1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

              GASTROINTESTINAL DRUGS ADVISORY SUBCOMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                        Wednesday, July 14, 2004

 

                               8:30 a.m.

 

 

 

                          ACS Conference Room

                               Room 1066

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                              PARTICIPANTS

 

         Ronald P. Fogel, M.D., Acting Chair

         Thomas H. Perez, M.P.H., R.Ph.,

            Executive Secretary

 

         MEMBERS:

 

         Alan Lewis Buchman, M.D.

         Byron Cryer, M.D.

         Alexander H. Krist, M.D.

         John T. LaMont, M.D.

         Robert A. Levine, M.D.

         David C. Metz, M.D.

         Weichung Joe Shih, Ph.D.

         David B. Sachar, M.D.

         Jose M. Vega, M.D., Industry Representative

 

         DRUG SAFETY AND RISK MANAGEMENT

         ADVISORY COMMITTEE (Voting):

 

         Brian L. Strom, M.D., M.P.H.

         Curt D. Furberg, M.D., Ph.D.

         Arthur A. Levin, M.P.H., Consumer Representative

 

         CONSULTANTS (Voting):

 

         Ralph D'Agostino, Ph.D.

         Allen Mangel, M.D., Ph.D.

 

         FEDERAL EMPLOYEE (Voting):

 

         Maria H. Sjogren, M.D.

 

         FDA STAFF:

 

         Robert Justice, M.D., Director, Division

            of Gastrointestinal and Coagulation

            Drug Products

         Robert Prizont, M.D., Medical Officer

         Garry Della'Zanna, D.O., M.Sc., Medical Officer

         Julie Beitz, M.D., Deputy Director, ODE III

                                                                 3

 

                            C O N T E N T S

 

      Call to Order, Introductions, Ronald Fogel, M.D.,          5

 

      Meeting Statement, Thomas H. Perez, M.P.H.                 8

 

      Opening Comments, Robert Justice, M.D., Director,

         Division Gastrointestinal and Coagulation Drug

         Products                                               11

 

      Novartis Presentation, Zelnorm, NDA 21-200:

 

      Introduction, John R. Cutt, Ph.D., Novartis

         Executive Director Global Head GI, Drug

         Regulatory Affairs                                     14

 

      Chronic Constipation: An Unresolved Problem for

         Many Patients, Charlene M. Prather, M.D., St.

         Louis University School of Medicine                    20

 

      Zelnorm: Efficacy and Safety in Chronic

         Constipation,

      Eslie Dennis, M.D., Novartis Senior Medical

         Director, GI Clinical Develop and Medical

         Affairs                                                40

 

      Zelnorm: Safety Overview, Bo Joelsson, M.D.,

         Novartis Senior Medical Director, Clinical R&D         69

 

      Fatality Cases, Michael Shetzline, M.D., Ph.D.,

         Novartis Senior Medical Director, U.S. Clinical

         Development and Medical Affairs                        82

 

      Zelnorm: Safety Overview (continued),

         Bo Joelsson, M.D.                                      92

 

      Benefit/Risk Assessment, Philip Schoenfeld, M.D.,

         University of Michigan School of Medicine              94

 

      Questions on Presentation                                116

 

      FDA Efficacy Presentation, Robert Prizont, M.D.,

         Medical Officer, Division of Gastrointestinal

         and Coagulation Drug Products                         158

                                                                 4

 

                      C O N T E N T S (Continued)

 

      Questions on Presentation                                173

 

      FDA Safety Presentation, Gary Della'Zanna, M.Sc.,

         Medical Officer, Division of Gastrointestinal

         and Coagulation Drug Products                         199

 

      Questions on Presentation                                220

 

      Open Public Hearing:

 

      Jeffrey D. Roberts, B.Sc., IBS Self Help Group           229

      Constance Hill                                           235

      Linda Roepke                                             241

 

      Clarification of Issues                                  249

 

      Discussion of Questions                                  295

 

      Adjournement                                             364

 

                                                                 5

 

                         P R O C E E D I N G S

 

                      Call to Order, Introductions

 

                DR. FOGEL:  Good morning.  My name is Ron

 

      Fogel.  I am acting chair for today's meeting of

 

      the Gastrointestinal Drugs Advisory Committee.

 

      Today's meeting deals with the new drug application

 

      of Zelnorm for the proposed indication of the

 

      treatment of patients with chronic constipation and

 

      relief of associated symptoms of straining hard or

 

      lumpy stools and infrequent defecation.

 

                There has been one change to today's

 

      agenda.  The agenda has been pushed back half an

 

      hour so the tentative time of adjournment is five

 

      o'clock.  Why don't we start by going around the

 

      table and introducing ourselves?  If we could start

 

      on my far left?

 

                DR. VEGA:  Jose Vega, from Amgen in

 

      California.

 

                DR. LEVIN:  Arthur Levin.  I am a member

 

      of the Drug Safety and Risk Management Advisory

 

      Committee.  I am a consumer representative and I am

 

      a guest as a consumer representative here today.

 

                                                                 6

 

                DR. STROM:  Brian Strom, University of

 

      Pennsylvania.  I am a recent graduate of the Drug

 

      Safety and Risk Management Advisory Committee--I

 

      have already forgotten the name of the committee!

 

      I am here as a special government employee, though

 

      that is not what is says there.

 

                DR. FURBERG:  I am Curt Furberg, from Wake

 

      Forrest University.  I am an active member of the

 

      Drug Safety and Risk Management Advisory Committee.

 

                DR. D'AGOSTINO:  Ralph D'Agostino, from

 

      Boston University, statistician, consultant to the

 

      FDA.

 

                DR. LAMONT:  I am Tom LaMont.  I am a

 

      member of the GIDAC.  I work at Beth Israel

 

      Hospital in Boston and Harvard Medical School.

 

                DR. LEVINE:  I am Bob Levine, State

 

      Medical University, Syracuse, New York, and I am a

 

      member of the GI advisory committee.

 

                DR. METZ:  David Metz, University of

 

      Pennsylvania.  I am on the GI drug advisory

 

      committee.

 

                DR. PEREZ:  Tom Perez, Executive Secretary

 

                                                                 7

 

      to this meeting.

 

                DR. FOGEL:  Ron Fogel, Henry Ford Health

 

      System, in Detroit.

 

                DR. SACHAR:  I am David Sachar, from Mount

 

      Sinai School of Medicine, in New York--my maiden

 

      voyage on the GI drug advisory committee.

 

                [Laughter]

 

                DR. BUCHMAN:  Alan Buchman, from

 

      Northwestern University, in Chicago, and this is

 

      also my first cruise with today as well.

 

                DR. MANGEL:  Allen Mangel, Research

 

      Triangle Institute.  I am a special government

 

      employee.

 

                DR. CRYER:  I am Byron Cryer, from the

 

      Dallas VA Medical Center and UT Southwestern

 

      Medical School.  I am a member of the GI advisory

 

      committee.

 

                DR. DELLA'ZANNA:  Garry Della'Zanna,

 

      medical officer in the GI and Coagulation Drug

 

      Product Division.

 

                DR. JUSTICE:  Robert Justice, Director,

 

      Division of Gastrointestinal and Coagulation Drug

 

                                                                 8

 

      Products.

 

                DR. BEITZ:  Julie Beitz, Deputy Director

 

      in the Office of Drug Evaluation III.

 

                DR. FOGEL:  Thank you, all.  At this point

 

      Tom Perez will read the meeting statement.

 

                           Meeting Statement

 

                DR. PEREZ:  Thank you and good morning.

 

      The following announcement addresses the issue of

 

      conflict of interest with regard to this meeting,

 

      and is made part of the record to preclude even the

 

      appearance of such at this meeting.

 

                Based on the submitted agenda for the

 

      meeting and all financial interests reported by the

 

      committee participants, it has been determined that

 

      all interests in firms regulated by the Center for

 

      Drug Evaluation and Research present no potential

 

      for an appearance of a conflict of interest at this

 

      meeting, with the following exceptions:

 

                In accordance with 18 USC Section

 

      208(b)(3), full waivers have been granted to the

 

      following participants, Dr. Ronald Fogel has been

 

      granted a waiver for serving as a member of the

 

                                                                 9

 

      sponsor's speakers bureau.  His lectures are

 

      unrelated to the matter at issue and he receives

 

      less than $10,001 per year.

 

                Dr. Ralph D'Agostino has been granted a

 

      waiver for serving on a competitor's advisory board

 

      on unrelated matters.  He receives less than

 

      $10,001 per year.

 

                Dr. Byron Cryer has been granted a waiver

 

      under 21 USC 355(n)(4), amendment of Section 505 of

 

      the Food and Drug Administration Modernization Act,

 

      for ownership of stock in a competitor.  The stock

 

      is worth less than $5,001.  Because this interest

 

      falls below the de minimis exemption allowed under

 

      5 CFR 2640.202(a)(2) a waiver underlying 18 USC

 

      208(b)(3) is not required.

 

                Dr. David Metz has been granted waivers

 

      under 18 USC Section 208(b)(3) and 21 USC 355(n)(4)

 

      for his spouse's ownership of stock in a competitor

 

      valued from $50,001 to $100,000.

 

                Lastly, Dr. Allen Buchman has been granted

 

      waivers under 18 USC Section 208(b)(s) and 21 USC

 

      355(n)(4) for owning stock in a competitor valued

 

                                                                10

 

      from $25,001 to $50,000.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

      agency's Freedom of Information Office, Room 12A-30

 

      or the Parklawn Building.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which an FDA participant has a financial

 

      interest, the participants are aware of the need to

 

      exclude themselves from such involvement and their

 

      exclusion will be noted for the record.

 

                We would also like to note that Dr. Jose

 

      Vega has been invited to participate as an industry

 

      representative, acting on behalf of regulated

 

      industry.  Dr. Vega is employed by Amgen, Inc.

 

                With respect to all other participants, we

 

      ask in the interest of fairness that they address

 

      any current or previous financial involvement with

 

      any firm whose product they may wish to comment

 

      upon.  Thank you.

 

                DR. FOGEL:  Thank you.  At this time I

 

      will turn the meeting over to Dr. Justice, of the

 

                                                                11

 

      FDA, for opening comments.

 

                            Opening Comments

 

                DR. JUSTICE:  Good morning.  I would like

 

      to welcome everyone to today's meeting of the

 

      Gastrointestinal Drugs Advisory Committee, and I

 

      would especially like to welcome members of the

 

      committee and special government employees for

 

      taking the time to provide us with your advice.

 

                As you have heard, today we will be

 

      discussing the application for Zelnorm tablets for

 

      the proposed indication of treatment of chronic

 

      constipation.  Before going on to the

 

      presentations, I would just like to briefly go

 

      through the questions so you will have them in mind

 

      as you listen to the discussions.

 

                The first item is that we would like you

 

      to discuss the appropriateness of a primary

 

      efficacy endpoint of an increase of equal to or

 

      greater than 1 complete spontaneous bowel movement

 

      per week versus a total of greater than 3 complete

 

      spontaneous bowel movements per week.

 

                The second question is, is the population

 

                                                                12

 

      studied representative of patients with chronic

 

      constipation?  If not, how do the populations

 

      differ?

 

                The third question is only 9 to 16 percent

 

      of subjects were greater than or equal to 65 years

 

      of age and the treatment effect was significantly

 

      smaller in older patients.  Are these data adequate

 

      for an indication that is common in the elderly?

 

                The fourth efficacy question is that only

 

      9 to 14 percent of the subjects were male and the

 

      treatment effect was smaller in males than females.

 

      Are these data adequate to support approval of

 

      Zelnorm for use in the treatment of chronic

 

      constipation in males?

 

                The next question is are the clinical

 

      trial data adequate with respect to the population

 

      of non-irritable bowel syndrome patients with

 

      chronic constipation that is likely to be treated

 

      with Zelnorm?

 

                The next efficacy question is, is Zelnorm

 

      effective for the treatment of chronic constipation

 

      and associated symptoms?

 

                                                                13

 

                As far as the safety questions,

 

      postmarketing access of ischemic colitis and

 

      serious complications of diarrhea were not limited

 

      to patients with irritable bowel syndrome.  What

 

      are the implications of these adverse events from

 

      patients with chronic constipation?

 

                The next safety question is that the

 

      incidence of diarrhea and discontinuation due to

 

      diarrhea was higher in patients 65 years of age or

 

      older.  Is there sufficient information that

 

      Zelnorm is safe for use in this age group?

 

                The next safety question is do the adverse

 

      event data from the clinical trials and

 

      postmarketing surveillance provide adequate

 

      evidence of safety of Zelnorm for the treatment of

 

      chronic constipation?

 

                The next safety question is should the

 

      information on the postmarketing cases of ischemic

 

      colitis and intestinal ischemia be moved from the

 

      "precautions" section to the "warning" section of

 

      the package insert?

 

                Then, the final question will be the

 

                                                                14

 

      overall question of should Zelnorm be approved for

 

      the proposed indication of the treatment of

 

      patients with chronic constipation and relief of

 

      associated symptoms of straining, hard or lumpy

 

      stools, and infrequent defecation?

 

                With that, I will turn it back over to Dr.

 

      Fogel for Novartis' presentation.

 

                DR. FOGEL:  Thank you very much.  At this

 

      juncture I will turn the meeting over to Dr. John

 

      Cutt, Global Head of GI Drug Regulatory Affairs for

 

      Novartis, who will introduce the speakers and the

 

      presentations.  Thank you.

 

                         Novartis Presentation

 

                              Introduction

 

                DR. CUTT:  Thank you.  First I would like

 

      to thank Dr. Beitz, Dr. Justice--Dr. Prizont is not

 

      here yet--and Dr. Della'Zanna and the rest of the

 

      FDA reviewers, and Dr. Fogel and the rest of the

 

      advisory committee, and say good morning to you.

 

                My name is John Cutt.  As Dr. Fogel said,

 

      I am the executive director and the global head for

 

      the gastrointestinal regulatory group at Novartis,

 

                                                                15

 

      and it is my pleasure to share with you today the

 

      clinical data on chronic constipation that we have

 

      generated.

 

                Let me start out with the objectives, as

 

      we see them today for the meeting.  We would like

 

      to share the Zelnorm Phase 3 clinical data in

 

      support of a new indication.  Dr. Fogel read that

 

      before, I will read it again.  Zelnorm is indicated

 

      for the treatment of patients with chronic

 

      constipation and the relief of associated symptoms

 

      of straining, hard or lumpy stools, and infrequent

 

      defecation.

 

                The second topic that we are going to

 

      review today is the postmarketing safety data that

 

      we have generated since the approval of the drug in

 

      the United States in July of 2002.  This approval

 

      was for patients with irritable bowel syndrome with

 

      constipation.

 

                A brief introduction of the compound,

 

      Zelnorm is tegaserod maleate.  It is 5-HT                                

                                                                  4 receptor

 

      partial agonist with affinity for the 5-HT                               

                                                                     4

 

      receptor in the GI tract.  For its pharmacologic

 

                                                                16

 

      activity in the GI tract, Zelnorm enhances

 

      intestinal motility; increases intestinal

 

      secretion; and inhibits visceral sensitivity.  We

 

      have also demonstrated in clinical trials that

 

      Zelnorm can improve the constipation symptoms in

 

      patients with irritable bowel syndrome with

 

      constipation.

 

                So, these data together are the basis for

 

      the hypothesis that Zelnorm could be effective to

 

      treat patients suffering from chronic constipation.

 

                Novartis-designed clinical development

 

      program for chronic constipation included two

 

      randomized, placebo-controlled pivotal studies.

 

      Both the studies were 12 weeks in duration to

 

      assess the efficacy, safety and tolerability of the

 

      drug.  We studies both the 2 mg dose and the 6 mg

 

      dose BID versus placebo.  In total, there were

 

      2,612 patients that were studied.  The program also

 

      included one extension phase study which was added

 

      on to one of the pivotal studies.  This was a

 

      13-month extension for assessing the long-term

 

      safety of the compound.  The other pivotal studied

 

                                                                17

 

      included a 4-week withdrawal period.  Today what we

 

      are going to do is show you the results of these

 

      pivotal studies.

 

                We will also share with you the

 

      postmarketing clinical data that we have collected

 

      since the approval of the drug in the United States

 

      in July of 2002.  That approval was for the

 

      short-term treatment of women with irritable bowel

 

      syndrome whose primary bowel symptom is

 

      constipation.  The recommended dose is 6 mg BID for

 

      a period of up to 12 weeks.  At the time of the

 

      approval we demonstrated the efficacy, safety and

 

      tolerability in 5,319 patients in the clinical

 

      trial program.  At this point in time, now, we have

 

      generated data on 11,600 patients in clinical

 

      trials.  These patients were all treated with

 

      Zelnorm.  What this means is that it translates to

 

      approximately 3,456 patient-year exposure to the

 

      drug in the clinical trials.

 

                In terms of the worldwide clinical

 

      experience for the drug, Zelnorm is now approved in

 

      56 countries for the indication of IBS with

 

                                                                18

 

      constipation.  We have also received approval for

 

      the drug in 10 countries for the indication of

 

      chronic constipation that we are seeking from the

 

      advisory committee and the FDA.

 

                We first made the drug available to

 

      patients suffering from IBS-C in January of 2001 in

 

      the rest of the world.  So, at this point we have

 

      over 3 years of postmarketing experience with the

 

      drug in patients.  What this means is that we have

 

      treated approximately 3 million patients globally

 

      with the drug and about 2 million of those patients

 

      have been treated in the United States.  This now

 

      translates to about 362,000 patient-years of

 

      experience to Zelnorm.

 

                The safety data from the clinical trial

 

      setting and the postmarketing environment we

 

      believe supports a favorable safety profile for

 

      Zelnorm.  So, our conclusion from the data that you

 

      will see today during the presentations is that

 

      Zelnorm, at the recommended dose of 6 mg BID, is

 

      efficacious and safe for the treatment of patients

 

      with multiple symptoms of chronic constipation.

 

                                                                19

 

                What I want to do is review the agenda

 

      very briefly, the people that will be presenting

 

      for us.  First we have Dr. Charlene Prather.  She

 

      is from the St. Louis University and will speak

 

      about chronic constipation.  Her presentation is

 

      title an unresolved problem for many patients in

 

      clinical practice.

 

                She will be followed by Dr. Eslie Dennis.

 

      Eslie is from the Novartis clinical development and

 

      medical affairs department.  Dr. Dennis will

 

      present the efficacy and safety data from the

 

      pivotal studies.

 

                That will be followed by Dr. Bo Joelsson.

 

      He will present our overall clinical safety data

 

      and review some of the adverse events of special

 

      interest that we have agreed to talk about with the

 

      FDA.

 

                Finally, Dr. Philip Schoenfeld, who is the

 

      chief of the gastrointestinal group at the Veterans

 

      Hospital in Ann Arbor, at the University of

 

      Michigan, will conclude historical presentation

 

      with a benefit/risk assessment for the drug.

 

                                                                20

 

                We also have four consultants that have

 

      joined us today to answer questions that you may

 

      have.  The first one is Dr. Felix Arellano.  He is

 

      from the Risk Management Resources group.  His

 

      expertise is pharmacovigilance, epidemiology and

 

      risk management.  Then we have Dr. Gary Koch.  Dr.

 

      Gary Koch is from North Carolina, Chapel Hill.  He

 

      is an expert in biostatistics.  We have Dr. David

 

      Lieberman.  He is from the Oregon Health and

 

      Science University.  He will be here to answer any

 

      questions you have on the core database which is

 

      part of the presentation.

 

      Then we have Dr. Walter Peterson, a

 

      gastroenterologist from the University of Texas

 

      Southwestern.

 

                We have also a number of scientists and

 

      clinicians from Novartis who can answer any of the

 

      specific questions that you have on Zelnorm.

 

                Now I would like to invite Dr. Prather up

 

      to the podium.

 

                         Chronic Constipation:

 

                An Unresolved Problem for Many Patients

 

                                                                21

 

                DR. PRATHER:  Thank you, Dr. Cutt.  Dr.

 

      Fogel, committee members, ladies and gentlemen, my

 

      name is Charlene Prather.  As you heard, I am from

 

      St. Louis University.  I am a gastroenterologist.

 

      I have been in practice for over ten years.  My

 

      career has been dedicated to the clinical

 

      investigation and, importantly, the clinical

 

      treatment of patients with functional bowel

 

      disorders and gastrointestinal motility disorders.

 

      Chronic constipation is one of the very common

 

      problems that I see in my clinical practice and it

 

      is, indeed, an unresolved problem for many of the

 

      patients that come to see me.

 

                First I would like to review my

 

      presentation objectives.  I will begin with a

 

      definition of chronic constipation.  I will discuss

 

      epidemiology and resource utilization that is

 

      associated with chronic constipation.  I will

 

      review available therapies and the limitations that

 

      some of these therapies may have.  I will also

 

      summarize for you my feelings regarding the unmet

 

      medical need associated with chronic constipation.

 

                                                                22

 

                First, beginning with the definition of

 

      chronic constipation, there are a variety of ways

 

      to define constipation.  I have decided to define

 

      constipation into either primary causes of

 

      constipation or secondary causes of constipation.

 

                First let's discuss the secondary causes

 

      of chronic constipation.  Secondary causes include

 

      things such as drug-induced constipation.  We are

 

      certainly familiar with this with the narcotics we

 

      may give our chronic pain patients.  Metabolic

 

      factors--hypothyroidism, hypocalcemia may be

 

      associated with chronic constipation.  Importantly,

 

      co-morbid medical conditions.  We are certainly

 

      familiar with a variety of neurological disorders,

 

      such as Parkinson's disease, multiple sclerosis, in

 

      which constipation is an important complaint that

 

      many of these patients may bring to us.  However,

 

      this is not what I am here to discuss today.

 

                Today I would like to review primary

 

      constipation.  Again, with primary constipation we

 

      have learned much in the past several years

 

      regarding what causes primary constipation.  There

 

                                                                23

 

      may be impaired colonic transit or motor function,

 

      certainly an area that I am very interested in.  We

 

      often call this slow transit constipation.  This

 

      may result from a failure of the neurenteric

 

      function of the digestive system or from the

 

      gastrointestinal reflexes that are involved.  It

 

      may also result because there is a problem with the

 

      muscle, a failure of the muscular apparatus.

 

                We also can look at chronic constipation

 

      as a subgroup having ineffective defecation.  We

 

      also may call this functional outlet obstruction.

 

      This is really where there is a poor coordination

 

      in the muscular apparatus that is involved in the

 

      defecation process.  There are some other

 

      terminologies that may be used as well, such as

 

      pelvic dyssynergia or anismus may be a term that

 

      you have also heard.  Most cases of primary chronic

 

      constipation fall into neither of these categories.

 

      They are actually normal transit constipation.

 

                Constipation really isn't defined by

 

      physiologic testing; it is defined on the basis of

 

      symptoms.  In my practice the most common reported

 

                                                                24

 

      symptoms that I see coming from my patients are

 

      complaints of hard or lumpy stools; increased

 

      straining.  They may complain of infrequent bowel

 

      movements, but often the sensation of incomplete

 

      evacuation, really outcome having a satisfactory

 

      bowel movement and, not uncommonly, the complaint

 

      of gloating or fullness.  Typically, the longer

 

      they have gone since they had a bowel movement, you

 

      know, they are feeling more full and they may

 

      describe that as a bloated sort of sensation.

 

                When I think about chronic constipation,

 

      this is more persistent than intermittent or

 

      episodic constipation.  We are familiar with

 

      transient constipation that may occur as a result

 

      of a dietary change.  We may also see it in

 

      relation to travel.  When I think about what is the

 

      definition I will use for chronicity, it needs to

 

      have been present for several months duration and

 

      quite commonly, in my practice, these patients have

 

      had their constipation for years, frequently dating

 

      back to early adolescence or sometimes even

 

      childhood.

 

                                                                25

 

                Well, how valid are my ideas about what my

 

      patients bring me with those symptoms?  There

 

      actually have been some studies that have taken a

 

      look at this.  One of the first studies, performed

 

      by Dr. Robert Sandler, in North Carolina, took a

 

      look at a group of young adults, those around the

 

      university community.  These were individuals who

 

      had constipation and the symptoms they reported

 

      most often were, indeed, straining 52 percent of

 

      the time; hard stools, 44 percent of the time;

 

      wanted to have a bowel movement but were unable to,

 

      34 percent of the time; with infrequent stools

 

      being reported just 32 percent of the time.

 

                Now let's think about this.  Physicians

 

      were often called upon to think very quantitatively

 

      so we often think about the frequency as being the

 

      most important symptom in constipation.  But,

 

      clearly, our patients seem to be telling us

 

      something a bit different.  Now, this was not a

 

      population-based study so what actually happens in

 

      the population when we discuss symptoms and

 

      constipation?

 

                                                                26

 

                I have two studies to review with you.

 

      First is a study on the left, a large

 

      population-based, epidemiologic study by Stewart.

 

      He took a look at the symptoms most commonly

 

      reported in constipation.  Again, at the top we see

 

      the complaint--an incomplete bowel movement 83

 

      percent of the time.  Unsuccessful bowel movement,

 

      being called a stool but being unable to 65 percent

 

      of the time.  We see complaints of abdominal

 

      discomfort, needing to press on the abdomen in

 

      order to have a bowel movement; some abdominal

 

      bloating in a group of patients; but, again, down

 

      at the bottom of this list is frequency, with less

 

      than 3 bowel movements per week being reported by

 

      only 13 percent of this cohort.

 

                On the right hand of the slide is another

 

      population-based study by Pare.  Again we see

 

      similar findings, with straining right at the top.

 

      Again, near the bottom less than 3 bowel movements

 

      per week being less frequent in this case, in this

 

      population, 36 percent of the time.

 

                Now, I previously mentioned the subtypes

 

                                                                27

 

      of primary constipation that I considered.  Might

 

      it be slow transit constipation; might it be an

 

      outlet problem; or is it normal transit

 

      constipation?  Well, unfortunately, the symptoms

 

      don't help me differentiate between those different

 

      physiologic groups.  Fortunately, that is not

 

      necessary because in practice we don't use

 

      physiologic testing, nor do we use the patient

 

      symptoms to define which subgroup they belong in.

 

      This has been information we have really found out

 

      over the past several years.  We would like to

 

      think their symptoms will tell us exactly which

 

      subgroup they belong into but that just hasn't been

 

      the case.  In clinical practice and in clinical

 

      trials we really don't try to define the subtype of

 

      constipation based on either their symptoms or on

 

      physiologic testing.

 

                However, it is important that we have

 

      criteria for the use of clinical testing and having

 

      a relatively homogenous group of patients that we

 

      can take a look at.  An important stab at this has

 

      been the Rome criteria.  I would like to review

 

                                                                28

 

      with you the Rome II criteria that are used in the

 

      diagnosis of functional constipation.

 

                The Rome II diagnostic criteria include at

 

      least 12 weeks, which not be consecutive, in the

 

      past 12 months of 2 or more of the following

 

      symptoms:  These symptoms include straining, lumpy

 

      or hard stools, a sensation of incomplete

 

      evacuation, a sensation of anorectal obstruction or

 

      blockage, or having to use manual maneuvers, such

 

      as digitation, to facilitate defecation.  You see

 

      an asterisk by these because these need to have

 

      been present on at least a quarter of defecations.

 

      The other criterion is less than 3 defecations per

 

      week.

 

                Looking back at the top line, we see that

 

      it is 2 or more of the following symptoms.  So, a

 

      patient may have straining, lumpy or hard stools 25

 

      percent of the time and this would be consistent

 

      with the Rome II criteria for chronic constipation.

 

      Or, it could be that they do have less than 3

 

      defecations per week and a sensation of incomplete

 

      evacuation.  For this criterion loose stools must

 

                                                                29

 

      not be present and there should be insufficient

 

      criteria for irritable bowel syndrome.

 

                A caveat with the Rome criteria is that

 

      one of the criteria that they say is that I cannot

 

      use these criteria if my patients are already on

 

      laxatives.  So, these are criteria that are really

 

      appropriate for individuals who are not currently

 

      using laxatives.

 

                Using these definitions and, again, the

 

      Rome I definition was for the criteria from before,

 

      how common is chronic constipation in the general

 

      population?  These are some population-based

 

      studies and, depending on the criteria that have

 

      been used, we see a prevalence in the range of 4

 

      percent up to 16 percent.  This is a lot of

 

      patients that are complaining of constipation.

 

      However, not all of these patients are actually

 

      coming to see us.  A few of these studies actually

 

      looked at how many of these patients or individuals

 

      had actually sought physician care for the

 

      evaluation and treatment of constipation.

 

                What we see is that it is only about 25

 

                                                                30

 

      percent that actually come in to the physician's

 

      office in order to seek some sort of treatment.

 

                A little bit more about the prevalence,

 

      when we think about constipation we need to know

 

      what age groups might be affected.  In the Pare

 

      study he was able to divide this out.  In the green

 

      bars we see the Rome I criteria and in the magenta

 

      bars the Rome II criteria.  There are some slight

 

      differences, again, depending on the definition

 

      that has been used.  This is true of all of the

 

      epidemiologic studies, that we really need to

 

      understand the criteria.

 

                Well, what we see is that actually

 

      constipation is a bit more common in the younger

 

      age group, the 18-34 year-old age group.  This is

 

      consistent with my clinical practice.  We see that

 

      the prevalence is relatively flat when we take a

 

      look at the 35-49 year-old age group; the 50-64

 

      year-old age group; and even the over 64 year-ole

 

      age group.  So, constipation really affects all age

 

      groups.

 

                To summarize the epidemiology related with

 

                                                                31

 

      constipation quite briefly, chronic constipation

 

      is, indeed, common in the general population.

 

      Again, not all of these individuals come to see us.

 

      Approximately 25 percent actually seek physician

 

      care.  In data I have not presented, it is slightly

 

      more common in women than it is in men.  The female

 

      to male ratio ranges from 1.3 to 2.5.  Importantly,

 

      constipation affects all age groups.

 

                Now, how does this really reflect with

 

      what I see in my clinical practice?  In my clinical

 

      practice generally I see females.  Now, this may be

 

      because I am a female gastroenterologist, that is

 

      the obvious.  However, when I discuss this with my

 

      male colleagues they tell me that they too are

 

      seeing predominantly women that come to see them

 

      for chronic constipation.  Most of my patients have

 

      been symptomatic for many years, typically over 10

 

      years.  The majority have tried life style changes.

 

      They have tried fiber.  They have used

 

      over-the-counter laxatives prior to even seeking

 

      initial care from their primary care physicians.

 

      Most of them manage their constipation with

 

                                                                32

 

      combinations of these, a combination of fiber and

 

      laxatives.  The patients that come to me in my

 

      practice are predominantly referred to me by

 

      primary care physicians and I am also going to see

 

      patients that come from other gastroenterologists.

 

                Again, I really like my patient population

 

      and I like taking care of patients with functional

 

      bowel disorders.  These are not all crazy patients

 

      as I know some gastroenterologists think.  They

 

      actually cope reasonably well with their condition,

 

      however, they are not completely satisfied and they

 

      are looking for something a little bit better.

 

                So, what is the impact of this condition?

 

      Is it just kind of a minor annoyance to my

 

      patients?  I would like to present some data

 

      related to the impact this condition has in

 

      patients.  First I would like to take a look at

 

      quality of life.  There haven't been that many

 

      studies.  I will present three of the four studies

 

      I am aware of.

 

                In Olmstead County, Minnesota, individuals

 

      with chronic constipation reported a significant

 

                                                                33

 

      impact in quality of life with reduced SF-36

 

      scores.  Similarly, in Canada, people who have

 

      either self-reported or Rome II constipation also

 

      had worse SF-36 scores compared to the normal

 

      population.  In Australia, people with constipation

 

      had significantly worse SF-12 scores on both the

 

      mental and the physical components.  So, there is

 

      certainly an impact on these individuals' quality

 

      of life.

 

                Not only does chronic constipation impact

 

      quality of life, but it is also associated with

 

      increased healthcare utilization.  In this next

 

      slide we see that 5.7 million constipation-related

 

      outpatient visits do occur annually; 4.1 million of

 

      these are physician office-based visits.  However,

 

      there are 991,000 emergency room visits and 587,000

 

      hospital outpatient visits each year.

 

                The cost is a little bit difficult to get

 

      at as it relates to how expensive is this

 

      condition.  The one study that I found was from

 

      1997, a study by Rantis and colleagues, who found

 

      in patients who had been referred for tertiary care

 

                                                                34

 

      evaluation had costs for additional testing on the

 

      average of $2,752.  Again, in 2004 dollars I am

 

      sure that may be a bit more.  But the point is

 

      really that this disorder does have an impact both

 

      from a quality of life and from a healthcare

 

      utilization perspective.

 

                So, if this is affecting my patients'

 

      lives I would like to be able to treat them

 

      appropriately, and my goal of therapy is that I

 

      would like to be able to improve GI function in

 

      order to obtain relief of the key symptoms that my

 

      patients are bringing to me, and we have reviewed

 

      what these symptoms are.

 

                Well, what do we have available in order

 

      to do this?  Certainly we have fiber; laxatives, be

 

      they osmotic or stimulant laxatives.  We can use

 

      enemas or suppositories and we do have some

 

      miscellaneous agents that we use.  We can use a

 

      cholinergic agonist, such as bethanchol.  I don't

 

      think too many of the gastroenterologists have used

 

      that actually for treatment of constipation but it

 

      is available for us and we have used it in the

 

                                                                35

 

      past.  We may use a prostaglandin analog called

 

      misoprostil and we have also used

 

      colchicine--again, certainly not ideal agents but

 

      they are things that we do have available for us.

 

                Well, there are some challenges with these

 

      agents.  My patients tell me that they really

 

      aren't consistently getting relief.  There is a

 

      variable treatment response.  Importantly, for the

 

      constellation of constipation symptoms that we see

 

      the efficacy really has not been evaluated or

 

      demonstrated for most of these agents.

 

      Importantly, chronic constipation is just that, it

 

      is a chronic problem and most agents are indicated

 

      for less than or equal to 2 weeks of therapy.  I

 

      would certainly like to be able to offer my

 

      patients something on an ongoing basis.

 

                There are other limitations associated

 

      with these agents.  First is the worsening of some

 

      of the constipation symptoms that I am actually

 

      trying to treat.  I mean, who among us has not

 

      given fiber to patients only to have them come back

 

      a week or two later complaining of increased

 

                                                                36

 

      bloating and gas?  Likewise, these agents can also

 

      cause cramping, abdominal pain or colicky stools.

 

      Fortunately, complications are not common with the

 

      treatments that I use for treating constipation.  I

 

      do worry in some patients should they develop

 

      severe diarrhea which can result in hypovolemia or

 

      electrolyte disturbance.  Metabolic disturbances

 

      can occur, such as hypokalemia or hypomagnesemia

 

      depending on the agent I may have used.

 

                There are also other adverse effects

 

      which, fortunately, also are not too common.  We

 

      can see interference with concomitant drug

 

      absorption.  For instance, some laxatives when

 

      given with cipro may result in poor absorption of

 

      that medication or with theophylline.

 

                I am not too concerned about the

 

      structural changes that may occur in the gut

 

      mucosa, things such as melanosis coli or the abuse

 

      potential or dependency, although I can tell you my

 

      patients and many physicians do consider these to

 

      be obstacles to use of many of the agents that are

 

      currently available.  My patients certainly tell me

 

                                                                37

 

      that there is diminished therapeutic effect that

 

      they see that occurs over time when using these

 

      agents, causing them to have to escalate the drug

 

      usage and often with additional side effects

 

      associated with this.

 

                I am talking to my patients not being

 

      satisfied, and can I get at is there truly a

 

      quantitative effect that tells me how satisfied are

 

      patients or physicians with these therapies?  Well,

 

      there really isn't much out there.  Fortunately, a

 

      colleague of mine, Dr. Larry Schiller, has shared

 

      with me an abstract that he has submitted to The

 

      American College of Gastroenterology.  This is an

 

      Internet-based study that was done, and a group of

 

      physicians were asked are your patients completely

 

      satisfied with treatments for constipation?  The

 

      physicians overwhelmingly, 82 percent, said no, my

 

      patients are not completely satisfied.

 

                If you take a look at the box on the

 

      right, the reasons for dissatisfaction included

 

      lack of efficacy, 93 percent; safety or side

 

      effects, 57 percent; or other reasons such as taste

 

                                                                38

 

      or compliance in 27 percent.  In this group of

 

      physicians, 60 percent of physicians agreed that

 

      they do not have adequate products for treating

 

      their patients with chronic constipation, and 90

 

      percent of these physicians wanted better treatment

 

      options.  Physicians cited frustration with the

 

      current treatments as one of the top 3 reasons

 

      patients state for seeking care for their

 

      condition.

 

                Another study, a population-based study,

 

      also Internet based, took a look at patients who

 

      had seen a physician for constipation within the

 

      past year.  In this group of 557 patients, they

 

      were asked are you completely satisfied with your

 

      treatment for constipation?  Nearly half said no,

 

      they were not completely satisfied.  So, again,

 

      these are patients that have seen a physician

 

      within the past year that were obtained through a

 

      national database survey.  The reasons for

 

      dissatisfaction included efficacy, similar to the

 

      physicians, in 82 percent.  Patients weren't quite

 

      as concerned as physicians were about safety or

 

                                                                39

 

      side effects but still an important concern of

 

      theirs in 16 percent.  Other reasons, such as taste

 

      or not wanting to take the agents regularly, in 17

 

      percent.

 

                At the bottom of the slide we see two

 

      other references, one from Irvine and one from

 

      Ferrzzi.  These data support the findings that they

 

      found in their studies related to patient concerns

 

      regarding the currently available treatments for

 

      constipation.

 

                In conclusion, chronic constipation, in my

 

      opinion, is a condition that is truly in need of a

 

      better approach.  Constipation is characterized by

 

      a constellation of symptoms and we need to

 

      recognize what the symptoms are that our patients

 

      bring to us as being most important, including the

 

      complaints of straining and incomplete evacuation.

 

      Certainly, we want to remember frequency but this

 

      is not our patients' primary concern.  Chronic

 

      constipation is associated with high resource

 

      utilization and does have a significant negative

 

      impact on our patients' quality of life.  The

 

                                                                40

 

      current pharmacologic agents have some limitations

 

      and many patients and their physicians are not

 

      completely satisfied with the available therapies.

 

      I truly believe that better treatment options are

 

      needed for this condition.

 

                Thank you for allowing me to share with

 

      you today my thoughts about chronic constipation.

 

      This is obviously a topic of great importance to me

 

      and to my patients.  I am looking forward to

 

      hearing more from the other speakers today what I

 

      am sure will be a very lively and interesting

 

      discussion.

 

                    Zelnorm: Efficacy and Safety in

 

                          Chronic Constipation

 

                DR. DENNIS:  Thank you, Dr. Prather.  Dr.

 

      Fogel, members of the advisory committee, FDA

 

      representatives, ladies and gentlemen, good

 

      morning.  My name is Eslie Dennis and I am one of

 

      the senior medical directors for gastroenterology

 

      at Novartis Pharmaceuticals.  I am delighted to be

 

      here today to be able to share with you our chronic

 

      constipation program, and I thank you for the

 

                                                                41

 

      opportunity to do so.

 

                Over the next 30 minutes I will provide

 

      you with our rationale for studying patients with

 

      chronic constipation.  I will then highlight the

 

      study objectives of our Phase 3 program, walk you

 

      through the study design, and provide more

 

      specifics around the patient population that was

 

      studied.  Then I will present the efficacy data

 

      from our primary and secondary endpoints and,

 

      finally, the safety data for the 12-week

 

      double-blind, placebo-controlled studies and the

 

      safety data from the 13-month blinded extension

 

      study.

 

                Zelnorm is a 5-HT                                              

                             4 receptor partial

 

      agonist.  It is representative of a new class, the

 

      aminoguanidine indole, and it was designed

 

      specifically to act at 5-HT                                              

                             4 receptors in the GI

 

      tract.  The molecular structure of Zelnorm is based

 

      on serotonin which we know plays a crucial role in

 

      the normal functioning of the GI tract.  We also

 

      know that the action of serotonin at 5-HT                                

                                                                  4

 

      receptors is prokinetic.

 

                                                                42

 

                Our mechanism of action and preclinical

 

      data have demonstrated that tegaserod is, indeed, a

 

      promotility agent.  Tegaserod has been shown to

 

      augment peristalsis, thereby enhancing gut motility

 

      and decreasing transit time.  Furthermore, animal

 

      studies have shown that tegaserod increases

 

      chloride and water secretion which would improve

 

      stool consistency independent of the promotile

 

      effect of the drug.  In addition, we have the data

 

      from our IBS with constipation studies that confirm

 

      the significant improvement with Zelnorm compared

 

      to placebo on stool frequency, stool consistency

 

      and straining--all important benefits when treating

 

      chronic constipation.

 

                On the basis of our IBS with constipation

 

      studies, we felt that we could proceed directly to

 

      Phase 2 trials in chronic constipation without a

 

      formal Phase 2 program, and that we would use the

 

      same doses that were tested in our IBS-C Phase 3

 

      trials.

 

                Let me now walk you through the Phase 3

 

      chronic constipation program.  The study objectives

 

                                                                43

 

      were to evaluate the efficacy, tolerability and

 

      safety of 2 doses of Zelnorm, 2 mg BID and 6 mg

 

      BID, compared to placebo over a 12-week treatment

 

      period in patients with chronic constipation.

 

                We had 2 large randomized, double-blind,

 

      placebo-controlled clinical trials in our program.

 

      Study 2301 was conducted in 128 centers in 16

 

      countries in Europe and in Australia and South

 

      Africa.  The design consisted of a 2-week baseline

 

      period, followed by a 12-week treatment period with

 

      either Zelnorm 2 mg BID, 6 mg BID or placebo.

 

                One thousand, two hundred and sixty-four

 

      patients were randomized.  We chose the time line

 

      of 12 weeks of treatment for the core studies in

 

      keeping with the Rome committee guidelines

 

      regarding duration of clinical studies in

 

      functional bowel diseases for chronic therapies.

 

      The 2 doses of Zelnorm and the BID regimen were

 

      based on our experience with the previous

 

      dose-ranging and Phase 3 studies that were

 

      conducted in IBS-C patients.

 

                The initial 12-week treatment period was

 

                                                                44

 

      then followed by an optional 13-month extension

 

      period.  This extension period was double-blinded

 

      but there was no placebo arm.  So, patients who had

 

      received Zelnorm 2 mg BID or 6 mg BID remained on

 

      these doses and patients who had received placebo

 

      then received Zelnorm 6 mg BID in the extension,

 

      and 842 patients entered the extension study.

 

                The primary aim of the extension study was

 

      to provide long-term safety data for the 2 doses of

 

      Zelnorm.  Study 2302 was conducted in 105 centers

 

      in 7 countries in North and South America.  The

 

      study design was very similar, with a 2-week

 

      baseline period and a 12-week treatment period.

 

      However, in this study the 12-week treatment period

 

      was followed by a 4-week drug-free withdrawal

 

      phase.  A similar number of patients were

 

      randomized, 1,348.

 

                Patient inclusion and several of the

 

      endpoints, including the primary endpoint, were

 

      based on the number of complete, spontaneous bowel

 

      movements of CSBMs.  Let me clarify this

 

      terminology that we have used.  BMs refer to all

 

                                                                45

 

      bowel movements.  SBMs refer to spontaneous bowel

 

      movements.  Spontaneous means a non-laxative

 

      induced stool, in other words, no laxative or enema

 

      in the preceding 24 hours.  These can be stools

 

      with either complete evacuation or incomplete

 

      evacuation.  CSBMs refer to complete spontaneous

 

      bowel movements.  Complete is a subjective

 

      definition of a bowel movement that results in a

 

      sensation of complete evacuation.  We know that

 

      there are constipated patients out there who have

 

      more than 3 bowel movements a week but these are

 

      often small amounts of hard and lumpy stools with

 

      straining and incomplete evacuation, and these are

 

      patients that are not satisfied with the quality of

 

      their bowel movements.  So, complete spontaneous

 

      bowel movement captures the quality of a bowel

 

      movement that is not laxative induced and is a

 

      measure of both the quality and frequency.  We felt

 

      that this endpoint best captured what patients

 

      complain of, based on expert opinion and the

 

      published literature.

 

                A recent state-of-the-art review on

 

                                                                46

 

      chronic constipation in The New England Journal of

 

      Medicine referred to the large study that Dr.

 

      Prather has shown you, stating that constipation

 

      had been identified in this study as an inability

 

      to evacuate stool completely and spontaneously 3 or

 

      more times a week.

 

                Given that there is no recognized gold

 

      standard for endpoints in chronic constipation, it

 

      seemed very reasonable to use the SCBM endpoint as

 

      our primary endpoint.  In fact, this is a more

 

      stringent endpoint than using just bowel movements

 

      alone.  However, we recognize that different

 

      experts might request different analyses and

 

      different endpoints and so we defined a priori a

 

      number of secondary endpoints representing the

 

      multiple symptoms of chronic constipation that I

 

      will also be presenting to you today.

 

                We included males and females over the age

 

      of 18 years with chronic constipation.  Chronic was

 

      defined as at least 6 months of consistent

 

      symptoms.  Constipation was defined as less than 3

 

      complete, spontaneous bowel movements per week and

 

                                                                47

 

      one or more of the following 25 percent of the

 

      time, very hard or hard stools, sensation of

 

      incomplete evacuation, or straining at defecation.

 

      These criteria were based on the well-established

 

      Rome criteria.

 

                Patients were also required to have had a

 

      normal endoscopic of radiological evaluation of the

 

      bowel within the past 5 years and after the onset

 

      of symptoms.  In addition, there had to be no

 

      history or evidence of alarm features such as

 

      weight loss, rectal bleeding or anemia since the

 

      evaluation was performed.

 

                Patients were excluded if they had

 

      constipation for which the cause was known, in

 

      other words, secondary constipation as you can see

 

      listed on the slide.  So, we studied patients with

 

      chronic constipation of unknown cause.  In

 

      addition, patients on concomitant medications that

 

      could affect GI transit were excluded, as well as

 

      patients with fecal impaction requiring surgical or

 

      manual intervention.  These criteria were excluded

 

      based on a comprehensive history, thorough physical

 

                                                                48

 

      examination, as well as baseline ECG and laboratory

 

      assessments.

 

                At the end of a 2-week baseline period and

 

      just prior to randomization additional exclusion

 

      criteria were applied.  Patients were excluded if

 

      constipation could not be confirmed by the number

 

      of CSBMs, straining and/or very hard or hard stools

 

      recorded in daily diaries.  They were also excluded

 

      if they had loose or watery stools for more than 3

 

      of the 14 days and if they used laxatives outside

 

      of the guidelines for more than 2 of the 14 days.

 

      Patients were deemed to be non-compliant with diary

 

      completion if they entered less than 11 days in the

 

      daily diary and were subsequently also excluded.

 

                On a daily basis we assessed a number of

 

      parameters related to bowel habits--straining,

 

      stool frequency, stool form that we measured using

 

      the Bristol Stool Scale, and whether evacuation was

 

      complete or incomplete.  Patients were required to

 

      collect this data for each individual bowel

 

      movement, and we determined which bowel movement

 

      was spontaneous based on the daily diary data

 

                                                                49

 

      reflecting the time of administration of any rescue

 

      laxatives.

 

                On a weekly basis we asked about

 

      satisfaction with bowel habits, as well as

 

      bothersomeness of constipation, bothersomeness of a

 

      bowel movement distention or bloating and

 

      bothersomeness of abdominal discomfort or pain.

 

                Let's look at the patient disposition.

 

      Over 80 percent of randomized patients completed

 

      the study, with fewer than 20 percent

 

      discontinuations.  The most common reason for

 

      discontinuation was for unsatisfactory therapeutic

 

      effect, with the largest percentage being in the

 

      placebo group, as we might expect.  Adverse events

 

      accounted for similar numbers of discontinuations

 

      in the placebo and Zelnorm 2 mg BID groups, with a

 

      slightly higher percentage in the 6 mg BID group

 

      which was not statistically significant.  The

 

      pattern of disposition was similar in the 2 trials.

 

                Let's look at the results, starting with

 

      the demographic data.  These were very similar

 

      between the two studies.  The vast majority of

 

                                                                50

 

      patients, 86 and 90 percent, were female.  The mean

 

      age was 46 and 47 years, with a similar age range,

 

      from 18-88 years.  Fourteen percent and 12 percent

 

      were 65 years or older, and just under half the

 

      female population was postmenopausal.  The vast

 

      majority were Caucasian, more so in the European

 

      study.

 

                Patients were required to have had at

 

      least a 6-month history of constipation symptoms.

 

      As you can see, the mean duration of symptoms was

 

      considerably longer, 14.7 and 19.5 years.

 

                The means of the characteristics of bowel

 

      habit by history and during the 14-day baseline

 

      period are shown on the slide here.  However, as

 

      these baseline parameters would not be normally

 

      distributed in a constipated population it may be

 

      more relevant to look at median data at baseline.

 

      When we do so, we see from the history the duration

 

      of symptoms was 10 and 15 years, with hard or very

 

      hard stools 90 percent of the time and a median

 

      number of one SBM per week.  Now, in clinical

 

      practice the Rome criteria are applied to the

 

                                                                51

 

      history to make a diagnosis of chronic

 

      constipation.

 

                From the baseline diary data we see that

 

      the median number of CSBMs was zero and SBMs 2.5

 

      and 2.9.  So, these patients fulfilled the

 

      inclusion criteria of having less than 3 CSBMs per

 

      week.  In fact, they had less than 3 SBMs per week

 

      by history and by baseline median data.  In

 

      addition, the number of SBMs with straining per

 

      week was 2.0 and 2.5 so the majority of spontaneous

 

      bowel movements were associated with straining.

 

      This confirms that the patient population was,

 

      indeed, constipated and, indeed, had chronic

 

      constipation.

 

                I have outlined the study design, the

 

      patient population, demographics and the baseline

 

      characteristics.  Now let's look at the primary

 

      efficacy variable.  For this endpoint we defined a

 

      responder as having an increase of at least one

 

      complete spontaneous bowel movement per week on

 

      average during the first 4 weeks of the treatment

 

      compared to the 2 weeks at baseline.  They had to

 

                                                                52

 

      have had at least 7 days of treatment.

 

                The results were positive.  In study 2301

 

      the responder rates for Zelnorm were 35.6 percent

 

      for 2 mg BID, 40.2 percent for 6 mg BID compared to

 

      26.7 percent for placebo.

 

                In study 2302 the responder rates were

 

      41.4 percent with 2 mg, 43.2 percent with 6 mg BID

 

      compared to 25.1 percent on placebo.  The p values

 

      were significant.  The 6 mg BID dose was

 

      consistently more efficacious, with deltas of 13.5

 

      percent and 18.1 percent for the 2 studies.

 

                Now, in order to confirm sustained

 

      efficacy of Zelnorm we analyzed those patients with

 

      an increase of at least one complete spontaneous

 

      bowel movement per week on average over the entire

 

      12-week trial duration, compared to the baseline

 

      period of 2 weeks.

 

                Again the results were positive and

 

      consistent with the results for the primary

 

      efficacy variable.  A treatment effect for the 6 mg

 

      BID dose over placebo of 13 and 18 percentage

 

      points for the 2 trials respectively was

 

                                                                53

 

      demonstrated.

 

                When we look at weekly responder rates

 

      using this responder definition, we can see that

 

      the effect of Zelnorm is seen early, within the

 

      first week, and is sustained throughout the entire

 

      treatment period.  In study 2302 we can see that

 

      the treatment effect is lost once the drug is

 

      withdrawn.  The percentage of responders in both

 

      Zelnorm groups reached the level of placebo within

 

      2 weeks after termination of treatment.  The

 

      results with the 6 mg BID dose are consistently

 

      superior to placebo, and here I am showing you the

 

      data for this dose alone so that you can more

 

      clearly see the benefit.

 

                When we look at the number of CSBMs, there

 

      is a marked increase within the first week of

 

      treatment with a significant improvement over

 

      placebo.  The number of CSBMs decreased on

 

      withdrawal of the drug, approaching but not

 

      reaching the level observed during the baseline

 

      period.  There was no rebound effect demonstrated.

 

      The effect was again more consistent with the  6 mg

 

                                                                54

 

      BID dose, which you can see more clearly on this

 

      slide.

 

                In order to further assess the benefit of

 

      Zelnorm, we conducted analyses on other

 

      constipation assessments which we defined a priori.

 

      Let me share these results with you.  Let's start

 

      with satisfaction with bowel habits.  Now, this is

 

      an important endpoint and an important measure of

 

      clinically relevant benefit.  The Rome committee

 

      has advocated the use of global endpoints and

 

      satisfaction really is a composite subjective

 

      assessment by the patient.  We asked the question

 

      how satisfied were you with your bowel habits over

 

      the past week?  We used a 5-point ordinal scale,

 

      with zero being a very great deal satisfied and 4

 

      being not at all satisfied.  So, improvement was

 

      represented by a decrease in the satisfaction

 

      score.

 

                Here we defined a responder as having a

 

      mean decrease of 1 or more on the 5-point scale

 

      over 12 weeks compared to baseline.  We

 

      subsequently have validated this data relating

 

                                                                55

 

      satisfaction scores to a relative shift in

 

      distribution, and we have looked at baseline

 

      standard deviations and week 12 standard deviations

 

      and a 1-point change on this score is associated

 

      with significant effect sizes.  We saw significant

 

      superiority of both doses of Zelnorm compared to

 

      placebo in this satisfaction endpoint.

 

                Stool form is another important marker of

 

      constipation, and also showed significant

 

      improvement

 

      on Zelnorm.  Stool form was 2.5 and 2.8 at baseline

 

      in the 2 studies respectively and on treatment with

 

      Zelnorm.  On treatment with Zelnorm this was

 

      maintained at around a score of 3.5 on the Bristol

 

      Stool Scale.

 

                On this slide you can see the change from

 

      baseline in stool form, which showed significant

 

      benefit over placebo for nearly all weeks.  Again,

 

      we can see the loss of benefit during the

 

      withdrawal period.

 

                What about straining, yet another

 

      important symptom of constipation?  For each bowel

 

                                                                56

 

      movement we asked the question did you have any

 

      straining?  This was a 3-point scale and the

 

      possible responses were zero, no straining; 1,

 

      acceptable straining; and 2, too much straining.

 

      We did not capture straining in the absence of a

 

      bowel movement.  We subsequently analyzed straining

 

      scores for spontaneous bowel movements and saw

 

      significant improvement on Zelnorm compared to

 

      placebo which was consistent over time, as we saw

 

      with the other variables.

 

                Now, what about the bothersomeness

 

      questions?  On a weekly basis patients were asked

 

      to evaluate the bothersomeness of constipation.

 

      Now, this is a global assessment in keeping with

 

      the global satisfaction assessment.

 

                In addition, we looked at the

 

      bothersomeness of a bowel movement bloating and

 

      distention and bothersomeness of abdominal

 

      discomfort.  As you heard from Dr. Prather earlier,

 

      patients with chronic constipation can present with

 

      bloating and abdominal discomfort, and we can see

 

      significant improvement in the bothersomeness of

 

                                                                57

 

      constipation on Zelnorm for both doses in both

 

      studies.  For abdominal bloating and distention and

 

      abdominal discomfort and pain we saw improvement in

 

      these symptoms in both studies, reaching

 

      statistical significance for the 2 doses in study

 

      2302.

 

                As you also heard from Dr. Prather, many

 

      of the currently available therapies for

 

      constipation in fact aggravate the symptoms of

 

      abdominal bloating and abdominal discomfort so this

 

      is another important benefit of Zelnorm.

 

                So, I have presented several secondary

 

      endpoints.  Now the question we asked ourselves was

 

      is there an association between responders for the

 

      primary endpoint and responders for the secondary

 

      efficacy variables.  Well, as you can see on this

 

      slide, there is a strong positive association

 

      between responders for the primary endpoint and

 

      response to secondary variables.  Remember, the

 

      primary responder definition was an increase of at

 

      least one CSBM per week compared to baseline over

 

      the first 4 weeks of the treatment.

 

                                                                58

 

                Improvement on stool form is represented

 

      by a positive increase, while improvement on the

 

      other variables is represented by a decrease in

 

      scores.  You can see the clear-cut difference

 

      between responders and non-responders, which is

 

      significant for each endpoint, which supports the

 

      CSBM primary endpoint.

 

                Now I will walk you through some of the

 

      additional analyses that were done.  In discussions

 

      with the FDA early last year, some other responder

 

      analyses were requested prior to database lock.

 

      One of these define a responder was having at least

 

      3 CSBMs per week for the first 4 weeks of the

 

      study.

 

                Now, this was a fixed definition with no

 

      comparison to baseline, and this was a high hurdle

 

      to achieve considering that the patient population

 

      had a median number of CSBMs of zero and a mean

 

      number of CSBMs of 0.5 at baseline.  So, reaching a

 

      level of greater than or equal to 3 CSBMs per week

 

      represents on average a 6-fold increase required to

 

      meet this responder definition.  As you can see

 

                                                                59

 

      though, Zelnorm was significantly better than

 

      placebo.  Both doses in both studies were

 

      significant, with deltas of 9 percent for the 6 mg

 

      BID dose in the 2 studies.  We saw similar results

 

      using this responder definition over the 12-week

 

      treatment period, with deltas of 9 and 11 percent

 

      for the 6 mg BID dose.

 

                So, we have demonstrated significant

 

      benefit of Zelnorm compared to placebo for our

 

      primary endpoint, and we have demonstrated

 

      significant benefit of Zelnorm compared to placebo

 

      in these analyses that were requested by the FDA.

 

                Let us now look at the effect of the

 

      number of bowel movements at baseline on response.

 

      Now, bearing in mind that we used the concept of

 

      complete spontaneous bowel movements, which is a

 

      relatively new concept, we wanted to see if

 

      baseline number of bowel movements, and that is

 

      all-comers, would affect our primary efficacy

 

      variable.

 

                So, we looked at patients who had less

 

      than 3 bowel movements per week at baseline.  What

 

                                                                60

 

      you can see is that Zelnorm is equally effective in

 

      the group that has less than 3 bowel movements per

 

      week as it is in the group that has more than 3

 

      bowel movements per week at baseline.

 

                We also did various subgroup analyses.

 

      These were planned prospectively but we did not

 

      attempt to meet a minimum number of patients in any

 

      subgroup.  Subsequently, some of these groups had

 

      very few subjects and this is reflected in the wide

 

      confidence intervals.  It is important to remember

 

      that the purpose of subgroup analyses is not to

 

      demonstrate efficacy as these analyses are not

 

      powered to detect statistical significance.  The

 

      purpose of subgroup analyses is to ensure that the

 

      effect in any subgroup is consistent with the

 

      overall effect and that we are not seeing any

 

      negative trends.

 

                Here I am showing you the data for the 6

 

      mg BID dose, and we can see the positive odds

 

      ratios for almost all the subjects that we

 

      analyzed.  In the group 65 years and older there

 

      was a total of 88 patients in the 6 mg BID group

 

                                                                61

 

      and 117 patients in the placebo group, with an odds

 

      ratio of 1 for the overall population.

 

                For the male patients, there were 106 on 6

 

      mg BID and 93 on placebo.  The odds ratio was

 

      positive at 1.36, and improvement on Zelnorm was

 

      seen for most variables in men.

 

                One of the issues I want to address now is

 

      the question how many of these patients in this

 

      chronic constipation program were, in fact, IBS

 

      patients, and did this have an effect on our

 

      results.  We did not actively exclude IBS patients

 

      from the study but when we went back to the patient

 

      history only 4 percent of patients had a diagnosis

 

      of IBS in their history.

 

                As we did not administer the Rome

 

      questionnaire for IBS, we decided to take a

 

      conservative approach to try and identify patients

 

      that we thought may be potentially IBS-like.  So,

 

      we identified all patients in whom abdominal pain

 

      was the main complaint at baseline, and this was

 

      about 12 percent of our patients.  In addition, we

 

      included patients who had abdominal pain that may

 

                                                                62

 

      not necessarily have been their predominant symptom

 

      but they also had diarrhea together with this

 

      abdominal pain.  So, criteria (a) and (b) on this

 

      slide come from the history and criteria (c) comes

 

      from the baseline diary data.

 

                We came up with a total of 22 percent of

 

      our patients as possibly having IBS.  These were

 

      equally represented in the 3 treatment arms.  So,

 

      we felt confident that almost 80 percent of our

 

      patients were, indeed, chronic constipation

 

      patients and did not have IBS.  However, we were

 

      interested to see what the efficacy results would

 

      look like if we excluded those patients who were

 

      IBS-like.

 

                Here is the pooled data.  In this group,

 

      without IS-like features, in other words, the pure

 

      chronic constipation population, you can clearly

 

      see the benefit of Zelnorm with improvement over

 

      placebo of 40 percent in the 2 mg BID group and 18

 

      percent in the 6 mg BID group.  We can compare this

 

      to the deltas in the pooled ITT primary efficacy

 

      analysis in which there was a 13 percent delta in

 

                                                                63

 

      the 2 mg BID group and 16 percent delta in the 6 mg

 

      BID group.  So, in this pooled subgroup analysis

 

      the results in the pure chronic constipation group

 

      are even more robust than in the ITT analysis.

 

                So, I have presented data here that

 

      demonstrate the efficacy of Zelnorm in patients

 

      with chronic constipation.  The onset of action is

 

      early.  The effect is sustained, and there is no

 

      rebound phenomenon.

 

                We have measured the efficacy of Zelnorm

 

      using a number of parameters and Zelnorm is

 

      efficacious for multiple symptoms of chronic

 

      constipation which include straining, hard stools

 

      and infrequent stools, with overall improved

 

      satisfaction.  The 6 mg BIT dose has emerged as

 

      consistently more efficacious than the 2 mg BID

 

      dose.

 

                Now let's look at the safety data.  I am

 

      going to go through the 12-week data looking at

 

      exposure, adverse event profile, serious adverse

 

      events, and laboratory evaluations, and then the

 

      long-term safety profile from the extension study. 

 

                                                                64

 

      This was a 13-month extension study, providing a

 

      total of 16 months of data for the groups that

 

      received Zelnorm in the core study.

 

                Let's start with overall exposure.  The

 

      intended study duration was 84 days.  Exposure was

 

      comparable across all treatment groups.  The mean

 

      duration of treatment was 80 days, and 84 percent

 

      of patients completed at least 11 weeks of

 

      treatment and 69 percent had more than 85 days of

 

      exposure in this 12-week period.  The total number

 

      of patients who experienced any adverse event was

 

      60 percent in the placebo group, 57 percent in the

 

      6 mg BID group and 56 percent in the 2 mg BID

 

      group.  The most frequent adverse events were

 

      headache, nasopharyngitis , diarrhea, abdominal

 

      pain and nausea.  The only notable adverse event

 

      seen more frequently with Zelnorm was diarrhea, as

 

      you would expect given the pharmacodynamic action

 

      of this drug.

 

                When we look at the most frequent adverse

 

      events leading to discontinuation, we see abdominal

 

      pain, diarrhea, abdominal distension, nausea and

 

                                                                65

 

      headache.  On this table we have included all

 

      discontinuations in which there were at least 5

 

      patients on any dose of Zelnorm.  Overall, the only

 

      one where discontinuations appeared to be

 

      dose-dependent was diarrhea, with a discontinuation

 

      rate of less than 1.0 percent on the 6 mg BID dose

 

      and 0.3 percent for the 2 mg BID dose.

 

                Let's look at the diarrhea in more

 

      detail--4.2 percent with the 2 mg BID dose, 6.6

 

      percent with the 6 mg BID dose versus 3 percent

 

      with placebo.  Over 80 percent of patients who

 

      experienced diarrhea had only a single episode, and

 

      the median duration of the first episode was about

 

      2 days.  Most diarrhea occurred on the first day of

 

      treatment.

 

                When we look at the characteristics of the

 

      stool on the first day of diarrhea, the median

 

      number of bowel movements was 3 in the placebo

 

      group, 2 on Zelnorm 2 mg BID and 3 in the mg BID

 

      group.  The median stool form was essentially

 

      similar across all treatment groups at 5.7 for

 

      placebo and 6 and 6.3 for the 2 Zelnorm doses

 

                                                                66

 

      respectively.

 

                Most patients who had diarrhea continued

 

      on their medication and took no action.  There were

 

      more patients on 6 mg BID who adjusted their dose

 

      or temporarily interrupted therapy but there were

 

      very few patients who discontinued permanently

 

      because of diarrhea.  None of these cases met the

 

      definition of a serious adverse event or the

 

      definition of clinically significant consequences

 

      of diarrhea such as hypovolemia, hypokalemia or the

 

      need for IV fluids or electrolyte replacement.

 

                Let's look at serious adverse events.

 

      Incidence rates were comparable across all

 

      treatment groups.  There were very few

 

      discontinuations due to these serious adverse

 

      events.  There were no deaths during the course of

 

      the study but there was one death 67 days after the

 

      last dose of study medication in study 2302.  This

 

      was an 85 year-old man who had been on Zelnorm 2 mg

 

      BID.  He died from respiratory failure and

 

      mesothelioma secondary to preexisting asbestosis.

 

                We also evaluated a number of laboratory

 

                                                                67

 

      parameters.  There was a low frequency of notable

 

      abnormalities which were essentially similar across

 

      all treatment groups.

 

                The incidence of any abdominal or pelvic

 

      surgeries in the Zelnorm-treated group was lower

 

      than in the placebo group.  One patient in study

 

      2302, on Zelnorm 6 mg BID, had a cholecystectomy.

 

      The investigator assessed the event as not related

 

      to study medication.  The incidence of other

 

      surgeries was well balanced between Zelnorm and

 

      placebo.

 

                Now let's look at the 13-month extension

 

      study, and 842 patients entered the extension

 

      phase.  And, 61.7 percent were exposed to at least

 

      12 months of Zelnorm; 46 percent of patients

 

      discontinued over the 13 months.  Most

 

      discontinuations were for unsatisfactory

 

      therapeutic responses, with very few

 

      discontinuations for adverse events.  The same

 

      adverse events predominated as during the core

 

      period.  Frequencies followed the same pattern as

 

      seen in the core studies, although the incidence

 

                                                                68

 

      rates were generally higher due to the longer

 

      duration of exposure.  No relevant differences were

 

      seen in the rates between the 2 doses of Zelnorm.

 

      There were no deaths in the 13-month extension.

 

                So, to summarize our safety conclusions,

 

      the incidence of adverse events on Zelnorm in

 

      chronic constipation is similar to placebo, except

 

      for diarrhea, which is what we would expect from

 

      the pharmacodynamic profile.  There were low

 

      discontinuation rates due to adverse events.  The

 

      long-term safety profile was similar to the profile

 

      in the core 12-week studies.  Zelnorm, therefore,

 

      as been demonstrated to be safe and well tolerated

 

      in patients with chronic constipation.

 

                What are our final overall conclusions?

 

      Zelnorm is effective in the treatment of multiple

 

      symptoms of chronic constipation, with the 6 mg BID

 

      dose consistently more efficacious than the 2 mg

 

      BID dose.  Zelnorm improves satisfaction with bowel

 

      habits; straining; hard and lumpy stools; and

 

      infrequent bowel movements.  In addition, Zelnorm

 

      has a favorable safety profile.

 

                                                                69

 

                Therefore, we are asking for an approval

 

      for Zelnorm for the treatment of patients with

 

      chronic constipation and relief of associated

 

      symptoms of straining, hard or lumpy stools, and

 

      infrequent defecation.

 

                That concludes my presentation.  Thank you

 

      very much.  I would now like to introduce Dr. Bo

 

      Joelsson, vice president and head of clinical

 

      research and development for gastroenterology, who

 

      will present the general safety overview.  Dr.

 

      Joelsson?

 

                        Zelnorm Safety Overview

 

                DR. JOELSSON:  Good morning, Dr. Fogel,

 

      advisory committee, representatives from the FDA,

 

      ladies and gentlemen.  My name is Bo Joelsson and I

 

      am the head of GI research and development at

 

      Novartis.

 

                Today I will review with you the overall

 

      safety experience with Zelnorm, and demonstrate to

 

      you that Zelnorm is a safe and well-tolerated drug.

 

      This is what I am going to review with you today.

 

      First I will show that the positive safety profile

 

                                                                70

 

      of Zelnorm that was established at the time of

 

      approval in July, 2002 is confirmed in our chronic

 

      constipation clinical program.  Secondly, I will

 

      briefly present a few safety topics that we have

 

      agreed with the FDA to discuss at this meeting:

 

      serious consequences of diarrhea; rectal bleeding;

 

      ischemic colitis and other forms of intestinal

 

      ischemia; biliary tract disorders and ovarian

 

      cysts.  Finally, I will summarize our experience

 

      demonstrating that Zelnorm is a safe and well

 

      tolerated drug.

 

                The three most common adverse events that

 

      were reported at approval in July, 2002 were

 

      headache, abdominal pain and diarrhea, and the

 

      incidence of diarrhea was higher on Zelnorm.

 

                This slide shows that the adverse event

 

      data from the chronic constipation clinical trials

 

      compared favorably to the IBS constipation data.

 

      Headache incidence is similar between the treatment

 

      arms.  Abdominal pain was less common in the

 

      chronic constipation studies than in the IBS

 

      trials, demonstrating that the chronic constipation

 

                                                                71

 

      population is different from the IBS population

 

      which is characterized by abdominal pain.  The

 

      incidence of abdominal pain in Zelnorm and placebo

 

      treated patients indicates that abdominal pain as

 

      an adverse event is not related to Zelnorm

 

      treatment.  As in IBS, the reported incidence of

 

      diarrhea is higher on Zelnorm.  Adverse events

 

      leading to discontinuation are also low in the

 

      chronic constipation clinical trials.

 

                At approval in July, 2002 the incidence of

 

      serious adverse events was low.  This was 1.6

 

      percent on Zelnorm as compared to 1.1 percent on

 

      placebo.  Serious adverse events leading to

 

      discontinuation of study drug were 0.7 percent on

 

      Zelnorm and 0.6 on placebo.

 

                The incidence of serious adverse events in

 

      the chronic constipation clinical trials was

 

      similar to that in the IBS clinical program.  The

 

      incidence of serious adverse events leading to

 

      discontinuation was lower and identical in Zelnorm

 

      and placebo treated patients.

 

                The clinical trial adverse event data

 

                                                                72

 

      collected in chronic constipation clinical program

 

      supports and strengthens the positive safety

 

      profile established at the time of approval.  With

 

      the exception of diarrhea, the Zelnorm safety

 

      profile is similar to that of placebo.

 

                We have at this time experience with use

 

      of Zelnorm both from clinical trials in patients

 

      with IBS, chronic constipation and upper GI

 

      indications, as well as postmarketing clinical use.

 

      In clinical trials more than 15,000 patients have

 

      been included and more than 11,000 subjects have

 

      taken Zelnorm, which corresponds to 3,456

 

      patient-years of Zelnorm experience.  More than

 

      10,000 patients have been involved in controlled

 

      clinical trials and close to 7,000 of them have

 

      been on Zelnorm.

 

                Zelnorm is currently registered in 56

 

      countries worldwide.  It has been available since

 

      January, 2001 and here, in the United States, since

 

      July, 2002.  Approximately 3 million patients have

 

      been treated, 2 million in the United States.  That

 

      corresponds to more than 350,000 patient-years of

 

                                                                73

 

      treatment and more than 230,000 patient-years in

 

      the United States.

 

                We have agreed with the FDA to discuss

 

      several specific safety topics at this advisory

 

      committee meeting.  The first of these is serious

 

      consequences of diarrhea.  Diarrhea is an expected

 

      effect of Zelnorm in some patients due to the

 

      mechanism of action.  The diarrhea is generally

 

      mild, is generally transient and self-limiting, and

 

      rarely leads to serious consequences.

 

                A patient is defined as having a serious

 

      consequence of diarrhea if one or more of the

 

      following took place:  A serious adverse event was

 

      reported as defined by regulatory requirements; if

 

      hypokalemia occurred; if hypovolemia was diagnosed;

 

      if IV fluids were administered; or any medically

 

      significant events related to diarrhea occurred,

 

      such as hypotension, syncope or cardiac effects.

 

                We carefully reviewed our clinical trial

 

      experience of more than 11,000 patients using this

 

      definition in order to identify cases of serious

 

      consequences of diarrhea, and this is our clinical

 

                                                                74

 

      trial experience.  Six cases of serious

 

      consequences of diarrhea were found in the clinical

 

      studies on Zelnorm with more than 11,000 patients.

 

      Four of these patients required hospitalization.

 

      Two received IV fluids.  Two had actually possible

 

      other causes.  One reported gastroenteritis and one

 

      reported antibiotic-induced diarrhea.  All patients

 

      recovered without complications and four of them

 

      were actually able to continue on study medication

 

      after these episodes.

 

                From the postmarketing experience in

 

      approximately 3 million patients, 30 cases have

 

      been reported; 16 were hospitalized; 11 received IV

 

      fluids; 8 exhibited hypotension; 4, syncope; and 4

 

      were considered life-threatening by the reporting

 

      physician; 1 had hypokalemia.  One fatality from

 

      aspiration pneumonia was reported in a patient with

 

      acute pancreatitis and chronic liver cirrhosis.

 

                This demographic information on the 30

 

      patients with serious consequences of diarrhea in

 

      the postmarketing experience.  There was a wide age

 

      spectrum, 18 to 82 years.  The median age was 49

 

                                                                75

 

      years and only 9 patients were older than 65,

 

      indicating that this is not an elderly specific

 

      issue.  As is expected, most were women, reflecting

 

      the label in most countries.  Serious consequences

 

      of diarrhea mostly occurred in patients on 12 mg of

 

      Zelnorm per day but were also reported in some

 

      patients on a lower dose.

 

                In clinical trials diarrhea usually

 

      occurred during the first days of treatment, as we

 

      heard before.  This was also true for serious

 

      consequences of diarrhea in the postmarketing

 

      experience.  It occurred within 5 days in all cases

 

      and the median time was 1 day.

 

                In conclusion, serious consequences of

 

      diarrhea are rare in clinical trials and very

 

      rarely reported in the postmarketing experience.

 

      All cases resolved without sequelae.

 

                Rectal bleeding is of special interest

 

      because of its possible relationship with serious

 

      colon conditions.  We have carefully reviewed our

 

      clinical trial data for terms that indicate the

 

      presence of rectal bleeding, such as rectal

 

                                                                76

 

      hemorrhage, melena, hematochezia, etc., etc.  We

 

      found that the presence of rectal bleeding was very

 

      similar in patients on Zelnorm and placebo in our

 

      controlled clinical trials.

 

                From the postmarketing experience of

 

      approximately 3 million patients, 82 cases of

 

      rectal bleeding were reported. Twenty-one were

 

      reported in conjunction with suspected ischemic

 

      colitis; 1 from another form of intestinal

 

      ischemia; 3 from other forms of colitis.  In 23

 

      cases hemorrhoids were a possible source of

 

      bleeding.  The rest of the cases listed on this

 

      slide show varying etiologies.  Fifteen of the

 

      patients were not investigated.

 

                Our clinical trial data indicated a

 

      similar reporting rate in Zelnorm- and

 

      placebo-treated patients.  There are rare reports

 

      of rectal bleeding from postmarketing experience,

 

      which indicates that Zelnorm therapy is not

 

      causally related to the rectal bleeding.

 

                Now, the occurrence of ischemic colitis

 

      and other forms of intestinal ischemia is a concern

 

                                                                77

 

      with drugs used to treat IBS with diarrhea.  These

 

      drugs block the 5-HT                                                     

          3 receptor and, thus, have a

 

      very different mechanism of action than Zelnorm,

 

      which is a 5-HT                                                        4

receptor agonist used to treat IBS

 

      with constipation.  Nonetheless, since these are

 

      potentially serious conditions and Zelnorm affects

 

      the serotonin receptor, it is important to

 

      carefully assess whether Zelnorm therapy could

 

      increase the risk of intestinal ischemia.

 

                Ischemic colitis is a rare condition in

 

      the general population.  When it occurs, it is

 

      potentially serious but is generally mild and

 

      transient.  It is characterized by mucosal erosions

 

      seen at colonoscopy, with rectal bleeding and

 

      abdominal pain being the most common clinical

 

      presentations.  Usually no specific treatment is

 

      needed and surgical intervention is rarely

 

      indicated.

 

                While ischemic colitis is very rare in the

 

      general population, it is more commonly reported in

 

      IBS patients.  In a study from the Medi-Cal claims

 

      database, 179 cases per 100,000 patient-years were

 

                                                                78

 

      found in IBS patients versus 47 cases per 100,000

 

      patient-years in non-IBS patients.  In a study from

 

      the United Health Care claims database, with a

 

      younger patient population, the corresponding

 

      numbers were 43 in IBS patients and 7 in non-IBS

 

      patients.  In the CORI database which collects data

 

      from endoscopy units all over the United States,

 

      ischemic colitis was found in 93 per 100,000

 

      colonoscopies in patients with IBS-like symptoms

 

      while there were 21 cases per 100,000 screening

 

      colonoscopies in asymptomatic individuals.  All of

 

      these cases were endoscopically verified and in

 

      most cases supported by histology.

 

                It has been suggested by Dr. Brinker et

 

      al., from the FDA, that the increased incidence of

 

      ischemic colitis in IBS is the result of

 

      misdiagnosis.  Dr. Brinker published this analysis

 

      from the patients from the United Health Care

 

      study.  He found evidence for misdiagnosis during

 

      the first 3 weeks after IBS diagnosis.  However,

 

      when patients with IBS were followed for more than

 

      a year, he still found an increased rate of

 

                                                                79

 

      ischemic colitis, 53 per 100,000 patient-years.

 

                Thus, ischemic colitis can be misdiagnosed

 

      as IBS during the first weeks of treatment, but

 

      patients with a stable IBS diagnosis for more than

 

      1 year still have an increased risk of ischemic

 

      colitis diagnosis.

 

                Now, there are two, maybe more, possible

 

      hypotheses why the rate of ischemic colitis in IBS

 

      is increased.  Ascertainment bias because of the

 

      documented fact that IBS patients are investigated

 

      two to three times more than the general

 

      population, and/or because there are currently

 

      unknown common pathophysiological mechanisms that

 

      we don't know about today.

 

                We carefully reviewed all cases of rectal

 

      bleeding, colonoscopy and reports of colitis in our

 

      clinical trials to identify possible cases of

 

      ischemic colitis and there were no cases of

 

      ischemic colitis identified in any of our clinical

 

      trials involving more than 11,000 patients on

 

      Zelnorm.  However, one placebo case with ischemic

 

      colitis was identified in our clinical trials.

 

                                                                80

 

                From postmarketing experience as of June

 

      1, 2004, 26 cases of suspected ischemic colitis

 

      have been reported.  This corresponds to a

 

      reporting rate of 7 cases per 100,000 patient-years

 

      worldwide and 12 per 100,000 patient-years in the

 

      United States.  This rate is consistent with the

 

      background rate incidence in IBS patients.

 

                The reported cases of ischemic colitis do

 

      not exhibit any distinct pattern with regard to

 

      duration of treatment, dose of drug, age of

 

      patients, co-morbid conditions, or other

 

      demographic subgroups.  The absence of ischemic

 

      colitis cases in clinical studies and the low

 

      reporting rate in postmarketing experience suggest

 

      that Zelnorm treatment does not increase the risk

 

      of ischemic colitis.

 

                Now, these findings are not surprising

 

      since Zelnorm is not expected to cause

 

      vasoconstriction as there are no 5-HT                                    

                                                        4 receptors in

 

      the human vascular system.  This is further

 

      supported by preclinical studies.  In vivo animal

 

      studies have demonstrated no effect on colonic

 

                                                                81

 

      vascular conductance which is a measure of vasal

 

      activity.  In addition, although tegaserod has

 

      negligible affinity for the 5-HT                                         

                                          3 receptor,

 

      tegaserod has affinity for the 5-HT1B receptor but

 

      it does not cause vasoconstriction, as illustrated

 

      in this graph.

 

                This graph depicts the results of adding

 

      sumatriptan and ergotamine, which are two known

 

      5-HT1B agonists, and tegaserod to a preparation of

 

      isolated coronary arteries from non-human primates.

 

      As expected, ergotamine and sumatriptan cause

 

      marked contraction while tegaserod has no effect.

 

                In conclusion, there is no evidence for a

 

      causal relationship between Zelnorm and ischemic

 

      colitis.  Preclinical studies have clearly

 

      demonstrated that tegaserod has no vasoconstrictive

 

      potential.  There have been no cases of ischemic

 

      colitis in clinical trials on Zelnorm, and the

 

      reporting rate in the postmarketing experience is

 

      consistent with the background rate of IC in the

 

      IBS population even taking under-reporting into

 

      account.  These data indicate that Zelnorm does not

 

                                                                82

 

      increase the risk of ischemic colitis.

 

                Now, there have been four spontaneous

 

      reports of fatalities in patients with intestinal

 

      ischemia from postmarketing reviews.  We take these

 

      reports very seriously and have investigated them

 

      thoroughly.  Based on our individual and careful

 

      review of each case, we are confident that Zelnorm

 

      did not cause these fatalities.

 

                The four fatalities are as follows: One

 

      case with untreated central line sepsis and

 

      ischemic colitis; one case of untreated chronic

 

      abdominal angina; one case with untreated

 

      hypothyroidism leading to severe fecal impaction;

 

      and one case of multi-organ failure from unknown

 

      cause.

 

                Dr. Shetzline has carefully investigated

 

      these cases and he will now discuss them in some

 

      detail with you.  Please, Dr. Shetzline?

 

                             Fatality Cases

 

                DR. SHETZLINE:  Thanks, Dr. Joelsson.  I

 

      am Michael Shetzline, an gastroenterologist and a

 

      senior medical director at Novartis, responsible

 

                                                                83

 

      for Zelnorm in the United States.  Myself and Dr.

 

      Christian Avery are clinical safety experts

 

      responsible for evaluation of these cases.

 

                I would like to review these cases in some

 

      detail.  Given the complicated nature of the cases,

 

      it is important for us to go into some detail in

 

      order to separate out and look at the medical

 

      issues and make them clear.  The first case is a 76

 

      year-old woman.  Her past medical history is

 

      significant for 16 years of constipation.  She had

 

      IBS with constipation diagnosed in the year 2000

 

      and started on Zelnorm in November of 2002.  She

 

      also had dementia of the Alzheimer's type.

 

                In late August of 2003, after 282 days of

 

      Zelnorm use the patient was found "down" at home.

 

      She presented at the emergency department and was

 

      admitted with abdominal pain, vomiting,

 

      hypotension, hypothermia and altered mental status.

 

      Her urine eventually grew E. coli and an abdominal

 

      CT noted dilated loops of small bowel, consistent

 

      with partial small bowel obstruction,

 

      diverticulosis and focal ischemic changes of the

 

                                                                84

 

      left colon.  She was treated with antibiotics and

 

      hydration.

 

                During this admission she had a

 

      colonoscopy for an incidental episode of guaiac

 

      positive stool, and this revealed sigmoid and

 

      splenic flexure ulcers with areas of regeneration

 

      and healing, consistent with ischemic colitis.

 

      Zelnorm was discontinued at this time.  Biopsies

 

      were consistent with ischemic colitis and she was

 

      placed on bowel rest and provided total parenteral

 

      nutrition.

 

                She was eventually transferred to an

 

      extended care facility and had two colonoscopies on

 

      September 17th and 19th.  Both noted improved

 

      colonic mucosa, resolving ischemic colitis.  This

 

      is the usual expected course of ischemic colitis.

 

      However, she remained on TPN, total parenteral

 

      nutrition.  She became hypotensive with E. coli UTI

 

      and was readmitted on September 26th for failure to

 

      thrive, febrile and more acutely ill.

 

                After discussion with the family and

 

      patient, no heroic surgical interventions and/or

 

                                                                85

 

      CPR were to be performed; only supportive care.

 

      She was diagnosed with central line sepsis and,

 

      given her medical co-morbidities and discussion

 

      with the patient and family, a "do not resuscitate"

 

      order was initiated.  Her antibiotics were

 

      discontinue on October 1st and she expired.  In

 

      summary, this event of ischemic colitis resulted

 

      from hypotension and possibly urosepsis.

 

                The second case is a 66 year-old female

 

      who had a past medical history of hypertension,

 

      chronic obstructive pulmonary disease and tobacco

 

      abuse.  She had a prior stroke in 1997 due to small

 

      vessel disease, and carried a prior diagnosis of

 

      non-specific chronic colitis.  Significantly, she

 

      had symptoms of abdominal angina for 2-3 years

 

      characterized by chronic abdominal pain with food

 

      intake, and this resulted in 36 lbs of weight loss

 

      during this interval.  Her IBS was diagnosed in

 

      January of 2000.

 

                In October of 2003 she had continued and

 

      more severe post-prandial abdominal pain and

 

      constipation.  On October 10th she was given

 

                                                                86

 

      samples of Zelnorm, 6 mg BID, by her primary care

 

      physician.  She was not given a prescription and

 

      her caregiver, who was responsible for

 

      administering all her medications, the medications

 

      taken by the patient, does not recall the patient

 

      taking Zelnorm.  He does specifically recall her

 

      increasing use of Vicodin due to this more severe

 

      abdominal pain.

 

                On October 15th she was admitted to the

 

      hospital with severe abdominal pain and bloody

 

      diarrhea.  Zelnorm was not listed as an active

 

      medication in any of her admission documents.

 

                On the 19th she developed acute abdomen

 

      and had an exploratory laparotomy for, quote,

 

      probable chronic intestinal ischemia, acutely

 

      worse, end quote.  The laparotomy revealed

 

      infarcted bowel from the ligament of Treitz to the

 

      terminal ileum, cecum, and proximal ascending

 

      colon, consistent with occlusion of the superior

 

      mesenteric artery.  Given the extensive bowel

 

      necrosis, comfort measures were provided and she

 

      expired.  The cause of death was listed as bowel

 

                                                                87

 

      infarction due to peripheral vascular disease.  In

 

      summary, this is the natural history of end-stage

 

      chronic abdominal or mesenteric angina and it is

 

      likely Zelnorm was not taken by this patient.

 

                The third case is a 41 year-old woman who

 

      had a very significant past medical history of

 

      chronic obstructive pulmonary disease.  She had a

 

      very extensive history of tobacco abuse, with 60-90

 

      pack-years of tobacco use for a 41 year-old woman.

 

      She also had asthma, prior alcohol and illicit drug

 

      use, as well as obsessive-compulsive disorder.  She

 

      had peripheral vascular disease with claudication,

 

      constipation, recurrent urinary tract infections

 

      and hypothyroidism.  She also had a significant

 

      abdominal event due to appendectomy with a rupture

 

      which resulted in abscess formation and a partial

 

      colectomy.  She had medical and medication

 

      non-compliance, as noted in a primary care visit

 

      from November of 2003.

 

                This individual was presumably prescribed

 

      Zelnorm in March of 2003, however, these documents

 

      were not available for review.  We have no

 

                                                                88

 

      follow-up from the March presumed prescription and

 

      the November primary care records which document

 

      her non-compliance.  She developed severe abdominal

 

      pain and she collapsed with a cardiorespiratory

 

      arrest.  After an emergency medical service call

 

      she was resuscitated and admitted.

 

                It is important to note that admission

 

      documents list only her Lithobid and Seroquel as

 

      active medications.  They do not list Zelnorm or

 

      her thyroid supplement.  These documents include

 

      emergency medical service notes at home, admission

 

      notes and multiple physician evaluations.

 

                On admission, her abdominal x-ray revealed

 

      free air in the abdomen and an exploratory

 

      laparotomy demonstrated a rectal sigmoid densely

 

      packed with rock-hard stool.  She had ischemic

 

      colitis and enteritis involving the colon and

 

      terminal ileum and early gangrene of the distal

 

      bowel.  She had marked dilatation, a picture

 

      consistent with toxic megacolon.

 

                She had a sub-total colectomy with

 

      ileostomy and was treated with ventilatory support,

 

                                                                89

 

      broad-spectrum antibiotics and vasopressors.  A

 

      subsequent neurology evaluation revealed anoxic

 

      brain injury with diffuse edema and a suspicion of

 

      herniation.  She developed multi-organ failure and

 

      expired three days after admission.  In summary,

 

      this patient had a bowel obstruction from likely

 

      untreated hypothyroidism due to her medication

 

      non-compliance and a secondary perforation.  Given

 

      her medical and medication non-compliance, it is

 

      likely she never took Zelnorm.

 

                The last case is a 67 year-old woman who

 

      had a very significant history of heart disease,

 

      with known coronary disease, a prior coronary

 

      bypass graft procedure, angioplasty with stent

 

      placements, known occluded grafts, congestive heart

 

      failure, hypotension, atrial fibrillation and

 

      diabetes.  She had chronic and acute renal failure.

 

      She was on Zelnorm 6 mg BID for an unknown

 

      indication from June 16th to August 7th, the date

 

      of this event.

 

                She as admitted at this time with

 

      progressive shoulder and chest pain, as well as

 

                                                                90

 

      shortness of breath, and was hospitalized, on

 

      telemetry for a rule-out myocardial infarction, on

 

      August 7th.  On admission, her abdomen was soft,

 

      non-tender.  Her lungs had few bibasal rales and

 

      her extremities showed trace pedal edema.

 

                It is important to note that at this time

 

      she had no diarrhea, no melena and no bright red

 

      per rectum.  On hospital day 3 she complained of

 

      abdominal pain and nausea, and surgical consult

 

      indicated a soft abdomen which was not distended.

 

      She did, however, have left lower quadrant

 

      tenderness and a questionable diverticulitis.  An

 

      abdominal x-ray at this time showed a large amount

 

      of fecal material in the colon  There was no

 

      gaseous distention or free air.

 

                On the same day laboratory results

 

      indicated an amylase of over 7,000 and a lipase of

 

      over 400.  A pulmonary consult for dyspnea

 

      indicated respiratory failure and she required

 

      mechanical ventilation.  At this time she was

 

      evaluated for bronchitis, pneumonia, rule-out

 

      abdominal sepsis, rule-out ischemic colitis,

 

                                                                91

 

      coronary disease and hypotension.

 

                A clinical evaluation noted, quote, in

 

      view of her acute deterioration and chronic medical

 

      problems, her prognosis is extremely poor.

 

      Consequently, continuation of heroic interventions

 

      may be inappropriate, end of quote.  A cardiologist

 

      summary indicated hypotension and it was felt that

 

      the patient had a catastrophic abdominal event.

 

      This may have included ischemic bowel, possible

 

      perforation, pancreatitis, acute renal failure, all

 

      in addition to her known co-morbidities of ischemic

 

      cardiomyopathy, congestive heart failure, renal

 

      failure and diabetes.  The patient was made a "no

 

      code" and died on hospital day 4.

 

                The death certificate listed

 

      cardiorespiratory failure as the primary immediate

 

      cause of death.  Other factors included shock,

 

      pancreatitis and inflammatory bowel disease.  In

 

      summary, this patient experienced cardiovascular

 

      collapse with a history of coronary disease and

 

      congestive heart failure, as well as other medical

 

      co-morbidities.  This was likely unrelated to

 

                                                                92

 

      Zelnorm.

 

                Now I would like to return the safety

 

      update to Dr. Joelsson.

 

                  Zelnorm: Safety Overview (continued)

 

                DR. JOELSSON:  Thank you, Dr. Shetzline.

 

      In summary, these four cases, as you may

 

      understand, are very complicated.  In two cases it

 

      is actually unclear if the patients actually took

 

      Zelnorm in the first place.  In our opinion and

 

      those of external experts that have reviewed these

 

      cases, the evidence does not support that the death

 

      of these patients was caused by or contributed to

 

      by Zelnorm.

 

                At the time of approval in July, 2002,

 

      biliary tract disorders were discussed because

 

      there was an imbalance of cholecystectomies

 

      introduction he clinical trials.  When pooling the

 

      clinical trial data, there is still an imbalance in

 

      favor of placebo, although smaller than was seen in

 

      the approval trials.

 

                An adjudication was performed with outside

 

      experts, resulting in a rate of 0.06 percent in

 

                                                                93

 

      Zelnorm-treated patients versus 0.03 percent on

 

      placebo.

 

                In the postmarketing experience there were

 

      30 reports of biliary tract events in approximately

 

      3 million patients, and 18 were cholecystectomies;

 

      2 were cholelithiasis; and 10 were other events.

 

      There were no serious sequelae reported from these

 

      patients.

 

                In order to further elucidate the possible

 

      effects of Zelnorm on gallbladder function a very

 

      thorough study was performed using dynamic

 

      ultrasound measurements.  No effect on gallbladder

 

      function was detected.  There was no impact on

 

      ejection fraction, ejection rate and period, or

 

      maximal emptying.  There was no impact on fasting

 

      and residual volume, and there were no stimulus

 

      effects on gallbladder contraction during fasting.

 

      Based on this data, it is unlikely that Zelnorm

 

      affects gallbladder function.

 

                At approval there was also discussion

 

      about ovarian cysts.  However, ovarian cysts are

 

      very well balanced in the clinical trials and there

 

                                                                94

 

      are very rare reports from the postmarketing

 

      experience.  Our conclusion from these data is that

 

      Zelnorm treatment does not increase the risk of

 

      ovarian cysts.

 

                Zelnorm has been extensively studied in

 

      clinical trials and postmarketing experience, and

 

      the safety profile of Zelnorm is very favorable.

 

      In fact, Zelnorm has the overall safety profile of

 

      placebo, with the only exception being diarrhea.

 

      However, serious consequences of diarrhea are very

 

      rare and do not result in significant clinical

 

      sequelae.  Evidence from either clinical trials or

 

      postmarketing experience does not suggest that

 

      Zelnorm increases the risk of rectal bleeding,

 

      ischemic colitis, other forms of intestinal

 

      ischemia, cholecystectomies or ovarian cysts.

 

                Zelnorm is a safe and well-tolerated drug

 

      that has a safety profile that supports its use in

 

      chronic constipation patients.  Thank you.  I would

 

      now like to introduce Dr. Schoenfeld who will

 

      discuss with you his benefit/risk assessment.

 

                        Benefit/Risk Assessment

 

                                                                95

 

                DR. SCHOENFELD:  Well, good morning, Dr.

 

      Fogel, members of the advisory committee, FDA

 

      officers, audience members.  I am Philip

 

      Schoenfeld, a gastroenterologist at the University

 

      of Michigan School of Medicine.  It is my pleasure

 

      to present a risk/benefit analysis of the use of

 

      tegaserod and traditional therapies for the

 

      management of constipation.

 

                Now, I sympathize with the members of the

 

      advisory committee.  You have been sitting here now

 

      for over an hour and a half.  I imagine that I

 

      should keep this presentation brief but also as

 

      stimulating as possible to maintain your attention.

 

      I am going to present an evidence-based medicine

 

      analysis, revising the randomized, controlled trial

 

      data about the efficacy for tegaserod and

 

      traditional therapies in the management of

 

      constipation, and review the best available

 

      clinical trial data about the safety of tegaserod

 

      and traditional therapies in the management of

 

      constipation.

 

                I think it is particularly important to

 

                                                                96

 

      consider the risk/benefit analysis not only for

 

      tegaserod but also for alternative therapies for

 

      constipation because, as a practicing

 

      gastroenterologist, when I am treating a patient

 

      with constipation I have to consider the

 

      risk/benefit analysis for all of these possible

 

      treatments when I select the best possible

 

      treatment for my patient, and I certainly think

 

      this is an important topic.  As Dr. Prather pointed

 

      out during her presentation, constipation is

 

      common.  It negatively impacts the quality of life

 

      for patients who actively seek medical care, and

 

      many constipated patients are dissatisfied with

 

      available treatments.

 

                Let's stop for a moment and think about

 

      that last statement, and look at the randomized,

 

      controlled trial data about traditional therapies

 

      for constipation to try to determine why

 

      constipated patients might not be satisfied with

 

      available therapies.

 

                This is a partial list of the commonly

 

      used treatments for constipation.  They include

 

                                                                97

 

      surface-acting agents like dioctyl sodium

 

      sulfosuccinate--I had to practice saying that and

 

      hereafter I will refer to it as Colace; bulking

 

      agents like psyllium; stimulant laxatives and

 

      osmotic laxatives like PEG-3350.  These are all

 

      FDA-approved treatments for constipation.

 

                Dr. Prizont, in his efficacy section in

 

      the FDA briefing document, provided a brief but

 

      very balanced review about traditional therapies

 

      for constipation.  He specifically noted that there

 

      are some randomized, controlled trials looking at

 

      the benefits of traditional therapies for

 

      constipation but many of these were conducted under

 

      deficient designs.  In other words, many of these

 

      studies did not meet the Rome committee criteria

 

      for appropriate design of a functional GI disorder

 

      trial.  They had inappropriately small sample

 

      sizes.  They had inadequate blinding.  They had

 

      very vague or imprecise criteria to identify

 

      patients with constipation.

 

                Now, in the briefing document Dr. Prizont

 

      concluded that these trials revealed little

 

                                                                98

 

      differences between laxatives and modest

 

      improvement over placebo.  He actually referenced

 

      the most recent and most comprehensive

 

      meta-analysis about traditional therapies for

 

      laxatives, conducted by Jones and Nick Talley and

 

      colleagues.  In fact, the actual title of that

 

      meta-analysis is "The Lack of Objective Evidence of

 

      Efficacy of Laxatives in Chronic Constipation."

 

      That is quite a provocative title.

 

                Let's delve into that study a little bit

 

      further to see how they came up with that.  In

 

      brief trials of 4 weeks or less in duration, they

 

      found that laxatives increased stool frequency by

 

      about 2 stools per week compared to baseline.

 

      Placebo increased stool frequency by about 1 stool

 

      per week compared to baseline.  But as you note,

 

      the 95 percent confidence intervals here for

 

      placebo and laxatives are superimposed, not clearly

 

      demonstrating a difference in efficacy.

 

                For trials of 5-12 weeks in duration the

 

      results are less impressive.  Laxatives increased

 

      stool frequency by only 1 bowel movement per week

 

                                                                99

 

      versus placebo-treated patients who had an increase

 

      in stool frequency of 1.5 bowel movements per week.

 

                Now, I think we should be cautious about

 

      interpreting these results.  This is a

 

      meta-analysis that provides a single summary

 

      statistic and combines the results from bulking

 

      agents, stimulant laxatives and osmotic laxatives.

 

      So, it might be more beneficial to look at a

 

      systematic review that at least separated out

 

      bulking agents from other types of laxatives.

 

                That is actually available.  The other

 

      well-designed, systematic review about traditional

 

      therapies for constipation comes from Tramonte and

 

      Cindy Mulrow and colleagues, at the Cochrane Center

 

      in San Antonio, Texas.  They separated out bulking

 

      agents versus laxatives and found that bulking

 

      agents increase stool frequency by about 1.4 stools

 

      per week compared to baseline and laxatives

 

      increase stool frequency by about 1.5 stools per

 

      week compared to baseline.  So, their study

 

      conclusions were that fiber and laxatives do appear

 

      to modestly increase stool frequency over placebo. 

 

                                                               100

 

      They also concluded that it was unknown if these

 

      agents would improve general well being or global

 

      satisfaction because this endpoint wasn't examined

 

      in many of these trials.

 

                Now, it is beyond the scope of my

 

      presentation to individually review each of the

 

      randomized, controlled trials looking at

 

      traditional therapies and I am sure you wouldn't

 

      want to sit through all of that.  But I will

 

      conclude by noting that the randomized, controlled

 

      trial evidence for psyllium, PEG-3355 and lactulose

 

      consistently demonstrates significant increases in

 

      stool frequency versus placebo.  On the other hand,

 

      other commonly used and FDA-approved treatments for

 

      constipation, such as bisacodyl, Surfak, Colace,

 

      consistently do not demonstrate a significant

 

      increase in stool frequency versus placebo.  It

 

      doesn't necessarily mean that these drugs are

 

      ineffective.  As Dr. Prizont noted, most of these

 

      RCTs were carried out under deficient designs and

 

      if appropriately designed studies that met the Rome

 

      committee criteria were conducted, we might be able

 

                                                               101

 

      to demonstrate efficacy.  Nevertheless, when I am

 

      selecting a treatment for constipation I have to

 

      consider not just my clinical experience but also

 

      the randomized, controlled trial data of efficacy

 

      as well as the clinical trial data of safety.

 

                There are several other issues for

 

      discussion today.  First, whether or not the

 

      clinical trial data are adequate with respect to

 

      the chronic constipation population that is likely

 

      to be treated with tegaserod.  I would just

 

      reemphasize part of Dr. Dennis' presentation, the

 

      two Novartis randomized, controlled trials

 

      contained inclusion criteria that are very similar

 

      to the Rome II committee criteria for functional

 

      constipation.  In fact, in some ways they are more

 

      stringent.

 

                Patients had to have greater than 6 months

 

      of symptoms by the Novartis criteria, whereas the

 

      Rome criteria require only 12 weeks, which need not

 

      be consecutive, of symptoms in the previous year.

 

      The Novartis criteria required that patients have

 

      fewer than 3 spontaneous bowel movements per week. 

 

                                                               102

 

      That is not an actually requirement to meet the

 

      Rome committee criteria for functional

 

      constipation.  A patient, for example, who just had

 

      straining and lumpy, hard stools for 12

 

      non-consecutive weeks would meet the Rome committee

 

      criteria for functional constipation.

 

                Certainly, I think it is very true that 78

 

      percent of the patients in these RCTs appear to

 

      have chronic constipation while as many as 22

 

      percent had some symptoms of abdominal discomfort

 

      that might have led them to be classified as IBS

 

      with constipation.  Nevertheless, Miss Mealey, the

 

      FDA statistical reviewer, in her very thorough and

 

      comprehensive statistical review noted that the

 

      responder rates for the constipated patients in

 

      these trials who didn't have IBS-like symptoms were

 

      similar to the overall responder rates.  In fact,

 

      they tended to do better than the overall response

 

      rates that were recorded.

 

                Certainly, the issue has been raised about

 

      whether or not we may have subtypes of patients

 

      with slow transit constipation included in this

 

                                                               103

 

      trial.  As a clinician, my main point about that

 

      would be that the AGA's medical position statement

 

      about that provides essentially identical treatment

 

      algorithms whether somebody has normal transit

 

      constipation or slow transit constipation.  So, my

 

      choice of therapy wouldn't necessarily differ based

 

      on whether or not there might have been some

 

      patients with slow transit constipation included in

 

      these trials.

 

                Another issue for discussion is the

 

      appropriateness of a primary endpoint of an

 

      increase of 1 or more complete spontaneous bowel

 

      movements per week compared to baseline versus the

 

      percentage of patients who attained 3 or more

 

      complete spontaneous bowel movements per week.

 

      This is a difficult issue.  The Rome II committee

 

      actually couldn't come to a consensus about what

 

      was the most appropriate endpoint for trials of IBS

 

      and functional constipation.  They recognized that

 

      there are multiple symptoms present in patients

 

      with these lower GI functional disorders.  They

 

      actually stated that in addition to whatever

 

                                                               104

 

      primary endpoint is chosen, there should be a

 

      select number of a priori defined secondary

 

      endpoints that reflect the multiple symptoms that

 

      are present in patients with these functional GI

 

      disorders.

 

                In fact, Sander Van Zanten and his

 

      colleagues, who were on the subcommittee of the

 

      Rome committee who laid out the appropriate design

 

      of a trial of a functional GI disorder, actually

 

      stated that global improvement in satisfaction may

 

      be the most appropriate endpoint.  That is an a

 

      prior defined secondary endpoint in the 2 Novartis

 

      randomized, controlled trials, that patients on

 

      tegaserod 6 mg BID were significantly more likely

 

      to be responders for global satisfaction than

 

      patients that were on placebo.  This is not only a

 

      significant difference but, in my opinion, a

 

      clinically important difference where the magnitude

 

      of benefit is 9-12 percent more for patients on

 

      tegaserod 6 mg BID who were responders for global

 

      satisfaction compared to patients on placebo.

 

                Again, there were a select number of a

 

                                                               105

 

      priori defined secondary endpoints included, to try

 

      to contrast that with traditional therapies that

 

      patients on tegaserod 6 mg BID had 1.9 to 2 more

 

      spontaneous bowel movements per week compared to

 

      patients on placebo who had about 0.9 to 1 more

 

      spontaneous bowel movements per week.  These are

 

      statistically significant differences.

 

                If we do decide to apply the FDA's

 

      criteria that patients have to have 3 or more

 

      spontaneous bowel movements per week, and we look

 

      at the proportion of patients who attained what is

 

      a pretty high therapeutic goal, we still see that

 

      almost twice as many patients on tegaserod

 

      experienced 3 or more complete spontaneous bowel

 

      movements per week compared to patients on placebo

 

      and the magnitude of this difference, whether we

 

      look at 4 weeks or the entire 12-week trials, is

 

      approximately 10 percent.  Again, in my opinion,

 

      that is a clinically important difference.

 

                So, in conclusion for efficacy, I would

 

      state that the randomized, controlled trial data

 

      about the efficacy of tegaserod is very robust and

 

                                                               106

 

      precise.  These are the best designed, most

 

      comprehensive trials about treatments for

 

      constipation that are available among all the

 

      treatments that we have available for constipation.

 

      The study population does reflect patients with

 

      chronic constipation and the a priori defined

 

      primary and secondary endpoints do reflect the

 

      multiple symptoms that patients with constipation

 

      have, and these RCT data consistently demonstrate

 

      that tegaserod produces significant and clinically

 

      important improvement in the multiple symptoms of

 

      constipation.

 

                Let's move on to safety.  Unfortunately,

 

      there is very little data about the safety of

 

      traditional therapies for constipation.  The most

 

      recent and comprehensive meta-analysis by Jones,

 

      Nick Talley and colleagues actually didn't even

 

      address the issue because the data were so scant.

 

      If we do go back to the systematic review performed

 

      by Tramonte and Cindy Mulrow and colleagues from

 

      the Cochrane Center in San Antonio, Texas, they

 

      specifically noted that few studies used

 

                                                               107

 

      standardized techniques to assess adverse events.

 

      They also did note that they did not identify any

 

      significant differences in adverse events between

 

      laxatives and placebo.  So, they concluded that

 

      although there is no evidence that laxatives are

 

      unduly harmful, the data available are very limited

 

      and short-term.

 

                Thus, we are really left with looking at

 

      the prescribing information and case report data to

 

      try to get an idea about what adverse events are

 

      associated with commonly used laxatives.  We see

 

      for bulking agents that fecal impaction and large

 

      bowel obstruction have been reported, and even

 

      acute esophageal obstruction when bulking agents

 

      aren't taken with adequate amounts of water.

 

      Anaphylaxis has been reported with psyllium.  Among

 

      osmotic agents all different types of electrolyte

 

      abnormalities have been reported, specifically with

 

      magnesium-based agents that are used on a regular

 

      basis.  Stimulant laxatives have been associated

 

      with both electrolyte imbalances as well as

 

      abdominal cramps.  All of these agents have been

 

                                                               108

 

      reported to have been associated with diarrhea.

 

                So, another issue for discussion is

 

      whether or not the clinical trial data and

 

      postmarketing surveillance data provide adequate

 

      evidence of safety.  I pause here for a moment,

 

      looking at the title of this slide, to just note

 

      that the clinical trial safety data where patients

 

      are followed per protocol probably provides at

 

      least the most precise safety data that we have

 

      available to us.  When we look at the clinical

 

      trial safety data available for tegaserod we see

 

      that in the Novartis 2 randomized, controlled

 

      trials over 2,600 patients with constipation were

 

      enrolled.  Over 1,700 received tegaserod.  In the

 

      whole clinical trial safety database you have over

 

      11,000 patients treated with tegaserod and over

 

      3,400 patient-years of tegaserod use followed

 

      within the context of clinical trials.  I would

 

      suggest that infers that there is very robust and

 

      precise clinical trial safety data for tegaserod,

 

      certainly more robust and precise clinical trial

 

      safety data than what we have available for any

 

                                                               109

 

      other treatment of constipation.

 

                That very precise data allows us to

 

      estimate what is the likelihood of serious adverse

 

      events for constipated patients using tegaserod or

 

      placebo.  We see essentially similar rates.  And,

 

      that very robust and precise safety data let's us

 

      quantify the likelihood of diarrhea as an adverse

 

      event.  Among constipated patients we see that it

 

      is reported as an adverse event in 5 percent of

 

      patients in clinical trials versus 3 percent in

 

      patients on placebo.  We see that 0.6 percent of

 

      patients treated with tegaserod actually

 

      discontinued the medication because of the severity

 

      of their diarrhea.  When we look at the entire

 

      clinical trial database we can estimate that the

 

      likelihood of clinically serious consequences of

 

      diarrhea--going to the emergency department because

 

      of dehydration and getting IV fluids, virtually

 

      being hospitalized because of syncopal

 

      episode--occurs in 0.04 percent or 1 in 2,500

 

      patients treated with tegaserod.

 

                To conclude, let's turn to the safety

 

                                                               110

 

      issue about ischemic colitis.  Obviously as

 

      gastroenterologists, as primary care providers for

 

      patients, we are concerned about the issue of

 

      ischemic colitis because it has been brought to our

 

      attention by our clinical experience with

 

      alosetron.  Alosetron, again, is an antagonist of

 

      the 5-HT                                            3 serotonin receptor

as opposed to

 

      tegaserod that is an agonist of the 5-HT                                 

                                                                4 serotonin

 

      receptor.  We know from the clinical trial data

 

      that there were 17 cases of ischemic colitis among

 

      the 10,805 alosetron-treated patients in those

 

      clinical trials.  That calculates out to a rate of

 

      5.9 cases of ischemic colitis per 1,000

 

      patient-years based on the clinical trial data.

 

                I would also like to point out the fact

 

      that among placebo-treated patients with IBS the

 

      rate of ischemic colitis was 1.1 cases per 1,000

 

      patient-years.  Even in the context of this

 

      clinical trial, there was a background rate of

 

      ischemic colitis among patients treated with

 

      placebo.

 

                So, what can we do about comparing the

 

                                                               111

 

      issue of ischemic colitis with tegaserod patients

 

      treated for constipation versus other patients

 

      treated for constipation?  The only other treatment

 

      for constipation that has any breadth of clinical

 

      trial safety data is PEG-3350.  In their new drug

 

      application to the FDA they reported a rate of

 

      ischemic colitis in their clinical trial safety

 

      data of 3 cases per 1,000 patient-years.  I want to

 

      emphasize that that is an extrapolation.  The exact

 

      number is that there was 1 case of ischemic colitis

 

      among 300 patient-years of clinical trial safety

 

      data when they submitted their new drug

 

      application.  That is the only other treatment for

 

      constipation where we have any breadth of clinical

 

      trial safety data to estimate the likelihood of

 

      patients experiencing ischemic colitis.

 

                What is the data for tegaserod?  Zero

 

      cases among 11,640 tegaserod-treated patients

 

      studied over 3,400 patient-years of exposure

 

      versus, among all the clinical trial database for

 

      placebo-treated patients, 1 probable case of

 

      ischemic colitis among 4,267 placebo-treated

 

                                                               112

 

      patients followed for 780 patient-years of

 

      exposure.

 

                Now, the FDA officials wanted to identify,

 

      based on that clinical trial data--zero cases among

 

      all the patients followed in the clinical trial

 

      database--what would be the maximal rate of

 

      ischemic colitis that still could be occurring

 

      within 95 percent confidence intervals.  So, they

 

      did their statistical analysis based initially on

 

      the 7,000 tegaserod-treated patients in clinical

 

      trials that they had reviewed and they came up with

 

      a maximal ischemic colitis rate, within the

 

      confines of 95 percent confidence intervals, of 1

 

      case in approximately 2,000 patients, based on the

 

      fact that there were zero reported cases among over

 

      7,000 patients.

 

                If we give the up to date analysis based

 

      on all 11,640 tegaserod-treated patients, then a

 

      similar statistical analysis would shoe that the

 

      maximal rate within 95 percent confidence

 

      intervals, considering there are zero cases among

 

      11,640 patients, would be 1 case in 3,883 patients.

 

                                                               113

 

                In order to be balanced, I think we should

 

      consider the placebo patients too.  The same

 

      statistical analysis shows that their maximal rate

 

      would be 1 case in 867 placebo-treated patients.

 

                This analysis is still based on very few

 

      cases of ischemic colitis.  So, I certainly

 

      understand the need to look at postmarketing

 

      surveillance data.  In the U.S. over 2 million

 

      prescriptions, accounting for over 233,000

 

      patient-years of use; 26 reported cases of possible

 

      ischemic colitis, equating to a rate of

 

      approximately 12 cases per 100,0000 patient- years.

 

                Again, as pointed out during Dr.

 

      Joelsson's presentation, patients with irritable

 

      bowel syndrome seem to be diagnosed with ischemic

 

      colitis more often than the general population.  It

 

      may be an ascertainment bias because these patients

 

      tend to be scoped more frequently.  It may be due

 

      to an unknown pathophysiologic factor.  Obviously,

 

      there is recent research to indicate there are true

 

      pathophysiologic differences among IBS patients.

 

      But regardless of which epidemiologic study we look

 

                                                               114

 

      at, all the available epidemiologic data indicates

 

      that patients with IBS are 3-4 times more likely to

 

      be diagnosed with ischemic colitis than is the

 

      general population, and the rates vary depending on

 

      the age of the population that is examined.

 

      Obviously, the Medi-Cal population tended to be

 

      older than the patients studied in the United

 

      Health Care study and, thus, we are seeing a higher

 

      rate of ischemic colitis both in the general

 

      population and in the IBS population.

 

                I certainly comment Dr. Brinker.  He did a

 

      very interesting analysis of the United Health Care

 

      base and identified that, clearly, when a patient

 

      is diagnosed with IBS their rate of getting

 

      subsequently diagnosed with ischemic colitis within

 

      the next 3 weeks is very high.  Those patients

 

      almost certainly are patients that are misdiagnosed

 

      with IBS when they really have ischemic colitis.

 

      Nevertheless, the same analysis found that patients

 

      who had a stable IBS diagnosis for over 1 year

 

      still had a rate of 53 cases per 100,000

 

      patient-years compared to the general population

 

                                                               115

 

      where it was 7 cases per 100,000 patient-years.

 

                I do want to make particular note here.

 

      When I talked about the clinical trial data my

 

      denominator was 1,000 patient-years.  We have now

 

      shifted.  All the postmarketing surveillance data

 

      is based on a denominator of 100,000 patient-years

 

      of use.

 

                Postmarketing surveillance data for IBS

 

      patients treated with tegaserod is 12 cases per

 

      100,000 patient-years, which is 4- to 15-fold lower

 

      than the expected rate, although I certainly

 

      understand there may be some under-reporting, and

 

      it very difficult to get an estimate for how often

 

      that occurs.

 

                So, in conclusion, I certainly think that

 

      the clinical trial safety data for tegaserod is

 

      more robust and more precise than it is for any

 

      other treatment that we have available for

 

      constipation.  This safety data allows us to have a

 

      very precise estimate of the likelihood of

 

      clinically serious consequences of diarrhea, but

 

      the evidence doesn't support an association between

 

                                                               116

 

      tegaserod and ischemic colitis.

 

                When I do a risk/benefit analysis I see

 

      the benefits being this robust clinical trial data

 

      that demonstrates that tegaserod is efficacious for

 

      the treatment of constipation, especially the

 

      multiple symptoms of constipation, and that the

 

      safety data is more robust than it is for any other

 

      treatment I might choose and that safety data from

 

      clinical trials demonstrates to me that there is a

 

      very low but finite risk of clinically serious

 

      consequences of diarrhea.

 

                So, that analysis demonstrates to me that

 

      tegaserod has a very favorable risk/benefit profile

 

      in the management of chronic constipation, and that

 

      it compares very favorably with the risk/benefit

 

      analysis for any other therapy that I might choose

 

      to use to treat patients with constipation.  Thanks

 

      very, very much for your attention and I will turn

 

      the program back over to Dr. Fogel.

 

                       Questions on Presentations

 

                DR. FOGEL:  I would like to thank the

 

      presenters for their informative presentations.  At

 

                                                               117

 

      this juncture we turn the meeting over to the

 

      committee for questions to the presenters.  Dr.

 

      D'Agostino I think had his hand up first, and then

 

      Dr. Sachar.

 

                DR. D'AGOSTINO:  When I saw there was a

 

      two-hour presentation I said, my God, they will

 

      never take that long but it actually was a great

 

      presentation.  Thank you very much.

 

                I have a comment about the subset

 

      analysis, which we will have to address later.  I

 

      understand that you look at subsets for consistency

 

      and not necessarily expecting to see significant

 

      results, but shouldn't we be concerned that we are

 

      not seeing the effect lying on the right side with

 

      the elderly greater than or equal to 65 and the

 

      males, and the Blacks?  Can you give us some words

 

      on how we can feel comfort that you aren't seeing

 

      the effect in greater than or equal to 65 year-old

 

      individuals and also males, and I would like

 

      something on the Blacks also.

 

                DR. DENNIS:  Thank you for that question.

 

      Yes, absolutely.  Can I have slide AQ-16, please? 

 

                                                               118

 

      We will start off with the elderly population since

 

      that was the question that you asked initially.  As

 

      you know, we only randomized 13 percent of our

 

      patients that were 65 years or older, and this is

 

      the responders by age group looking at our primary

 

      efficacy analysis.

 

                What we can see in the group that is 65

 

      years and older is that we are seeing a treatment

 

      effect in the patients that are on Zelnorm.  We are

 

      also seeing an effect in patients on placebo as

 

      well.  So, the interesting thing though is that we

 

      can break this down further by looking at the older

 

      population by age and by gender.

 

                If I could have the next slide, please,

 

      which is AQ-17, let me show you what happens when

 

      we break it down into further subsets.  On the top

 

      row we are seeing female patients and on the bottom

 

      row we are seeing male patients.  The patients that

 

      are less than 65 years old--if we start with that

 

      column on the left-hand side, we can see that the

 

      effect in the younger female population is similar

 

      to the effect in the younger male population. 

 

                                                               119

 

      Remember that we have much fewer numbers in terms

 

      of the male group so we don't reach statistical

 

      significance because, as I said before, these

 

      subgroup analyses are not powered to detect

 

      statistical significance.  So, I think we are

 

      seeing a consistent effect in the men that are 65

 

      years and younger that we are seeing in the female

 

      population.

 

                If we look at the slide on the right-hand

 

      side, and let's turn to the elderly population, we

 

      do see an effect in female population.  Of course,

 

      the effect size is slightly smaller--again, small

 

      numbers of patients, and when we will look at the

 

      male patient population that are 65 years and older

 

      we are seeing that there really is no effect

 

      looking at it on this particular analysis.

 

                But I am going to take it one step further

 

      and take out those patients that we felt were

 

      probably IBS-like because, if you remember, in our

 

      overall efficacy analysis when we took that group

 

      out the efficacy was slightly more robust.

 

                So, if I can have the next slide, which is

 

                                                               120

 

      AQ-18, this shows you what happens when we take out

 

      those patients that are IBS-like.  I am going to

 

      focus your attention on that male population that

 

      is 65 years and older.  You can see that in the

 

      previous analysis--here we have really small

 

      numbers of patients.  We are dealing with 20

 

      patients in that group that are on 6 mg BID.  So,

 

      the responders that we saw in the previous analysis

 

      were all chronic constipation patients and when we

 

      take out the other patients that have IBS obviously

 

      our denominator changes and, you know, we see a

 

      much more different effect looking at these

 

      numbers.  But I do want to caution that these are

 

      very small numbers when we are looking at these

 

      subgroup analyses.

 

                But if we look at the four different

 

      quadrants I think we can see the effect in the

 

      patients less than 65 is similar in men as it is in

 

      women.  I think we are seeing an effect in elderly

 

      females, and I think we are seeing an effect in

 

      elderly males when you take out the IBS-like

 

      subset.

 

                                                               121

 

                DR. FOGEL:  Dr. Sachar?

 

                DR. SACHAR:  With the permission of the

 

      chair, if I could address some questions to each of

 

      the four major presenters, Dr. Schoenfeld, when you

 

      presented your efficacy data in slides 13 and 14

 

      you appeared to have limited your analysis only to

 

      the highest dose tegaserod of 6 mg BID.  Yet, when

 

      you discussed the adverse effects you combined the

 

      2 mg and the 6 mg doses.  It would seem to me if

 

      you really want to look at a benefit/risk ratio we

 

      really ought to look at a comparison for the same

 

      doses.  If we were to do that, we would find in

 

      your slide 21 that it really isn't 5.4 percent of

 

      patients but is actually 6.6 percent of patients

 

      who had some adverse effect with diarrhea at the

 

      equivalent dose, at the 6 mg dose.

 

                I am not a professional statistician but

 

      if we go a little further we might say that since

 

      the number needed to treat--to get some benefit,

 

      some demonstrated benefit from this drug is

 

      approximately 10.  It ranged between 9-11 in all

 

      the analyses.  It is approximately 10.  The number

 

                                                               122

 

      needed to treat to see some adverse effect from

 

      diarrhea is actually about 2.8 at the equivalent

 

      dose.  So, would it be fair to say that for every 3

 

      patients who get some benefit from this drug 1 will

 

      experience some diarrhea?

 

                DR. SCHOENFELD:  No, I would not go along

 

      with that and I think there are multiple points

 

      there to address.  The first one is that all of us

 

      have conducted clinical trials and, as we

 

      recognize, reporting an adverse event in the

 

      context of a clinical trial is not the same as

 

      suffering a clinically important adverse event.

 

      When these patients are followed in the context of

 

      clinical trials, to paraphrase, your study nurse

 

      may say, "anything unusual happen in the past

 

      week?"  And, if the patient says, "I had a little

 

      bit of diarrhea last Thursday," that becomes an

 

      adverse event.  What is probably a much more

 

      appropriate adverse event category to assess,

 

      clinically important adverse events, is how often

 

      patients stop their medication due to diarrhea.

 

      Obviously, here it is 0.6 percent.

 

                                                               123

 

                Having said that, I certainly take your

 

      comment appropriately, that if you look at the 6 mg

 

      BID dose the rate at which diarrhea was reported as

 

      an adverse event is about 6.6 or 6.7.  For the

 

      broader issue though of safety, my own

 

      experience--and there are other experts here that

 

      have far more experience in safety issues--is that

 

      when we look at efficacy we want to look at what is

 

      going to be most likely the dose that is utilized.

 

      But in safety we tend to look at multiple different

 

      dose ranges to find out what the benefit is.

 

                Having said that, I think a subgroup

 

      analysis about what the rate would be for 6 mg BID

 

      versus 2 mg BID would be helpful, although I will

 

      mention for the most serious adverse events that we

 

      are concerned about here, which in my mind are

 

      really ischemic colitis, when you look at 6 mg BID

 

      or 2 mg BID it is still going to be zero events.

 

      You are just going to change your denominator a

 

      bit.  And, the majority of patients in these trials

 

      were treated with 6 mg BID.

 

                DR. SACHAR:  Agreed.  When you talk about

 

                                                               124

 

      the diarrhea issue that brings me to the one

 

      question for Dr. Joelsson, and that is simply that

 

      you did discuss the physiologically serious

 

      consequences and those were obviously very, very

 

      low.  Did anybody record whether any patient with

 

      diarrhea had any episode of incontinence?

 

                DR. JOELSSON:  We have not that recorded.

 

      I cannot answer that.

 

                DR. SACHAR:  Because that is sort of an

 

      impact thing.

 

                DR. JOELSSON:  Yes.

 

                DR. SACHAR:  And for Dr. Dennis, in slide

 

      46--

 

                DR. DENNIS:  I will flash it up on the

 

      screen.

 

                DR. SACHAR:  Yes, it is very important, as

 

      everybody has indicated, that when you excluded IBS

 

      from the analysis you still showed efficacy.  I

 

      think that is a very important point.  But you

 

      showed us the data for doing that only at week 1-4.

 

                DR. DENNIS:  Yes.

 

                DR. SACHAR:  Do you have any data on that

 

                                                               125

 

      for the 12-week point?

 

                DR. DENNIS:  It looked similar.  I don't

 

      have the data on a slide but it does look similar

 

      over the 12-week treatment period.

 

                DR. SACHAR:  It is the same approximately?

 

                DR. DENNIS:  Yes.

 

                DR. SACHAR:  Great, fine.  In slide 13 you

 

      showed us that, in terms of the inclusion criteria,

 

      they had to have a bowel evaluation within the past

 

      5 years.  Do I take that to mean that if some

 

      patients had early constipation symptoms 3 years

 

      ago or 4 years ago or 5 years ago and they had a

 

      barium enema, and then more recently the symptoms

 

      persisted or worsened and they represent that they

 

      would be eligible to go in this study without any

 

      new reexamination?

 

                DR. DENNIS:  If they had had a bowel

 

      evaluation that was after the onset of symptoms and

 

      the symptoms remained the same within the past 5

 

      years there was no need for them to have a

 

      reevaluation.  However, if there was any change in

 

      the symptoms or if there were any alarm features,

 

                                                               126

 

      as I said, anything that suggested rectal bleeding,

 

      hemorrhage, anemia or any change in the pattern,

 

      those patients would have had to have a new

 

      evaluation.  But it was stable patients who had

 

      been having symptoms that had remained the same

 

      within the time they had the evaluation.

 

                DR. SACHAR:  Great!  My last question is

 

      for Dr. Prather.  I am not actually familiar with

 

      the Canadian study of Pare et al., but you

 

      indicated it was a population study.  Does the

 

      population in that study represent the group

 

      receiving and taking medications for chronic

 

      constipation?  Is it a clinic-based or a true

 

      population-based study?  Because if it is truly

 

      population based it doesn't reflect people who are

 

      taking medications for their constipation.

 

                DR. PRATHER:  It was, indeed, a

 

      population-based study but that would include

 

      all-comers with constipation that were actually in

 

      the population.  So, it didn't discriminate against

 

      individuals who may or may not have seen a

 

      physician for their constipation.

 

                                                               127

 

                DR. SACHAR:  Right, so that means that in

 

      Larry Schiller's study that you showed in slides 19

 

      and 20 with all the dissatisfaction, that included

 

      patients who had taken over-the-counter

 

      preparations or had seen a GP, or something, and

 

      had been perfectly satisfied?  Or, was it only the

 

      dissatisfied patients who sought out GI specialists

 

      who were in that study?

 

                DR. PRATHER:  This included

 

      individuals--it was a study that was done through

 

      the Internet that was representative of the U.S.

 

      population, but with the initial questions,

 

      actually to get into the study they had to have

 

      seen a physician within the past 12 months for

 

      constipation.

 

                DR. SACHAR:  A physician or a

 

      gastroenterologist?

 

                DR. PRATHER:  Actually, these were primary

 

      care physicians predominantly, yes.

 

                DR. FOGEL:  To increase the number of

 

      questions that we can ask during our time frame, I

 

      would like the members of the committee to keep

 

                                                               128

 

      their comments brief.  I am going to take the

 

      prerogative of the chair and ask my questions of

 

      Dr. Dennis.

 

                Can you provide us additional details

 

      regarding the question that you asked for

 

      subjective global assessment, and can you tell us

 

      how the data was analyzed and whether responders

 

      had a persistent response over the 12 weeks of the

 

      study?

 

                DR. DENNIS:  We asked the question how

 

      satisfied were you with your bowel habits over the

 

      past week?  And, the responses were a very great

 

      deal satisfied; a good deal satisfied; moderately

 

      satisfied; hardly satisfied; and not at all

 

      satisfied.  We defined a responder as having a

 

      decrease of 1 on the satisfaction score.

 

                I am going to first show you some data on

 

      the persistence of satisfaction response and then I

 

      will call one of the statisticians to actually come

 

      up and explain to you the statistical analysis that

 

      was done.

 

                If I could have slide AQ-58, please?  This

 

                                                               129

 

      is an analysis that we did where we said to those

 

      patients that met the score of a very great deal

 

      satisfied and a good deal satisfied, so zero and 1,

 

      for at least 50 percent of the weeks of the whole

 

      trial, which is 12 weeks.  What we can see on the

 

      study is definitely a significant benefit of

 

      Zelnorm versus placebo when we look at patients

 

      that had satisfaction over 6 weeks of the 12-week

 

      treatment period.  So, I think we are seeing

 

      persistence of the satisfaction result.

 

                I am going to call upon Dr. Jeen Liu, who

 

      is our statistician, to come and respond to your

 

      question about how these were actually calculated.

 

                DR. LIU:  My name is Jeen Liu.  I am the

 

      statistician from Novartis responsible for this

 

      project.  The slide that Dr. Dennis just showed was

 

      a response rate that we defined--actually, she

 

      showed two slides for two time intervals, weeks 1-4

 

      weeks and 1-12.  What we did was we took the

 

      patient score at each week, averaged them over the

 

      respective time intervals, either 4 weeks or 12

 

      weeks, and compared that with the baseline score

 

                                                               130

 

      that each patient had during the 2 weeks prior to

 

      treatment, and got the difference and compared with

 

      it was a decrease of 1 or more.  If it is 1 or

 

      more, it is a responder; otherwise the patient was

 

      a non-responder.  Thank you.

 

                DR. FOGEL:  Thank you.  Dr. Metz?

 

                DR. METZ:  Great, thanks.  Just in the

 

      interest of time, I am going to float a few

 

      questions to you.  I want to thank you for a nice,

 

      comprehensive presentation.  Three areas to

 

      address, first of all, the problem with the

 

      subgroup analysis, as has been alluded to.  Can you

 

      perhaps tell me why you chose 65 years?  I would be

 

      more interested in actually seeing a median age

 

      above and below, perhaps divided into quartiles

 

      above that and see where you actually see your

 

      cut-off.  I am not sure why 65 is necessarily

 

      relevant.

 

                The second question will be a little bit

 

      about the loss of efficacy in one of your two

 

      pivotal trials in the 2 mg group.  It appears to me

 

      more because of the placebo effect increasing up to

 

                                                               131

 

      reach the 2 mg, but it makes one wonder a bit about

 

      a tolerance response, and that brings me to why you

 

      really chose the first 4 weeks.  This is something

 

      people are going to be using way beyond 12 weeks.

 

      So, why the first 4 weeks; why not 12 weeks and

 

      beyond as your primary outcome measurement?

 

                The third question is use of surrogate

 

      measurements, which you actually have in your

 

      binder but didn't talk about at all today.  That is

 

      the use of rescue medication and seeing any

 

      difference there as a sort of idea of, you know,

 

      you are seeing an effect because of using less

 

      rescue?  Can you address those three points,

 

      please?

 

                DR. JOELSSON:  While Dr. Dennis is

 

      thinking about the second question I can take the

 

      first question.  The analysis of patients above 65

 

      years and below 65 years is a very traditional

 

      analysis that we do, which is based on what the FDA

 

      wants us to do.  This is kind of the cookbook thing

 

      you do.  So, it is not that it was anything that we

 

      came up with; this is the traditional way of doing

 

                                                               132

 

      it, and we don't have the data the way that you

 

      describe.  I am sorry about that.

 

                DR. METZ:  Do you think that would be a

 

      useful examination to go through?

 

                DR. JOELSSON:  Yes, I agree.

 

                DR. DENNIS:  let me address the other

 

      questions.  I am first going to tackle the question

 

      that you asked about loss of efficacy.  I think

 

      what we see in these clinical studies is that the

 

      treatment effect of Zelnorm was sustained

 

      throughout the entire treatment period.  We did not

 

      see a decrease in the number of responder rates.

 

      There is certainly nothing to suggest that we saw a

 

      loss of efficacy in terms of the drug response

 

      itself.  Placebo responses, as we know, are not

 

      uncommon in clinical trials and we see them in all

 

      clinical trials.  You know, the issue is in some

 

      clinical trials placebo responses continue to rise.

 

                If I could go back to my core slide CE-28,

 

      this shows you the weekly responder definition over

 

      the 12-week treatment period, and I just want to

 

      really point out again that we are seeing that the

 

                                                               133

 

      efficacy is sustained throughout the entire

 

      treatment period.

 

                Maybe I can get a clarification, Dr. Metz.

 

      Were you referring specifically to the 2 mg dose in

 

      the 2301 study?

 

                DR. METZ:  That is correct.  Clearly, you

 

      don't see that in the 2302 but you do see it in the

 

      2301.

 

                DR. DENNIS:  Absolutely.  You know, I

 

      think the 6 mg BID dose has emerged consistently as

 

      being more efficacious and that is why we are going

 

      for that dose as an indication.  We have actually

 

      looked at what are the reasons that could have, you

 

      know, determined why we are seeing this in 2301 and

 

      not 2302 because these two studies were essentially

 

      identical in the core period.  The only differences

 

      that we can find are geographical.  2301 was done

 

      mainly in Europe and 2302 was done in North and

 

      South America.

 

                To address the question of why we chose a

 

      4-week duration period, I think that was because

 

      when physicians prescribe the drug they want to

 

                                                               134

 

      look at the effect size within 4 weeks.  They want

 

      to know is this drug going to work within 4 weeks

 

      or not.  So, we looked at 4 weeks as our primary

 

      endpoint but we also looked at it over 12 weeks to

 

      make sure that we would see sustained efficacy.

 

      So, we have the data for both of those two

 

      endpoints.

 

                DR. METZ:  Right, but the point I am

 

      making is that this is a chronic problem.  You are

 

      defining chronic constipation as something that has

 

      been around for more than 6 months--

 

                DR. DENNIS:  Sure.

 

                DR. METZ:  --and you are not going to

 

      treat for 4 weeks and then stop.

 

                DR. DENNIS:  And that is why we have a

 

      12-week treatment duration.

 

                The last question that you had was

 

      laxative use.  There were very strict guidelines

 

      for laxative use in these studies.  Patients were

 

      only allowed to take laxatives if they had not had

 

      a bowel action for 96 hours.  So, they had to wait

 

      96 hours from the time of their last bowel action

 

                                                               135

 

      before they could have a laxative.  When we looked

 

      at laxative intake in these particular studies, we

 

      measured how many patients took at least one dose

 

      of a laxative throughout the entire 12-week

 

      treatment period, and we found that about 50

 

      percent of patients in the study took a laxative at

 

      some point during the study.  But when we really

 

      break this down and we say how frequently were

 

      laxatives actually being taken, we find that

 

      laxative intake, in fact, was quite infrequent.

 

                This slide I am going to show you is going

 

      to show you laxative use by mean number of days.

 

      If you look at the baseline period, we see that

 

      laxatives were used about once every 11-12 days.

 

      In the double-blind, placebo group we see that

 

      laxatives were used about once every 14 days and

 

      about once every 18 days on Zelnorm.

 

                If I could have the next slide, which is

 

      AQ-62, this is going to show you the median days

 

      data.  Here we are seeing by median data of use

 

      that the baseline laxative use was about 14 days a

 

      week.  The median use of laxatives in the placebo

 

                                                               136

 

      group goes down to 0.11, which translates to 1

 

      every 64 days.  When you look at the

 

      Zelnorm-treated group we are seeing that that goes

 

      down to 0.08, which translates to once every 88

 

      days.  So, when you really look at it, laxative

 

      intake is really very infrequent.

 

                However, to speak to your point, we are

 

      seeing that there is more laxative use in the group

 

      on placebo than there is on Zelnorm, and if we are

 

      expecting to see a confounder because of that, we

 

      would expect to see it more in the placebo than we

 

      would in the Zelnorm.

 

                DR. FOGEL:  Dr. Cryer?

 

                DR. CRYER:  Dr. Dennis, I would just like

 

      to follow-up on this theme of the subgroup analysis

 

      in those who were greater than 65 and those who

 

      were men.  You very strongly make the point that

 

      Zelnorm, as you just showed us, has maintained

 

      efficacy over the 12-week period.  However, all of

 

      your slides that you showed us to support its

 

      observations in the subgroups of those who were

 

      greater than 65 or those who were men were the

 

                                                               137

 

      4-week data points.  So, I am wondering whether you

 

      can show us that, in fact, the sustained 12-week

 

      data in that subgroup of men and those who were

 

      greater than 65.

 

                DR. DENNIS:  Right.  The reason why we did

 

      the subgroup analysis on the 4-week data initially

 

      was because that was our primary endpoint and so

 

      that is why we determined to do that.

 

                I don't actually have the slides with me

 

      right now to show you the actual week 12 but I will

 

      just confer with my colleagues and make sure we

 

      have those before the end of the presentation.

 

                DR. CRYER:  I think this is a very

 

      important point because when you consider the

 

      potential target group for therapy, many of them,

 

      as we have learned from Dr. Prather, are going to

 

      be greater than 65 year-old age population.  So, I

 

      think in the assessment that we are making today it

 

      would be very, very helpful for us to specifically

 

      look at the effects in a target population.

 

                DR. DENNIS:  Right, and I will make sure

 

      we have those slides and we will come back to that.

 

                                                               138

 

                DR. FOGEL:  You can present those slides

 

      later.

 

                DR. DENNIS:  Right, thank you.

 

                DR. FOGEL:  The next question is by Dr.

 

      Buchman.