consistent with the protocol-specified definition of a

   2   responder.  You are using two different definitions of a

   3   responder or you are using two different ways of analyzing

   4   how you respond, one with laxative use and one without.  So,

   5   it is kind of confusing how you would interpret or combine

   6   the results on that basis.

   7             [Slide.]

   8             I am going to quickly go through a couple of

   9   reasons why not to pool to demonstrate efficacy in these

  10   studies.

  11             As presented by the sponsor, pooling of the

  12   studies to investigate the presence of a treatment effect

  13   did show statistical significance.  There was a 6 to 7

  14   percent treatment effect or 1 extra responder for every 14

  15   patients treated.  But each study did not show statistical

  16   significance on its own.

  17             You will recall that Study 301 showed significant

  18   results for both treatment groups, Study 307 did not show

  19   significant results for either treatment group, and Study

  20   351 showed significant results for the 12 mg group after a

  21   post-hoc analysis.

  22             For pooling to demonstrate efficacy is not

  23   appropriate in this situation because the pooled analysis

  24   was not prespecified in the protocol.  Also, the design of

  25   Study 307 is different.  It included a 4 to 12 mg titration

                                                                141

   1   group, and that is not the same as a 12 mg group.

   2             Also, because we have these different dose groups

   3   in the three studies, we have different endpoint

   4   interpretations.  Study 307 evaluates a fixed dose group and

   5   a titration dose group.  Studies 301 and 351 evaluate two

   6   fixed dose groups.

   7             Also, the dose titration done in 307 was based on

   8   the original definition of responder, which was complete or

   9   considerable relief 50 percent of the time, while the pooled

  10   analyses used the new definition of responder, which adds

  11   the component "somewhat relieved" 100 percent of the time. 

  12   So, that is confusing, as well.

  13             It is necessary to use consistent definitions of

  14   responder throughout an analysis.

  15             [Slide.]

  16             Also, pooling is not necessary in these studies

  17   because each one is adequately sized to show efficacy on a

  18   study by study basis.  In fact, the intent-to-treat sample

  19   size at study completion was larger than planned, and as you

  20   can see here, more than 15 percent in all three studies.

  21             Also, pooling gives no replication of the study

  22   results.

  23             [Slide.]

  24             In summary, we can say that a statistically

  25   significant treatment effect was demonstrated in female

                                                                142

   1   patients in Study 301 and supported in a post-hoc analysis

   2   of Study 351, but not replicated in Study 307.

   3             Also, a treatment effect was not demonstrated for

   4   either dose in Study 307, and we are asking the question

   5   why.

   6             Efficacy has not been adequately assessed in male

   7   patients.

   8             The effect of treatment on abdominal pain has not

   9   been adequately assessed and demonstrated.

  10             Also, all efficacy analyses need to take laxative

  11   use into account.

  12             The pooled study results are not appropriate to

  13   demonstrate treatment effect in this situation.

  14             DR. HANAUER:  You asked or you put in your

  15   discussion points here a number of questions to the

  16   committee.  I didn't have time to jot them down, and they

  17   are not in your notes.  Do you want us to handle those now

  18   or as part of the discussion, and if so, could we get a

  19   listing of them later for our discussion?

  20             DR. CASTILLO:  Yes, we will do that.

  21             DR. HANAUER:  Maybe you can just put them up on a

  22   single slide, and we will do it in the afternoon session.

  23             DR. CASTILLO:  Sure.

  24             DR. HANAUER:  Thanks.

  25                         Medical Reviewer

                                                                143

   1                       Raymond Joseph, M.D.

   2             DR. JOSEPH:  Good afternoon.  I am Dr. Joseph.  I

   3   am the medical officer who reviewed the Zelmac NDA.

   4             [Technical difficulties.]  As you see, I have no

   5   slides, which will make today's discussion very short.

   6             [Laughter.]

   7             Basically, as we have talked about all morning,

   8   one of the advantages of going last is that a lot of the

   9   slides that I was going to cover have been covered, so there

  10   will be partially a review and we can speed through them.

  11             [Slide.]

  12             Again, the proposed indication as we have been

  13   talking about all morning, the treatment of irritable bowel

  14   in patients who identify abdominal pain/discomfort and

  15   constipation as their predominant symptoms, abdominal pain

  16   and constipation.

  17             [Slide.]

  18             Quickly going over the Phase II studies,

  19   basically, Studies 251 and 202, the double-blind trials, the

  20   first study randomized 547 patients in 45 sites in North

  21   America and Europe, essentially, a dose-ranging study from 1

  22   mg/day, 4 mg/day, 12 mg/day, and 24 mg/day for 12 weeks.

  23             Study 202 essentially randomized 123 patients at

  24   16 sites in Europe and Canada.  It incorporated a dose-

  25   titration phase with 4 dose levels of tegaserod or placebo

                                                                144

   1   for 20 weeks.

   2             [Slide.]

   3             In essence, Study 251 showed that basically, 1

   4   mg/day was essentially equal to placebo in effect.  The 4 mg

   5   dose appeared to be the most effective dose.  No dose

   6   response was seen over the range from 4 to 24 mg/day.

   7             Study 202 showed that there was an increased

   8   response rate observed during some of the dose-titration

   9   from 4 to 12 mg.  With the results of these studies, it was

  10   noted that the 4 and 12 mg were the doses to be chosen for

  11   the Phase III trials.

  12             [Slide.]

  13             Again, these have all been gone over.  What the

  14   three studies have in common are that they were all placebo-

  15   controlled, double-blind, with levels of 4, 12, 4-week lead-

  16   in, 12-week treatment period.

  17             The difference was the dose titration from 4 to 12

  18   at 1 month in the 307 study.

  19             [Slide.]

  20             First, talking about Study 351, which was the

  21   first of the Phase III trials to be completed.  The protocol

  22   prespecified analysis failed to demonstrate any efficacy. 

  23   So, subsequently, the definition of responder has been

  24   changed, as we have mentioned today, to include somewhat

  25   relief 100 percent of the time.

                                                                145

   1             The SGA of abdominal discomfort/pain was changed

   2   to a secondary efficacy variable.

   3             Post-hoc analysis incorporating the above changes

   4   demonstrated efficacy for the 12 mg dose level only.

   5             These things led to the protocol amendments for

   6   Studies 301 and 307.

   7             [Slide.]

   8             Here are the three studies dealing with the SGA of

   9   relief.  The darker color shows the post-hoc analysis Study

  10   351, Studies 301 and 307.  As you can see, for the SGA of

  11   relief, the 12 mg dose only is statistically significant in

  12   the 351 study, and both doses, as has been mentioned earlier

  13   in the 301 study, and neither dose in 307.

  14             [Slide.]

  15             So, basically, our efficacy issues amount to pain

  16   was not adequately assessed as an efficacy endpoint. 

  17   Overall difference between drug and placebo group is 8

  18   percent.  Efficacy in males is not established, and the

  19   potential effect of laxatives.  I will talking about each of

  20   these in turn.

  21             [Slide.]

  22             With regard to abdominal pain, pain of course is

  23   an essential component of IBS.  When analyzed as a component

  24   of the SGA of relief, which as you know encompassed well-

  25   being and altered bowel function, it was statistically

                                                                146

   1   significant in Studies 351 and 301.

   2             However, when analyzed independently, no

   3   statistical difference was seen in Studies 301 and 307.

   4             [Slide.]

   5             Again, looking at the three studies for the SGA of

   6   abdominal pain/discomfort, no statistical significance in

   7   351, borderline perhaps in 301 for the 12 mg dose, and no

   8   statistical significance in 307.

   9             [Slide.]

  10             Overall efficacy, around 8 to 11 percent.  The

  11   effect of gender in this study group certainly would be up

  12   for discussion, and are these results clinically meaningful,

  13   also a point of discussion I would believe.

  14             [Slide.]

  15             Efficacy in males.  The study included 15 percent

  16   males.  The response to Zelmac in males was not different

  17   when compared to placebo.  The lack of differentiation from

  18   placebo may be due to inadequate sample size, or it may give

  19   rise to the question whether the disease is different in

  20   males.

  21             [Slide.]

  22             With regard to the laxative use, in the clinical

  23   trials, laxative use including bulking agents was allowed. 

  24   The use and timing of the laxatives may influence the

  25   response of the SGA of relief.

                                                                147

   1             The groups were similar in qualitative consumption

   2   between groups, however, quantitative differences were not

   3   assessed and may be affecting outcome in constipation study

   4   patients.

   5             [Slide.]

   6             In summary, the overall efficacy is shown in one

   7   of the studies, 301, for both the 4 and the 12 mg dose

   8   levels; Study 351 showed efficacy for the 12 mg dose level

   9   only; efficacy was not replicated in Study 307.

  10             Efficacy in males again not demonstrated.

  11             Laxative usage may have had an effect on efficacy.

  12             [Slide.]

  13             Turning to the safety aspect of the presentation,

  14   this is a slide just showing the most frequently reported

  15   adverse events in the Phase III studies.  Again, headache,

  16   abdominal pain, diarrhea, nausea, flatulence, et cetera,

  17   diarrhea being the only adverse event that was twice as

  18   frequent as placebo, 11.7 versus 5.4.

  19             These results were similar when you looked at the

  20   Phase II or the long term in terms of the types of side

  21   effects and their numbers.

  22             [Slide.]

  23             When you pool both the Phase II and Phase III

  24   studies, again, you see similar sorts of side effects, and

  25   again the diarrhea 2.1 percent versus 0.6 percent.  The rest

                                                                148

   1   are fairly similar in both placebo and tegaserod groups.

   2             [Slide.]

   3             A slide just showing the duration of exposure in

   4   the long-term studies, "n" being 675, so with one-day

   5   exposure, 100 percent of that 675 received it.  When you get

   6   down to about 270, it is 48 percent, and at the one-year

   7   level, it is 27.4 percent.

   8             [Slide.]

   9             Safety in general.  Approximately 72 percent of

  10   the Phase III patients experienced one adverse event.  Only

  11   diarrhea was statistically significantly different from

  12   placebo, 11.7 percent versus 5.4 with a p-value less than

  13   0.0001.

  14             The adverse events were only marginally greater in

  15   tegaserod groups versus placebo overall.

  16             The serious adverse events incidence was equal to

  17   tegaserod, roughly the 1.8 percent with placebo, and their

  18   profiles were similar.

  19             [Slide.]

  20             There was one death in the study.  In Study 301, a

  21   patient with a 14-year history of depression committed

  22   suicide on day 36 of the drug.  Her mother had also

  23   committed suicide.

  24             There were 5 severe adverse events in tegaserod

  25   that were possibly related to the test medication, 2 cases

                                                                149

   1   of abdominal pain, 1 case of gastritis, 1 case of

   2   supraventricular tachycardia, and 1 case of hypoglycemia.

   3             [Slide.]

   4             The diarrhea, which is roughly defined as greater

   5   than three bowel movements per day with a loose, watery

   6   consistency and a sense of urgency.

   7             Syncope was noted in tegaserod patients, eight

   8   tegaserod patients versus one in the placebo.  The p-value

   9   was not significant.

  10             Further details about the type of syncope or what

  11   other associated findings, I don't really have at this

  12   point.

  13             "Ovarian cysts" is in quotation marks because

  14   originally it was thought that there were eight cases of

  15   ovarian cysts in the tegaserod group and one case in the

  16   placebo group.

  17             [Slide.]

  18             Now, back to the diarrhea.  The incidence again,

  19   as stated, was highly significant.  In alternators, the

  20   incidence actually went up to 21 percent from 11.7.  By

  21   "alternators," we mean the patients who were judged to have

  22   alternating constipation and diarrhea.

  23             Discontinuation secondary to diarrhea was 2.1

  24   percent in tegaserod versus 0.6 in placebo, and that p-value

  25   was 0.002.

                                                                150

   1             Fifty percent of the diarrhea occurred during the

   2   first week, a lot of it occurring during the first day.  We

   3   haven't identified any contributing factors or protective

   4   factors.

   5             DR. HANAUER:  Where did you find the alternator

   6   term?  In alternators, how was that term defined or how are

   7   you defining that term, or where are you finding that

   8   terminology in the study?

   9             DR. JOSEPH:  Oh, that came in the sponsor's

  10   material that was given to me, and the value for 18 to 36

  11   percent was what they determined that fit the definition of

  12   equal to 25 percent of the time, diarrhea, loose stools,

  13   that sort of thing, so they were considered to be

  14   alternating constipation and diarrhea.

  15             DR. HANAUER:  Can we clarify, again, where did

  16   that come from, was that from the baseline period, was that

  17   from the --

  18             DR. JOSEPH:  This was at baseline, the 18 to 36 is

  19   the way I understood it from the material submitted to me.

  20             DR. LEFKOWITZ:  I can clarify that if you would

  21   like.  We tried to look at people who may have had an

  22   alternating component to their diarrhea in several ways, one

  23   being based on the history that they gave and the Rome

  24   criteria, at least one of those three diarrhea criterias. 

  25   That was 36 percent of the population.

                                                                151

   1             At least in our calculations, the diarrhea rate in

   2   those patients were 14 percent on drug, 6 percent on

   3   placebo, and we also looked at patients who had greater than

   4   three bowel movements or watery, loose stools during the

   5   baseline at least 25 percent of the time.

   6             In those patients, it was 5 versus 17 percent, and

   7   then in the category I showed you earlier, with low

   8   consistency of less than 3.5, we had 5 versus 18 percent in

   9   terms of diarrhea rate.

  10             So, those were different ways we looked at people

  11   who may have had an alternating component.  I could show

  12   those slides later if you would like.

  13             DR. HANAUER:  Maybe we will come back later

  14   because I think it is confusing us because of the entry

  15   criteria, which was supposed to be constipation-predominant,

  16   but that included people that were predefined?

  17             DR. LEFKOWITZ:  No, these patients were not

  18   predefined.  Our indication is constipation-predominant. 

  19   Some of these, because the disease varies over time, over

  20   the month of baseline, we looked at people who may have had,

  21   through one reason or another, perhaps a diarrheal

  22   component, as well, so those were the numbers in the data

  23   that I gave you.

  24             DR. HANAUER:  Not for now, but for later, can you

  25   look at just the patients who were constipation-predominant

                                                                152

   1   excluding the alternators for your analysis?

   2             DR. LEFKOWITZ:  Sure.  In other words, I think it

   3   would be the converse of those groups that I gave you.  I

   4   could show you two slides later perhaps that would clarify

   5   that.

   6             DR. HANAUER:  Hugo.

   7             DR. GALLO-TORRES:  Are we saying that these are

   8   alternators during the course of the trial, but they were

   9   not identified as alternators by previous history?  These

  10   patients had a 10-year history of IBS, right?

  11             DR. LEFKOWITZ:  Yes.

  12             DR. GALLO-TORRES:  They behaved as alternators

  13   even though they were randomized as constipation-prone

  14   patients, is that correct?

  15             DR. LEFKOWITZ:  The criteria that was

  16   constipation-predominant, because IBS, obviously, one, as

  17   was shown in one of the earlier slides, people can change

  18   over time, so over that month baseline, we did look at

  19   patients, as I just described, who may have had some

  20   symptoms perhaps that would also be consistent with a

  21   diarrhea component.

  22             They were not predefined or prerandomized. 

  23   Whether one wants to use the word "alternator," I am not

  24   sure, perhaps just people who during baseline may have had a

  25   component.

                                                                153

   1             DR. GALLO-TORRES:  Was that definition based on

   2   one-month data, one-week data, daily data, how did that

   3   definition of alternator come about?

   4             DR. LEFKOWITZ:  We did not -- and let me be clear

   5   -- we do not suggest that we have efficacy or studied

   6   alternating disease.  We studies constipation-predominant

   7   disease based on the Rome I criteria at the time, ensured

   8   that they had an element of abdominal pain for

   9   randomization, I think similar perhaps to what would be done

  10   in clinical practice, and they were randomized.

  11             We simply looked at people who, over the four-week

  12   baseline period, we looked at some of their symptoms and

  13   just wanted to look at them to make sure that they would not

  14   run into trouble perhaps who may be prone to diarrhea.

  15             We also performed a safety study in diarrhea-

  16   predominant, which we could share with you at a later time

  17   if you are interested in that study, as well.

  18             DR. GALLO-TORRES:  Thank you.

  19             DR. HANAUER:  I am sorry to interrupt your

  20   presentation, but these are things for clarity.

  21             DR. WISON:  I guess the one question was during

  22   the screening period, if data presented itself that the

  23   person was perhaps diarrhea-predominant or principally an

  24   alternator, were they then rejected from randomization?  I

  25   guess that is the critical question that one would have.

                                                                154

   1             DR. LEFKOWITZ:  Sure.  Based on clinical criteria,

   2   the investigators were to evaluate patients, and if they

   3   were felt to have diarrhea by clinical criteria as opposed

   4   to strict number of bowel movements and stool consistency,

   5   but if they were felt to have diarrhea at least 25 percent

   6   of the time, they were not to be randomized into the study.

   7             Now some patients may have, based on their diary,

   8   recorded a certain number of bowel movements who fulfilled

   9   the criteria, but the investigator did not feel that they

  10   had diarrhea that would exclude them from randomization.

  11             DR. HANAUER:  Again, later on, can you show us how

  12   many people were assessed at baseline and then excluded

  13   before randomization, so we get an idea of how many people

  14   really were dropped before they were randomized?

  15             DR. LEFKOWITZ:  It was 21 to 27 percent, but we

  16   could show you the breakdown, sure.

  17             DR. JOSEPH:  So, as I was saying before, we

  18   haven't identified any contributing factors to the diarrhea

  19   or protective factors per se.

  20             In the long-term study 209, the incidence was 14.6

  21   percent diarrhea and leading to discontinuation in about

  22   3.5.

  23             [Slide.]

  24             Talking about the ovarian cysts, as I stated

  25   earlier, originally, we were given the data that there were

                                                                155

   1   nine cases of ovarian cysts in the tegaserod group and one

   2   in the placebo.

   3             Of note, the patients who went to the operating

   4   room, there were five cases in the tegaserod group and none

   5   in the placebo.

   6             [Slide.]

   7             The patients undergoing surgery, all five cases

   8   were on the 12 mg/day dose, three were from the long-term

   9   study 209, one for each from 307 and 351, none from the

  10   placebo group.

  11             [Slide.]

  12             I am just going to quickly go through these five

  13   cases that went to the OR.

  14             The first case as a 50-year-old white female with

  15   a 10-year history of ovarian cyst.  She had no abdominal

  16   pain.  She underwent elective surgery performed on day 334

  17   of drug.

  18             The surgery revealed a benign tumor, and no cyst. 

  19   So, we felt obviously that this was not associated with the

  20   test medication.

  21             Let's go to the next case.

  22             [Slide.]

  23             Case No. 2.  A 45-year-old white female, had a

  24   past history of hysterectomy.  She did experience abdominal

  25   pain.  She went to the OR on day 261 of drug.  Her surgery

                                                                156

   1   consisted of a bilateral salpingo-oophorectomy, and her

   2   postoperative diagnosis was adhesions, and there was no

   3   mention of a cyst.

   4             [Slide.]

   5             Case No. 3.  A 37-year-old black female with a

   6   past history also of hysterectomy.  She experienced

   7   abdominal pain on day 100 of drug.  CT scan revealed a 2.7

   8   cm right ovarian cyst.  The surgery, due to continued pain,

   9   was performed approximately five weeks later, and that

  10   consisted of a right salpingo-oophorectomy, lysis of

  11   adhesions, and appendectomy.

  12             The pathology in this case showed a 1 cm

  13   peritubular cyst, adhesions, and a normal appendix.

  14             [Slide.]

  15             Case No. 4.  A 35-year-old female.  She presented

  16   unknown.  We have no idea whether she had pain, et cetera. 

  17   Her surgery occurred on day 306 of the drug.  Pathology

  18   consisted of multiple ovarian cysts, including a 3.5 cm

  19   partially luteinized follicle cyst, and adenomyosis of the

  20   uterus.

  21             [Slide.]

  22             Last case.  A 13-year-old white female.  She also

  23   had a past history of bilateral ovarian cysts.  She

  24   presented on day 87 of drug with a right-sided abdominal

  25   pain.

                                                                157

   1             The surgery was a laparoscopic resection of the

   2   right ovarian cyst, thought to be around 4 to 5 cm, and an

   3   appendectomy.  The ovarian cyst seen at surgery was lysed

   4   and drained.

   5             The pathology report showed early appendicitis.

   6             [Slide.]

   7             In summary, the relationship between the drug and

   8   ovarian cysts is unknown, although when we looked further at

   9   the data, it appears not as worrisome as the 8 to 1 that we

  10   originally saw.

  11             Three of the five previous cases had pelvic

  12   surgery.  Adhesions were seen in two, one had early

  13   appendicitis.

  14             The pharmacologic effects of the drug - perhaps

  15   may be not causative in terms of ovarian cysts, et cetera,

  16   but is there something in the smooth muscle contracting

  17   activity of this affecting a hollow viscus perhaps in the

  18   pelvis that might be calling attention or focusing attention

  19   to pain in the lower abdomen.  This, I believe would be a

  20   subject for discussion later.

  21             [Slide.]

  22             After another case was uncovered of ovarian cysts,

  23   I don't know because the case is still blinded, a 43-year-

  24   old female who had a tubal ligation with reversal about

  25   three years later.  She was diagnosed with ovarian cysts via

                                                                158

   1   a sonogram on day 23 of drug.

   2             This resolved on its own with her menstrual cycle

   3   and she was discontinued from the trial due to nausea and

   4   flatulence that had nothing to do with the cyst.

   5             [Slide.]

   6             When you look at 301-E-01 and 307-E-01 are

   7   extended studies of 301 and 307.  The incidence of diarrhea

   8   in 301 extended went to 15 percent with a 3.5 percent

   9   discontinuation rate, and in 307 extended study, it went to

  10   24 percent with a 5.1 discontinuation rate.

  11             [Slide.]

  12             With the follow-up 120-day safety data,

  13   appendicitis, in the NDA, there was the one case, the 13-

  14   year-old female that I showed earlier.  In the safety

  15   update, there were three cases - a 34-year-old female who

  16   had had three doses, a 44-year-old female who was on day 71,

  17   and 56-year-old female on day 224.

  18             [Slide.]

  19             The adverse events occurring more frequently in

  20   the tegaserod group - syncope with a nonsignificant p-value;

  21   diarrhea with a highly significant p-value; the ovarian cyst

  22   issue, the significance of which is unclear at present; and

  23   the relationship of Zelmac to risk of abdominal pathology

  24   leading to surgery is unknown, and I think that would be a

  25   subject for discussion later.

                                                                159

   1             That's the end.  Thank you.

   2             DR. HANAUER:  Any questions for the FDA?

   3             DR. LAINE:  Just to get a clarification and

   4   confirmation about the dropping of the primary efficacy

   5   endpoint of abdominal pain.  Your report stated that this wa

   6   done after the results of 351 were known, is that correct?

   7             DR. TALARICO:  Yes.

   8             DR. LAINE:  I was just wondering how come or what

   9   was the reasoning behind the decision to allow, so to speak,

  10   or to drop that primary efficacy as an endpoint.  Were there

  11   kind of methodologic issues?  I mean they talk about the

  12   problems with VAS, I guess, in their handout.

  13             I mean the first one, you were arguing I guess the

  14   overall relief issue you were suggesting or they were

  15   suggesting was too stringent.  Was there something about the

  16   abdominal pain that made you want to drop that as an

  17   endpoint, as well, primary endpoint?  I wasn't clear on

  18   that.  Anybody can address that.

  19             DR. GALLO-TORRES:  Rather than we answering that

  20   question, I would like to ask the sponsor to reply to that,

  21   please.

  22             DR. LEFKOWITZ:  In regard to the abdominal pain,

  23   first, I think it may be helpful just to back up a little

  24   and review where our two primary efficacy variables came

  25   from.

                                                                160

   1             As I mentioned before, there was both lack of

   2   consensus in the medical community and at the Agency.  In

   3   consultation with the Agency, we were first recommended to

   4   use an endpoint of abdominal pain.  Subsequent to that, we

   5   were recommended to use an overall relief measure.  That is

   6   where the second efficacy variable came from.  We thought it

   7   best, therefore, to use both as the primary efficacy

   8   variables.

   9             I don't think by making an issue of abdominal

  10   discomfort as secondary means that we don't consider

  11   abdominal pain an important component of IBS.  Clearly, we

  12   do, clearly, the altered bowel habit is an important

  13   component of IBS.

  14             What we were faced with was an evolving field in

  15   terms of IBS.  At the time that we knew the results of 351,

  16   there were recent recommendations related that the overall

  17   integrative measures should be the primary outcome measure

  18   in IBS.  In addition to that, it would be very -- and I

  19   think we were able to come up with what we thought was a

  20   reasonable modification of that primary efficacy measure and

  21   make it both clinically relevant and we thought potentially

  22   more sensitive, whereas, in a visual analog scale, there

  23   were issues about trying to redefine what a responder is, so

  24   we thought it best at that point to continue with the

  25   overall relief as a single primary outcome measure, which

                                                                161

   1   was the overall integrative measure now consistent with what

   2   was being recommended in the field, and to use the SGA of

   3   abdominal pain as a secondary measure as one of the

   4   components of IBS.

   5             Clearly, too, however, we fully realized that this

   6   would increase our statistical power with less multiple

   7   comparisons giving the two doses and the two primary

   8   endpoints.  But whether it is a secondary or a primary, I

   9   think the point being we showed significance in overall

  10   relief with abdominal pain, showing favorable effects at

  11   least in 301 with a significant p-value.

  12             So, that is sort of our take.

  13             DR. LAINE:  I guess I am just trying, because, I

  14   mean there may be a fine line, but, you know, a change of

  15   primary endpoint is a fairly big thing obviously in a large

  16   clinical trial, and I guess the question is, is it because

  17   it didn't work or is there really good methodologic reasons

  18   to change it.

  19             I mean you can argue that in your first one, you

  20   documented because your placebo rate, that, you know, it was

  21   too stringent, and it was perhaps reasonable to change.  I

  22   am just wondering if you have the same kind of, you know,

  23   methodologic excuse, if you will, to change it.

  24             It just looks convenient to drop it, obviously, if

  25   it didn't work in the first study, and I just wanted to have

                                                                162

   1   more justification, I guess, for dropping it.

   2             DR. KOCH:  Gary Koch, statistical consultant from

   3   the University of North Carolina.

   4             The methodologic technical reason for dropping the

   5   second endpoint was that in Study 351, with two doses and

   6   two endpoints, and for those two endpoints, success would be

   7   declared if there was significance on either one of them.

   8             There was not a rule of having to have

   9   significance on both of them.  It was a significance on

  10   either one of them.  What that created is four comparisons. 

  11   So, if there was only an effect on one endpoint at one dose,

  12   the p-value would have had to be below 0.05 divided by 4,

  13   0.0125.

  14             So, one had a situation in which the criterion for

  15   significance would have been 0.0125 if only one of the

  16   endpoints was sensitive and only one of the doses was

  17   efficacious.

  18             So, when the analysis of Study 351 was completed,

  19   the assessment identified a way to come up with only one

  20   endpoint, so that multiplicity adjustments only had to be

  21   made across the two doses, that is, if only one of the doses

  22   worked, the p-value criterion would have been a p less than

  23   0.025.

  24             Assessment of how to produce a more sensitive

  25   endpoint was more feasible on the SGA of relief rather than

                                                                163

   1   on the one for abdominal pain/discomfort or even a composite

   2   of relief with pain and discomfort.

   3             Relief was emphasized because in some sense it

   4   incorporated pain and discomfort, and because of the way the

   5   categorical scale was structured, it lent itself more

   6   favorably to bring in patients who had somewhat relief 100

   7   percent of the time as a fairly good response, and the

   8   information on that was shown in the presentation.

   9             But the main reason why it was moved from primary

  10   to secondary was to reduce the extent of multiplicity in

  11   multiple comparisons, so that when the assessment was done

  12   in the next two studies, it basically done with a method

  13   where there were only two comparisons at the primary level

  14   that had to be taken into account.

  15             DR. LAINE:  Just so I have the timing of

  16   everything that went on right, I understood, though, that

  17   that first amendment, which was done before the studies were

  18   done, was done in order to increase the sample size to allow

  19   for these multiple comparisons and do have the two primary

  20   endpoints.  So, that was initially already factored in, is

  21   that correct?

  22             DR. KOCH:  Well, my understanding is yes, the

  23   original sample size increase when the second point was

  24   added, based on the assumption that the treatment effect was

  25   at a 15 percent level difference, did allow for that.

                                                                164

   1             Now, if the true treatment effect is closer to 10

   2   percent, then, of course, that kind of additional stringency

   3   means that you cannot incorporate the multiplicity

   4   adjustment.  So, if the true treatment effect is closer to

   5   the 10 percent than it is the 15 percent, you can't handle a

   6   multiplicity adjustment that pushes you down to 0.0125, but

   7   you certainly can accommodate one that pushes you to 0.025.

   8             DR. LAINE:  So, was 15 percent chosen as a

   9   clinically meaningful difference, and did that clinically

  10   meaningful difference change to 10 percent, or what was

  11   going on with that?

  12             DR. KOCH:  Well, I think the sponsor is better

  13   able to answer that.

  14             DR. LEFKOWITZ:  Again, sizing of studies based on

  15   a 15 percent difference is what we had expected to see in

  16   our Phase III studies based through experience.  I don't

  17   think one can interpret what one sizes a study on as to what

  18   is clinically meaningful.  I think that is a clinical term

  19   based on a benefit-risk of safety and efficacy.

  20             As I mentioned before, if you really look -- and

  21   that is based on an intent-to-treat analysis conservative

  22   approach -- if you really look at in what was an unselected

  23   population, if you really look at the month to month, the

  24   laxative, nonadjusted responses, you consistently are at 10

  25   to 15 percent.

                                                                165

   1             If you would like to look at the female population

   2   in particular, then, you are much closer to the 15 percent

   3   treatment difference.

   4             DR. HANAUER:  We are going to break for lunch for

   5   an hour and reconvene at 1:30, but I want to put a slight

   6   charge to the sponsor, to Drs. Camilleri, Wald, and Cohen.

   7             One of the problems we are having to deal with is

   8   that we are looking at a drug for irritable bowel for

   9   constipation-predominant, and the Rome criteria have been

  10   described, and similar to the last application we were

  11   reviewing months ago for alosetron, that was taking a

  12   patient population that were diarrhea-predominant, we are

  13   seeing overlaps of patients where the diarrhea-predominants

  14   with alosetron are having significant complications of

  15   constipation.

  16             You are presenting a group that are constipation-

  17   predominant with the most obvious complication being

  18   diarrhea.  We would hope from the committee to be able to

  19   come up with some guidances, guidelines, recommendations to

  20   how to select the population that is going to get the best

  21   benefit from the drug with the least likelihood of side

  22   effects.

  23             So, I want you guys to come up with some

  24   descriptions of how we or the clinical world should be

  25   allocating this drug to those specific groups, do the Rome

                                                                166

   1   criteria help, is there any recommendation that we can

   2   eventually give, but that is for after lunch.

   3             So, enjoy your lunch and we will see you at 1:30.

   4             [Whereupon, at 12:30 p.m., the proceedings were

   5   recessed, to be resumed at 1:30 p.m.]

                                                                167

   1                        AFTERNOON  SESSION

   2                                                    [1:35 p.m.]

   3             DR. HANAUER:  Good afternoon.  To give you the

   4   lowdown for this afternoon, we are going to begin with the

   5   open public hearing this afternoon, and then we will move

   6   back to the questions that we had asked the sponsor to

   7   address, and then discuss the questions that the Agency has

   8   asked the committee to address.

   9             At this point, I would like to invite Nancy Norton

  10   up to speak on behalf of the International Foundation for

  11   Functional Bowel Disease.  Welcome back.

  12             MS. NORTON:  Thank you.

  13             DR. HANAUER:  Did we do you good the last time?

  14             MS. NORTON:  Oh, I think so, yes.

  15                       Open Public Hearing

  16             MS. NORTON:  Before I begin, I would just like to

  17   say that I am here on behalf of patients and that my

  18   expenses have not been supported by any particular

  19   pharmaceutical company.

  20             Members of the Committee, thank you for the

  21   opportunity to appear before you today.  I am the founder

  22   and president of the International Foundation for Functional

  23   Gastrointestinal Disorders and establish current chairman of

  24   the Digestive Disease National Coalition.

  25             The IFFGD addresses the needs of individuals with

                                                                168

   1   functional gastrointestinal disorders, irritable bowel

   2   syndrome being the most predominant one.

   3             As the founder of IFFGD, I began the organization

   4   in 1991 when there was no specific medical treatment offered

   5   to patients living with irritable bowel syndrome.  It wasn't

   6   until the mid-1990's that we saw a stronger interest in the

   7   functional GI disorders and IBS in particular.

   8             As you heard today, irritable bowel syndrome is a

   9   chronic complex of symptoms, affecting as much as 20 percent

  10   of the population.  Symptoms include abdominal pain,

  11   bloating, constipation, diarrhea and fecal soiling.  These

  12   common dysfunctions strike people from all walks of life and

  13   result in a significant toll of human suffering and

  14   disability.

  15             Irritable bowel syndrome represents one of the

  16   most common conditions encountered by gastroenterologists

  17   and general internists.  It accounts for 20 to 50 percent of

  18   all referrals to gastroenterology clinics.  Approximately 70

  19   percent of individuals with IBS in the community are female,

  20   with the incidence being reported as high as 90 percent in

  21   medical centers.

  22             In the U.S. Householder Survey of Functional

  23   Gastrointestinal Disorders, Prevalence, Sociodemography and

  24   Health Impact, Drossman reported individuals with IBS will

  25   miss 13.4 days of work annually as opposed to the 4.9

                                                                169

   1   national average.  IBS alone has recently been called a

   2   multi-billion dollar problem by the gastroenterology

   3   community.

   4             Survey data by Talley reflect that patients with

   5   IBS incurred an annual health care bill of $742 (1992

   6   dollars) compared to $429 for those without the condition.

   7             Data also reveals that there is an increased risk

   8   of unnecessary abdominal surgery correlated by IBS patients.

   9             Hysterectomy or ovarian surgery has been reported

  10   in female patients with IBS as high as 47 to 55 percent and

  11   has been performed more often than in comparison groups.

  12             One of our goals has been to move the research

  13   field forward to provide a better understanding of the

  14   pathophysiology of IBS and the underlying mechanisms with

  15   the hope that one day better medical management and

  16   treatments will be available to treat patients with IBS.

  17             We are making progress.  We are seeing the

  18   development and approval of drugs designed specifically for

  19   the treatment of IBS.  I think it is important to recognize

  20   that the spectrum of symptoms that an IBS patient faces can

  21   range from severe constipation to severe diarrhea, or

  22   perhaps alternating between the two, all the while dealing

  23   with the pain that accompanies irritable bowel syndrome.  It

  24   is difficult to imagine the impact of IBS without personally

  25   experiencing this chronic disorder.

                                                                170

   1             If these drugs are found to be safe and effective,

   2   I would urge you to make them available to the patients who

   3   so desperately need them.

   4             The toll of IBS is on the individual's quality of

   5   life and discomfort, affecting almost every aspect of their

   6   life.  Each day presents itself with uncertainty, not

   7   knowing if their day will be plagued by bowel symptoms or

   8   not.

   9             The World Health Organization has defined Quality

  10   of Life as being "not only the absence of disease and

  11   infirmity but also the presence of physical, mental, and

  12   social well being."  Quality of life may also be defined as

  13   an individual's overall satisfaction with life and one's

  14   general sense of person well being.  It also includes their

  15   functional capacity and their own perception of disease.

  16             Health Related Quality of Life includes:  physical

  17   function, somatic sensation, psychologic state, and social

  18   interactions that are affected by one's health status.

  19             Health related quality of life indicators are

  20   subjective.  Their validation lies primarily with the

  21   patient.

  22             Eisen, Locke, and Provenzale report

  23   gastroenterologists spend 50 percent of their time caring

  24   for patients with functional bowel disorders.  These

  25   disorders do not have mortality or physiological endpoints,

                                                                171

   1   thus, the evaluation of health related quality of life

   2   becomes critically important.

   3             Patrick, Drossman and colleagues developed the IBS

   4   Quality of Life Measures that distinguishes symptoms,

   5   functional states, perceived quality of life and social

   6   disability components.  Their results confirmed that IBS has

   7   a broad and significant impact on a person's quality of life

   8   in addition to the disease activity and symptom impact.

   9             At IFFGD, we talk to tens of thousands of

  10   individuals who live with IBS and there is a constant theme

  11   that we hear from women and men.  They consistently confirm

  12   the isolation that many IBS sufferers experience.

  13             Partly, this is because IBS is very difficult for

  14   most people to discuss.  Many patients believe it would help

  15   if they could talk about their condition and share their

  16   experiences.  But the reality for them is that even mild

  17   symptoms can be very embarrassing to discuss.

  18             More severe symptoms like unpredictable pain,

  19   urgency and bowel incontinence are close to unmentionable

  20   for many sufferers.  Interviews with IBS patients

  21   consistently reveal that few talk about their symptoms with

  22   anyone else.  Indeed, many patients go to great lengths to

  23   hide from others their condition and their own distress.

  24             What does distress feel like if you have IBS?

  25             If you are a person with constipation-predominant

                                                                172

   1   IBS, chances are your distress and pain will increase with

   2   each day that passes that you do not have a bowel movement. 

   3   The feeling of fullness and bloating, the pressure that

   4   begins in your rib cage, the distention in your stomach, the

   5   ache through your midsection, the cramping in your

   6   intestines causes you to double over in pain.

   7             Each day that passes that you are not able to

   8   evacuate, you find yourself straining to have a bowel

   9   movement.  We all know that continual straining to have a

  10   bowel movement may eventually cause more severe problems in

  11   the future, like rectal prolapse, which may result in fecal

  12   incontinence and ultimately surgical intervention.

  13             For the IBS patient, the pain and discomfort is

  14   now, and they need to relieve that pain.

  15             We see so many messages about constipation and

  16   diarrhea through the media that I think that people often

  17   lose sight of just how severe these conditions can be when

  18   you are faced with them as a chronic condition.

  19             Who stops to think about the fact that IBS

  20   patients with constipation are afraid to leave their home or

  21   be in a social situation because of continual gas and

  22   bloating that they experience with their constipation?

  23             There is little compassion when it comes to

  24   understanding bowel disorders and the impact that they have

  25   on people's lives.

                                                                173

   1             IBS affects not only one's professional life, but

   2   also their personal life as well.  It is difficult to plan

   3   trips, to eat in a restaurant, or even go shopping. 

   4   Friendships, intimate relationships, and one's sex life are

   5   affected by it.  There is no spontaneity in life for the

   6   person who lives with IBS.

   7             There is a quiet anxiety, an anticipatory response

   8   to perhaps what will be next.  One may be depressed at times

   9   feeling that their life is out of control or at the very

  10   least that their life is controlled by their bowel.

  11             We live life from the edge of the room never

  12   willing to truly participate to the fullest for fear of

  13   having to find the quickest way out.  There is a loss. 

  14   There is lost potential.

  15             IBS is invisible to others, but it affects every

  16   aspect of our life.  Who would know our pain and oftentimes

  17   the shame that we feel except those who are closest to us. 

  18   There are times when we feel very isolated because of our

  19   IBS.

  20             There is a loss of spontaneity when symptoms may

  21   intrude at any time.  Plans made often need to be changed. 

  22   IBS is unpredictable.  One can wake up in the morning

  23   feeling fine and within a short time encounter abdominal

  24   cramping to the point that you are doubled over in pain and

  25   unable to function.

                                                                174

   1             The unpredictable bowel symptoms may make it next

   2   to impossible to leave home.  For those of us who are

   3   attempting to manage our symptoms in the workplace and in

   4   social settings, we may find ourselves stranded in public

   5   restrooms until we feel some sense of security around our

   6   bowel.  Public restrooms become a nightmare for us.

   7             IBS patients are to be credited for the personal

   8   strength that they find each day to even just walk outside

   9   the door and into life while attempting to manage their

  10   bowel.

  11             Few of you here today had to think about your

  12   bowel management program.  You most likely came today with

  13   little thought, if any, as to are the public restrooms close

  14   at hand, how long would the taxi ride be from the hotel,

  15   where was your seat on the airplane, is it an aisle seat or

  16   a window seat.

  17             These are just the little things that most of us

  18   don't give a second thought to.  The person with IBS is

  19   thinking all the time about logistically how do they get

  20   through the day.  For many people with IBS, the risk of

  21   leaving familiar surroundings is just too great.  Their life

  22   is truly diminished little by little.

  23             If there is any question in your mind as to the

  24   need to provide medical treatment to millions of individuals

  25   who suffer from IBS, please, let me share one more

                                                                175

   1   experience with you.

   2             On January 27th, Camille Grammer, who suffers from

   3   IBS, appeared with her husband Kelsey Grammer on the Today

   4   show with Katie Couric, on behalf of IFFGD.  The foundation

   5   received over 12,000 phone calls from people looking for

   6   help.  The 12,000 people who called are just the tip of the

   7   iceberg of those who need help.  Today, you are in a

   8   position to provide it.

   9             Many of those people expressed how alone they

  10   felt.  They were looking for someone to tell them that there

  11   is a reason to be hopeful for their future and that medical

  12   science is working to find answers for them.

  13             You are here to make recommendations on a

  14   potential new drug treatment for IBS that may provide relief

  15   for a significant proportion of the IBS population.

  16             If Zelmac is shown to be safe and effective, it

  17   will represent a significant step forward in providing

  18   treatment for sufferers of IBS.

  19             Thank you.

  20             DR. HANAUER:  Thank you.

  21             Does anyone have questions for Ms. Norton?

  22             [No response.]

  23             DR. HANAUER:  Thank you, Ms. Norton.

  24             Are there any other public comments before we move

  25   ahead?

                                                                176

   1             [No response.]

   2             DR. HANAUER:  We left before the break with me

   3   trying to pose a question back to the sponsor and the

   4   consultants as to whether or not we can really classify

   5   patients adequately into the different subtypes of IBS, and

   6   I would be interested if Dr. Wald would like to comment on

   7   that.

   8                     Responses from Novartis

   9             DR. WALD:  Yes.  Could I have QA178.

  10             [Slide.]

  11             We obviously gave considerable attention to your

  12   request and tried to clarify for whom this drug might be

  13   used and on the basis of the data that we have.  So, we

  14   would indicate once again that it is indicated for the

  15   treatment of female patients with IBS defined as abdominal

  16   pain/discomfort, and altered bowel habit in whom

  17   constipation is the current predominant symptom.

  18             The issue of constipation was one that we

  19   carefully thought about and our response is based in large

  20   part by the Rome criteria, a consensus of experts who have

  21   talked about constipation, and with the growing realization

  22   that what our patients mean about constipation is often

  23   different than what physicians think of, and therefore, the

  24   old, very narrow definition of infrequent bowel movements is

  25   really inadequately to describe what patients mean when they

                                                                177

   1   say they are constipated.

   2             So, we would define constipation as a current

   3   decrease in bowel movements, below the accepted number of

   4   three per week, passage of hard or difficult to pass stools,

   5   excessive straining at defecation, and we might choose

   6   greater than 25 percent of the time, which is Rome or

   7   whatever the clinician's definition, or a sense of

   8   incomplete evacuation.

   9             Any one of those or combination would be

  10   acceptable as a definition of constipation as we clinically

  11   understand it.

  12             DR. HANAUER:  Now, going back to the clinical

  13   trials to support this indication, are these the patients

  14   who were entered into the trial, did they meet these

  15   criteria for constipation?

  16             DR. WALD:  I think that is an important question

  17   that was raised by Dr. Joseph and perhaps even misspoken by

  18   us.  If I could have the fourth slide on my presentation for

  19   the overview, which would be the Rome II criteria, but we

  20   can use Rome II and Rome I as examples of what I am talking

  21   about to make the point.

  22             [Slide.]

  23             I would remind those of us talking about

  24   constipation that according to the Rome criteria upon which

  25   this study entry was based, that what we are talking about

                                                                178

   1   is the preceding 12 months in which there are at least 12

   2   weeks or more, again need not be consecutive, of which

   3   abdominal discomfort or pain is associated with two of the

   4   three features that we have talked about.

   5             Therefore, it is conceivable that an individual

   6   undergoing a four-week baseline trial prior to entry could

   7   have what we might call diarrhea, yet, would still fulfill

   8   the criteria which were based upon the clinician's

   9   evaluation using very specific criteria.

  10             While for the individual patient, that clinician

  11   might choose not to use a drug like tegaserod at that point

  12   in time, we would anticipate that this patient would revert,

  13   if you will, back to their constipation-predominant disorder

  14   for which they were being enrolled.

  15             So, I don't think we have alternators in our

  16   studies, those who we can tease out, and so forth.  I think

  17   that all of the patients that were in this trial fulfilled

  18   the criteria, which was based upon the preceding 12 months

  19   prior to entry into their study.

  20             In other words, the four-week trial at baseline

  21   does not invalidate the previous year's pattern upon which

  22   these patients were classified.  I think we all as

  23   clinicians here know that patients will vacillate back and

  24   forth, sometimes having diarrhea, sometimes having normal

  25   bowel function, but their predominant pattern will be what

                                                                179

   1   we what we have defined as constipation-predominant IBS.

   2             DR. HANAUER:  Thank you.  You are a good

   3   politician.

   4             Yes, Dr. Wison and then Dr. Wolfe.

   5             DR. WISON:  I guess one question that I have then,

   6   what was the goal of the four-week period theoretically?

   7             DR. LEFKOWITZ:  The goal of the four-week period I

   8   think was twofold:  one, to establish baseline comparisons

   9   to compare the treatment effect to, and I think, two, is to

  10   get the patients used to filling out the daily diary and the

  11   study conditions.

  12             DR. WOLFE:  I want to try and word this properly. 

  13   Is constipation sort of a moving target, and if you are

  14   using the strict definition of at least 12 weeks during the

  15   previous 12 months, but the slide before you stated that the

  16   patients had constipation at that particular moment in time,

  17   then, they could really enter the study without really

  18   having constipation at that time?

  19             DR. WALD:  Yes, I think that is correct, that even

  20   though they fulfilled the definition, in that four-week

  21   period they could exhibit what we might define as diarrhea

  22   predominants.  That was not to invalidate your diagnosis

  23   according to Rome criteria.

  24             Rome is very strict in terms -- it is not for the

  25   day to day or individual care of a patient, it is to enroll

                                                                180

   1   patients into studies that are hopefully more homogeneous

   2   than in the past, and also it is useful for large

   3   epidemiologic studies which, of course, are often based upon

   4   recall.  So, there are limitations, as well as advantages,

   5   of using Rome criteria, or any other criteria for that

   6   matter.

   7             DR. HANAUER:  But for the Rome criteria -- and

   8   please correct me if I am wrong -- they are established for

   9   the diagnosis of irritable bowel syndrome, but have they

  10   been established for the subcategorization into the three

  11   types that you are speaking of and that you we have been

  12   alluding to?

  13             DR. WOLFE:  And also really, this is a question

  14   regarding the use of this drug, is this drug really going to

  15   be a drug used long term, or is it better for people who

  16   actually have an exacerbation of their symptoms for the

  17   short term?

  18             DR. WALD:  Which question should I answer first?

  19             DR. HANAUER:  Answer mine first.

  20             [Laughter.]

  21             DR. WALD:  You know, that is a very good idea. 

  22   Now, what was your question?

  23             [Laughter.]

  24             DR. HANAUER:  With the Rome criteria to establish

  25   diagnosis of irritable bowel syndrome, but we are moving on

                                                                181

   1   now in a previous submission and this submission for a

   2   specific subcategory of IBS, and do those criteria really

   3   allow categorization?

   4             DR. WALD:  Well, if you look specifically at Rome,

   5   there is a diagnosis for irritable bowel, and then there are

   6   subcategories for things like functional constipation,

   7   functional diarrhea.  The use of constipation-predominant

   8   and diarrhea-predominant, I think is historical in an

   9   attempt to further subdefine, recognizing that there are

  10   patients will either go back and forth, the so-called

  11   alternators who have 25 percent of this and that, or those

  12   who may have some diarrhea, but still are predominately

  13   constipated.

  14             The issue is validation, of course.  Not all in

  15   this room I am sure agree with Rome or all of its

  16   subcategories, but it is probably the most recent and best

  17   attempt to bring some order out of chaos, and so we accept

  18   the limitations of Rome.

  19             I don't think we ought to hold to it hard and

  20   fast, but in the alternative and what we had before, I think

  21   it is a quantum jump and the studies that are now being done

  22   on fixed criteria, such as this, although they will never be

  23   perfect in a disorder in which you lack a biologic disease

  24   marker, well, sure, we have been advanced compared to what

  25   we had in the preceding 20 or 30 years.

                                                                182

   1             Of course, it is a moving target.  Now, the issue

   2   of constipation, and is it a moving target is what you

   3   wanted to know -- you know, for clinicians, there are

   4   patients who will good weeks and bad weeks.  The reason for

   5   doing, in my own opinion, 12-week trials is to try to tease

   6   out placebo response rates and to make sure that whatever

   7   effect you are seeing is durable.

   8             In the marketplace, in the clinician's office, I

   9   am sure that doctors will use this drug very differently,

  10   recognizing that IBS is episodic, that there are periods of

  11   time, perhaps weeks or months, in which you want to use the

  12   drug, and then backing off.

  13             So, I don't think that this study seeks to define

  14   how it will be used, simply that it could be used for

  15   certain defined patterns, and it remains for others to then

  16   determine, and then the postmarketing surveillance, if we

  17   should come to that, how the drug would be used.

  18             I myself would imagine using it for only a few

  19   weeks at a time in many patients who are episodic, but not

  20   using it for a full 12 weeks.

  21             DR. HANAUER:  I think actually what we are trying

  22   to do is help everyone understand the problem and actually

  23   help to understand some of the data from the trial, and that

  24   is my impression that we are dealing with a disease that

  25   does -- I agree with you in everything you have said -- that

                                                                183

   1   does tend to be cyclic and that the problem that we are

   2   confronted with is giving a constant medication for three

   3   months at a time is going to even out those cycles, and that

   4   is why we don't see as prominent a difference as the

   5   sponsors would have predicted in the beginning.

   6             On the other hand, there may be a way to, and what

   7   we are trying to do, is help the Agency come up with -- and

   8   the sponsor -- come up with an indication that would be

   9   clinically useful for those who are going to be prescribing

  10   the drug and the patients, Ms. Norton and her group, who are

  11   going to be taking the drug.

  12             One of the concepts that I might throw out is that

  13   it is not necessarily the concept of the phase of the

  14   disease.  As you mentioned, you might only give this during

  15   the constipation phase of irritable bowel rather than

  16   constantly for a period of time, but I don't want to consume

  17   the conversation.

  18             DR. WALD:  Just as a clinician now, just looking

  19   at the data, I would probably be remiss if a patient who had

  20   constipation-predominant symptoms came into my office with

  21   two weeks of diarrhea, and then I gave a drug whose

  22   potential side effects would be diarrhea.  I think I would

  23   wait until they were unhappy and telling me that they

  24   weren't having a bowel movement again.

  25             DR. HANAUER:  Dr. Richter.

                                                                184

   1             DR. RICHTER:  Steve, let me follow up on this with

   2   Arnie, and Mike may want to answer this.  As I understand

   3   the Rome, this definition is more so for the clinician.  I

   4   mean this is your ultimate recall definition.

   5             Your patient comes in the office to see you or I. 

   6   They are complaining about constipation.  You take a

   7   history.  You get constipation and pain.  You try to get

   8   some type of a quantification from their history over the

   9   last year what they have been.

  10             I am not sure how accurate that is, but right now

  11   we know that is about the best that we can do.  So, this

  12   kind of puts you into a global group, this patient looks she

  13   primarily falls into a constipated type of IBS.

  14             But then doesn't your lead-in phase, doesn't this

  15   baseline phase, shouldn't it allow you to really quantify

  16   and qualify that more accurately?  That is what I am

  17   bothered about by the demographics.

  18             I have no problem that this is IBS pain, it's just

  19   describing this as IBS constipation pain that bothers me,

  20   because again, of the demographics of the patients, the

  21   number of bowel movements they are having, the fact that

  22   only a third of them have hard stools, and yet the stool

  23   consistency score, which averages 4.7, is somewhere between

  24   neither loose nor hard or somewhat hard, which is about what

  25   I have every day.

                                                                185

   1             [Laughter.]

   2             DR. RICHTER:  But the point that I am making,

   3   though, is that your baseline characteristics of this is

   4   really your hard endpoint for what your patient group is

   5   that goes in, not the recall based on 12 months, because I

   6   have problems even with recall based on a week, because that

   7   recall based on a week, they may be feeling good those last

   8   two days, and they are going to say every day they have been

   9   feeling well.

  10             DR. WALD:  I think your points are very well

  11   taken, and we all know the limitations of recall versus

  12   prospectively applied data, both in constipation and in IBS,

  13   and perhaps most disorders that we deal with.

  14             The only way to invalidate the diagnosis based on

  15   recall, if we use Rome, is to prospectively follow

  16   individuals for a year, and that, of course, would be

  17   logistically impossible.

  18             You would have to show that in the next year,

  19   after you decided that you wanted to enroll these people,

  20   that they for a year fulfilled their criteria of

  21   constipation-predominant.  You can't do that.

  22             So, we accept the limitations that a month may not

  23   be representative, but even perhaps there are people who

  24   miss-recall, but I think it is the best we can, and besides

  25   those patients I believe are rather evenly divided amongst

                                                                186

   1   the placebo and the active drug thing, so you hope by

   2   unbiasing, blinded studies, randomization, that you try to

   3   even that out.

   4             But again I would emphasize that Rome is useful

   5   for a clinician often to avoid misdiagnosing IBS, but it has

   6   not been validated as an office practice tool for that

   7   patient who walks into your office and where you are

   8   deciding does this person have IBS or not.

   9             It is best suited for large-scale epidemiologic

  10   studies and the kinds of studies that we have had presented

  11   here in the fall and now again here, and with its

  12   limitations.

  13             DR. HANAUER:  Michael.

  14             DR. CAMILLERI:  May I take the liberty for a

  15   couple of minutes.  I think that a number of very good

  16   points have been made, and one of the reasons why the

  17   clinicians at lunchtime came up with the added concept of

  18   current predominant constipation is really fueled by the

  19   comment that Dr. Richter just made, that if you look at the

  20   mean consistency and frequency data, you actually dilute out

  21   the interesting and significant message that we have seen

  22   this morning, and I would just like to reiterate three

  23   points very rapidly on the slides.

  24             [Slide.]

  25             The first is QA77 indicating that in that four-

                                                                187

   1   week run-in period, which Dr. Richter is telling us is a

   2   nice way to enrich our study population and characterize it,

   3   there are 60-something, almost 70 percent of patients who

   4   fulfill criteria either for frequency or hard or very hard

   5   stool.  Therefore, the majority of these patients in fact

   6   prove to have the constipation-predominant irritable bowel

   7   syndrome currently in the context of the study.

   8             [Slide.]

   9             The next point I would like to bring to your

  10   attention is ESG123, and here what we are going to see is

  11   the influence of current in the four-week run-in period,

  12   stool consistency, ESG123, and stool frequency, and what we

  13   see here is that if patients have more than three bowel

  14   movements per week, there is no efficacy of the medication

  15   or if they have loose stools.

  16             On the other hand, in these 2,000-odd patients, if

  17   they have less than three bowel movements a week or absence

  18   of loose stools, you will see the efficacy of the medication

  19   grouped across the three studies, and a similar result is

  20   also shown on 125, but I won't waste the committee's time.

  21             The point I think that clinicians at lunchtime

  22   would like to bring to the attention of the committee is

  23   that it is the current symptom of constipation defined not

  24   necessarily by frequency, but by consistency, difficulty

  25   with stool passage, excessive straining that would suggest

                                                                188

   1   that this medication has an added benefit, and indeed, by

   2   meeting all of the stool data, as Dr. Richter predicted, or

   3   as you predicted, Mr. Chairman, there is actually a dilution

   4   of the effect of the medication.

   5             Thank you for your attention.

   6             DR. HANAUER:  Before you go -- so, your patient

   7   takes the drug and gets out of the constipation phase.  The

   8   studies have shown continuation of it.  Is that what you are

   9   going to do in practice?

  10             DR. CAMILLERI:  Mr. Chairman, you obviously know

  11   that in the context of a clinical trial, one is bound by the

  12   need to fulfill the trial criteria.  Clearly, as Dr. Wald

  13   indicated earlier, and I am sure Dr. Cohen will suggest

  14   after I have moved away from this microphone, I suspect that

  15   we will all recommend that for patients who seem to be going

  16   into remission, it would be appropriate to suggest a drug

  17   holiday and stop the medication, but I defer to his --

  18             DR. HANAUER:  But your indications and the

  19   marketing, hence, the marketing of this appear to be as if

  20   it would be given as a continuous course over three months,

  21   was showing three-month data on that.

  22             The issue is should labeling be modified -- I am

  23   putting it back to you guys, and eventually we will come to

  24   this -- should labeling be modified, so that it should be

  25   used during a phase or to treat the symptoms of.

                                                                189

   1             DR. CAMILLERI:  It is often established clinical

   2   practice among people who see a large number of these

   3   patients, that when the patient goes into remission, you

   4   would obviously try to withdraw the medication, and I think

   5   that the only way in which the label can be written

   6   presumably is as it relates to the way in which the clinical

   7   trial was performed.

   8             DR. HANAUER:  Right, but as you pointed out in the

   9   very beginning, 80 percent of these patients are seen by

  10   primary care physicians, not gastroenterologists, who are

  11   not the sophisticated nature of you or your colleagues or

  12   many or some of us at the table here.

  13             DR. CAMILLERI:  I think you for that compliment. 

  14   Nevertheless, I do have a lot of confidence in our primary

  15   care and general practice colleagues, and I think we should

  16   defer to your committee to help in the decision as to how

  17   this medication would be given, and I think it would be

  18   consistent with what you and I as gastroenterologist

  19   clinicians do in our practice.

  20             Thank you.

  21             DR. HANAUER:  Thank you.

  22             Dr. Cohen.

  23             DR. COHEN:  Can I please have that 178 slide back.

  24             [Slide.]

  25             I would just comment.  I think there is a great

                                                                190

   1   deal of confusion here.  The Rome criteria are very good for

   2   doing large population-based studies, and is also very

   3   valuable for the clinician to identify clinically the

   4   patient with the irritable bowel syndrome, and not only has

   5   clinical diagnostic criteria, but it has exclusion criteria,

   6   and it is being widely adapted by, for example, the American

   7   College of Physicians are recommending that this be used for

   8   the identification of patients with irritable bowel.

   9             Indeed, now, you have asked the question, Dr.

  10   Hanauer, about the indication, and I think this indication,

  11   as stated here, carries a lot of important components. 

  12   First, treatment of female patients with irritable bowel

  13   syndrome, and the definition of abdominal pain and altered

  14   bowel habit with constipation being the predominant current

  15   symptom, and the word "current" is critical, and the word

  16   "predominant" is critical in that definition.

  17             The patient may have had in the prior 12 months or

  18   20 years have had other components, but that when that

  19   patient presents, the patient then identifies the type of

  20   syndrome that they have current, predominant symptom of

  21   constipation, and then at the lunch table, we discussed the

  22   definition of constipation, which cannot be a narrow

  23   definition that we were going down or the pathway we were

  24   pursuing at the presentation this morning.

  25             It has to be defined clinically.  A decrease in

                                                                191

   1   bowel movements, hard, difficult to pass stools, straining

   2   at defecation or feeling of incomplete evacuation.

   3             My sense is that the clinician will treat this

   4   drug until the patient goes into some sort of clinical

   5   remission, and in some patients it would be a 12-week

   6   period, in some people it is going to be a long-term

   7   therapy.  It is not going to be on-demand therapy.

   8             So, I think the definition as you charged us here,

   9   the proposed indication is encompassing of the kinds of

  10   patients that I believe we would like to see be treated with

  11   this medication.

  12             DR. LEFKOWITZ:  Mr. Chairman, if I may just make a

  13   couple points.  One of the reasons that we conducted our

  14   trials this way, that is, based it on clinical history, is

  15   that we can answer the question what happens when patients

  16   are treated with this drug who are liable to have diarrhea

  17   intermittently, how will they do on the drug.  Otherwise, I

  18   would be standing here today without an answer to that

  19   question, and I could tell you in our Phase III trials, the

  20   incidence in diarrhea was about 3 to 1, 15 percent versus 5

  21   percent in these patients.

  22             As I mentioned before, we also did a study in

  23   diarrhea-predominant patients, which had very similar

  24   results, but we saw no serious adverse events, very low

  25   discontinuations, so we were able to answer that question,

                                                                192

   1   and that was one of the reasons we approached it that way.

   2             If I may also just take the liberty, based on that

   3   statement, which showed in female patients, if I could show

   4   Slide QA18 --

   5             [Slide.]

   6             I just wanted to again show the results in female

   7   patients as the magnitude of effects certainly came up. 

   8   Here is the total population in 351, female patients in 301,

   9   female patients in 301, not much difference in 307 again on

  10   the SGA of relief, and in the next slide, 19 --

  11             [Slide.]

  12             Shown here are the monthly results.  These are

  13   patients again remaining on the drug in practice, and in

  14   301, the prospective endpoint in 301 and the SGA relief, you

  15   do see response rates around the 15 percent mark.

  16             Further, if I could have Slide ESG31 dealing with

  17   the issue of abdominal pain in women --

  18             [Slide.]

  19             Shown here are the results of abdominal

  20   discomfort/pain in women at endpoint, fully adjusted values,

  21   intent-to-treat analysis, Study 351, a 9 percent difference, 

  22   Study 301, a 10 percent difference, and let me point out

  23   that even if the SGA of abdominal discomfort was retained as

  24   a primary endpoint, in Study B301, this result would be

  25   statistically significant in the female population.

                                                                193

   1             Thank you.

   2             DR. WOLFE:  One question that was brought up

   3   before by Joel was are we convinced that the decrease in

   4   pain was due to an improvement in constipation, and that

   5   could be answered by certain studies, I am not sure if they

   6   were done in the past or not.

   7             If this is a drug which blocks afferents, then, by

   8   doing distension studies, balloon distension on this drug,

   9   you should be able to have better tolerance toward

  10   distension.  Was that done?

  11             DR. LEFKOWITZ:  We performed one study in visceral

  12   sensitivity using a 4 mg dose, looking at rectal distension,

  13   and in that study we did not see an effect on visceral

  14   sensitivity.  I might add, however, these small studies,

  15   which used a lower dose, and I don't know that is a

  16   particular best model to look at visceral sensitivity in

  17   man.

  18             DR. WOLFE:  In women.

  19             DR. LEFKOWITZ:  Yes.

  20             DR. WOLFE:  No 12 mg doses at all?

  21             DR. LEFKOWITZ:  No, we did not.

  22             DR. SMITH:  This may seem a bit facetious, but why

  23   don't we market placebo?  You have a 40 or 50 percent

  24   response rate in the first two weeks, when some of the daily

  25   symptom calendaring, and if we are looking for a treatment

                                                                194

   1   that addresses the syndrome, to recognize that it is a

   2   syndrome that has both psychological, psychosocial, and

   3   physiologic parameters that are distorted and affecting

   4   success and failure, but how does the placebo work, and why

   5   does it work so very well?

   6             DR. WOLFE:  We actually have been using placebo

   7   for many years because a lot of the drugs we use for IBS

   8   have never really been tested, and many of them are very old

   9   drugs, which have been used historically.

  10             DR. WALD:  That was exactly the point I was going

  11   to make, that we already are using placebo.  If we define a

  12   drug that we are using, prescription or nonprescription, has

  13   never been more effective than placebo, and that is the

  14   story of irritable bowel syndrome.

  15             How placebo works and why placebo works is

  16   unclear.  Certainly, the concept that placebo works best is

  17   psychoneurotic individuals is probably not correct. 

  18   Placebos are more likely to work in people who want to get

  19   better than people who don't, and whether that is working on

  20   endorphins or other kinds of things, we don't know, but that

  21   has been the experience of all clinically based entities

  22   where there is a huge response.

  23             One might even conclude that in certain cases of

  24   inflammatory bowel disease, peptic ulcer, that placebos have

  25   a certain heal rate as well.  So, it is a very potent tool

                                                                195

   1   to use as long as the placebo that you are using doesn't

   2   carry with it any significant side effects.

   3             DR. HANAUER:  There are ways.  These studies did

   4   not show the placebo was better than no treatment.

   5             DR. COHEN:  But I would comment that going back in

   6   gastroenterology when we had our first drug, the first H2

   7   antagonist, that was a very prominent finding, and people

   8   were astounded at the very strong placebo response in GI

   9   trials for diseases where you actually had an organic lesion

  10   like a duodenal ulcer or a gastric ulcer, patients with

  11   esophagitis, and it seems to be consistent in

  12   gastrointestinal syndromes and diseases, and somewhat

  13   different than other disorders like cardiovascular and

  14   pulmonary disease, but I think you can ask the same question

  15   for many of the treatments that we have in GI.

  16             DR. RICHTER:  For anyone in the Novartis group,

  17   this is a three-month study.  We have defined IBS as a

  18   disease which cycles and has to at least have 12 weeks of

  19   whatever your predominant pain complaint is or constipation

  20   complaint.

  21             Can we get some evidence of prolonged efficacy

  22   past three months from your long-term studies, particularly

  23   your patients that have been in there a year, how does their

  24   response at six months and a year compare to their three-

  25   month response, does that continue?  You see an acute

                                                                196

   1   response and then abate some, does that plateau and stay

   2   plateauing?

   3             DR. LEFKOWITZ:  Yes.  As you pointed out, we only

   4   have control data after three months.  In the long-term

   5   study, those patients who actually complete the study, and

   6   using a response definition in that case of

   7   complete/considerable relief in this open label study,

   8   approximately 65 percent of patients had a response at the

   9   end of 12 months.

  10             If you look at patients who had a response -- and

  11   clearly, people have dropped out of the study -- if you look

  12   at patients who were responders at month 3, and then what

  13   happened to them over the 12 months, 60 percent of those

  14   patients remained in the study and were responders at month

  15   12, with approximately 20 percent of the patients having

  16   dropped out and 20 percent of the patients being non-

  17   responders.

  18             DR. RICHTER:  What that is signifying, Martin, is

  19   that even over that year's period of time, then, you have

  20   people that are not responding or dropping for other

  21   reasons.  So, you are continuing actually, if anything, this

  22   drug doesn't plateau its effect out, this drug does have a

  23   falling decline in the efficacy over a year's period of

  24   time.

  25             DR. LEFKOWITZ:  No, I am not sure one can conclude

                                                                197

   1   --

   2             DR. RICHTER:  Well, you said at the end of three

   3   months, that that represents -- the question I am asking, if

   4   at the end of three months you get 100 percent responders --

   5             DR. LEFKOWITZ:  Correct.

   6             DR. RICHTER:  Then, what are those 100 percent

   7   responders doing at the end of a year?  If they are not in

   8   the study at the end of the year, I consider that a non-

   9   responder.

  10             DR. LEFKOWITZ:  I understand that.  The answer

  11   again is that 60 percent of those patients at month 3 are in

  12   the study, at month 12, unresponders, but clearly, we do not

  13   have a placebo control.  I would submit if we did have a

  14   placebo control, you would certainly potentially see a

  15   difference.  So, I think 60 percent of patients with

  16   irritable bowel syndrome maintaining a response in a waxing

  17   and waning disease is I think fairly reasonable.

  18             DR. HANAUER:  I am just pondering your last

  19   statement because I am not certain that you have shown

  20   maintenance of a response over a period of time, and that

  21   would be if we get into very subtle differences here,

  22   between the difference of maintenance of a response and

  23   intermittent treatment of this, which is what you are

  24   hearing most of your consultants and the members at the

  25   table thinking the way they would use it.

                                                                198

   1             DR. LEFKOWITZ:  Yes, we did look in our clinical

   2   trials of patients who responded at month 1 and what

   3   proportion of them remained responders at the end of the

   4   study, if you are interested in those data.

   5             DR. HANAUER:  Sure.

   6             DR. LEFKOWITZ:  That is in the ER file.  That

   7   would be ER8.

   8             [Slide.]

   9             Again, these are people who were responders at

  10   month 1 to the drug, and then in 351, 301, 307, as you can

  11   see, most patients, whether on placebo or on the drug, more

  12   here in 351 on the drug remained responders at endpoint with

  13   similar rates across the three studies.

  14             So, it was a persistent response, but it was also

  15   largely a persistent response in the placebo patients, as

  16   well.

  17             DR. WISON:  Just one point, though.  You don't

  18   have any of the data for once people stopped, whether they

  19   returned to their baseline or whether that response was

  20   maintained, is that correct?

  21             DR. LEFKOWITZ:  That is correct, in a controlled

  22   fashion we did not collect that data, yes.

  23             DR. TALARICO:  Do you have any evidence if there

  24   is any rebound phenomenon when patients stopped the drug?

  25             DR. LEFKOWITZ:  I am sorry?

                                                                199

   1             DR. TALARICO:  Any worsening of the symptoms when

   2   they discontinued the drug?

   3             DR. LEFKOWITZ:  Again, we did not keep this

   4   patient in the study, but we did not get any reports from

   5   the sites.  We collect safety after 30 days in these

   6   patients, and have had no evidence of that.

   7             DR. HANAUER:  There must be follow-up data on

   8   these patients in some way for safety, I presume, I haven't

   9   seen serious adverse events in the next months, that they

  10   became obstipated and needed surgery or anything like that?

  11             DR. LEFKOWITZ:  No, that is correct.  We collect

  12   serious adverse events at least for 30 days, and often get

  13   reports well beyond 30 days, and we have gotten several

  14   serious adverse events in the population both on placebo and

  15   drug following completion of the study.

  16             DR. HANAUER:  Does the Agency have data on, for

  17   instance, an adverse event, such as constipation, 30 days

  18   afterwards, was that submitted in?

  19             DR. LEFKOWITZ:  Sure, we submit all serious

  20   adverse events that are reported to us.

  21             DR. HANAUER:  Other questions from the committee? 

  22   Dr. Hammes.

  23             DR. HAMMES:  Do you have any data on duration of

  24   effect, single dose duration of effect, or how long after

  25   stopping you have a duration?

                                                                200

   1             DR. LEFKOWITZ:  You mean a single dose study in

   2   terms of --

   3             DR. HAMMES:  Well, we know that when things bind

   4   receptors, some of them can be insurmountable and stick

   5   around for a week or until new receptors are made.  What

   6   does this drug behave like at the receptor?

   7             DR. LEFKOWITZ:  I think perhaps Jim McLeod might

   8   be able to give some information from some of the healthy

   9   volunteers or other studies.

  10             DR. McLEOD:  Most of our data is on control

  11   because we are usually looking at pharmacokinetics, but we

  12   did several control trials with placebo.  What we observed

  13   was similar to Marty's during the multiple dose situation

  14   where most of the gastrointestinal adverse events, and since

  15   we are not looking at an effect, we are just looking at

  16   adverse events, occurred on the first and second day.

  17             Then, we saw very few over the ensuing two weeks,

  18   which was the longest period that we dosed in the control

  19   situation where we intensely gathered this information.

  20             We did a series of studies where we looked at the

  21   pharmacokinetics in a cross-over manner, so we would

  22   administer the drug, a single dose predominantly or one or

  23   two doses, and then we would bring them back either a week

  24   later or some period thereafter.

  25             The effect again occurs when the drug is

                                                                201

   1   readministered, so we do see a number of increased bowel

   2   movements on the first day of readministration a week later,

   3   and then subsequently, we have done three, four, or five

   4   cross-overs like this, so in terms of the effect, this

   5   receptor or its physiologic consequences seems to recover

   6   within a week.

   7             DR. HANAUER:  Dr. Ferry is kind of quiet, but I

   8   will use his prerogative.  IBS and constipation are common

   9   in children.  Do we have data at all in children?

  10             DR. FERRY:  That is what I was looking for.  You

  11   had one 13-year-old patient with ovarian cysts.  I don't

  12   know how many other children you had in the study.

  13             DR. LEFKOWITZ:  In Study 351, the age limit was

  14   12.  Although we didn't go to pediatricians, we tried to

  15   find GI sites who had told us that they dealt with a lot of

  16   adolescents.  In fact, we only enrolled I believe it was

  17   three adolescents into 351.  We have submitted a proposal to

  18   the Agency for a pediatric study that is under discussion

  19   right now.

  20             DR. WOLFE:  I am forgetting what was asked and

  21   what was presented.  Do you have any data to tease out or to

  22   stratify according to the real severe constipation versus

  23   the mild constipation, looking at response rates, was there

  24   any difference?

  25             DR. LEFKOWITZ:  We looked at data based on

                                                                202

   1   abdominal pain severity, because data in the literature

   2   suggesting that patients with more severe pain may be less

   3   responsive.  So, that is the stratification that we did do.

   4             But the 12 mg dose with data I could show you,

   5   there was no difference between mild -- we broke it into

   6   tertiles, and there was no difference.  For the 4 mg dose,

   7   there seemed to be a difference with people with severe pain

   8   less likely to respond.

   9             DR. WOLFE:  That was pain only, though.

  10             DR. LEFKOWITZ:  That was pain only.

  11             DR. WOLFE:  Because the pain is just so difficult

  12   to quantify.  Constipation, at least you can get some

  13   quantification.

  14             DR. LEFKOWITZ:  If you want to go to ESG125.

  15             [Slide.]

  16             This is a slide I showed before, and I am not sure

  17   that this fully answers your question, because we don't look

  18   at patients with very severe pain, but again, this was a

  19   small number of patients in the study who had stools 3.5 on

  20   the scale with 3 being somewhat loose.  These are sort of

  21   the middle group, and half the population with the cutoff on

  22   4.5.  This was the data I showed you earlier.

  23             I guess you might be interested in the people

  24   further out on the scale, but we didn't break out the data

  25   that way.

                                                                203

   1             DR. WOLFE:  Any statistical analysis of these

   2   patients?

   3             DR. LEFKOWITZ:  In terms of?

   4             DR. WOLFE:  Any statistical difference in --

   5             DR. LEFKOWITZ:  I mean clearly between here and

   6   here, they looked quite similar.  We didn't run formal

   7   statistics on this data.

   8             DR. HANAUER:  Other questions to the sponsor from

   9   the committee?

  10             [No response.]

  11             DR. HANAUER:  I want to handle a few questions

  12   that were left over from the statistical group before we go

  13   to the big picture questions that the Agency has asked the

  14   committee.

  15             Going back to the statistical assessment, and the

  16   sponsor can address some of these questions, too, the first

  17   issue is that the summary from Statistics said that there

  18   was a significant treatment effect demonstrated in female

  19   patients in Study 301, that was supported by the post-hoc

  20   analysis in 351, but not replicated in 307.

  21             What is the difference?  Why was there no effect

  22   seen in 307?  A treatment effect was not demonstrated for

  23   either dose in 307.  I am asking you or the sponsor.

  24             DR. WOLFE:  No one knows.  We can't give an

  25   answer, we can only speculate, but I think I have two

                                                                204

   1   explanations why -- I don't think 307 -- first of all, the

   2   dose escalation I think just enhances the placebo response

   3   because if one works, three is better, so you are just

   4   actually help encourage those.

   5             If you looked, they had a sharp rise, at least

   6   some of the data they had a sharp rise in improvement as

   7   they escalated, even placebo.  So, I think that study right

   8   there really may have hurt them.

   9             DR. HANAUER:  Along those lines, were the number

  10   of tablets a day increased, or was the dose increased in

  11   dummy tablets?

  12             DR. LEFKOWITZ:  The number of tablets were kept

  13   constant, at two tablets twice a day.  By study design, the

  14   patients were not supposed to know when they were being dose

  15   escalated.  Clearly, the study coordinators knew because

  16   they had to give them the correct drug supply.

  17             We certainly suspect that the patients did know

  18   that week before was the time of dose titration, however.

  19             DR. HANAUER:  You think they knew.

  20             DR. LEFKOWITZ:  Yes.  That would be my

  21   speculation, speculation.

  22             DR. WOLFE:  The other reason is that from 4 to 12,

  23   regardless of the question of desensitization and

  24   tachyphylaxis being, yes, less common with partial agonists,

  25   it still does occur, and if you have a little bit of a drug

                                                                205

   1   working, you up the dose at that point, you will not

   2   probably have the effect that you would have by starting off

   3   with a higher dose in the beginning.

   4             So, it is all speculation, but again, I don't

   5   think there is a very good dose response curve demonstrated

   6   for this drug, and the doses may have actually, 4 and 12, as

   7   far as -- we can't measure acid secretion.  I mean we don't

   8   have an objective parameter to measure here.

   9             It makes it very difficult to really determine

  10   what is the optimal dose.  You are looking at symptoms only. 

  11   So, for that reason, 4 and 12 are going to be very similar

  12   in regard to the response.

  13             DR. LAINE:  I was going to ask actually, the

  14   sponsor, experts, or anybody else, the only trial that was

  15   clearly positive, 301, was done completely in Europe.  351

  16   was done in the United States and did not achieve the

  17   primary endpoints, and 307 was done two-thirds in the United

  18   States.

  19             Certainly, in other GI diseases, we have dramatic

  20   differences in responses between the U.S. and extra U.S.

  21   populations.  Do we have data on IBS and differences that

  22   occur in different populations?  This is again the only

  23   study that was positive was the European study without U.S.

  24   patients.

  25             DR. LEFKOWITZ:  As I showed earlier, what we

                                                                206

   1   looked at were the demographics of the patients, the

   2   baseline characteristics of the patients, and they were

   3   almost --

   4             DR. LAINE:  That is not really the point.  The

   5   point is do we have -- we have lots of, as we talked about

   6   at lunch, lots of peptic ulcer studies that showed marked

   7   differences between healing rates in the United States and

   8   Europe, H. pylori, I mean there is lots of different

   9   precedents for that.

  10             I am not really talking about your study, because

  11   your study clearly did show a difference in response between

  12   -- or it seems to me at least -- between European and non-

  13   European, or European and U.S. studies.

  14             What I am asking is are there other studies to

  15   show similar differences in responses depending on different

  16   countries?  I mean there have been previous IBS studies

  17   either the Glaxo's information or other studies that we have

  18   had in the past.

  19             DR. LEFKOWITZ:  I can't comment on the other

  20   studies.  I would just submit that my interpretation of the

  21   data is that the response rates in Europe and U.S. were

  22   overall quite similar, 301 and 351, the results were quite

  23   consistent between the two studies.

  24             DR. LAINE:  The only problem is 351 was really,

  25   you know, was positive only after you had already seen the

                                                                207

   1   results, so I think we have to take that with a grain of

   2   salt or at least certainly not as a pivotal trial.

   3             DR. LEFKOWITZ:  I understand that, but what my

   4   point is, however, is that the overall response rates, the

   5   treatment differences in those two studies were actually

   6   quite similar.

   7             DR. HOUN:  The Glaxo experience was U.S. only for

   8   those pivotal trials.

   9             DR. HANAUER:  Other comments regarding that 307? 

  10   Did you want to say anything about 307?

  11             DR. SURAWICZ:  No.  It is just that I don't think

  12   the panel can answer why 307 wasn't successful.  The company

  13   would.  I think they have done an excellent job in their

  14   presentation and handling questions, and it is obvious that

  15   the placebo rate is -- the response rate is so high there. 

  16   Why those things happened, I don't think we will ever know.

  17             DR. HANAUER:  The other question back from

  18   Statistics was whether or not the effect, has the effect of

  19   treatment on abdominal pain been adequately assessed, the

  20   specific aspect of abdominal pain.

  21             Are you comfortable with the way that that was

  22   evaluated in these trials?

  23             DR. LAINE:  Are you asking how it was evaluated or

  24   what the results were?

  25             DR. HANAUER:  That was one of Sonia's questions.

                                                                208

   1             DR. LAINE:  I am asking to kind of clarify, are

   2   you saying do we think the scale that they used was

   3   appropriate or inappropriate, or are you saying that since

   4   it didn't achieve statistical significance, we don't think

   5   they have documented that they have abdominal pain relief?

   6             DR. CASTILLO:  I think the Division wants to know

   7   if it was adequately assessed.

   8             DR. HANAUER:  You mean is the instrument an

   9   adequate assessment?

  10             DR. LAINE:  I am not sure that we are the ones to

  11   say about the instrument.  If the instrument is adequate,

  12   then, their endpoint was not significant in their trials. 

  13   Their secondary analysis looked at that obviously, and gave

  14   different views, but they had a lot more data points there

  15   to show small differences being statistically significant.

  16             So,  I mean I would say that their primary

  17   endpoint of pain, if it was an adequate instrument, did not

  18   demonstrate abdominal pain relief, but on the other hand, I

  19   can't comment on whether that scale is indeed the proper

  20   instrument.

  21             DR. TALARICO:  The question was whether it was

  22   adequately represented in the study population, and from the

  23   result, is there any trend that indicates should that

  24   population be expanded, that efficacy may be demonstrated.

  25             The other question that we would like an answer,

                                                                209

   1   is the disease the same in men and female, is there a

   2   physiological -- as part of the IBS.

   3             DR. LAINE:  The men doesn't seem to matter anymore

   4   because they have already changed their proposed indication

   5   to female, so it seems it is really a --

   6             DR. CASTILLO:  I think the question is in the

   7   overall picture of constipation-predominant IBS, pain is an

   8   important clinical component of it, and has it been

   9   adequately assessed in these trials.  I think that was what

  10   we were looking for.

  11             DR. GALLO-TORRES:  One is pain by whatever means

  12   isolated by itself, even by a VAS.  That is one way of

  13   assessing pain alone.  If one assesses pain as a component

  14   of a global parameter, that is really the core of the

  15   question, which one is more applicable and more useful, more

  16   meaningful, which would of the two approaches, and has the

  17   sponsor done the proper evaluation of pain.

  18             DR. LAINE:  Remember there was the one question

  19   that we accepted in the previous alosetron submission.  Does

  20   somebody have that readily available, exactly what that

  21   question asked by way of comparison?  That was a global

  22   question, if you remember, do you feel better.  Did that

  23   specifically say pain or was it generally, how do you feel?

  24             DR. GALLO-TORRES:  There is a question with the

  25   alosetron included that were irritable bowel syndrome pain

                                                                210

   1   and discomfort.  That was a very meaningful type of

   2   question.

   3             DR. LAINE:  It said irritable --

   4             DR. GALLO-TORRES:  Irritable bowel syndrome pain

   5   and/or discomfort.

   6             DR. LAINE:  All I am asking I guess was that one

   7   that we accepted last time, was that specifically pain --

   8   certainly, the Rome criteria still requires pain or

   9   discomfort as the primary reason for having a symptom in IBS

  10   with the constipation being -- and the other bowel habits --

  11   being contributory.

  12             So, I would think you would still want to make

  13   sure pain and discomfort it seems is still the number one

  14   issue presumably in irritable bowel syndrome, although

  15   patients certainly complain about all the other aspects of

  16   bloating and alteration of bowel habits, as well.

  17             DR. HANAUER:  Dr. Camilleri and then Dr. Wolfe.

  18             DR. CAMILLERI:  I was just going to provide the

  19   information, that the question in the other trial posed the

  20   following question:  Have you achieved adequate relief of

  21   your pain or discomfort, and it pertains to the past week?

  22             DR. HANAUER:  Thank you.  Dr. Wolfe.

  23             DR. WOLFE:  I wasn't here for the other one, but

  24   these people don't come here with isolated pain, it's a

  25   whole syndrome, and I think the pain question has been

                                                                211

   1   looked at fairly carefully, but the overall quality of life

   2   question, I am not sure if that has been answered.

   3             That is my biggest question.  The other thing,

   4   too, when we see patients like this, some of these comments

   5   bring back nightmares or daymares.  These patients, I rarely

   6   aim for a complete relief, so maybe the original questions

   7   have not been realistic, and partial relief on a scale may

   8   have been a better question to ask.  What you do

   9   retrospectively is a different question all together.

  10             DR. LAINE:  It seems to me that I guess the

  11   question being asked, though, is if pain is indeed

  12   important, their primary and secondary endpoint of pain did

  13   not achieve significance except I guess in 301 with the

  14   higher dose.

  15             However, when they did the secondary analysis of

  16   pain with the many data points, they did have significance,

  17   so the question I guess is if they didn't achieve it in

  18   their primary analysis of pain, is that important, is that

  19   one of the things you are asking?

  20             In other words, if they don't achieve it in pain

  21   in two of the three studies.

  22             DR. COHEN:  I would just comment that when you

  23   look at it as a secondary efficacy variable over the course

  24   of the study, for one study 301, for 11 of the 12 weeks

  25   there was less pain, to me, in terms of measurement of pain,

                                                                212

   1   and there is a whole science of pain reduction, that was

   2   clinically significant, as well as statistically

   3   significant.

   4             I think the question that you are raising, was

   5   that enough to give the patient overall relief, and that is

   6   reflected in the global relief.  I think if you look at the

   7   data both as a statistician and as a clinician, I think

   8   there is clinical relief of the major components of IBS as I

   9   presented it.

  10             I think the question that you are asking is

  11   whether or not that is enough of a relief, and I think that

  12   is a very hard -- I don't know if anybody can answer that.

  13             DR. HANAUER:  Which brings us to the second

  14   question up there, which is behind us, are the therapeutic

  15   gains seen clinically significant, clinically meaningful.

  16             DR. COHEN:  I can answer that.  I think that in a

  17   disease or a syndrome where there is nothing out there,

  18   there is no efficacious parameter, over the years in

  19   practice we have gone through all of the drugs including

  20   calcium channel antagonists, things that weren't even

  21   mentioned on Dr. Wald's slide, and nothing has had proven

  22   efficacy.

  23             So, if you are looking at a margin of

  24   effectiveness of an agent, and it does relieve pain, it

  25   improves bowel function, I personally think it's clinically

                                                                213

   1   meaningful, and the term that I used, I said it was a

   2   moderately effective drug for the relief of the pain and the

   3   constipation in this group of patients.

   4             DR. LAINE:  What I was going to raise, though, is

   5   that methodologically, you would think you would first look

   6   at your primary evaluation of pain, and when you looked at

   7   that, you didn't show significance.

   8             It was when you started looking at your secondary

   9   evaluations, you did show significance -- excuse me -- you

  10   showed it in one trial with 12 mg, I don't mean to diminish

  11   that.  Then, you started to show significance.

  12             DR. HANAUER:  Okay.  But what you were asking

  13   early on, is a 0.2 --

  14             DR. LAINE:  Right, 0.2 on a scale of 6.

  15             DR. HANAUER:  -- meaningful, not significant.

  16             DR. LAINE:  Or can a patient even discriminate

  17   that.

  18             DR. HANAUER:  I think that is really the question

  19   at hand at the moment that the Agency wants to know, is

  20   whether the therapeutic gains -- we understand where they

  21   were statistically significant -- now, is that 0.2 or

  22   whatever percentage clinically meaningful.

  23             Dr. Wald.  We won't pay attention, but we will

  24   listen.

  25             DR. WALD:  I think if we get away from the

                                                                214

   1   statistics, that what you have is a big dilutional effect. 

   2   You have many patients who are getting better on the

   3   placebo, and then you have other patients who are not

   4   getting better either with placebo or the drug.

   5             Then, you have about 10 percent of these patients

   6   getting better and accounting for the difference, which is

   7   only an average or a mean on those slides.

   8             So, if you took the 10 percent and you took those

   9   averages of 0.2 or 0.3, you could be dealing in those 10

  10   percent with 2 or 3, not 0.2 or 0.3.

  11             So, it seems to me intuitively that for those

  12   patients who did experience relief beyond placebo, that

  13   those are probably clinically significant changes.

  14             DR. HANAUER:  Do you want us to poll the panel on

  15   these questions or no, you have got a sense on this aspect. 

  16   Okay.  Dosage, we are going to come to I think in the main

  17   questions.  I think we are going to hit all of these in the

  18   main questions.

  19             What I would like to do is take a 10-minute break

  20   now and then we will come back and go through the list of

  21   the questions of the Agency.  We will definitely reconvene

  22   exactly at 3:00.

  23             [Break.]

  24                     Discussion and Questions

  25             DR. HANAUER:  Setting a bit of the ground rules

                                                                215

   1   for the questions, you have seen the questions, you should

   2   all take out of the packet, so the committee has the

   3   questions.

   4             The ground rule that we have been asked to do is

   5   to address the questions as they stand.  Now, we understand

   6   the sponsor, Novartis, has written another potential

   7   indication up on the board, which we appreciate their

   8   flexibility, but we are going to go back to what we were

   9   asked to assess from the data that was provided at hand, and

  10   then we can go back at the end of this and talk about

  11   modifying the statement of indication.

  12             Quite specifically, the statement is that Novartis

  13   Pharmaceuticals Corporation has requested approval for

  14   Zelmac (tegaserod) Tablets for the treatment of irritable

  15   bowel syndrome in patients who identify abdominal

  16   pain/discomfort and constipation as their predominant

  17   symptoms.  The sponsor recommends a dose of 6 mg po BID

  18   within 30 minutes prior to a meal.

  19             So, the first question that the committee has been

  20   asked to ponder is:

  21             1.  Has efficacy been demonstrated in both men and

  22   women with constipation-predominant IBS?  If not, in which

  23   gender was efficacy demonstrated?

  24             I think let's just take the issue of men right now

  25   as a simple point.

                                                                216

   1             Any discussion on the issue of whether or not

   2   efficacy has been demonstrated in men?  Any discussion?

   3             [No response.]

   4             DR. HANAUER:  We now go for a vote.

   5             Has this been demonstrated to be effective in men?

   6             Dr. Wolfe.

   7             DR. WOLFE:  No.

   8             DR. HANAUER:  Dr. Smith.

   9             DR. SMITH:  No.

  10             DR. HANAUER:  Dr. Richter.

  11             DR. RICHTER:  No.

  12             DR. HANAUER:  Dr. Buyalos.

  13             DR. BUYALOS:  No.

  14             DR. HANAUER:  Dr. Laine.

  15             DR. LAINE:  No.

  16             DR. HANAUER:  Dr. Ferry.

  17             DR. FERRY:  No.

  18             DR. HANAUER:  No.

  19             DR. SURAWICZ:  No.  Men are different.

  20             DR. WISON:  No.

  21             DR. HAMMES:  No.

  22             DR. HANAUER:  Now for the tough parts.  Okay.  We

  23   are going to limit this then to women for our discussion.

  24             Has efficacy been demonstrated in women with

  25   constipation-predominant IBS?  Then, we will go back to

                                                                217

   1   specifics.

   2             DR. HAMMES:  Yes.

   3             DR. WISON:  Yes, depending on our definition on

   4   efficacy.

   5             DR. SURAWICZ:  Well, I wasn't here in November,

   6   but I read the transcripts, and I understand that that drug

   7   had an efficacy of 10 percent above placebo, and that's the

   8   same here, so I think we have made that decision, and the

   9   answer is yes.

  10             DR. HANAUER:  Yes.

  11             DR. FERRY:  I am going to vote yes, too.

  12             DR. LAINE:  No.

  13             DR. BUYALOS:  No.

  14             DR. RICHTER:  No.

  15             DR. SMITH:  Minimal, yes.

  16             DR. WOLFE:  Equivocally, yes.

  17             DR. HANAUER:  This is not a plurality here.  It is

  18   not necessarily democratic.  This is an advisory committee,

  19   so they take advice as to speaks loudest.

  20             Now, the question is assuming yes, which of the

  21   follow doses have demonstrated efficacy, and the options are

  22   4 mg/day, 12 mg/day, or the titration?

  23             Why don't we just discuss this point.  Michael.

  24             DR. WOLFE:  The way it looks, the data looks, if I

  25   want to say yes, and I did, 12 mg would be the dose.

                                                                218

   1             DR. HANAUER:  Dr. Smith.

   2             DR. SMITH:  12 mg.

   3             DR. RICHTER:  I go with 12 mg.

   4             DR. BUYALOS:  12 mg.

   5             DR. HANAUER:  You can't say anything.  You don't

   6   think it's effective, but I will let you comment, but not

   7   vote.

   8             DR. LAINE:  I think there is minimal dose

   9   response, but certainly in some studies, only 12 mg did make

  10   the primary endpoint, so 12 mg.

  11             DR. FERRY:  I would say 12 mg is the dose to go

  12   with.  I think that was the closest, best response.

  13             DR. HAMMES:  I actually thought that both were

  14   fairly comparable, but I think that since we don't see any

  15   significant dose-related toxicity, I would say it is 4 to

  16   12.

  17             DR. SURAWICZ:  I favor that, as well.  I mean why

  18   use a higher dose if some people, even though it's a small

  19   number, would have response at a smaller dose, and then as a

  20   clinician, you never like to use your whole regimen at the

  21   beginning.  You always like to start with something, and if

  22   it doesn't work, you can increase the dose and see if that

  23   works.  So, as a clinician, I would be much more comfortable

  24   with Option No. 3, titrated dose regimen from 4 to 12.

  25             DR. WISON:  I would say that 4 in the initial dose

                                                                219

   1   trials was an effective dose, and subsequently in the

   2   others, was not different, so I would go with 4.

   3             DR. HAMMES:  If our first duty is to do no harm,

   4   and given the great placebo effect, I would say start with

   5   1, but I would go with the titrated regimen, start with 4. 

   6   Why use 12 if 4 works.

   7             DR. HANAUER:  Do you guys want to follow up any of

   8   these?

   9             DR. WOLFE:  Can we discuss this?

  10             DR. HANAUER:  Sure.  Now you say this.

  11             DR. WOLFE:  I am not sure if I agree with that.  I

  12   understand the point, starting this thing 4 versus 12, but

  13   there are some suggestions that titrating may not work, may

  14   actually cause more problems.

  15             Why not say 12 for a short period of time and then

  16   if you want to try, some studies in the future, so you

  17   maintain your patients at 4, certain patients that need

  18   maintenance therapy, go down, but if you wanted to use the

  19   analogy of patients with reflux disease, we don't use a

  20   lower dose of PPI and then go to a higher one.  We start

  21   with the dose of PPI and then see if we can sometimes go to

  22   a lower one.

  23             DR. HANAUER:  Let me comment for a moment.  We are

  24   not describing clinical practice here and what we should

  25   really be doing as an individual patient.  What we are doing

                                                                220

   1   is making recommendations for dosing, labeling for the

   2   Agency, and how you use the drug will be reflective on your

   3   experience and everything else.

   4             DR. WOLFE:  Then, I will go back to what the data

   5   did show.  The data did show that titration to a higher dose

   6   was the weakest response of all, so I would really question

   7   whether we should really use titration as our parameter for

   8   dosing.

   9             DR. LAINE:  I mean I hate to be data driven on

  10   this committee, but, you know, if we look at their results,

  11   I mean the places where they did achieve response in 301

  12   with relief in abdominal pain was the higher dose, and not

  13   the lower dose.

  14             If we look at their non-pivotal 351 in retrospect,

  15   again, it was 12 mg.  So, it would strike me, although I

  16   agree there is not much of a dose response, the one they

  17   have shown more likely to work is 12.

  18             In addition, the only reason you use the low dose

  19   first is if you have concerns about cost, which we are not

  20   discussing, or safety, which I don't think we have seen any

  21   concerns about at the higher dose, or side effects, which I

  22   don't think we have seen any dose-related effects.

  23             So, although typically, you know, we are taught to

  24   use the lowest dose first, if there is no safety, cost, or

  25   tolerability issue, I am not sure there really is any point

                                                                221

   1   to worry about that.

   2             DR. HAMMES:  My discussion on this I am not

   3   convinced, due to the heterogeneity of the groups, that

   4   there is a difference between 4 and the 12 based on all the

   5   composite data that we have seen.

   6             DR. WOLFE:  I realize men are not very responsive

   7   or sensitive, but is it possible that the dosing for men was

   8   too low?  Men are generally bigger than women, and is it

   9   possible that men were getting too low doses and no response

  10   was seen?  I don't think that is the case, but it is still a

  11   possibility.

  12             DR. HANAUER:  Absolutely a possibility, and one of

  13   our subsequent questions will be to the issues of future

  14   trials, what information needs to be gathered.

  15             DR. HAMMES:  Just a little rebuttal on the dose

  16   ranging study.  The reason, the way I look at it, that they

  17   didn't see significance is because the placebo effect went

  18   up through the course of the study, rather than the fact

  19   that they got less of a response from the drug, it was the

  20   increase in placebo effect.

  21             DR. WOLFE:  One question.  Did they get more of a

  22   response?  I can't remember.  Did it go up?  Did it

  23   significantly go up during the trial, during the dose

  24   escalation, did the response significantly improve from 4 to

  25   12 with the placebo?

                                                                222

   1             DR. LEFKOWITZ:  For the abdominal pain, it

   2   significantly improved; for the SGA of relief, it did not.

   3             DR. HANAUER:  There is a little bit of confusion

   4   from everyone's standpoint of who really does get to vote,

   5   and the guests don't get to vote.  You can vote, but it is

   6   not counted.  So, I am going to ask Tom to recap the vote on

   7   those first things, so we know.

   8             Do you want to go through them?

   9             MR. PEREZ:  On Vote No. 1 regarding efficacy in

  10   men, it was unanimous.  Efficacy in women, there were two

  11   no's, the rest were yes.  What doses demonstrated efficacy: 

  12   4, we had a vote of 1; 12, we had a vote of 4; titrate, 3.

  13             DR. HOUN:  Let's just identify the guests are our

  14   two OB-GYN experts.

  15             DR. HANAUER:  Dr. Smith and Dr. Buyalos.

  16             DR. HOUN:  I guess I want to clarify the vote on

  17   female.  I had thought that initially, there were three no

  18   votes by Dr. Buyalos, Dr. Laine, and Richter.  So, Dr.

  19   Buyalos' vote is not official.

  20             DR. HANAUER:  We won't confuse you anymore.  We

  21   won't let them vote.

  22             Next question.  Comment -- and we will have

  23   discussion before we have a vote -- but comment on the

  24   following findings of the carcinogenicity studies.

  25             First, mucosal hyperplasia and adenocarcinoma of

                                                                223

   1   the small intestine were observed in CD-1 mice at the dose

   2   of 600 mg/kg/day, but not at the 200 or 60 mg/kg/day.

   3             Comments from the committee?

   4             Dr. Wolfe, your comments on that?

   5             DR. WOLFE:  So?  It doesn't bother me.

   6             DR. HANAUER:  That doesn't bother you.  Does it

   7   bother anybody on the committee?

   8             Taken out of any context, my issue and the reason

   9   I asked about colonic hyperplasia, what about patients who

  10   have pre-existing hyperplasia, such as the risk of growth in

  11   polyps?  Do we have any data on follow up of polyps with

  12   this?

  13             DR. WOLFE:  I was actually going to ask a question

  14   about that, too, and that is, any studies regarding

  15   mechanisms, are there any effects, for example, of those

  16   higher doses with cross-reactivity of the receptors

  17   decreasing acid secretion, for example, or decreasing the

  18   release of other peptides, allowing an increase in gastric,

  19   has that been looked at?

  20             DR. HANAUER:  Dr. Camilleri or one of your back-

  21   ups, any comments on what we can expect, is there fallout

  22   from 5-HT4 agonism, partial agonism?  It there peripheral

  23   damage in government terms?  Collateral damage, excuse me.

  24             DR. PFANNKUCHE:  There is no clear evidence at 5-

  25   HT4 except as involved in, let's say, growth factor release,

                                                                224

   1   today, there is no evidence.

   2             DR. HANAUER:  Any evidence of cocarcinogenicity

   3   with anything else?  I know I may be asking an impossible

   4   question.

   5             DR. PFANNKUCHE:  No.  I mean we can also go back

   6   to cisapride that was mentioned previously as a model

   7   compound, which can actually act as a 5-HT4 agonist, those

   8   gastroprokinetic agents like cisapride.  I mean they are in

   9   use, and to my knowledge, it has never been reported.

  10             DR. WOLFE:  Is there any deconjugation?  Any

  11   changes there in the lumen to cause these effects with the

  12   drug?  I can't think of any, it doesn't really bother me,

  13   but I am trying to think of a mechanism why that would be

  14   the case, and I can't think of any.

  15             DR. PFANNKUCHE:  No, not in the context of  5-HT4

  16   except the stimulation.

  17             DR. HANAUER:  So, is this prohibitive according to

  18   anybody on the committee?

  19             [No response.]

  20             DR. HANAUER:  So, we will just say a unanimous no,

  21   it is not an important feature.

  22             The second question is the apparent increase of

  23   incidence of ovarian follicular cysts at 110 weeks of age

  24   was observed in rats, and then we had the reports of

  25   potential ovarian cysts.

                                                                225

   1             What I would like is the two OB-GYN consultants to

   2   comment first and then we will find out whether there is

   3   more of an opinion from the panel.

   4             DR. BUYALOS:  First off, ovarian cysts is a very

   5   generic term.  It really doesn't mean anything to an OB-GYN

   6   per se.  In the course of follicular genesis, cyst

   7   formations form, so there are a number of different studies

   8   in different mice and rat species, if you expose them to

   9   things such as androgens early in their gestation that allow

  10   these multiple nonspecific cystic structures on the ovary.

  11             So, I don't find this troubling in the slightest.

  12             DR. SMITH:  I concur.  I believe that it is a true

  13   finding in the female Wistar rats, but I would never want to

  14   equate the physiology of a female Wistar rat to human

  15   females, and I think that this is just a documented

  16   incidental finding with no clinical relevance, especially in

  17   light of the human data.

  18             DR. HANAUER:  Was the sponsor's spin on the

  19   ovarian cyst team in the clinical trial also adequate for

  20   you?

  21             DR. SMITH:  Absolutely.

  22             DR. BUYALOS:  Yes, it was.

  23             DR. HANAUER:  Is there any dissent or concern from

  24   the other panel members regarding the animal studies or the

  25   human studies with ovarian cysts?

                                                                226

   1             [No response.]

   2             DR. HANAUER:  So, that is a unanimous also.

   3             In the clinical trials, diarrhea was seen in

   4   greater proportion in patients receiving Zelmac.  Comments

   5   regarding this?

   6             DR. WOLFE:  The drug worked.  I would have been

   7   worried if we hadn't seen it.

   8             DR. RICHTER:  Exactly like Michael said, the fact

   9   that you see diarrhea again confirms that this is having a

  10   positive mechanism on motility and peristalsis.

  11             DR. HANAUER:  I think the Agency's context of this

  12   is that was the converse.  With the approval of alosetron,

  13   constipation was the adverse event that was most commonly

  14   seen, and has led to potential serious adverse events.

  15             Within the context of diarrhea, are any additional

  16   warnings or is this diarrhea that might be out of proportion

  17   to something that could be handled on a day-to-day, non-

  18   severe basis?

  19             DR. WOLFE:  Constipation in general, I want to

  20   generalize it, is generally more severe.  A problem could be

  21   much more serious.  Diarrhea, as long as it's self-limited

  22   and you stop the drug and it goes away, it is a terrible

  23   nuisance, but if it's reversible, there is generally no harm

  24   in most cases.

  25             DR. HANAUER:  I don't know.  I think you are

                                                                227

   1   making light of the, quote "diarrhea," but diarrhea is a

   2   huge clinical problem.

   3             DR. WOLFE:  As long as it goes away, as long as it

   4   stops is what I am saying, it stops right away.

   5             DR. HANAUER:  Right.  What you are saying is the

   6   diarrhea that you have heard about related to the clinical

   7   trials is not a severe diarrhea that you are concerned

   8   about.

   9             DR. WOLFE:  Right, yes.

  10             DR. HANAUER:  Joel.

  11             DR. RICHTER:  I would agree, Steve.  I think it

  12   tends to be a mild problem.  It looks like only about 2 to 5

  13   percent of patients are discontinuing the studies because of

  14   it, and apparently it looks like if you stop the medication,

  15   the diarrhea goes away.

  16             DR. HANAUER:  It looked like that alosetron, too,

  17   as far as the patient until marketing when we have seen some

  18   serious events.

  19             Do you feel that what you have heard requires any

  20   postmarketing surveillance regarding the severity of

  21   diarrhea?

  22             DR. LAINE:  Could I just ask, Steve, were there

  23   any hospitalizations for diarrhea among these

  24   discontinuations?

  25             DR. LEFKOWITZ:  There were no serious adverse

                                                                228

   1   events reported for diarrhea.  There was also no electrolyte

   2   problems that the patients ran into due to the diarrhea.

   3             DR. LAINE:  So, no significant dehydration

   4   problem?

   5             DR. LEFKOWITZ:  That is correct.

   6             DR. HANAUER:  By the way, I am not trying to imply

   7   anything.  I am just trying to get everything out early, so

   8   that we don't have to go through this, as they say, do this

   9   again next year.

  10             DR. FERRY:  Can I ask one more?  Were there

  11   patients in the study you had diarrhea that it didn't

  12   resolve, or the ones that didn't drop out, what happened to

  13   the diarrhea?

  14             DR. LEFKOWITZ:  Most of the patients who had

  15   diarrhea in fact stayed in the study.  The dropout rate was

  16   1.6 percent for the tegaserod group, the incidence being 12

  17   percent.  Most patients either stopped the drug and then the

  18   drug was reintroduced and they were able to continue in the

  19   study.

  20             DR. HANAUER:  I just want to hear this again.  No

  21   hospitalizations for diarrhea, no treatment for dehydration?

  22             DR. LEFKOWITZ:  Certainly no electrolyte

  23   abnormalities reported to us, and as far as we know, no

  24   clear-ups of the dehydration.

  25             DR. HANAUER:  Thank you.

                                                                229

   1             DR. FERRY:  I was just going to say that is

   2   important, I mean if we are talking about labeling later on,

   3   with what has happened to alosetron, if we want to be

   4   careful with this, it sounds like most of the patients in

   5   the study did stop the drug temporarily, it wasn't like they

   6   continued it and the diarrhea just went away, so that may be

   7   a consideration that we should address.

   8             DR. LEFKOWITZ:  Yes, 30 percent of the patients

   9   who had diarrhea within the first two weeks missed at least

  10   one dose of the drug.  So, in fact, most patients were able

  11   to continue in the study, and the diarrhea would resolve.

  12             DR. HANAUER:  From the Agency, did we address that

  13   adequately for you guys?  Yes?  Okay.

  14             The next issue relates to the lower abdominal pain

  15   and the laparotomy in a greater proportion of patients

  16   receiving Zelmac.

  17             Any comments from the committee regarding this

  18   issue?  Again, from the OB-GYNees, this is not troublesome

  19   to you?  Anyone find a problem or a comment?

  20             [No response.]

  21             DR. HANAUER:  Agency, Hugo, is there a concern?

  22             DR. GALLO-TORRES:  Some lingering concern about

  23   that in my mind.  How often do you see surgical

  24   interventions in patients with IBS?

  25             DR. HANAUER:  That is difficult, because you have

                                                                230

   1   asked the OB-GYNees, you are going to see the numerator, if

   2   you ask us, we see the denominator.

   3             DR. SMITH:  We are going to see a different

   4   population, but the general rule of thumb in OB-GYN is that

   5   of women who are presenting with abdominal and pelvic pain,

   6   abdominal pelvic pain chronic in recurrence, 40 percent is

   7   due to pelvic disease, 40 percent is gastrointestinal

   8   disorder, such as irritable bowel or chronic constipation. 

   9   A tremendous number of these ladies go through laparoscopic

  10   procedures to diagnose it, only to find large, distended

  11   intestines and colon.  So, the diagnosis of constipation is

  12   made with a perfectly normal pelvis.

  13             Then, there is a bunch of other less common

  14   etiologies for the chronic pelvic pain that can range from

  15   urinary tract to pelvic floor triggers and musculoskeletal

  16   problems, but 40 percent of all abdominal pelvic pain that

  17   we see as OB-GYNs is actually constipation and irritable

  18   bowel.

  19             DR. GALLO-TORRES:  What proportion, more or less,

  20   of those patients have appendicitis?

  21             DR. SMITH:  A small percentage, because that would

  22   be short-term pain.  Very few patient really are presenting

  23   with chronic appendicitis, so, you know, the one lady who

  24   came here had a background of chronic pain, but what was

  25   going on is that she had an acute appendicitis at that time,

                                                                231

   1   unrelated to medicine.  It was just an incidental occurrence

   2   during the study period, and that was also -- was that the

   3   13-year-old?  I am not sure.

   4             DR. GALLO-TORRES:  And a final question related to

   5   this.  How many of those patients have adhesions as a

   6   previous history?

   7             DR. SMITH:  How many of those patients have

   8   adhesions?

   9             DR. GALLO-TORRES:  Yes, adhesions.

  10             DR. SMITH:  I think a fair number of the 40

  11   percent who have pelvic pathology are going to be having

  12   abdominal pelvic adhesions as an explanation for the chronic

  13   pain, but the flip side is that an awful lot of patients

  14   with adhesive disease have absolutely no pain symptoms at

  15   all.

  16             So, it is not a tight correlation at all between

  17   the presence and absence of adhesive disease and the

  18   presence and absence of chronic abdominal pelvic complaints,

  19   but my impression in reviewing the case reports is that I

  20   have no suspicion of a relationship between the medication

  21   and adhesive disease or a propensity towards having a

  22   laparotomy, and think that in some cases, personally, that

  23   it was treatment failure and breaking through of the

  24   medication and worsening of the irritable bowel syndrome

  25   that was the actual stimulus for the surgical intervention.

                                                                232

   1             DR. BUYALOS:  I would agree with that, and in

   2   fact, if you look at the algorithm for pelvic pain in

   3   gynecology, we have typically treated with medical

   4   therapies, oral contraceptives or non-steroidal,

   5   inflammatory type products, but as part of that algorithm, a

   6   diagnostic laparoscopy is frequently employed.

   7             We are seeing a different population than

   8   gastroenterologists obviously, and the second thing is the

   9   histories are very muddy on the case reports that they have,

  10   but a substantial proportion of them were having prior one

  11   to two years beforehand, so I don't find it in the least

  12   concerning from that perspective.

  13             DR. HANAUER:  Thank you.  So, I think you have a

  14   unanimous no conflict from the committee on this.

  15             We are now going to some of the critical

  16   questions, which is, on the basis of your benefit-risk

  17   evaluation, which is going to be key word for tomorrow, do

  18   you recommend that Zelmac be approved for the indication

  19   requested by the sponsor, that I stated above, which is

  20   approval for Zelmac tablets for the treatment of irritable

  21   bowel syndrome in patients who identify abdominal

  22   pain/discomfort and constipation as their predominant

  23   symptoms?

  24             For that indication, do you recommend approval?

  25             DR. WOLFE:  Is there a length of time attached to

                                                                233

   1   that?

   2             DR. HANAUER:  What you saw is what you get.  You

   3   don't have to answer now.  That's a legitimate question, and

   4   there is no length of time assessed on that.

   5             DR. WOLFE:  I mean at least minimally, it should

   6   add in there short term.  At this point, I think that is all

   7   we have seen.  It doesn't say short term from what you just

   8   read.

   9             DR. HANAUER:  By "short term," do you mean three

  10   months, 12 weeks?

  11             DR. WOLFE:  That is what I just asked, but at

  12   least it should say short term.  We will define what short

  13   terms means later on.  I don't think it should be

  14   indefinite.

  15             DR. HANAUER:  This is a comment phase.  You are

  16   not voting on it.

  17             DR. WOLFE:  I think it should be short term, and I

  18   would say 4 to 6 weeks right now is all I would say, because

  19   I think the benefit -- I didn't see the benefit really

  20   getting that much greater as time went on.

  21             DR. LAINE:  I would say you have to go with what

  22   the studies did, and although I didn't vote for it, I mean

  23   if you are going to approve it, you are approving it on the

  24   basis of the studies, so it seems to me you have to say 12

  25   weeks, so you can't say more, you can't say less, it's 12

                                                                234

   1   weeks.

   2             DR. HANAUER:  Do you have to say anything?

   3             DR. HOUN:  Or are you recommending other studies,

   4   the short-term study?

   5             DR. HANAUER:  We will come to that.

   6             DR. LAINE:  My view would be you would say that

   7   because I think nowadays you are trying to be, you know, you

   8   get the indication based on what studies you did, not on

   9   what we kind of assume.  So I would probably -- I don't know

  10   that you want to approve -- if you don't say anything, then,

  11   that means you can use it for years and years, which people

  12   are going to do anyway, but I think it would be reasonable

  13   now, before further studies are done, just to go with what

  14   their trials were, so I would say 12 weeks.

  15             DR. WOLFE:  Is that what we are doing?  We just

  16   took men out, and the study wasn't done to look at women

  17   only, it was done to look at people, and we just took men

  18   out and made it for women only.

  19             So, I think we have the right to look at both the

  20   gender, as well as the length of time.

  21             DR. HANAUER:  Absolutely.  You are here to make

  22   recommendations.

  23             Other comments on this issue?  Joanne.

  24             DR. WISON:  We are somewhat hindered in making

  25   recommendations of duration, because if we knew that

                                                                235

   1   symptoms recurred immediately upon discontinuing the

   2   medication, then, we could make a recommendation for longer

   3   periods up to 12 weeks, but as it stands now, people got

   4   maximal response in shorter periods of time.

   5             So, therefore, I would go with your recommendation

   6   for a shorter duration.

   7             DR. HANAUER:  So, do you have a recommendation

   8   regarding -- Dr. Wolfe said 4 to 6 weeks based on --

   9             DR. WISON:  Looking at some of the data, looking

  10   at what the response has maxed out, and it was somewhere

  11   like 4 to 6 weeks.

  12             DR. HANAUER:  Dr. Wolfe.

  13             I will point out as a clinician, as well as a

  14   chairman here, once you put a duration on it, you are going

  15   to get all sorts of hassles from third-party payers saying

  16   that you have over-extended your duration.

  17             Now, that is not the Agency's concern, but that's

  18   a clinician's concern.

  19             DR. WOLFE:  But the thing is where do you stop? 

  20   You say, well, for 12 weeks, let's go on for 12 years.

  21             DR. HANAUER:  The point is do you want to really

  22   put in a term limit, do you want to have term limits on this

  23   indication?

  24             DR. WOLFE:  There is precedence to that.  I mean

  25   this has been done for other diseases, as well.  I mean

                                                                236

   1   unfortunately, it was done for reflux disease, because it

   2   was treated like peptic ulcer for years and years, but with

   3   the proper studies, we realized that longer term treatment

   4   was necessary.

   5             I don't think we have shown that here yet.  We

   6   haven't seen trials beyond that, and the longer it is

   7   treated, 12 week starts to sound like more of a chronic use

   8   to me.  I don't know.  I arbitrarily said 4 to 6 weeks, it

   9   was arbitrary.

  10             DR. HANAUER:  I would just again in the discussion

  11   phase argue against that.  To me, what we have heard the

  12   likely use is going to be intermittent by the experts, but

  13   if you put a 4 to 6 week term on it, your third parties are

  14   going to stop the treatment if you decide to reinitiate it

  15   or give it longer.

  16             DR. RICHTER:  Steve, I would go with what Loren

  17   was suggesting.  Both he and I voted no on this, but based

  18   on the data, if you were talking about a recommendation --

  19             DR. HANAUER:  Well, you voted no, that it wasn't

  20   effective.  You didn't say to approve it.

  21             DR. RICHTER:  I would give the length of duration

  22   of this as up to 12 weeks, because that is what your data is

  23   showing, and that allows you both options.  You could use it

  24   for a shorter period of time if that's what the patient is

  25   telling you they only need it to, and it also protects you

                                                                237

   1   from the third-party payers who don't want you necessarily

   2   to extend it indefinitely, and we don't have any definite

   3   date on this medication at this point in time.

   4             DR. WOLFE:  Once again, is that our job to worry

   5   about whether third-party payers are paying or not?

   6             DR. HANAUER:  Your job isn't, but I am being --

   7             DR. WOLFE:  I understand, you are being a

   8   clinician, too.  We have the same trouble, getting all these

   9   letters from managed care.

  10             I am thinking of other PI's that say effective

  11   therapy has not been demonstrated beyond a certain period of

  12   time.  Have we demonstrated an effect beyond 4 to 6 weeks?

  13             DR. HANAUER:  Dr. Smith.

  14             DR. SMITH:  Well, I disagree that the common

  15   usage, speculation, of course, is going to be short and

  16   intermittent term.  Patients call into the office.  They

  17   will get a prescription by telephone, and they will refill

  18   it by auxiliary staff in the office.

  19             If what happens in the primary care physician's

  20   office is anywhere similar to what happens in an OB-GYN's

  21   office, who will be prescribing this just as readily, one,

  22   the physicians will not have read the medical literature,

  23   they will go by whatever is being in service by the

  24   representatives from the company, and I would vote very

  25   strongly that it's approved for short-term treatment, and

                                                                238

   1   you don't have to specify short term, and that the efficacy

   2   with prolonged treatment and recurrent treatment is not

   3   proven, and it is up to the company to establish the

   4   efficacy, as Dr. Laine said, with alternate forms of use, to

   5   say that it is okay to use it three times every two years or

   6   for 16 consecutive months, there is no proof, and I think

   7   that the Agency has a responsibility to protect the public

   8   from misinterpretation or embellishment of the true data.

   9             The data itself is relatively weak, to begin with.

  10             DR. FERRY:  I am not too much in favor of limiting

  11   a time period.  I think that complicates things for a lot of

  12   reasons, and I understand the concern about not really

  13   knowing long-term use, but this is a -- I mean it appears to

  14   be a pretty safe drug.

  15             My guess is patients are going to want to use

  16   this, the ones that get some benefit, and I sort of hate to

  17   see it constrained that it only be used for three months.  I

  18   do think there is some real merit in doing some follow-up

  19   studies to find out the true use long term, but I am not in

  20   favor of setting a time limit on it.

  21             DR. HANAUER:  Other comments regarding this?  Yes,

  22   Dick.

  23             DR. HAMMES:  To put on my consumer's

  24   representative hat here, by all accounts, this is a chronic

  25   disease by definition, I guess.  We are looking back 12

                                                                239

   1   months to get them enrolled in it.

   2             We have evidence that it is effective out to 12

   3   weeks.  We don't really know what happens beyond that, but

   4   we do have safety data out a year or more, I believe, and it

   5   is a very safe drug.  So, I don't think we need to put any

   6   limit on it.  We can state that it has been shown to be

   7   effective out to 12 weeks, but I don't think we need to

   8   limit it.

   9             DR. WOLFE:  I really disagree with that.  I think

  10   the most you can say right now is 12 weeks.  Whether you can

  11   go beyond that, studies have to be done to show efficacy

  12   beyond that time period.

  13             This is again, and I hate to use the analogy of

  14   other disorders, but we have the acute phrase treatment and

  15   maintenance phase treatment, and this is a chronic disorder

  16   which is different from other chronic disorders, that this

  17   waxes and wanes much more so than other disorders that are

  18   chronic, and the short-term treatment may be effective in

  19   certain individuals, and they get treated pulse by pulse

  20   therapy instead of by chronic therapy, maintenance therapy.

  21             DR. HANAUER:  Joel.

  22             DR. RICHTER:  I just want to reemphasize what Mike

  23   says.  I mean I don't see how you can extend efficacy data

  24   any longer than the study is.  You can say this medication

  25   is safe for up to a year, but there is no placebo-controlled

                                                                240

   1   efficacy data past the data that we have for 12 weeks, and I

   2   don't think you can make a recommendation past 12 weeks.

   3             DR. HANAUER:  We have time for labeling

   4   modifications, but the first question is, "On the basis of

   5   the benefit-risk, do you recommend that Zelmac be approved

   6   for the treatment of irritable bowel syndrome in patients

   7   who identify abdominal pain/discomfort and constipation as

   8   their predominant symptoms?"

   9             Dr. Wolfe.

  10             DR. WOLFE:  Yes.

  11             DR. HANAUER:  No, you don't.  You want it in

  12   females.

  13             DR. WOLFE:  Yes.

  14             DR. RICHTER:  No.

  15             DR. HANAUER:  Dr. Laine.

  16             DR. LAINE:  No.

  17             DR. FERRY:  Well, if we throw females in, yes.  I

  18   wouldn't do it this way.

  19             DR. HANAUER:  So, do it this way, and then you can

  20   modify it.

  21             DR. FERRY:  So, it's no.

  22             DR. SURAWICZ:  I think I am missing what the

  23   controversy is here.

  24             DR. HANAUER:  Well, the controversy is the

  25   semantics of the labeling as is written up there.  There is

                                                                241

   1   other subtleties --

   2             DR. WOLFE:  If it's all people, I would think it

   3   was no.

   4             DR. HANAUER:  Would you agree with the labeling of

   5   Zelmac Tablets for the treatment of irritable bowel syndrome

   6   in patients who identify abdominal pain/discomfort and

   7   constipation as their predominant symptoms?

   8             DR. SURAWICZ:  Well, we have already talked about

   9   its lack of efficacy in men, so is that -- are we rehashing

  10   this again?

  11             DR. HANAUER:  No, we are voting.

  12             DR. SURAWICZ:  We are voting to approve or not

  13   approve?  I vote to approve.

  14             DR. WISON:  I vote no.

  15             DR. HANAUER:  No.

  16             DR. WOLFE:  Steve, I will have to change my vote

  17   because I thought we were talking about women only.

  18             DR. HANAUER:  That is why I interrupted you.

  19             DR. WOLFE:  I say no.

  20             DR. HANAUER:  Okay.

  21             DR. SURAWICZ:  But we already talked about that.

  22             DR. HANAUER:  Yes, but now this is a vote.

  23             DR. SURAWICZ:  But we voted before.

  24             DR. HANAUER:  No, you voted whether you thought it

  25   was effective.

                                                                242

   1             DR. SURAWICZ:  And we were unanimous that it

   2   wasn't effective in men.

   3             DR. HANAUER:  Right, but we are sticking with that

   4   label, because we were asked to stick to it.  Now, you can

   5   modify it if you would like.

   6             DR. SURAWICZ:  Great.  Let's modify it.

   7             DR. HANAUER:  How would you like to modify it, Dr.

   8   Surawicz?

   9             DR. SURAWICZ:  For use in women.

  10             DR. HANAUER:  Any other comments on the labeling

  11   modification?

  12             DR. WOLFE:  Again, I think we have to come up with

  13   a time limit, and maximally 12 except things say short term

  14   in parentheses, as a compromise, 6 to 12 weeks.

  15             DR. LAINE:  I like up to 12, the way Joel said it,

  16   even if I voted no.

  17             DR. HANAUER:  Any other comments regarding the

  18   labeling before we come back to some of these individual

  19   amendments?  I particularly have one, and that is, I am

  20   uncomfortable with the discussion of with the labeling that

  21   says, "For treatment of irritable bowel syndrome in patients

  22   who identify abdominal pain/discomfort."

  23             My view is that the labeling should read, "For the

  24   treatment of abdominal pain and constipation in patients

  25   with irritable bowel syndrome."  To me, that is a more

                                                                243

   1   sensible labeling because you are treating symptoms and it

   2   is not treating a long-term disease.

   3             That is what we have looked at, that is what the

   4   sponsor looked at.

   5             DR. WOLFE:  You may avoid, by doing what you are

   6   saying, you may actually avoid people just saying, well,

   7   here is another new drug, and we just go ahead and use it

   8   for IBS, and not pay attention that there is a difference of

   9   IBS.

  10             DR. HANAUER:  That is why I said it that way.

  11             DR. WOLFE:  I think you are right.  It's

  12   commendable.

  13             DR. SURAWICZ:  The only concern I have with that

  14   is that if people don't read the entire sentence, and they

  15   are treating any abdominal pain and constipation with this

  16   drug, then, it is going to be a disaster.

  17             DR. WOLFE:  I don't know if it's going to be a

  18   disaster or not.

  19             DR. SURAWICZ:  Well, yeah, because you are going

  20   to be treating colon cancer and bowel obstruction, and all

  21   kinds of stuff that causes abdominal pain.

  22             DR. HANAUER:  My approach also separates it from

  23   the other drug, which is the treatment of irritable bowel

  24   syndrome in patients with diarrhea-predominant.  Here, you

  25   know, IBS is IBS, whatever.  I think that you are really

                                                                244

   1   treating the symptoms of abdominal pain and constipation in

   2   patients with irritable bowel rather than treating irritable

   3   bowel syndrome in general.

   4             DR. BUYALOS:  Steve, is this a common phenomenon? 

   5   What other chronic condition is a medication approved, which

   6   is gender specific?  I am not familiar with that.

   7             DR. HANAUER:  Birth control.

   8             DR. BUYALOS:  I am talking about a chronic

   9   condition which affects both sexes.

  10             DR. HANAUER:  According to the sponsors and

  11   others, there is a gender difference in the affectation, in

  12   the incidence.  As a matter of fact, alosetron, which is the

  13   other drug that was approved for diarrhea-predominant, was

  14   also only effective in women.

  15             DR. BUYALOS:  Maybe that was a power phenomenon

  16   also with the number of subjects in the study.

  17             DR. HANAUER:  Well, women have power, but that

  18   didn't seem to be the issue seriously.

  19             The next question is what labeling recommendations

  20   -- we are in the process of addressing this, and I guess we

  21   should take different aspects of it.  I presume everyone on

  22   the panel -- and I don't mean to vote for them -- agrees

  23   that this should be limited to women, right?  So, the

  24   indication should have females in it.  Any dissent regarding

  25   that?

                                                                245

   1             [No response.]

   2             DR. HANAUER:  Unanimous that the labeling should

   3   discuss women.

   4             I will just take them in order that they were

   5   brought up.  The second is the term limits.  Do you want to

   6   make a statement of proposal?  Was your proposal short-term

   7   treatment?

   8             DR. WOLFE:  Short term use.  It should say short

   9   term and then in parentheses take a week number.  Again,

  10   there is going to be some arguments here, but I agree with

  11   Loren and with Joel, that it should really say up to 12

  12   weeks, but looking at the data, I didn't see much effect

  13   over 6 weeks, but I don't have any objection to 12 weeks.

  14             DR. HANAUER:  Well, make a proposal then.

  15             DR. WOLFE:  Short term parentheses up to 12 weeks.

  16             DR. LAINE:  I agree.

  17             DR. HANAUER:  Loren has agreed already.  George,

  18   comments?

  19             DR. FERRY:  I am still wondering what -- what does

  20   that mean actually?  That means that a doctor prescribing

  21   this cannot -- I mean should not refill it after three --

  22             DR. LAINE:  No, because we don't set clinical

  23   practice.  All it means is that like a representative can't

  24   perhaps go to the doctor and tell them that they should use

  25   it beyond 12 weeks.

                                                                246

   1             DR. FERRY:  How will it read?  How does this

   2   translate into what would actually be written down?  You

   3   should stop this drug at 3 months, you should not use it

   4   longer than 3 months?

   5             DR. RICHTER:  It would be no different than -- I

   6   just cannot conceive of giving an indication for a drug

   7   longer than you have the efficacy data and the study, and if

   8   you want to say, well, the issues are chronic disease, this

   9   is no more of a chronic disease than reflux disease.  So,

  10   when the PPI's come out of the H2 blockers, we gave those

  11   drugs for 3 months, then, we would stop those, and then when

  12   the patient's symptoms relapsed, we would start them back

  13   until we had the maintenance data from the companies, and

  14   then we do maintenance therapy now.

  15             DR. WOLFE:  We actually started using it long term

  16   before that.  We had studies in the literature showing long-

  17   term effects, but here we don't have any studies, and we

  18   have nothing in the literature suggesting this drug works

  19   longer.

  20             Again, what people do in practice is their

  21   business, but we don't have data beyond that.

  22             DR. HANAUER:  Other comments?  Yes, Dick.

  23             DR. HAMMES:  I still think by putting a limit on

  24   it, clearly, you are going to be making this unavailable via

  25   third-party payers, HMOs, or what have you, for people that

                                                                247

   1   need it after 3 months, and I don't think there is any data

   2   to suggest that it was not effective after 3 months, and I

   3   really don't see any kind of data that indicates that we

   4   should be proactive and put that kind of limit on it,

   5   considering the effect that it is going to have on people

   6   that may need it.

   7             DR. HANAUER:  Of the voting members, how many feel

   8   -- just raise your hand if you feel there should be a short

   9   term up to 12 week information on it?

  10             [Show of hands.]  Six.

  11             DR. HANAUER:  Opposed to that?

  12             [Show of hands.]  Two.

  13             DR. HANAUER:  Two.  And the opposition states no

  14   limit, no term limit, or you want to make a proposal or just

  15   a comment?

  16             DR. HAMMES:  I don't think it needs to be

  17   mentioned in the labeling.

  18             DR. HANAUER:  Timing need to be mentioned,

  19   Christina?

  20             DR. SURAWICZ:  No.

  21             DR. HANAUER:  The third aspect of the labeling was

  22   my notion of a label for the short-term treatment of

  23   abdominal pain/discomfort and constipation secondary to

  24   irritable bowel syndrome.

  25             Additional comments regarding that?

                                                                248

   1             DR. LAINE:  Could we have the alosetron label read

   2   to us perhaps?  In other words, how was it written in terms

   3   of diarrhea-predominant?  I mean we could perhaps use that

   4   as a precedent.

   5             DR. HANAUER:  I don't need if you need a precedent

   6   or a fix.

   7             DR. WOLFE:  Steve, can you say constipation,

   8   abdominal pain type irritable bowel syndrome, because

   9   secondary to is -- associated with --

  10             DR. HANAUER:  I don't want to say type because I

  11   don't think that they have shown that it is really effective

  12   in -- that they can effectively type it is the problem.

  13             DR. WOLFE:  It is important, though, they are

  14   going to start using it in people who have an obstruction,

  15   an obstructing lesion of some sort without really --

  16             DR. HANAUER:  Contributed to irritable bowel

  17   syndrome.  You don't have to accept it, you can oppose it.

  18             DR. WOLFE:  I like the idea, but I think we need

  19   some careful terminology here.

  20             DR. HANAUER:  So, the Agency will think through

  21   that terminology of how you want to modify it.  I think you

  22   get a sense that there are different ways of saying this

  23   that may impact upon the usage and miss-usage.

  24             Aside from the short term that Dr. Wolfe has

  25   already imposed, are there any other labeling

                                                                249

   1   recommendations to reduce the potential risks of Zelmac, the

   2   potential risks being diarrhea, right?  Is it necessary to

   3   black box diarrhea?

   4             DR. WOLFE:  List that as a side effect.

   5             DR. HANAUER:  As a side effect or a

   6   contraindication?

   7             DR. WOLFE:  Well, it's a contraindication and side

   8   effect.

   9             DR. LAINE:  I think it would be reasonable to,

  10   because of the constipation issue, with alosetron to be

  11   reasonable, not to black box it, but just to mention that

  12   patients with predominant diarrhea or with -- you know, we

  13   have to figure out the wording -- but who have diarrhea a

  14   significant portion of the time should not receive this

  15   medication, or something along those lines perhaps, at least

  16   now until we get further information.

  17             DR. HANAUER:  Or that diarrhea is the most common

  18   side effect.  As a precaution?  Tom wants to know.  You guys

  19   can figure that one out, that is pretty straightforward.

  20             Now, I think these are the really important

  21   aspects now.  Dr. Houn, do you still care if operations are

  22   necessary, what proportion is acceptable?  The committee

  23   really doesn't predict that that is going to be a problem.

  24             DR. HOUN:  Do you think there should be

  25   surveillance on that?

                                                                250

   1             DR. HANAUER:  Does the committee think that there

   2   should be surveillance regarding specifically the risks for

   3   operations in patients, exploratory surgery?

   4             DR. WOLFE:  Any question that came up should be

   5   watched carefully as far as I am concerned.

   6             DR. HANAUER:  Okay.  If you should watch it, how

   7   should they watch it?  Does this require a case controlled

   8   study?  I think you heard from the OB-GYNees, and we know in

   9   our practice, that oftentimes women with abdominal pain

  10   associated with irritable bowel or whatever end up going to

  11   laparoscopy as a diagnostic maneuver, and if they are going

  12   to separate this as an issue of the background population of

  13   this group of people, is there a way that they should do

  14   that?

  15             DR. WOLFE:  There are postmarketing surveillance

  16   studies to do postmarketing surveillance.

  17             DR. HANAUER:  What study?

  18             DR. WOLFE:  Long term on patients on this drug

  19   open label.  There are several studies that I could see

  20   being done in the future, and that is one of them, do an

  21   open label study, follow patients out, you know, follow

  22   patients who have been taking it out for a certain period of

  23   time.

  24             DR. HANAUER:  How would you ascertain then if

  25   whatever proportion of patients go through surgery is an

                                                                251

   1   increased risk?  These are the kind of things that they want

   2   to know, right?  Aren't I getting to your points here?

   3             DR. HOUN:  Appropriate control group.

   4             DR. HANAUER:  What would be an appropriate

   5   control?

   6             DR. WOLFE:  People treated by other means, people

   7   treated with fiber only, people treated "in traditional

   8   ways."  It can't be a double-blind, obviously, it can't be

   9   double-blind.  It has to be a surveillance study of some

  10   sort in which people are relying on reports or else relying

  11   on -- I don't know.

  12             DR. RICHTER:  I think you are going to have to do

  13   some maintenance studies with this medication versus

  14   placebo, probably with the same study design that we use in

  15   ulcer disease or GERD.  Get a group of people that have had

  16   a good response to the medication, and then at that point in

  17   time, over a year's period, randomize them to either

  18   maintenance medication or placebo unknown, and follow that

  19   group out for efficacy over a year, and also look at some of

  20   these other side effects because based on what we know, if

  21   you are going to use the weaker endpoint of some relief, you

  22   are going to have 40 or 50 percent of your patients staying

  23   in the study on placebo.

  24             That will give you a pretty good idea then, over a

  25   year's period of time, as a control population for the

                                                                252

   1   issues that are coming up.

   2             DR. HANAUER:  So, a maintenance trial for patients

   3   who have responded.

   4             DR. RICHTER:  Right, yes.

   5             DR. WOLFE:  I would stress, though, if we are

   6   going to use 12 mg as the dose, maintenance studies should

   7   be done at lower doses, as well, to see if a lower dose can

   8   maintain the patients once --

   9             DR. HANAUER:  So your concept is a dose ranging

  10   maintenance trial.

  11             DR. WOLFE:  Yes.

  12             DR. HANAUER:  Loren, any comments?

  13             DR. LAINE:  I agree with the idea of the long-term

  14   maintenance trial for killing two birds with one stone. 

  15   Personally, if we do approve just 12 mg, would be happy just

  16   to have it 12 mg, so I don't think I see any reason to

  17   complicate things by going down to 4 mg maintenance.

  18             DR. HANAUER:  Comments on this end?

  19             DR. WISON:  The lowest maintenance dose possible

  20   would certainly -- since we will be dealing with young

  21   women, I would favor looking at the lowest possible doses.

  22             DR. HANAUER:  Other comments?  Dr. Ferry, would

  23   like to try it on children?

  24             DR. FERRY:  I am so glad you brought that up. 

  25   Thank you very much.  As a matter of fact, there are some

                                                                253

   1   issues in children that this drug might be very important

   2   for.  I think there is still some confusion in children

   3   whether younger children actually have irritable bowel

   4   syndrome, but there are some very close similarities with

   5   chronic recurrent abdominal pain, which is often accompanied

   6   by mild constipation.

   7             I think there are some very clear-cut indications

   8   to study this in children, because I think there is going to

   9   be a great interest in pediatric GI people finding some

  10   solution to a disorder we have absolutely no treatment for

  11   at all, that is very chronic and disabling in terms of time

  12   lost from school.

  13             So, yes, I think pediatric studies, and I am

  14   thinking of the age between 5 and 12, not adolescents so

  15   much, but the younger children.

  16             DR. HANAUER:  From the pharmacokinetic and

  17   pharmacodynamic data that you have seen, do you think

  18   additional dose ranging studies are going to be necessary in

  19   kids?

  20             DR. FERRY:  I think they probably are.  For one

  21   thing, just looking at the data presented for men, where the

  22   drug doesn't work, but the weights are considerably higher,

  23   so I think figuring out a weight/kg dose for children is

  24   going to be important, so, yes, there are going to have to

  25   be some dose ranging studies in children and

                                                                254

   1   pharmacokinetics to prove just what really works, and also

   2   in a younger age group, the question is going to come up

   3   about the type of vehicle to deliver this drug, as well,

   4   whether it can be crushed, mixed in syrup, just whatever, so

   5   there are other important issues about how to deliver it.

   6             DR. HANAUER:  Do you think there might be gender

   7   differences in children as there are in adults?

   8             DR. FERRY:  I have no idea, although I will tell

   9   you, chronic abdominal pain is more common in girls in our

  10   practice than it is in boys.

  11             DR. HANAUER:  So, you would try to get an adequate

  12   sample size of both genders?

  13             DR. FERRY:  I would, yes.

  14             DR. WOLFE:  The prepubertal, too?  Do you see the

  15   same thing?

  16             DR. FERRY:  With recurrent abdominal pain?

  17             DR. WOLFE:  Yes.

  18             DR. FERRY:  Yes, it is prepubertal, and

  19   adolescents tend to have a pretty, in my experience, typical

  20   adult pattern irritable bowel syndrome.  Under age 12, this

  21   recurrent chronic abdominal pain has never responded to any

  22   of the medications that adults have used traditionally

  23   without any proof of efficacy.  They don't respond to fiber,

  24   they don't respond to anticholinergics.

  25             Our postulated mechanism is that there is a

                                                                255

   1   heightened sensory reception in the pain fibers from the

   2   autonomic nervous system and from the gut to do this, which

   3   maybe makes this drug an even better drug for children.

   4             DR. WOLFE:  Would there be any reason to do some

   5   studies again men, using even higher doses, to see if men do

   6   require a higher dose?

   7             DR. HANAUER:  Do you think so?

   8             DR. WOLFE:  I think it would be worth a try. 

   9   Again, the problem when we had that low a response rate and

  10   took that many that will show it, it is going to take more

  11   men to show it, and I think possibly higher doses.

  12             DR. HANAUER:  Let's ask Dr. Camilleri that, get

  13   him back into this.  One issue is are we dosing high enough

  14   in men, does the peristaltic activity that has been

  15   demonstrated in the clinical studies, the nonclinical

  16   trials, is that the same in men as it is in women, or is

  17   there a gender difference regarding that?

  18             DR. CAMILLERI:  Regrettably, the sample size in

  19   those mechanistic or pharmacodynamic studies is too small to

  20   really tell, but I think the point raised by Dr. Wolfe is a

  21   very relevant one, as is the point by Dr. Ferry, that dose

  22   responsiveness is almost as important as adequate sample

  23   size in this case.

  24             DR. HANAUER:  Other comments?  Michael.

  25             DR. WOLFE:  As long as Dr. Camilleri is up here,

                                                                256

   1   is it worthwhile to get more convincing data?  It is not

   2   going to make a difference in approval, but I would like to

   3   see really a cross-over design study to see again, just to

   4   add more information, although we may have it with the

   5   maintenance study, if we place certain people on drug, put

   6   them on placebo, and see what happens to them.  That may

   7   answer the question and again kill two birds with one stone.

   8             DR. HANAUER:  That would also be addressed in the

   9   maintenance trial where patients are re-randomized, and you

  10   would see whether or not there is a "rebound" effect.

  11             From additional studies, I would also recommend

  12   that the sponsor be a PRN versus a continuous use.  My sense

  13   is that the majority of the physicians, the consultants are

  14   looking to use this for intermittent symptoms and allow

  15   patients to use it intermittently and assess the quality of

  16   life compared to those who are getting a placebo .

  17             I think that would address the questions, many of

  18   the questions that we have asked.

  19             DR. WOLFE:  Is our charge also to make

  20   recommendations regarding, not advertising, but how the drug

  21   is promoted, because I don't think we should think give the

  22   impression to anybody that this is a replacement for fiber,

  23   for example.  This is adjunctive therapy to people taking

  24   fiber.

  25             DR. HANAUER:  That certainly is an important point

                                                                257

   1   since the patients in the clinical trials were treated, were

   2   continued on their fiber therapy.

   3             Do you want to comment on that Lilia?

   4             DR. TALARICO:  In a way, yes, it would be an

   5   adjunctive therapy to whatever the other treatment for IBS,

   6   but I have another question.  The modification in the

   7   labeling, mention was made for the use of this drug for

   8   current symptoms of pain and constipation rather than the

   9   pattern.

  10             This would change the indication in the sense that

  11   it would limit to the time when the patient is actually

  12   experiencing the constipation.

  13             DR. HANAUER:  Right.

  14             DR. TALARICO:  What is the committee's suggestion?

  15             DR. HANAUER:  I think we agree with that.  Again,

  16   one of the issues is we don't want to see patients continued

  17   on this necessarily through diarrhea, because that doesn't

  18   make sense.

  19             DR. TALARICO:  The discontinuation when the

  20   symptoms subside is one thing, but the initiation of the

  21   treatment only when currently, the patient is experiencing

  22   pain and constipation rather than the patient having IBS

  23   with the pattern or predominantly by pain and constipation.

  24             DR. HANAUER:  I think the bottom line is -- and I

  25   don't want to speak as a whole -- but my interpretation of

                                                                258

   1   the data is that part of the reason that we see such a

   2   modest benefit is that it is a very heterogeneous group, and

   3   a lot of these people who are entered in the trials were

   4   what we would consider alternators rather than constipated

   5   patients.  I see the most important benefit in the patients

   6   really who were constipation-predominant, which is not the

   7   patients who swing from diarrhea to constipation, who I can

   8   envision being one week getting Zelmac, the next week

   9   getting another drug.

  10             DR. TALARICO:  But again, when should the patient

  11   start the treatment or limit the treatment if the patient is

  12   diagnosed with IBS, predominant, characterized by pain and

  13   constipation, can faster treatment just based on the

  14   diagnosis and the pattern of the IBS or just because --

  15             DR. HANAUER:  I think that is an excellent

  16   question and let me try and rephrase louder, so the

  17   committee can hear this.

  18             You are trying to ask can you really treat IBS

  19   consistently based upon a historical pattern.

  20             DR. TALARICO:  Exactly.

  21             DR. SURAWICZ:  I thought you were asking can you

  22   treat acutely or maintenance.

  23             DR. TALARICO:  Well, either way, when should the

  24   patient receive this if we limited the administration of the

  25   drug to 12 weeks because the trials were done with 12 weeks,

                                                                259

   1   if we allow the patient to stop the medication when the

   2   symptoms have subsided, when should the patient start the

   3   treatment?

   4             DR. SURAWICZ:  I would go back to what I learned

   5   when I was a student on Surgery from our chief of Surgery,

   6   that you can't make an asymptomatic patient feel better, so

   7   I would opt for treating when there are symptoms, and not

   8   treating when they are asymptomatic.

   9             DR. HANAUER:  Unless you do demonstrate a

  10   maintenance benefit, until you demonstrate a maintenance

  11   benefit.

  12             Joel.

  13             DR. RICHTER:  I like the last ramification that

  14   the company gave us, where they emphasize IBS patients who

  15   currently have a problem with constipation.  I think that is

  16   the group we are talking about at least initiating this

  17   therapy for whatever period of time one wants to use it.

  18             DR. TALARICO:  That was the point

  19             DR. WOLFE:  As long as you are talking about other

  20   studies and what would help, I think, the company and help

  21   all of us are outcomes and cost analyses to show that

  22   treatment does not only make the patient feel better, which

  23   is very, very important, but also, as was shown in the very

  24   beginning, decreases days lost from work, increases

  25   productivity, and decreases all the indirect costs

                                                                260

   1   associated with this disease.

   2             DR. HANAUER:  Yes, I was intrigued by the company

   3   saying that this was a $12 billion disease.  My sense is

   4   that if this is improved, it is not going to be an $11

   5   billion disease.

   6             DR. RICHTER:  I mean I would emphasize the same

   7   thing that Mike did.  I really think these maintenance

   8   studies are going to be important because it allows you to

   9   look at a couple of things, and critical in the maintenance

  10   studies is going to be the use of some quality of life

  11   indicators to really see how these people are doing, and

  12   also attempt to do some type of a cost analysis data based

  13   on recurrent visits to physicians and studies being done.

  14             DR. HANAUER:  I agree.

  15             DR. HOUN:  Let me just summarize that the original

  16   Novartis proposal for it to be approved for IBS in patients

  17   who identify abdominal pain/discomfort and constipation as

  18   their predominant symptoms, I believe the vote was -- I have

  19   7 no and 1 yes, is that correct?

  20             However, in discussion of labeling, is it the

  21   committee's sense that should the indication change --

  22             [Electronic interference.]

  23             DR. HOUN:  [Continuing] -- for people who

  24   currently have these symptoms, that with those kinds of

  25   changes, the committee is favorable for that indication?

                                                                261

   1             DR. HANAUER:  Any dissents to that?  Yes.

   2             DR. LAINE:  I mean we have a dissent about the

   3   efficacy, but assuming it's being approved, I would agree

   4   with that, but the only thing I would want to make sure in

   5   that wording --

   6             DR. HANAUER:  Wait.  You are the dissent.  Given

   7   those stipulations --

   8             DR. LAINE:  I think it didn't change on my

   9   original vote, but given the fact that it is going ahead --

  10             DR. HOUN:  No, no, no.  I think if you still feel

  11   that the benefit-risk ratio is unfavorable, because efficacy

  12   wasn't demonstrated, you should state that.  I am just

  13   saying for those of you who felt the benefit-risk ratio is

  14   favorable, those are the kind of changes you folks are

  15   interested in.

  16             DR. LAINE:  Two comments.  One, I mean I didn't

  17   change my efficacy vote, but the one point I would make, and

  18   that is I would just want to make sure that constipation has

  19   to go along with abdominal pain/discomfort.

  20             I mean just the way you read it, I wouldn't want

  21   people to think they could use abdominal pain/discomfort or

  22   constipation.  I mean it's really people who have abdominal

  23   pain/discomfort and also have constipation.  So, I would

  24   just want that to be very clear in any labeling.

  25             DR. HANAUER:  Dr. Smith.

                                                                262

   1             DR. SMITH:  In the studies presented, all three of

   2   them, the mean age of the female patients was 43 to 45 years

   3   of age, which is really past the child-bearing age, but as

   4   you extend the utility of this agent, and it becomes

   5   available especially to OB-GYN physicians treating generally

   6   a younger age group, you are going to have the issue of

   7   pregnancy while taking the medicine become more important.

   8             There was only a handful of pregnancies out of

   9   2,000 patients, about 20 pregnancies perhaps, but as the age

  10   wear, and these ladies all had an average duration of the

  11   disease of 13 or 15 years, so you are going to see it being

  12   used in women in their late twenties and thirties, who are

  13   clearly of child-bearing potential, and that is going to be

  14   an issue that everyone is going to have to consider.

  15             DR. HOUN:  So, are you recommending a pregnancy

  16   registry?

  17             DR. SMITH:  I would think so, just as you have one

  18   for Prozac, the initial data showing that it was increasing

  19   the risk of miscarriage, and subsequent data showing no real

  20   increase.

  21             DR. HOUN:  Just a final issue was if the drug

  22   should be approved and the labeling was revised, there was

  23   some discussion and dissent in terms of should it be short

  24   term versus no statement of term, and that is how I think

  25   the committee --

                                                                263

   1             DR. RICHTER:  Didn't we vote on that issue,

   2   though, wasn't that issue 5 to 2 or 6 to 3?

   3             DR. HOUN:  Six to 2.

   4             DR. HANAUER:  Any other questions?  I think we

   5   have been through your list.  Anything else from the Agency

   6   that you would like to clarify from the committee, use us? 

   7   Use us or lose us.

   8             DR. FERRY:  One other question I had that I don't

   9   think we addressed, but I was just wondering if we should

  10   consider making a suggestion in the labeling about if

  11   diarrhea does occur with this drug, that the drug be

  12   temporarily stopped.

  13             DR. HANAUER:  Makes sense.

  14             Other comments?  Joel.

  15             DR. RICHTER:  Are we going to do part (b) of 5?

  16             DR. HANAUER:  I assume we had done it because we

  17   modified the thing, but go ahead.

  18             DR. HOUN:  I think the people who voted no should

  19   suggest studies that would increase their confidence for

  20   efficacy.

  21             DR. RICHTER:  I mean I would like to see a single

  22   U.S. study, because this drug, we are the FDA or we are

  23   making advice to the FDA for the United States, a single

  24   U.S. study which shows efficacy without having to do a post-

  25   hoc analysis, and I personally think that should be done

                                                                264

   1   with 12 mg, the higher dose, give you the best chance, and

   2   also use both a general assessment of pain, as well as a

   3   pain-specific score for your two primary efficacy points.

   4             I am very bothered that we are talking about -- I

   5   am very sympathetic to a group that don't have any drugs

   6   available to them -- but when you are talking about an

   7   efficacy in the individual patient of only 1 to 8, to 1 to

   8   15 women being helped, I would like to at least be able to

   9   say that there is a U.S. study done properly that shows

  10   this, and that would be combined with the European data to

  11   show that there is really true efficacy in the U.S.

  12   population.

  13             DR. LAINE:  I would concur obviously.  I also felt

  14   that I wasn't convinced by the data as presented, and I

  15   would have liked to have seen one pivotal trial in the U.S.

  16   that really did document efficacy.

  17             As I said, there was really only one trial that

  18   documented -- there was only one pivotal trial of 12 mg, and

  19   it did document efficacy in Europe, but not here.  So, I

  20   would concur.

  21             DR. HAMMES:  Along those lines, I would really

  22   like to see a cross-over design, they are their own

  23   controls, try to get is placebo effect out of the way.

  24             DR. RICHTER:  I mean the literature -- and Michael

  25   and Arnie can comment about it, too -- the literature in

                                                                265

   1   pain has been these cross-over designs never work, because

   2   they result in an adjustment of your pain scores.  You never

   3   know how long of a washout period to have.

   4             I think the best way to get at this long-term

   5   placebo response really is a maintenance, you know, trial,

   6   and then see what happens, but in the pain literature, they

   7   really try to stay away from these cross-over studies as

   8   much as they possibly can.

   9             DR. HANAUER:  With that, I would like to thank

  10   Novartis for an outstanding presentation and preparation and

  11   being able to address all the committee's questions.

  12             We will adjourn until 8:30 tomorrow morning.

  13             [Whereupon, at 4:12 p.m., the proceedings were

  14   recessed to be resumed at 8:30 a.m., Tuesday, June 27,

  15   2000.]