FOOD AND DRUG ADMINISTRATION



































                        Wednesday, July 14, 2004


                               8:30 a.m.




                          ACS Conference Room

                               Room 1066

                           5630 Fishers Lane

                          Rockville, Maryland





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

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

            Executive Secretary




         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



         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



                            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


      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



                      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




                         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




                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.




                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




                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




                DR. PEREZ:  Tom Perez, Executive Secretary




      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.




                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




                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




                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






                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




      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




      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




      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




      studied representative of patients with chronic


      constipation?  If not, how do the populations




                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?




                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




      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




                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,




      and it is my pleasure to share with you today the


      clinical data on chronic constipation that we have




                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




                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




                A brief introduction of the compound,


      Zelnorm is tegaserod maleate.  It is 5-HT                                

                                                                  4 receptor


      partial agonist with affinity for the 5-HT                               



      receptor in the GI tract.  For its pharmacologic




      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




                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




      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




      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.




                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




                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.




                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




                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




                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.




                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




      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




      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






                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






                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




      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




      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




                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




      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




      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




                To summarize the epidemiology related with




      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




      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




      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




      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




      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




      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




      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




      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




                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




      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




                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




                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




      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




                    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




      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




                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                                



      receptors is prokinetic.




                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




                Let me now walk you through the Phase 3


      chronic constipation program.  The study objectives




      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




      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




      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




      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




      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




      examination, as well as baseline ECG and laboratory




                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




      reflecting the time of administration of any rescue




                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




      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




                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




      history to make a diagnosis of chronic




                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




                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




      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






                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




      BID dose, which you can see more clearly on this




                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




                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




      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




      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




      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




      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




                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.




                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




                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




      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




                So, we looked at patients who had less


      than 3 bowel movements per week at baseline.  What




      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




      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




      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




                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




      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




                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. 




      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




      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




                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






                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




      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




                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




      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.




                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.




                        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




                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




      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




      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




      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




      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




      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




      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




      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




      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




                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




      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




      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.




                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




      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




      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




                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




      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




      left colon.  She was treated with antibiotics and




                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




                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




      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




      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




      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




      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,




      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




      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,




      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






                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




      Zelnorm-treated patients versus 0.03 percent on




                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




                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




      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




                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




                I think it is particularly important to




      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




      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




      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




      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. 




      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




      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




                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. 




      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




      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




      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




                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




      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




      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




                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




      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




      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




      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




      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




                So, what can we do about comparing the




      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




      patients followed for 780 patient-years of




                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.




                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




      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




      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




      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




      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? 




      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. 




      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




                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




      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






                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




      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.




                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




      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




                DR. DENNIS:  I will flash it up on the




                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




      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,




      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.




                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




                DR. SACHAR:  A physician or a




                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




      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




                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




      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




      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




                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




      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,




                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




      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




      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




                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




      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




                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




      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




      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




      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.




                DR. FOGEL:  You can present those slides




                DR. DENNIS:  Right, thank you.


                DR. FOGEL:  The next question is by Dr.