FOOD AND DRUG ADMINISTRATION















                            JOINT MEETING OF






                           ADVISORY COMMITTEE



                                VOLUME I

















                      Wednesday, February 16, 2005


                               8:00 a.m.








                          Hilton Gaithersburg

                           620 Perry Parkway

                         Gaithersburg, Maryland



                        P A R T I C I P A N T S


      Alastair J.J. Wood, M.D., Chair


      Arthritis Advisory Committee:


      Allan Gibofsky, M.D., J.D.

      Joan M. Bathon, M.D.

      Dennis W. Boulware, M.D.

      John J. Cush, M.D.

      Gary Stuart Hoffman, M.D.

      Norman T. Ilowite, M.D.

      Susan M. Manzi, M.D., M.P.H.


      Drug Safety and Risk Management Advisory Committee:


      Peter A. Gross, M.D.

      Stephanie Y. Crawford, Ph.D., M.P.H.

      Ruth S. Day, Ph.D.

      Curt D. Furberg, M.D., Ph.D.

      Jacqueline S. Gardner, Ph.D., M.P.H.

      Eric S. Holmboe, M.D.

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

      Louis A. Morris, Ph.D.

      Richard Platt, M.D., M.Sc.

      Robyn S. Shapiro, J.D.

      Annette Stemhagen, Dr.PH. Industry Representative


      FDA Consultants (Voting):


      Steven Abramson, M.D.

      Ralph B. D'Agostino, Ph.D.

      Robert H. Dworkin, Ph.D.

      Janet Elashoff, Ph.D.

      John T. Farrar, M.D.

      Leona M. Malone, L.C.S.W., Patient Representative

      Thomas Fleming, Ph.D.

      Charles H. Hennekens, M.D.

      Steven Nissen, M.D.

      Emil Paganini, M.D., FACP, FRCP

      Steven L. Shafer, M.D.

      Alastair J.J. Wood, M.D., Chair



                  P A R T I C I P A N T S (Continued)


      National Institutes of Health Participants



      Richard O. Cannon, III, M.D.

      Michael J. Domanski, M.D.

      Lawrence Friedman, M.D.

      FDA Consultants (Non-Voting):


      Byron Cryer, M.D. (Speaker and Discussant)

      Milton Packer, M.D. (Speaker only)

      Guest Speakers (Non-Voting):


      Garret A. FitzGerald, M.D.

      Ernest Hawk, M.D., M.P.H.

      Bernard Levin, M.D.

      Constantine Lyketsos, M.D., M.H.S.

      FDA Participants:


      Jonca Bull, M.D.

      David Graham, M.D., M.P.H.

      Brian Harvey, M.D.

      Sharon Hertz, M.D.

      John Jenkins, M.D., F.C.C.P.

      Sandy Kweder, M.D.

      Robert O'Neill, Ph.D.

      Joel Schiffenbauer, M.D.

      Paul Seligman, M.D.

      Robert Temple, M.D.

      Anne Trontell, M.D., M.P.H.

      Lourdes Villalba, M.D.

      James Witter, M.D., Ph.D.

      Steven Galson, M.D.

      Kimberly Littleton Topper, M.S., Executive




                            C O N T E N T S


      Call to Order:

                Alastair J. Wood, M.D., Chair                    6


      Conflict of Interest Statement:

                Kimberly Littleton Topper, M.S.,                13



                Steven Galson, M.D., MPH                        16


      Regulatory History

                 Jonca Bull, M.D.                               24


      Gastrointestinal Effects of NSAIDs and COX-2

      Specific Inhibitors

                Byron Cryer, M.D.,                              30


      Mechanism Based Adverse Cardiovascular Events and

         Specific Inhibitors of COX-2

                Garret FitzGerald,                              80


      Committe Questions to Speakers                           112


      Sponsor Presentation: Vioxx (Rofecoxib),

                   Peter S. Kim, M.D.                          130

                   Ned S. Braunstein, M.D.                     131


      FDA Presentation: Vioxx (Rofecoxib),

                   Lourdes Villalba, M.D.,                     227


      Committee Questions to the Speakers                      263


      Sponsor Presentation: Celebrex (Celecoxib),

                Joseph M. Feczko, M.D.                         293


      Cardiac Safety and Risk/Benefit Assessment of


                 Kenneth M. Verburg, Ph.D.                     295


      FDA Presentation: COX-2 CV Safety: Celecoxib,

                James Witter, M.D., Ph.D.,                     373


      NIH and Investigator Presentation: Celecoxib in

        Adenoma Prevention Trials: The APC Trial

        (Prevention of Sporadic Colorectal Adenomas with


                   Ernest Hawk, M.D.                           402



                      C O N T E N T S (Continued)


      NIH Investigator Presentation: The PreSAP Trial

        (Prevention of Colorectal Sporadic Adenomatous


                 Bernard Levin, M.D.                           422


      Committee Questions to Speakers                          427


      Sponsor Presentation: Cardiovascular Safety and

         Risk/Benefit Assessment of Valdecoxib and


                Kenneth M. Verburg, Ph.D.                      443


      Concluding Comments

                Joseph M. Feczko, M.D.                         465


      FDA Presentation: COX-2 CV Safety:


                   James Witter, M.D., Ph.D.                   493


      Bayer and Roche Joint Presentation on Naproxen,

                   Leonard M. Baum, R.Ph.                      509


         Safety Data

                 Martin H. Huber, M.D.                         517


      Committee Questions to Speakers                          527



                         P R O C E E D I N G S


                             Call to Order


                DR. WOOD:  Let's get started.  For those


      of you who missed the memo, this is the committee


      to discuss the safety and efficacy of COX-2


      inhibitors.  It is worth perhaps just giving some


      thought to why we are here.  We are here to


      evaluate the relative efficacy and risk of these


      drugs, and to decide whether the benefits from


      these drugs outweigh the risk, in contrast to


      whether the risks outweigh the benefits.


                It is probably also worth just saying what


      we are not here for.  We are not here to delegate


      blame or revisit the past.  We are here to look


      into the future and determine what we should do in


      the future.  It is important I think for everybody


      to remember that as we move through the




                I guess the first thing to do is let


      people at this enormous table introduce themselves.


      Let's start down in this corner with John.


                DR. JENKINS:  Good morning.  I am John



      Jenkins.  I am Director of the Office of New Drugs


      in the Center for Drug Evaluation at FDA.


                DR. O'NEILL:  I am Bob O'Neill.  I am the


      Director of the Office of Biostatistics in CDER.


                DR. BULL:  Good morning.  I am Jonca Bull,


      the Director of the Office of Drug Evaluation V, in


      the Office of New Drugs.


                DR. GALSON:  I am Steven Galson, the


      Acting Director of CDER.


                DR. TRONTELL:  Anne Trontell, Deputy


      Director of the Office of Drug Safety.


                DR. SHAFER:  Steve Shafer.  I am not the


      director of anything.  I am a Professor of


      Anesthesia at Stanford and Biopharmaceutical


      Science at UCSF.


                DR. HENNEKENS:  Charlie Hennekens at the


      University of Miami School of Medicine and Florida


      Atlantic University.


                DR. FRIEDMAN:  Larry Friedman, from the


      National Heart, Lung and Blood Institute.


                DR. PAGANINI:  Emil Paganini, a


      nephrologist out of the Cleveland Clinic.


                MS. SHAPIRO:  Robyn Shapiro, I direct the


      Center for of Bioethics of the Medical College of


      Wisconsin.  I am a Professor of Bioethics there and



      I chair the Health Law Practice Group at Michael,


      Best and Friedreich.


                DR. CANNON:  I am Richard Cannon.  I am


      Clinical Director of the Division of Intramural


      Research, NHBLI, National Institutes of Health.


                DR. MORRIS:  Lou Morris, President, Lou


      Morris and Associates.


                DR. D'AGOSTINO:  Ralph D'Agostino,


      biostatistician from Boston University and the


      Framingham Study.


                DR. ILOWITE:  Norm Ilowite, Schneider


      Children's Hospital and Rheumatology at Albert


      Einstein College of Medicine.


                MR. LEVIN:  Arthur Levin, Director of the


      Center for Clinical Consumers and consumer


      representative on the Drug Safety Committee.


                MS. MALONE:  I am Leona Malone.  I am a


      licensed clinical social worker and I am here as a


      patient representative for the Arthritis Committee,



      and I have struggled with rheumatoid arthritis and


      osteoarthritis for 35 years.


                DR. BATHON:  Joan Bathon, Johns Hopkins


      University, Department of Medicine, Division of




                DR. CUSH:  I am Jack Cush.  I am a


      rheumatologist from Presbyterian Hospital, Dallas.


                DR. GIBOFSKY:  Allan Gibofsky, Professor


      of Medicine and Public Health, Cornell University;


      Adjunct Professor of Law at Fordham University; and


      I am Chair of the Arthritis Advisory Committee.


                MS. TOPPER:  Kimberly Topper, with the


      FDA.  I am the Executive Secretary for the




                DR. GROSS:  I am Peter Gross.  I am


      Professor of Medicine and Community Health in New


      Jersey Medical School; Chair of Medicine,


      Hackensack University Medical Center; and I chair


      the Drug Safety and Risk Management Advisory




                DR. HOLMBOE:  I am Eric Holmboe, Vice


      President for Evaluation Research at the American



      Board of Internal Medicine.


                DR. FARRAR:  I am John Farrar.  I am a


      neurologist and epidemiologist at the Center for


      Clinical Epidemiology and Biostatistics at the


      University of Pennsylvania.


                DR. MANZI:  I am Susan Manzi.  I am a


      rheumatologist from the University of Pittsburgh


      Medical Center, and with an appointment in


      epidemiology at the Graduate School of Public




                DR. HOFFMAN:  I am Gary Hoffman.  I am


      Professor and Chairman of Rheumatic and Immunologic


      Diseases at the Cleveland Clinic.


                DR. DWORKIN:  Hi.  I am Bob Dworkin.  I am


      Professor of Anesthesiology and Neurology at the


      University of Rochester School of Medicine.


                DR. BOULWARE:  I am Dennis Boulware,


      Professor of Medicine, and rheumatologist at the


      University of Alabama at Birmingham, and member of


      the Arthritis Advisory Committee.


                DR. DOMANSKI:  I am Mike Domanski.  I am a


      cardiologist.  I head the Clinical Trials Group at



      the National Heart, Lung and Blood Institute.


                DR. FLEMING:  Thomas Fleming, Chair of


      Biostatistics, University of Washington.


                DR. FURBERG:  Curt Furberg, Professor of


      Public Health Sciences, Wake Forest University.  I


      am a member of the Drug Safety and Risk Management


      Advisory Committee.


                DR. DAY:  Ruth Day, Duke University,


      Director of the Medical Cognition Lab, and a member


      of the Drug Safety Committee.


                DR. PLATT:  I am Richard Platt.  I am


      Professor and Chair of the Harvard Medical School,


      Harvard Pilgrim Healthcare Department, Ambulatory


      Care and Prevention.  I am principal investigator


      of one of the HHRQ centers for education and


      research in therapeutics.  I am a member of the


      Drug Safety Committee.


                DR. GARDNER:  I am Jacqueline Gardner,


      University of Washington School of Pharmacy and


      Pharmaceutical Outcomes Research Program.  I am on


      the Drug Safety and Risk Management Committee.


                DR. ELASHOFF:  Janet Elashoff,



      Biostatistics, Cedars-Sinai and UCLA.


                DR. NISSEN:  I am Steve Nissen.  I am the


      Medical Director of Cleveland Clinic Cardiovascular


      Coordinating Center.  I am a cardiologist, and I am


      the Chair of the Cardiorenal Advisory Panel for the




                DR. ABRAMSON:  Steve Abramson, I am


      Chairman of Rheumatology at NYU and the Hospital


      for Joint Diseases.


                DR. CRYER:  I am Byron Cryer.  I am a


      gastroenterologist from the University of Texas


      Southwestern Medical School in Dallas, and the


      Dallas VA Medical Center.  My role here today is as


      an FDA consultant to this group and as a member of


      the Gastrointestinal Drugs Advisory Committee.


                DR. STEMHAGEN:  I am Annette Stemhagen.  I


      am an epidemiologist with Covance and I am the


      industry representative to the Drug Safety and Risk


      Management Committee.


                DR. WOOD:  I am Alastair Wood.  I am the


      Associate Dean at Vanderbilt and Professor of


      Medicine and Professor of Pharmacology.


                Now we will have the "reading of the


      lesson" from Kimberly Topper.


                     Conflict of Interest Statement



                MS. TOPPER:  The following announcement


      addresses the issue of conflict of interest with


      respect to this meeting, and is made part of the


      record to preclude even the appearance of such.


      Based on the agenda, it has been determined that


      the topics of today's meeting are issues of broad


      applicability and there are no products being


      approved.  Unlike issues before a committee in


      which a particular product is discussed, issues of


      broader applicability include many industrial


      sponsors and academic institutions.


                All special government employees have been


      screened for their financial interests as they may


      apply to the general topics at hand.  To determine


      if any conflict of interests existed, the agency


      has reviewed the agenda and all relevant financial


      interests reported by the meeting participants.


      The Food and Drug Administration has granted


      general matters waivers to the special government



      employees participating in the meeting who require


      a waiver under Title 18 United States Code, Section


      208.  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


      of the Parklawn Building.


                Because general topics impact so many


      entities, it is not practical to recite all


      potential conflicts of interest as they apply to


      each member, consultant and guest speaker.  FDA


      acknowledges that there may be potential conflicts


      of interest but, because of the general nature of


      the discussions before the committee, these


      potential conflicts are mitigated.


                Further, during today's session Dr.


      Bernard Levin will be presenting data on the


      prevention of colorectal sporadic adenomatous


      polyps trial, the PreSAP trial, a Pfizer-sponsored


      clinical trial.  We would like to note for the


      record that Dr. Levin is attending this meeting as


      a consultant to Pfizer.


                With respect to FDA's invited industry



      representative, we would also like to disclose that


      Dr. Annette Stemhagen is participating in this


      meeting as a non-voting industry representative,


      acting on behalf of regulated industry.  Dr.


      Stemhagen's role on this committee is to represent


      industry interests in general and not one


      particular company.  Dr. Stemhagen is the Vice


      President of Strategic Development Services for


      Covance Periapproval Services, Inc.


                In the event that the discussions involve


      any other products or firms not already on the


      agenda for which FDA participants have a financial


      interest, the participant's involvement and their


      exclusion will be noted for the record.


                With respect to all other participants, we


      ask in the interest of fairness that they address


      any current or previous financial involvement with


      any firm whose product they may wish to comment


      upon.  Thank you.


                DR. WOOD:  For those of you still


      standing, there are apparently seats in the


      overflow room.  Let's go right on to the first



      speaker, who is Steve Galson.  Steve?




                DR. GALSON:  Thank you.  I want to welcome


      everyone and thanks in particular to our Chair, Dr.


      Alastair Wood, committee members, special guests,


      members of the public and FDA staff who have really


      done a tremendous job in putting together a


      particularly and unusually complex meeting.


                We have some special guests today that I


      want to point out.  We have representatives from


      the drug regulatory authorities of the member


      countries of the European Union and six separate


      countries--Canada, Japan, Singapore, Australia,


      Switzerland and Mexico, and I really want to


      welcome them.  Thank you for being with us.  We


      also have several guests from congressional staff


      offices and we are very pleased that they are with


      us as well to learn about this important issue.


                There is really an unprecedented level of


      international attention to one of our advisory


      committees today, and we are very proud that this


      is taking place and we think it represents a new



      level of collaboration and discussion around the


      world about an emerging public health issue.


                Many millions of people all over the world


      are taking the products that we are discussing.


      Indeed, they depend on them for a range of


      conditions from the mild to the severe and


      life-threatening.  We must keep the interests and


      health of these patients front and center in these




                I wouldn't be complete in this


      introduction if I didn't acknowledge the


      controversy surrounding these products,


      particularly over the last year.  I want to


      emphasize that we are anxious to hear all points of


      views from the advisory committee and, of course,


      from agency staff.  It goes without saying that all


      FDA staff are free to make any presentation without


      fear of any retaliation.  I don't want anyone


      sitting around this table to be shy.


                Also, we look forward to hearing a wide


      range of views from the more than 50 members of the


      public who are going to be making brief statements



      later in the meeting.  I want to remind the public


      that all members of this committee have been


      carefully screened for conflicts of interest and we


      have used the same standards in this process that


      we have used for other committees and similar




                A few comments about the challenging


      risk/benefit balance that the agency must achieve


      in making its regulatory decisions:  Although you


      have all heard strong opinions in the media and


      medical literature about safety issues related to


      the drugs we are discussing, our job and, indeed,


      your job is to assess any safety concerns when


      balanced by the benefit of these products.  We


      cannot lose sight of the reduced morbidity, pain


      and suffering achieved by the products that are


      under discussion and the real impact on people that


      changes in the regulatory status may entail.


                You will be assessing the risk/benefit


      balance of these products this week in the midst of


      a changing information environment and this


      represents a particular challenge.  We are aware of



      at least a half dozen ongoing meta-analyses and


      huge population-based studies, in addition to


      several of the studies you will hear about this


      week for which data analysis continues as we speak.


      Although we have a full three days, the time really


      isn't long enough to hear details about every


      single ongoing, or incomplete, or unreviewed study


      of which we are aware.  Leaving them out of the


      agenda has absolutely nothing to do with wanting to


      keep information from you and everything to do with


      allowing you to focus so that you have time to get


      to our critical advisory questions.


                We must be very cautious about


      interpreting data for regulatory decision-making


      that has not been thoroughly vetted and peer


      reviewed, and even more cautious about interpreting


      data of preliminary studies that are not even


      complete.  You will be hearing about some data in


      these categories and I would remind you to exercise


      caution in their interpretation.


                As scientists, we have all seen examples


      of ongoing studies whose findings have changed as



      analysis is in the final stages, or examples where


      inadvertent errors have led to misclassification in


      epidemiologic studies, or when data that comes in


      at the end of the data gathering stage influences


      results.  In today's 24-hour news environment, it


      is difficult to not react to these incomplete


      reports but we must go back to the basics of


      relying on sound science and use the peer review


      system to strengthen findings before utilizing them


      to make regulatory decisions.


                Lastly on the risk/benefit balance, as you


      members know but it is sometimes difficult for us


      to convey to the public, our job at FDA and your


      job in the advisory group is to balance risks and


      benefits on a population basis for the nation as a


      whole.  This is very different from the


      risk/benefit assessment physicians do with


      individual patients where specific risks of the


      medications, family history, a patient's risk


      tolerance and other factors must be taken into


      consideration.  A drug may, based on the weight of


      evidence, have a positive benefit/risk balance for



      the population leading to approval, yet, cause


      grievous harm in a specific subset of individuals.


      We say over and over again that all drugs have


      risks, but when a person you know suffers an


      adverse event the faulty assumption is sometimes


      made that we must have made a mistake in the




                I would also like to mention an unusual


      feature of many of the data from the trials you


      will be hearing over the next few days.  The data


      on safety of these drugs is, as I have mentioned,


      unusually complex and represents the fact that


      clinical trial methodology to look at


      cardiovascular effects as adverse events has


      changed dramatically.  When discussions began about


      cardiovascular safety of NSAIDs there was no


      standard methodology by which cardiovascular


      adverse events were confirmed or categorized.


      Analyses vary by trial.  Confirmatory processes


      vary by trial.  Only after the VIGOR trial did the


      methods of establishing confirmatory processes and


      standardization become better established.  Of



      course, in population-based cohorts and case


      control studies case reporting and confirmation is


      both rudimentary and completely inconsistent


      between studies.


                In addition, as you know already, unlike


      drugs designed to treat cardiovascular disease,


      these trials have not been designed to do a full


      cardiovascular assessment.  So, major pieces of


      information that you might like to have are simply


      not available.  So, in many ways we are forced to


      compare apples to oranges in these trials and


      studies, and when you are not doing that you are


      trying to draw conclusions based on insufficient


      information, making your task even harder.


                In spite of all the ambiguity, work in


      progress, changing standards and questions, we ask


      you for the miraculous job of crystal clarity in


      your responses to our questions.  We know this is


      tough on such challenging scientific and


      controversial issues, and we are enormously


      grateful to you because we know that you all are up


      to this challenge.  The agency will act rapidly



      within the next few weeks to act on the


      recommendations you communicate to us over the next


      few days.


                I would like to quickly go to the agenda.


      Today through midday tomorrow you will hear from


      sponsor companies, FDA staff and NIH researchers


      about data on both approved and unapproved COX-2


      selective and non-selective products.  Tomorrow


      afternoon we have 54 members of the public


      registered to speak.  On Friday you will hear about


      important methodological issues in interpretation


      of these studies, and then we will move on to the




                Again, thank you and on behalf of the FDA


      I wish you the very best of luck on this important


      endeavor.  Thanks, Dr. Wood.


                DR. WOOD:  Thanks a lot.  Two additional


      people have joined the cast of thousands that we


      have at the table, and perhaps it would be worth


      having them introduce themselves.  Bob, you go




                DR. TEMPLE:  I am Bob Temple.  I am



      Director of the Office of Medical Policy.


                DR. WOOD:  Stephanie?


                DR. CRAWFORD:  Thank you, Mr. Chair.


      Stephanie Crawford--good morning--University of


      Illinois at Chicago, College of Pharmacy; member of


      the Drug Safety and Risk Management Advisory




                DR. SELIGMAN:  Good morning.  This is Paul


      Seligman.  I am the Director of the Office of


      Pharmacoepidemiology and Statistical Science.


                DR. WOOD:  Is there anyone else I didn't


      notice arrive?  No?  Then, let's move on to the


      next speaker.  Jonca?


                           Regulatory History


                DR. BULL:  Good morning.  Again, I would


      like to extend a warm welcome to the members of the


      committee and to extend and acknowledge a


      particular thanks to our staff at FDA, specifically


      Dr. Villalba, Dr. Witter, Dr. Schiffenbauer from


      our team, our statistical staff, and colleagues in


      the Office of Drug Safety who have put in countless


      hours in preparation for this meeting.


                The NSAID class is one that probably


      everybody in this room has a product in their


      medicine cabinet that is a member.  It is a large



      class of marketed products for both OTC and


      prescription indication use.  It is a wide range of


      products with varying risk/benefit profiles.  Their


      approved indications are for short-term use such as


      dysmenorrhea and acute pain; chronic use for


      osteoarthritis, rheumatoid arthritis, familial


      adenomatous polyposis in the example of Celebrex.


      So, clearly, we have drugs that for everyone, from


      the young female with cramps to the senior citizen


      with arthritic pain, have importance and clearly


      there is a need for them in the marketplace.  There


      are other proposed uses that are known to be under


      investigation, and you will hear about studies in


      the setting of Alzheimer's disease, as well as


      sporadic polyp prevention.


                I would like to briefly review some of the


      regulatory history for these products, going back


      to December of 1986 when there was a public


      advisory committee meeting that discussed the GI



      paragraph and databases were discussed at that




                This was followed in 1995 where revisions


      for the NSAID class label were discussed, as well


      as a subsequent advisory committee in 1998 when the


      new science of the COX-2s were discussed and their


      potential enhanced safety for GI benefit.


                In December of 1998 an advisory committee


      was held to discuss the data for Celebrex, followed


      in December of 1998 when that drug was approved


      first in this new class of products.  In April of


      1999 an advisory committee was held for Vioxx,


      followed by its approval in May of 1999.  We held


      another advisory committee meeting in 2001 which


      discussed the large outcome studies which sponsors


      had undertaken to further evaluate how clinically


      meaningful the data from endoscopic studies was in


      order to further evaluate the enhanced GI safety




                This time line has several points I would


      like to bring to your attention.  The first IND for


      these products came in 1994 so we are dealing with



      a relatively short time line, given that this is


      year 2005, in drug development, marketing and an


      evolving picture for safety.


                The products below the time line are the


      ones that have been approved, and I would like to


      bring your attention to those above the line,


      Arcoxia, Prexige, the IV formulation of Bextra


      which have not been approved in the United States


      due to insufficient safety data.


                The COX-2 agents--are they different?  In


      what way?  When we look at risk to benefit, how do


      these agents differ from the traditional NSAIDs?


      Can a clinically meaningful benefit for GI safety


      and less risk, that is for CV risk, renal risk,


      hepatic risk, allergy--can that be characterized?


      What additional study is needed to better


      understand the science of COX-2 inhibition?


                When we think in terms of labeling risk


      management, what risk management options are


      appropriate in this settings, ranging from


      potential withdrawal of the product to labeling




                Certainly there are lessons learned for


      drug development.  I cite a quote at the end of an


      article by Dr. Temple and Marty Himmel, in JAMA in



      May, 2002, and I think the statement is quite a


      relevant one to our deliberation, that no


      improvements in drug development can completely


      eliminate the risk of unexpected events.


                Looking at large NDA databases is helpful


      but continued monitoring is essential to assess


      evolving risk profiles for new products.


      Certainly, the impact of aggressive marketing must


      be taken into account for these unknowns of drug




                Dr. Galson has already gone through the


      schedule for the meeting.  I will just briefly


      allude to our framework for this deliberation.


      Following me, Dr. Byron Cryer will be discussing


      the gastrointestinal effects of the NSAIDs and


      COX-2 specific inhibitors; followed by Dr. Garret


      FitzGerald on mechanisms for cardiovascular risk


      from inhibition of COX-2s.  This will be followed


      by a presentation by Merck and the FDA presentation



      by Dr. Lourdes Villalba.


                This afternoon you will hear from Pfizer


      and their review of cardiovascular safety and


      risk/benefit assessment of celecoxib, followed by


      the FDA presentation by Dr. James Witter.  There


      will be a presentation then on the NIH-sponsored


      colon polyp prevention trials, with subsequent


      presentations by Pfizer on valdecoxib and


      parecoxib, and an FDA presentation on valdecoxib.


      This will be followed by Bayer and Roche discussing




                Tomorrow you will hear about the


      epidemiologic studies, followed in the afternoon by


      the open public hearing and committee discussion.


                Day three in the morning will focus on the


      Alzheimer's prevention trials.  The ADAPT trial


      will be discussed that morning by Dr. Constantine


      Lyketsos; followed by a presentation by Dr. Milton


      Packer on interpretation of cardiovascular events;


      a presentation by Dr. Robert Temple on clinical


      trial design and patient safety, future directions


      for COX-2 selective agents; and a presentation by



      Dr. Robert O'Neill on issues in projecting


      increased risk of cardiovascular events to the


      exposed population.  Dr. Sharon Hertz will then


      present a summary of the meeting presentations


      prior to the afternoon discussion of our questions.


                Again, our thanks to the committee members


      for taking time from their extraordinarily busy


      schedules for this important meeting as we reach


      another milestone in the regulatory history of


      these products.


                DR. WOOD:  Thanks very much.  Let's just


      go straight on to the next speaker, who is Dr.


      Byron Cryer who is going to talk on the GI effects.


      Dr. Cryer?


                   Gastrointestinal Effects of NSAIDs


                     and COX-2 Specific Inhibitors


                DR. CRYER:  Thank you.  For the purposes


      of full disclosure, I would first like it to be


      noted that I have been invited to give this


      presentation by the Analgesic and Anti-Inflammatory


      Division of the FDA.  I do have relationships with


      sponsors of products being mentioned in today's



      presentation, however, I am not being paid for my


      participation in this meeting nor for my


      presentation today.


                For those of you not familiar with me, I


      am a gastroenterologist and I am thrilled that the


      FDA has been begun this meeting with the focus on


      this subject because many of us have forgotten that


      the initial reason for the development of the class


      of the COX-2 specific inhibitors was entirely


      because of the gastrointestinal effects of the


      non-steroidal anti-inflammatory drugs and, for that


      reason, I think it is very appropriate that we have


      this review of the gastrointestinal effects of


      NSAIDs and what the data say from the GI


      perspective about the gastrointestinal effects of


      COX-2 specific inhibitors.


                From the perspective of the NSAIDs risk,


      listed here are several of the known risks


      associated with the non-steroidal anti-inflammatory


      drugs, the gastrointestinal risks, the cardiorenal


      risks and the anti-platelet concerns.  Among these,


      as the group knows, the adverse concerns of



      greatest risk historically were the


      gastrointestinal effects that present with features


      such as ulcers, perforations, bleeding, obstruction


      strictures and many other interesting


      manifestations.  Over the last several years, added


      to this list and a focus of this meeting are


      cardiovascular concerns of the non-steroidal


      anti-inflammatory drugs but my perspective are the


      issues listed at the top, the gastrointestinal




                When looking more extensively at what the


      specific gastrointestinal effects of NSAIDs are, we


      have learned that NSAIDs have effects throughout


      the GI tract.  The upper gastrointestinal effects


      are the most pronounced but there are some very


      interesting effects that we see throughout the GI


      tract, such as in the small intestine and colon.


      In recent years we have had an increasing focus on


      lower gastrointestinal effects of NSAIDs, a very


      interesting phenomenon.  Several have been assessed


      by endoscopic means but there has been a lot of


      discussion as to what are the clinically relevant



      untoward major events that might happen in the


      lower gastrointestinal tract.  While this is


      debated with respect to the prevalence of lower GI


      effects, these effects are likely somewhere in the


      range of 10-20 percent of total gastrointestinal


      effects that happen within the GI tract


      attributable to NSAIDs.  Clearly, the major effects


      of NSAIDs in the GI tract are in the upper


      gastrointestinal tract, such as ulcers more


      commonly in the stomach and the duodenum, and


      concerns such as gastrointestinal bleeding,


      perforations and obstructions.  So, that is really


      the focus upon which the strategies were developed


      to increase NSAID safety within the


      gastrointestinal tract.


                With respect to the epidemiology of ulcer


      disease in general, some very interesting phenomena


      have been observed which have persisted into recent


      years.  But the overall summary of the phenomenon


      that I would like to focus your attention to is


      that while in recent years the overall incidence of


      uncomplicated ulcers, both gastric and duodenal,



      has been markedly declining in the U.S. and


      worldwide, very interestingly, the incidence of


      complications, specifically gastrointestinal


      bleeding, has not declined in similar proportions


      and, in fact, has persisted or increased.  This


      phenomenon, in particular the bleeding, has been


      felt to be a manifestation of the effects of the


      non-steroidal anti-inflammatory drugs within the GI




                This problem presents itself clearly with


      respect to morbidity and, unfortunately, mortality


      and several hundreds of thousands of


      hospitalizations.  The costs have been debated.


      The actual quantified amount of mortality in the


      U.S. is also a number that is debated.  The 16,500


      estimate is probably an overestimate.  But the


      bottom line is that NSAIDs are clearly associated


      with morbidity, mortality and costs in this country


      as well as worldwide, and this is has been the


      issue that has led to the discussions of the need


      for increasing gastrointestinal safety for NSAIDs.


                So, the various ways in which these



      assessments have been done has ranged from studies


      which we have seen over the years that have been


      short-term evaluations of physiologic or


      pharmacologic effects on healthy volunteers to the


      more relevant studies of the gastrointestinal


      effects of these drugs in arthritis patients.


      These studies have ranged from long-term endoscopy


      studies to a fewer number but very important


      studies that have assessed clinical events such as


      symptomatic ulcers, GI bleeding, perforation and




                Over the years there has been extensive


      discussion as to the relevance of the endoscopy


      studies and how the endoscopic observations with


      NSAIDs might relate to the outcome studies.  One of


      the criticisms of the endoscopic studies is that


      the endoscopic lesions are numerous.  They are


      mostly only known from endoscopies that are done as


      a part of a scheduled study and they are


      asymptomatic.  However, what we have learned from


      comparing the numerous endoscopic studies to


      observations that have been seen in the outcome



      studies is that the relative proportions in terms


      of outcomes seen in endoscopic studies tend to be


      predictive of what one would expect to see in an


      outcome study.  So, we have come full circle then


      in our understanding of the role of endoscopic


      studies and, at least in the gastroenterology


      community, we now feel that there is some


      substantial value in endoscopic studies and that


      they are predictive of what one might expect to see


      in outcome trials.


                Now, with respect to what we see in these


      types of trials, when one looks endoscopically


      there is a range of findings in people who are


      taking high doses of NSAIDs.  In greater than 90


      percent, if one were to look, we would see this


      phenomenon of NSAID gastropathy, which is this


      constellation of erosions and hemorrhages but it is


      mostly asymptomatic, mostly not clinically




                With respect to incidences of asymptomatic


      endoscopic ulcers, gastric ulcers happen two to


      three times more commonly than the duodenal ulcers,



      with the ranges that are shown on the slide.


      Again, these lesions are mostly asymptomatic and


      don't progress in the majority of individuals to


      clinically untoward gastrointestinal events.


                What these things look like--this is an


      endoscopic photograph of gastropathy demonstrating


      the constellation of hemorrhages and erosions that,


      again, are going to be mostly asymptomatic, ranging


      to a picture, shown here, of an endoscopic ulcer


      seen in the antrum of the stomach of an NSAID user.


                The more clinically concerning endpoint,


      that being clinically significant ulcers, occurs


      with the non-selective NSAIDs on average about 2


      percent, with a range of about 1-4 percent.  This


      range and this mean are important numbers as


      benchmarks to remember because they will become


      relevant as we discuss some of the outcome studies


      that have been conducted with the COX-2 specific




                Having reviewed what the risks are, I


      would now like to move the discussion to what our


      strategies have been to reduce the risk of the



      gastrointestinal complications with NSAIDs.  It is


      a simple strategy and most experts will recommend


      identifying the patient population who might be at


      risk and this is based upon identification of risk


      factors.  Then, once having identified susceptible


      populations for risk, one employs strategies that


      would reduce risk, such as either the use of


      gastroprotective drugs or the use of safer NSAIDs,


      and the category of safer NSAIDs clearly involves


      the subclass of the COX-2 specific inhibitors.


                With regard to identification of risk


      factors, a risk factor not commonly mentioned is


      the NSAIDs themselves.  NSAIDs clearly provide risk


      for gastrointestinal effects.  Shown here are


      various NSAIDs available by class and by


      prescription in the United States.  As you can see,


      they have been divided into traditional NSAIDs,


      non-salicylates; aspirin related, salicylate-based


      compounds; and then COX-2 inhibitors which are


      currently available, in development or previously


      available in the U.S.


                With regard to identifying patient



      characteristics which may suggest risk, these have


      been extensively studied and they are listed here,


      things such as increasing age and the threshold age


      is widely debated but one category that has been


      suggested would be those greater than 65, let's


      say.  Clearly history of GI ulceration; having had


      a complication; concomitant drugs such as


      corticosteroids or anticoagulants; cardiovascular


      disease, interestingly, such as CHF; and this issue


      of multiple NSAIDs all increase the risk.


                Of this list that the group is very


      familiar with, the one that has probably not been


      as widely appreciated and one which has been


      highlighted from some of the outcome trials of the


      COX-2 specific inhibitors is this issue of multiple


      NSAIDs, and it is a risk factor that presents


      itself in the context of a patient profile, a


      patient who takes prescribed NSAIDs along with


      either low doses of aspirin of over-the-counter


      NSAIDs.  Since we know that the risk for


      NSAID-related gastrointestinal events is related to


      dose, what one accomplishes in this group of



      multiple NSAIDs is essentially to increase the


      overall dose of NSAIDs delivered.


                With regard to the strategies after having


      identified the susceptible population, the first


      category essentially is that of co-therapeutic


      gastroprotection.  As alluded to a minute ago, it


      would be desirable to use the lowest effective dose


      of an NSAID.  Then really the two prevailing


      gastroprotective or co-therapy strategies that we


      have are the use of either misoprostol or proton


      pump inhibitors.


                Several studies have been done in either


      of these categories.  I will just highlight for


      purposes of discussion two outcome trials that I


      think nicely demonstrate the effectiveness of these


      strategies.  With regard to misoprostol, the most


      widely quoted study was the outcome trial, the


      MUCOSA trial in which misoprostol was given to


      patients who were chronically taking NSAIDs over 6


      months and were demonstrated to be associated with


      a 40 percent or less reduction in gastrointestinal




                From the perspective of the PPI outcome


      trials, there have been fewer evaluations but there


      have been, in fact, some evaluations for clinically



      relevant outcomes for PPIs, this being one example


      of a trial which was actually not intended in its


      design to evaluate outcomes of a proton pump


      inhibitor in patients taking NSAIDs but,


      nevertheless, provided us with some insight into


      the potential effects from the perspective of


      gastrointestinal outcomes.


                This was a trial that was designed with


      the question in mind of whether or not H. pylori


      eradication prior to starting an NSAID would be an


      effective therapy or not for the reduction


      potentially of NSAID-related bleeds.  So, in this


      group of H. pylori infected NSAID users, half of


      them were treated for their H. pylori infections


      prior to being started on an NSAID and acted as a


      control.  The other half were given a proton pump


      inhibitor.  In this specific instance omeprazole.


                What was observed, very interestingly, at


      the end of 6 months is that in this instance there



      was a 76 percent reduction in the subsequent


      incidence of upper gastrointestinal bleeding in the


      group that had received the proton pump inhibitor




                From the perspective of the safer NSAIDs,


      this is a story that is also well known.  Its focus


      today is really to look at specifically the COX-2


      specific inhibitors shown on the far right.  The


      concept has been widely discussed and is arguably


      somewhat simplistic, but for the sake of today's


      discussion, as the group knows, it is highlighted


      by the observation that there are 2 COX isoforms


      available, COX-2 and COX-1, and that COX-1 is the


      isoform which is primarily responsible for the


      protective prostaglandins in the stomach which


      typically protect against injury.  Once inhibited


      by non-selective NSAIDs, the prostaglandin products


      produced by COX-1 lead to an increased


      susceptibility for injury.  The concept at least


      for COX-2 specific NSAIDs in that they have limited


      inhibitory effects on COX-1 is that they would


      likely not inhibit prostaglandins, likely not be



      associated with ulcers, and likely be associated


      with a reduction in clinically significant


      gastrointestinal untoward events with NSAIDs.


                Having said that, there have been a few


      gastrointestinal outcome trials that have been


      designed to evaluation whether or not the COX-2


      inhibitors would meet this objective or not.  Shown


      here are two of the outcome trials with rofecoxib


      and celecoxib.


                As the group knows, there has also


      recently been another completed outcome trial with


      lumiracoxib.  In general, the outcome trials have


      compared COX-2 specific inhibitors at higher than


      usual therapeutic doses for osteoarthritis to


      non-selective NSAIDs and evaluated the clinically


      significant events on average over a year.  The


      major difference of importance between the outcome


      trials with celecoxib and rofecoxib was the


      inclusion or exclusion of low doses of aspirin.  We


      know that low doses of aspirin are ulcerogenic.  In


      the CLASS trial 21 percent of patients took low


      doses of aspirin, 325 mg/day or less, and none of



      the patients in the rofecoxib experience were


      taking low doses of aspirin.


                The principal gastrointestinal


      observations from the CLASS trial are, as shown


      here in this figure, taken from the publication in


      the JAMA, which represents the 6-month data point


      from this year-long trial.  In the top panel are


      all the patients who were evaluated in the trial


      who were taking either celecoxib or one of the


      non-selective NSAIDs, ibuprofen or diclofenac.  As


      you note, there was a numeric but not statistically


      significant reduction in ulcer complications in the


      overall group, remembering that 21 percent of the


      patients in the CLASS trial were taking low doses


      of aspirin and that some of the ulcer effects were


      related to the effects of aspirin.


                So, to get a better concept of the effects


      of a COX inhibitor compared to non-selective


      NSAIDs, the middle panel looks exclusively at the


      patients in this 6-month evaluation of the CLASS


      trial who were not taking aspirin, just celecoxib,


      ibuprofen or diclofenac.  As you observe in this



      middle panel, there were statistically significant


      reductions associated for GI outcomes with


      celecoxib when compared to traditional NSAIDs in


      the absence of aspirin at 6 months.


                However, for those of you who were here


      four years ago this month at the long-term safety


      evaluations of the FDA, the entire CLASS trial data


      set was evaluated with respect to gastrointestinal


      complications.  When compared to either ibuprofen


      or diclofenac alone or combined, with respect to


      complications there were not statistically


      significant gastrointestinal reductions in events


      associated, as you can see, with celecoxib.


                With regard to the VIGOR trial, just to


      refresh the group's memory, this was clearly


      exclusively an evaluation of rofecoxib versus


      naproxen.  There was no low dose aspirin.  Their


      observations were straightforward in with respect


      to either primary or secondary event being


      confirmed upper GI events or complicated events.


      There was a statistically significant reduction


      associated with rofecoxib compared to naproxen.


                As I have mentioned, there has also been a


      similar in design outcome study with lumiracoxib.


      The variable observations between these outcomes



      trials have led to extensive debate in the medical


      and scientific communities as to why one might have


      observed differences with respect to


      gastrointestinal endpoints between the outcome


      trials of COX-2 specific inhibitors.


                While I don't have time to get into the


      nuances and specifics of that debate, one point


      that I would like to bring to the group's attention


      that I do think is worthwhile reviewing is that, to


      the extent that there were differences between the


      observations in the outcome trials, these


      differences may have had more to do with


      differences in ulcerogenic effects with the


      traditional NSAID comparators such as naproxen,


      ibuprofen and diclofenac than they may have had to


      do with differences with respect to ulcerogenic


      effects between rofecoxib and celecoxib.


                The point to be highlighted is that the


      non-selective NSAIDs differ with regard to their



      ulcerogenic effects and that the delta, the


      difference observed between a COX-2 inhibitor and a


      non-selective NSAID will matter, and it will be


      based upon the choice of comparator being used.  I


      am not here to speak about cardiovascular effects.


      Dr. Garret FitzGerald will talk about


      cardiovascular issues in the talk to follow.  But I


      would like to point out that this concept of


      differences in COX-1 effects of non-selective


      NSAIDs is also applicable when we turn to a


      discussion of considerations of potential


      differences in cardiovascular observations between


      the trials of COX-2 inhibitors.


                Having pointed out the data with the COX-2


      specific inhibitors, I would like to mention that


      there are other potential approaches, and I would


      like to turn the discussion to a consideration, as


      shown on the bottom, of potentially older, safer


      NSAIDs that may be associated with gastrointestinal


      safety, agents such as the non-acetylated


      salicylates, nabumetone, diclofenac and etodolac.


                I mention this because--these are not



      gastrointestinal events, this is a reflection of in


      vitro evaluations of COX-1 versus COX-2 selectivity


      of various NSAIDs.  On the left, in the green, are


      NSAIDs which have increasing in vitro COX-1


      selectivity and are going in the negative


      direction; on the right, is increasing COX-2


      selectivity.  When one evaluates COX-2 selectivity


      in vitro, there is a group of NSAIDs which fall


      within this mid-range category of what I would call


      moderately COX-2 selective, and this COX-2


      selectivity of agents such as meloxicam or etodolac


      may be predictive of what one might see in outcome




                Taking etodolac as an example, when it was


      evaluated with respect to gastrointestinal outcomes


      compared to a non-selective NSAID such as naproxen,


      shown in the upper panel, there was a statistically


      significant, greater than 50 percent, reduction in


      gastrointestinal outcomes associated with an agent


      such as etodolac.  So, this leads me to conclude,


      over here in this group of category for COX-2


      specific inhibitors, that there are agents which



      have COX-2 selective activity which had not been


      widely appreciated historically.


                Since aspirin was such and important


      phenomenon in outcome trials, I think it is


      relevant to review the gastrointestinal effects of


      low doses of aspirin.  This has been looked at


      mostly from an epidemiologic perspective, and


      trials such as this have tended to show a


      dose-response relationship.  Although not


      statistically significant in this case, clearly


      lower doses, at least numerically, of aspirin such


      as 75 mg were associated with a lower rate of


      clinically relevant gastrointestinal bleeding than


      higher doses such as 300 mg.  In this instance, at


      least numerically from 75 to 300 mg, the odds ratio


      of clinically relevant upper gastrointestinal bleed




                Because of the risk associated with very


      low doses of aspirin such as 75 mg, doses of


      aspirin that have been quite low, such as 10 mg,


      have been evaluated in human studies to assess the


      question of whether or not there would be any daily



      orally administered dose of aspirin which would be


      without gastrointestinal effects.


                When measured by use of an intermediate


      marker that would be of COX inhibition or


      measurement of gastrointestinal prostaglandins,


      daily doses of aspirin given out to 3 months, as


      low as 10 mg, were associated with as great of a


      reduction of gastrointestinal COX as seen with 320,


      and gastric ulcerations were observed with a dose


      of aspirin that was as low as 10 mg, suggesting


      that there is likely not a dose of aspirin that


      would be effective that would be daily administered


      that would be without gastrointestinal risk.


                Another commonly asked question would be


      the potential benefit of an enteric coating or


      buffered preparation of aspirin.  When assessed in


      this cohort from the Framingham trial of patients


      who were taking various formulations of low dose


      aspirin, as one sees that there was no appreciable


      reduction in gastrointestinal bleeding associated


      with either enteric coating of aspirin or buffered


      aspirin when compared to plain, non-enteric,



      non-buffered aspirin preparations.


                Coming back to the risk factor which I


      mentioned had been not widely appreciated, the risk


      factor of multiple NSAID use, that is, combining


      low dose aspirin with a non-selective NSAID or


      COX-2 specific inhibitor, I think it is valuable to


      appreciate for a moment the actual risk, numerical


      risk, contributed by the addition of aspirin to


      another prescribed NSAID.


                From this population study in Denmark, it


      was apparent that when one combines the use of low


      dose aspirin and a non-selective NSAID the risk of


      having a clinically significant bleed, upper


      gastrointestinal bleed, more than doubled, such


      that several people would feel that the risk of a


      6-fold increase in the combination of a


      non-selective NSAID plus aspirin is sufficiently


      high that this population of users would need to be


      further risk reduced.


                These are data with non-selective NSAIDs.


      The data with respect to COX-2 specific inhibitors


      have come primarily from a few sources.  In this



      previous figure in which we saw earlier the 6-month


      data from the CLASS trial we stopped with the


      middle panel and had events in individuals taking


      celecoxib or non-selective NSAIDs in the absence of




                But when one looks at the bottom panel,


      rates of events, complications or symptomatic


      ulcers and ulcer complications in individuals who


      were taking one of these agents in the face of low


      doses of aspirin, it is clear that the use of low


      dose aspirin in the face of a COX-2 specific


      inhibitor markedly increased the rates of


      gastrointestinal events.


                But a point that I would like you to focus


      your attention on is the actual incidence of events


      in the patients who were taking either aspirin in


      combination with a COX inhibitor or non-selective


      NSAID.  You will remember that the problem that led


      to really the focus and development of classes of


      safer NSAIDs is an incidence of ulcer complications


      of 1-4 percent in the population that takes


      non-selective NSAIDs.  When one looks at the



      incidence of events that occurs annualized in


      patients who take aspirin, at least derived from


      the data in the CLASS trial, it is clear that the


      incidence that was observed of 2-6 percent is


      higher than the original problem.


                So, I would like to summarize with respect


      to the effects of low dose aspirin that low dose


      aspirin clearly increases the risk and mitigates


      the potential gastrointestinal beneficial effects


      of a COX-2 specific inhibitor.  These observations


      have been seen in other experiences with regard to


      the total lack of outcome data which I previously


      showed you, where we stopped on the top panel.


      When looking at the observations in patients taking


      low doses of aspirin, the beneficial effects of


      total lack disappear.


                In endoscopic trials recently we have also


      seen this effect of aspirin in this trial over 12


      weeks in which either aspirin was given alone or in


      combination with rofecoxib and compared to


      ibuprofen.  Focusing on the rofecoxib plus aspirin


      comparison, rofecoxib plus aspirin users have a



      similar, equivalent incidence of endoscopic


      ulcerations to non-selective NSAIDs such as


      ibuprofen.  So, the short conceptual way of


      summarizing this is a COX-2 specific inhibitor plus


      aspirin equals the effects of a non-selective


      traditional NSAID.


                The gastrointestinal discussion that we


      have had so far has pointed out some of the


      potential gastrointestinal effect benefits of a


      safer class of agents such as a COX-2 specific


      inhibitor.  Clearly, the gastrointestinal benefit


      does not exist in the face of aspirin and what we


      have recently learned is that the gastrointestinal


      benefit derived from a class of safer agents in the


      GI tract might be mitigated by adverse events in


      other areas, and other areas for consideration for


      this week's meeting are potential cardiovascular




                Given the limitations of COX-2 specific


      inhibitors and low dose aspirin users or when there


      may be potential cardiovascular concerns, one


      question that we have been asked to address would



      be in a potential world of no COX-2 specific


      inhibitors would we return to the problem of


      several gastrointestinal bleeds, hospitalizations


      or mortality?


                Well, this brings us back to the question


      of what might be the other approaches to accomplish


      the objective of reductions in GI events.  We have


      discussed some of the older, safer NSAIDs.  There


      are NSAIDs in development such as nitric oxide


      NSAIDs or phosphatidylcholine NSAIDs, the effects


      of which we are unsure of now and they are


      currently being evaluated.  But the other


      prevailing strategy to accomplish this objective


      would be the consideration of a non-selective NSAID


      plus co-therapy with either a proton pump inhibitor


      or misoprostol.


                Data in support of the proton inhibitor


      approach have been looked at in several trials, one


      example of which is shown here, endoscopic


      ulceration in NSAID users receiving co-therapy with


      either placebo, a proton pump inhibitor or


      misoprostol.  What the data pretty consistently say



      is that proton pump inhibitors have similar ability


      to misoprostol to prevent recurrent ulceration in


      NSAID users.


                Given that there are two prevailing


      approaches to accomplishing GI safety, either COX-2


      specific inhibitor alone or a non-selective NSAID


      plus a PPI, an important question which has


      presented itself for evaluation has been how might


      these two approaches compare directly and this is


      an important question to consider when considering


      the alternatives to having a world potentially in


      which there might not be COX-2 specific inhibitors


      available.  Could GI safety be accomplished?


                Well, this question has been asked at


      least in two trials or similar design in which high


      risk NSAID users--high risk being defined as people


      who previously had a history of bleeding ulcers.


      Once the ulcers were healed, they were then placed


      on either of the combination of non-selective NSAID


      plus a proton pump inhibitor or a COX-2 specific


      inhibitor, and then were followed for 6 months for


      rates of recurrent gastrointestinal bleeding.  The



      results of one of these trials has been fully


      published in a peer reviewed journals, shown here.


                The two endpoints being looked at--on the


      right are outcomes such as upper gastrointestinal


      bleeding; on the left are the results of endoscopic


      ulceration.  Either of these endpoints tells us


      that the approach of a non-selective NSAID plus a


      PPI appears comparable to the COX-2 specific


      inhibitor approach for achieving the objective of


      reductions in GI safety.  However, two important


      points that I would like to point out to the group


      are, one, we have endoscopy on the left and


      outcomes, GI bleeding, on the right.  Again, the


      endoscopic ulcerations that are seen in the trials


      generally predict what one would see in an outcomes


      study but, more importantly, if one looks at the


      actual rates of events which occurred, on the


      right, 5 percent and 6 percent with either approach


      in a group of individuals at high risk, meaning


      they previously had a history of gastrointestinal


      bleed, it is clear that either approach, either


      NSAID plus PPI or COX-2 specific inhibitor, is



      sufficiently adequate to reduce the rates of events


      back to a comfortable range.  The rates of events


      seen here in a high risk population are similar to


      the initial problem for which these approaches were




                In conclusion I have several observations.


      The untoward gastrointestinal effects of NSAIDs, as


      we know, cause considerable morbidity, mortality


      and cost.  Secondly, COX-2 specific inhibitors were


      developed principally to achieve a reduction in


      NSAID gastrointestinal toxicity.  That was a very


      desirable objective to be reached.  But very


      interestingly, as we just reviewed, this objective


      has been partially reached.  It seems that the risk


      reduction may not be achieved to the extent that we


      would have liked in patients who are at high risk


      for gastrointestinal bleeding, and the reason this


      is important is that that is clinically the target


      group of interest for risk reduction.


                Paradoxically, I did not mention that if


      one looks at subgroup analyses of outcome studies


      it appears that people who are at lower baseline



      gastrointestinal risk do have a benefit from


      receiving a COX-2 specific inhibitor.  However, the


      low risk group has a low prevalence of this problem


      of NSAID-related gastrointestinal events in the




                So COX-2 inhibitors, it appears, have been


      widely used by patients who are not at high risk


      for GI effects, and we have reviewed over the last


      several minutes that there are some limitations


      with COX inhibitors.  In my opinion, there is no


      great clinical need for COX-2 specific inhibitors


      in patients who are at baseline at low GI risk.  It


      is also clear that there is no GI benefit in


      patients who are concurrently taking aspirin.  We


      are here to discuss the possibility that


      cardiovascular concerns may exist for some groups


      of patients.


                So, the strategies to reduce the


      gastrointestinal effects of NSAIDs should focus on


      patients at greatest risk.  Just to reiterate, the


      patients at greatest risk may not be sufficiently


      risk reduced by either of the prevailing strategies



      which we currently have available clinically.  For


      such patients, COX-2 specific inhibitors may be an


      attractive option but it looks like the target


      group of interest may not have the anticipated




                For patients who are taking low dose


      aspirin or, if cardiovascular concerns were to


      exist, we have been asked to consider that if there


      were a world without COX-2 specific inhibitors how


      might we accomplish this objective, and it is clear


      that there are other strategies available that may


      lead to a reduction in NSAID GI effects.  Thank you


      very much.


                DR. WOOD:  Thank you very much.  Byron,


      could you just stay there in case there are


      specific questions for you while the slides are up?


      I have one.  Could you put up slide 4 again?  That


      shows data through 1990.


                DR. CRYER:  Yes.


                DR. WOOD:  What surprised me is Jim Freis


      has updated that data through 2000, and that


      dramatically changes what that slide looks like. 



      In fact, he found a 67 percent decline since 1990


      in complicated ulcers, the vast majority of which


      occurred actually before COX-2 specific inhibitors


      went on the market.  So, I am interested, first of


      all, in why you chose to present 15-year old data


      when there is new data out there that contradicts


      that, and whether you would like to comment on his


      publications from which this data came as well.


                DR. CRYER:  Sure.  It is correct that


      there are newer data available that have


      demonstrated a reduction in gastrointestinal bleeds


      on a population basis.  On the other hand, it is


      also very true that this problem of


      gastrointestinal bleeding with NSAIDs continues to


      be a significant problem despite its more recent


      decline.  But, more importantly, he also


      highlighted a very important observation which is


      that the declines in gastrointestinal bleeding that


      have been seen in populations preceded the


      introduction of COX-2 specific inhibitors, and


      there are some data sets to suggest, at least in


      the U.S., that hospitalizations for



      gastrointestinal bleeding since the introduction of


      COX-2 specific inhibitors have not markedly


      declined compared to hospitalizations prior to


      their introduction.


                DR. WOOD:  Right.  So, most of the 67


      percent decline occurred before these drugs went to


      the market, and that 67 percent occurs from the


      points on your slide here.


                DR. CRYER:  Point well taken.


                DR. WOOD:  And one other point of


      clarification I guess, the data you showed from


      CLASS, was that data from the predefined endpoint


      of the study at 18 months or the 6-month analysis


      that was published?


                DR. CRYER:  Just for sake of review, I


      have pointed out both time-dependent endpoints.


      The endpoint that was published and shown here, in


      the JAMA, was the predefined 6-month data and the


      endpoints that are shown here represent an


      evaluation of the entire data set.  There are


      clearly differences in the conclusions about the


      effects of celecoxib which varied by time and



      varied by whether one evaluates the data at 6


      months or evaluates the entire data set.


                DR. WOOD:  Just remind us, at 18 months


      what did the data set show?


                DR. CRYER:  At 13 months the data, with


      respect to complications, indicate that there was


      no statistically significant reduction in upper


      gastrointestinal complications associated with


      celecoxib, at a dose of 400 twice daily, when


      compared to either diclofenac or ibuprofen


      individually or when compared to both of them


      together.  I will point out for the sake of fair


      balance that this data does include the 21 percent


      of individuals who were taking low doses of




                DR. WOOD:  Other questions from the


      committee?  Dr. Nissen?


                DR. NISSEN:  Yes, this 1-4 percent rate, I


      am interested in understanding the time-dependent


      hazard.  If a patient is put on a non-selective


      NSAID and, let's say, for the first year has no GI


      events, is the risk in the second and third and



      fourth years the same as it is in the first year?


      In other words, once you know that a patient is


      tolerating an NSAID are they no longer at high




                DR. CRYER:  There are a few answers,


      sub-answers to that question.  It is a complicated


      discussion.  What is clear that risk persists, that


      even in the individual who did not develop a


      complication in year one, that individual continues


      to have risk in subsequent years--two, three, four,


      etc.  There are data sets that suggest that the


      period of highest susceptibility, highest risk is


      within the first three months of administration.


      Having said that, there are other data sets to the


      contrary.  This incidence of gastrointestinal


      events that are time-dependent in individuals has


      been difficult to assess primarily based upon a


      concept of selection of susceptible individuals.


      People drop out because of other reasons such as


      dyspepsia.  So, it is difficult to get a firm


      estimate on that.  But it is clear, in summary,


      that the risk after one year or after any period of



      time is always persistent as long as the NSAID


      exposure is present.


                DR. NISSEN:  Two more quick questions.  I


      didn't see any analysis of COX-2 plus low dose


      aspirin versus a non-selective NSAID plus low dose


      aspirin.  The reason I am asking that is that, as a


      cardiologist, in my patients who are taking


      conventional NSAIDs, if they need aspirin for


      cardiovascular prophylaxis I give them aspirin.


      So, the question is are there any studies looking


      at NSAID plus aspirin versus COX-2 specific


      inhibitor plus aspirin?


                DR. CRYER:  Well, the CLASS trial


      addressed that question in a subpopulation of


      individuals which was under-powered statistically


      to give a definitive answer to that question.  That


      is an ongoing debate within the medical


      communities.  I will say, however, that while the


      debate continues what is clear is that with either


      approach COX-2 specific inhibitor plus aspirin or


      non-selective inhibitor plus aspirin the ensuing


      rates of gastrointestinal events are too high for



      us to feel comfortable that we have risk-reduced


      those patients sufficiently.


                DR. NISSEN:  And a final question,


      symptoms of dyspepsia are obviously one of the


      issues as well, and I want to make sure I


      understand what fraction of the population, let's


      say an osteoarthritis population, simply cannot


      tolerate NSAIDs because of GI discomfort.  Do we


      have data on that?


                DR. CRYER:  Sure.  A couple of comments


      about dyspepsia which I didn't mention, NSAID


      dyspepsia is common.  Its prevalence varies


      depending on how dyspepsia has been defined in


      trials, and because there have been variable


      definitions of dyspepsia, its reported rates have


      varied anywhere from 10-30 percent of NSAID users,


      but it is clearly more common than complications.


                In the patient who has dyspepsia, the


      presence of dyspepsia is not predictive of the


      patient who might have risk.  In most of these


      studies dyspepsia, in my way of thinking, is


      considered more of a nuisance issue that can be



      controlled symptomatically with acid reduction


      rather than something that presents significant


      gastrointestinal concern.


                DR. WOOD:  Dr. Gibofsky?


                DR. GIBOFSKY:  You commented extensively


      on the upper GI risk but in your second slide you


      correctly pointed out that there are problems with


      traditional medications affecting the structures of


      the GI tract below the ligament of triads.  Could


      you comment somewhat on the data comparing the


      effect of COX-2 specific inhibitors versus


      traditional non-steroidals with or without proton


      pump inhibitor protection on the lower GI tract?


                DR. CRYER:  There have been fewer data


      sets which have assessed the lower gastrointestinal


      events with NSAIDs. A few comments on the types of


      studies that have been done, there have been


      studies using pill endoscopy which have indicated


      that lesions, endoscopic ulcers and erosions occur


      in the lower gastrointestinal tract contributed to


      by non-selective NSAIDs, an effect which can be


      reduced by a COX-2 specific inhibitor, an effect



      which is not reduced by the co-therapy approach of


      adding a PPI to a non-selective NSAID.  I am


      speaking of the lower gastrointestinal effects.


                Having said that, again similar to the


      endoscopic ulcer story, these endoscopically


      detected lesions in the lower gastrointestinal


      tract probably have very limited clinical


      relevance.  When lower gastrointestinal clinically


      significant events have been assessed from the


      prospective trials, the one noted most commonly in


      the literature is an assessment of the VIGOR trial


      looking at the effects of rofecoxib compared to


      naproxen, in which case a 40-50 percent reduction


      was seen in lower gastrointestinal events with


      rofecoxib compared to naproxen, again to reiterate,


      a reduction which would not be expected to be


      observed with the proton pump inhibitor approach.


                Having said that, in that assessment of


      the rofecoxib experience there was an inclusion in


      the definition of lower GI events of individuals


      who had had reductions in hemoglobin and hematocrit


      and who did not otherwise have clinically apparent



      gastrointestinal bleeding.


                Probably the best assessment in terms of


      the risk of lower gastrointestinal events on NSAIDs


      comes from population-based observational studies.


      While there is variance in that estimate, it looks


      like the lower gastrointestinal events probably


      contribute 10-20 percent of clinically relevant


      events when compared to all GI events that might


      happen on NSAIDs.


                DR. GIBOFSKY:  One last quick point, would


      your recognize that there might well be a


      population of patients whom you would stratify as


      low GI risk who, nevertheless because of either


      intolerance, as the last speaker asked, or lack of


      efficacy to traditional non-steroidals, would be


      candidates for another class of agents?


                DR. CRYER:  Sure.  Their NSAID dyspepsia


      is a common phenomenon.  I will say that when


      dyspepsia has been carefully evaluated in the


      prospective trials of COX-2 specific inhibitors in


      general there tends to be a reduction in the rates


      of dyspepsia associated with the COX-2 specific



      inhibitors.  However, when one evaluates the


      absolute reduction in rates of dyspepsia in the


      trials it generally tends to be a few percentage


      points.  Finally, some of the other strategies that


      were mentioned to accomplish risk reduction, for


      reduction in GI events in patients on NSAIDs, also


      accomplished reductions in dyspepsia in patients


      who might experience NSAID-related dyspepsia.


                DR. WOOD:  Dr. Cush?


                DR. CUSH:  Byron, two time questions.


      One, is there a time point at which peptic


      ulcerations and bleeds plateau over time in NSAID


      users or COX-2 users?  Second, what is the longest


      data set that we have as far as the use of a COX-2


      agent in a clinical trial where observation is


      carried out?  Do we have two-year data; five-year




                DR. CRYER:  Right.  There does appear to


      be some plateau-ing of the effect.  The data sets


      do suggest that after long-term exposure the rates


      of events with longer-term exposure are not as


      great as rates of events with initial exposure to



      NSAIDs but, again, that may be attributable to the


      phenomenon of dropping out of susceptibles.   The


      second portion of your question, Jack, was?


                DR. CUSH:  What is the longest data set we


      have on COX-2 agents?


                DR. CRYER:  Well, when one looks at the


      trials, the prospectively defined outcome


      trials--we have CLASS, TARGET, VIGOR--there are


      periods of observation out to 13 months.  Having


      said that, we certainly have longer periods of


      observations of COX-2 specific inhibitors for


      trials in which the specific outcome of interest


      was defined for an endpoint that was other than


      upper GI bleeding, so specific polyp reduction,


      Alzheimer's disease, other trials that we certainly


      will hear about over the course of the next few


      days, many of which have gone out to periods as


      much as 3 years.


                DR. WOOD:  Is there anyone else who has a


      question that specifically addresses something on a


      slide that the speaker could show again?  If not,


      we will come back to these questions and ask you,



      Byron, if you would, to be available this




                DR. CRYER:  Yes.


                DR. WOOD:  Are there any questions that


      somebody has specifically?  Tom?


                DR. FLEMING:  Yes, could we go back to the


      slide that showed the CLASS trial with the time to


      complicated ulcer?


                DR. CRYER:  There were two.  You can tell


      me which one you are referring to, this or the




                DR. FLEMING:  Both, this and the next.


      Basically, here what you are showing us is that in


      the presence of aspirin there doesn't seem to be a


      reduction in the complicated ulcers although in


      those that are not taking aspirin there is this


      reduction of about two-thirds.  If you go to the


      next slide, that is at 6 months.  Hence, we see at


      6 months this reduction in the rate in the


      celecoxib group that is driven by those patients


      who are not on aspirin.  But that effect, as you


      noted, has disappeared out at a year.


                I know that is making a lot of a single


      data set but is this suggestive of the possibility


      that, in response to Steve Nissen's question, there



      could be a group that is more susceptible and what


      you are doing, in the presence of aspirin, is


      achieving not effect; in the absence of aspirin you


      are achieving a delayed effect but, in essence, you


      are going to have the same overall incidence by a


      year even with the COX-2 specific inhibitor?


                DR. CRYER:  Sure, your point is that there


      are likely subgroups of susceptibility for GI risk


      on NSAIDs or on COX-2 specific inhibitors.  But I


      would say also that underlying that argument, which


      I think is accurate, is the observation which


      confounds the whole discussion, which I have


      mentioned previously, which is that early on in any


      of these trials you are going to remove the most


      susceptible of the individuals and those who


      actually persist in the trial tend to be the least


      susceptible subpopulation.


                DR. FLEMING:  Indeed, but that is the


      essence of what I am saying, and this would be



      consistent then with the theory that if there is a


      particular susceptible group, that group is going


      to have a higher risk and it is, in fact, going to


      have complicated ulcers.  They just occur somewhat


      sooner with the non-specific NSAIDs.  The COX-2s


      are not preventing that, they are just delaying the


      time to the occurrence.


                DR. CRYER:  I think we are in agreement




                DR. WOOD:  Richard?


                DR. PLATT:  To extend that, on slide 13


      you list some risk factors for NSAID-associated GI


      toxicity.  Can you tell us how well those


      discriminate low risk individuals from high risk


      individuals?  And, if they do, what fraction of the


      population falls into low risk, medium risk, high


      risk?  And, quantitatively what are those risks?


                DR. CRYER:  That is a complicated question


      but it is an important one.  When people like


      myself have shown these risks we commonly lead to


      the assumption that these risk are numerically


      equivalent, which they are not.  There are certain



      risk factors which clearly place one individual at


      higher risk than others.  The highest risk most


      consistently seen in trials would be that of having


      had a previous history of a gastrointestinal


      bleeding ulcer.  But not far behind that would be


      the risk of taking an anticoagulant, such as


      Coumadin, in association with a non-selective


      NSAID.  Age as a risk factor is a variable one.


      Although we suggest in our discussions of this that


      there may be a threshold of age below which one may


      be not at risk and above which at risk for having


      it.  In fact, it is a continuum.  In fact, the risk


      contributed by age is about a 2 percent increase in


      risk per decade of life, such that people who are


      in their 80s are at very high risk, much higher


      risk than people who are in their 40s.


                With respect to your question of


      quantifying the risk in a population, that is a


      difficult issue because all of these risk factors


      do not individually present themselves in any one


      patient.  The more risk factors one has--two risk


      factors present greater risk than one; three



      greater than two.  I would say, having said that


      and trying to give you a reasonable estimate, in my


      opinion the percentage of NSAID users who would


      likely be candidates for this is probably somewhere


      on the order of 20-25 percent, depending on how one


      assesses that.  If one looks at an OA or RA


      population and concludes that age in and of itself


      is a risk factor, then you are close to 80 or 90


      percent of the population that might be at risk


      based upon that risk factor of age.  So, it really


      depends on which risk factor, and it really depends


      on the quantitative contribution of the risk factor


      being described.  But, certainly, I would say the


      one that most clearly and consistently has


      presented itself as highest risk in the various


      trials has been the risk factor of having had a


      previous bleeding ulcer, and it is the one that I


      would like to underscore which does not appear to


      be sufficiently risk-reduced by either of the


      strategies which we have available.


                DR. WOOD:  Any other questions that are so


      burning that they have to be asked now and not in



      the discussion?  Ralph?  Burning?  And let's try


      and make the answers as brief as we can.


                DR. D'AGOSTINO:  What are the consequences


      of complicated ulcers in, say, the CLASS trial


      where you do see this differential and this


      catching up?  Do they follow to see the


      consequences of these ulcers?  Were they different


      over the time period?


                DR. CRYER:  I am sorry, I don't




                DR. D'AGOSTINO:  What are the


      consequences?  What happened to these subjects


      after?  Were they reversible, the ulcer?  Does it


      lead to mortality?


                DR. CRYER:  Right, what I assume is


      driving your question is whether there are


      differences in mortality--


                DR. D'AGOSTINO:  Well, morbidity,


      mortality, what happens.


                DR. CRYER:  Well, clearly, morbid effects


      are hospitalization and the complications of them


      having a massive gastrointestinal bleed, which can



      be several.  The ultimate complication or


      consequence of these morbid effects is mortality


      and in these outcome trials there were no


      differences in the level of mortality.  With regard


      to the various other consequences, most of them are


      clearly going to be reversible after having


      suffered a significant hospitalization.


                DR. WOOD:  Any other smoking questions?




                DR. GROSS:  A question on the third to


      last slide, on recurrent ulcer bleeding in high


      risk patients, the so-called non-selective NSAIDs


      selected diclofenac to compare with celecoxib.


                DR. CRYER:  Yes.


                DR. GROSS:  Diclofenac is roughly


      comparable in COX-2 selectivity.  Is that the right


      drug to test with PPI to show that the PPI plus a


      non-selective NSAID is comparable to a COX-2


      inhibitor like celecoxib?  Should they have picked


      a non-selective NSAID that was less selective for




                DR. CRYER:  Sure.  Your point is very well



      taken and it is one which I tried to underscore


      throughout the talk, which is that there are


      clearly differences in the COX-1, i.e.,


      ulcerogenic, effects of non-selective NSAIDs.


      Diclofenac clearly is an agent which is associated


      with a lower rate of gastrointestinal ulceration


      and complications than non-selective NSAIDs.  So,


      in this evaluation of the comparison of diclofenac


      plus omeprazole compared to celecoxib there is a


      valid discussion that the results may have been


      biased in favor of the diclofenac plus omeprazole




                The reason I showed that is that that was


      a fully published paper.  There are, however, other


      trials not yet fully peer reviewed, which have been


      presented in the gastrointestinal community,


      looking at other NSAIDs, such as naproxen plus a


      proton pump inhibitor compared to the COX-2


      specific inhibitor approach, and the results of


      those observations again are comparable endpoints


      between the two strategies.


                DR. WOOD:  I am going to move us on now



      and we will come back after the next talk.  Dr.


      Cryer, we would like you to come back up if there


      are questions at that time as well.  The next


      speaker is Dr. Garret FitzGerald.  Garret?


             Mechanism Based Adverse Cardiovascular Events


                    and Specific Inhibitors of COX-2


                DR. FITZGERALD:  Thank you, Dr. Wood.  You


      are, please, going to have to forgive me, I feel


      quite nauseated;  I have a touch of the flu and I


      took a medicine to reduce my temperature, but I am


      not prepared to tell you what it is!




                I would like to thank Dr. Wood and the FDA


      and the committee for the opportunity to visit


      Gaithersburg at this time of the year.




                When I boarded the Metro last night at


      Union Station and began the apparently interminable


      trip to the sylvan embrace of Shady Grove I thought


      to myself it might be useful to try and summarize


      for you a message that will derive from my talk.


      The message is that, just as low dose aspirin



      affords cardioprotection and a small but absolute


      risk of serious GI bleeds, as you heard from Byron


      just now, through inhibition of COX-1, so specific


      inhibitors of cyclooxygenase-2 afford


      gastroprotection and a small but absolute risk of


      cardiovascular events.  So, I have titled my talk


      mechanism-based adverse cardiovascular events and


      specific inhibitors of COX-2.


                Well, as every lawyer and broker and


      journalist knows, this is the cyclooxygenase


      catalyzed pathway of arachidonic acid metabolism.


      Arachidonic acid is mobilized for release from cell


      membranes by activation of phospholipases and it is


      subject to metabolism by two enzymes which we call


      prostaglandin JH synthases 1 and 2 but which are


      known more commonly as cyclooxygenases 1 and 2.


      They give rise to a series of lipid products called


      prostaglandins which activate receptors and have


      very diverse biological effects.


                One of the reasons we are here is that


      this, although depicted in a very simplistic way,


      is actually a quite complex system.  To illustrate



      that, I will just mention two of these lipid


      products, prostaglandin E-2 and prostacyclin or


      prostaglandin I-2.  When formed by


      cyclooxygenase-1, these two lipid products afford


      gastroprotection, and our thinking is that the


      common GI adverse events of typical non-steroidal


      anti-inflammatory drugs reflect the inhibition of


      COX-1-derived PGI-2 and PGE-2, thereby, exposing


      people to gastroduodenal liability.


                But it turns out that when the very same


      lipids, prostacyclin and prostaglandin E-2, are


      formed by cyclooxygenase-2 as opposed to


      cyclooxygenase-1 they mediate pain and


      inflammation.  Indeed, it is the suppression of the


      formation of these two prostaglandins by COX-2


      inhibitors that retains the anti-inflammatory and


      analgesic efficacy of traditional non-steroidal


      anti-inflammatory drugs which inhibit the two


      enzymes together.


                But it turns out that these two


      prostaglandins, prostaglandin I-2 and prostaglandin


      E-2, formed by cyclooxygenase-2 also afford



      cardioprotection which can manifest itself in


      various ways, and suppression of that capability is


      the cogent mechanism which explains the


      cardiovascular hazard which has emerged.


                Well, I am sure this audience well knows


      that cyclooxygenase-2 inhibitors do not inhibit


      platelet aggregation, a way that we look at


      platelet activation in people that have been


      administered drugs.  This just illustrates the


      absence of an effect at several doses of celecoxib


      in healthy volunteers compared to the inhibition of


      this signal by a mixed inhibitor at the time of


      peak drug action.  Of course, that reflects the


      absence of cyclooxygenase-2.  There should be a big


      shade here on this Western Blot if it was present


      but, unlike cyclooxygenase-1, which is there in


      abundance, cyclooxygenase-2 is not present in


      mature human platelets.


                The wrinkle in all of this is that if you


      look at two structurally distinct members of the


      class of COX-2 inhibitors, the depression of the


      formation of that protective lipid, prostacyclin,



      as reflected by urinary excretion of its major


      metabolite which, believe it or not, is the gold


      standard of how you look at prostaglandin formation


      in people--this depression is comparable on


      specific inhibitors of COX-2 with the depression we


      see with structurally distinct mixed inhibitors


      like ibuprofen and indomethacin.


                So, one might logically deduce from this


      that even under physiological conditions, never


      mind under conditions of pathology, a COX-2 might


      be induced by cytokines for example.  It is a


      dominant source of prostacyclin.  We hypothesized


      at the time that that reflected a mechanism which


      had been described in vitro by Topper and Jim


      Broney and which is illustrated here, which is when


      you subject endothelial cells to laminar shear


      force, which mimics the effect of the blood stream


      on the lining of blood vessels, you up-regulate the




                Well, that raised a question rather than


      answered a question even though it anteceded the


      approval of the first of these drugs.  The first



      proof of principle that prostacyclin did actually


      modulate cardiovascular function in vivo stems from


      this study where we used mice lacking the


      prostacyclin receptor, known as the IP, or the


      thromboxane receptor, known as the TP, or both


      together.  Thromboxane is the lipid which is formed


      by COX-1 in platelets and has harmful effects on


      the heart and cardiovascular system, and


      suppression of thromboxane reflects the


      cardioprotection of low dose aspirin.


                In these studies we looked at the response


      to vascular injury in mice and we found that there


      was a signal of increased proliferation in response


      to vascular injury in the mice lacking the


      prostacyclin receptor which accorded with its in


      vitro properties.


                Furthermore, when you injure the lining of


      a blood vessels in a mouse, just as if you do it in


      humans by performing an angioplasty, you get an


      attendant increase in platelet activation which is


      reflected by a time-dependent increase in excretion


      of a major thromboxane metabolite.  We were



      interested to see that this signal was grossly


      augmented in the absence of the prostacyclin


      receptor, and that all of these reflections of the


      phenotype could be rescued by co-incidental


      deletion of the thromboxane receptor along with the


      prostacyclin receptor.


                Now, these studies were criticized as to


      their relevance to the COX-2 inhibitor story mainly


      because people said, well, you have taken away the


      prostacyclin receptor but when we give the drugs,


      although we suppress prostacyclin, we do it to a


      substantial but incomplete degree, maybe 60-80


      percent on average.


                So, we performed these studies in another


      model of induced thrombogenesis in mice where we


      injured the vasculature in a free radical catalyzed


      fashion.  In these studies we looked at the effect


      of a biochemically selective regimen of a COX-2


      inhibitor, and we found that the response time to


      the thrombogenic stimulus was significantly


      accelerated.  Furthermore, as opposed to looking at


      the absence of both copies of the prostacyclin



      receptor, we looked at the effect of deletion of


      just one copy and we found a significant and


      intermediate phenotype.


                More recently we have devised a technique


      which permits us to remove cyclooxygenase-2 from


      particular cells.  What I am showing here is the


      removal of only one copy of cyclooxygenase-2 from


      endothelial cells.  As you can see, that also


      accelerates the response to a thrombogenic


      stimulus.  So, these new studies are proof of


      concept of precisely the mechanism that we


      originally proposed.


                Well, I think this is a point that we will


      come back to.  We have some scientific evidence


      that there is a very non-linear relationship


      between inhibition of the capacity of platelets to


      make COX-1 derived thromboxane and inhibition of


      thromboxane-dependent function, that is,




                To get into the red zone for inhibition of


      platelet function you certainly have to be in


      excess of 95 percent inhibition of capacity, more



      like up in the 98 percent range.  Where we have


      actually almost no experimental evidence is whether


      there is a discordance between that and the


      relationship between inhibition of prostacyclin and


      inhibition of its protective cardiovascular


      function.  Perhaps the intermediate phenotype of


      the prostacyclin receptor deleted mice losing one


      copy of the gene may suggest that that is so.


                So, we are back in the mouse model of


      induced thrombosis.  The reason I am showing you


      this slide is that a theme that will recur and is


      relevant to the clinical consideration is whether


      inhibition of COX-1, along with inhibition of


      COX-2, modulates the implications of inhibiting




                So, in these studies we have looked at the


      rescue from thrombosis induced by intravenously


      administering arachidonic acid to mice at two


      different doses in mice that either lack completely


      COX-1 or in mice that lack 98 percent of the


      capacity to make COX-1 derived thromboxane by


      platelets.  As you can see, these two genetically



      modified mice behaved very similarly in terms of


      the rescue from arachidonic acid induced thrombosis


      or, indeed, the time to complete occlusion induced


      by the thrombogenic stimulus I showed you in the


      earlier slide.  This accords with that


      non-linearity of the relationship for COX-1 that I


      showed you.  You would expect that to be suppressed


      in the 98 percent inhibited mice.


                Now, that is all very well because it is


      in mice.  So, you would way, well, how would we


      address this in terms of seeking a proof of concept


      in people?  Well, if you delete the prostacyclin


      receptor mice don't fall over dead with thrombosis.


      They are more responsive to thrombogenic stimuli.


      So, if you wish to seek proof of concept in people,


      you would move to a population that had hemostatic


      activation and you would postulate that in such a


      population you would detect a signal faster and in


      a smaller study than might otherwise be the case.


                Indeed, given the widespread recognition


      that patients undergoing coronary-artery bypass


      grafting exhibit hemostatic activation, and some



      suggestion also that they may be a model of aspirin


      resistance, it is perhaps unsurprising that we are


      able to detect a clear signal of cardiovascular


      hazard in two placebo-controlled trials in this




                Now, when I think of people at risk of


      thrombosis when one is considering where one goes


      with these drugs, I tend to think of middle-aged or


      elderly people who have suffered a myocardial


      infarction or stroke.  But I think it is important


      to remember that risk of thrombosis can manifest


      itself in susceptibility to this cardiovascular


      hazard of these drugs in other populations.


                This is a ventilation perfusion scan of a


      23 year-old athlete who had been on the pill for 3


      years, who went on a 6-hour car journey, having


      been put on valdecoxib for the antecedent 8 days


      and, at the end of the trip, developed left-sided


      chest pain; was misdiagnosed and continued on


      valdecoxib for another 10 days; had right-sided


      pleuritic chest pain that led to this VQ scan.


                This is purely an anecdote but it brings



      to mind that individuals who have environmental


      predisposition to thrombosis, with a relatively


      small absolute risk such as being on the pill or


      prolonged stasis or genetic predispositions like


      Factor V Leiden, might be susceptible to a


      geometric interaction of relatively low risk from


      this class of drugs.


                So, as far as thrombosis is concerned,


      where does this take us?  Well, first of all, we


      have evidence that at least in vitro COX-2 can be


      induced in endothelial cells and produce


      prostacyclin.  We have evidence that it constrains


      platelet activation and thrombogenesis in vivo.


      Suppression of prostacyclin does not cause


      spontaneous thrombosis but augments the response to


      thrombogenic stimuli in vivo.  So, the hazard from


      coxibs would be expected to be particularly evident


      in those otherwise predisposed to thrombosis, and


      we have evidence that this hazard is modulated by


      inhibition of COX-1 in the appropriate zone.


                Well, there has been a lot of talk, as we


      all know, about mechanisms and one of the things I



      have found really curious is the notion that


      hypertension is a distinct mechanism.  People get


      hypertension on traditional non-steroidal


      anti-inflammatory drugs as well as COX-2 inhibitors


      for a reason.  The reason is the same mechanism.


      Illustrated here from studies in mice by Matt


      Breyer and his colleagues is how inhibition of


      COX-2, shown in red, will augment the pressor


      response to an infused pressor like angiotensin-II.


      Again, as in the setting of thrombosis, COX-1 is


      not neutral.  As you can see, if he uses a


      selective inhibitor of COX-1 he attenuates the


      response to angiotensin-II.


                Now, these studies have been complemented


      by congruent data with gene-deleted mice.  They


      raise the prospect that the incidence of


      hypertension would reflect not only the degree of


      inhibition of COX-2 but the selectivity with which


      it is attained.  Indeed, in this week's Archives we


      have the first epidemiological evidence consistent


      with that concept.


                Now, the products of COX-2 that buffer the



      response to pressor agents include prostacyclin and


      PGE-2.  Here we are looking at the effect on blood


      pressure, of deletion of the prostacyclin receptor


      and, as you can see, blood pressure is elevated and


      the response to salt loading is increased.  One


      sees exactly the same phenotype deleting one of the


      receptors for PGE-2.


                So, as far as blood pressure is concerned,


      suppression of COX-2 derived PGI-2 and PGE-2


      increases blood pressure and augments the response


      to hypertensive stimuli in mice.  Deletion or


      inhibition of COX-1 depresses the response to


      vasoconstrictors in vivo so again we see COX-1


      modulating the hazard from COX-2 inhibition.


      Hypertension on NSAIDs would be expected to relate


      to the inhibition of COX-2 and the selectivity with


      which it is attained.


                Let's think of a more chronically


      unfolding cardiovascular hazard.  These data


      arbitration taken from Narumiya.  They are looking


      at the development of atherosclerosis in a


      genetically prone mouse, and you can see that



      deletion of the prostacyclin receptor accelerates


      atherogenesis in male ApoeE-deficient mice.  In


      fact, the impact was most particularly marked at


      initiation and early development of




                By contrast, deletion of the thromboxane


      receptor does the complete reverse, and other


      studies conducted by us and others have shown that


      inhibition of COX-1 selectively or antagonism of


      the thromboxane receptor will have the same effect


      as deleting the thromboxane receptor, as shown




                So, as far as atherosclerosis is


      concerned, we see this buffering capacity between


      COX-1 and COX-2.  Furthermore, we have shown


      recently that in a different genetically proned


      mouse model deletion of the prostacyclin receptor


      and inhibition of COX-2 dependent formation of


      prostacyclin is important in affording the


      atheroprotection conferred by estrogen in female




                So, here we see the atheroprotection in



      terms of reduction of lesion development with


      estrogen treatment in vasectomized mice being


      dramatically reduced by deletion of the


      prostacyclin receptor, which raises a whole new set


      of questions about the use of these drugs in


      premenopausal women.


                So, as far as this other manifestation of


      a cardiovascular hazard is concerned, initiation


      and acceleration of early atherogenesis occurs in


      response to deletion of the prostacyclin receptor.


      I haven't gotten into mechanism but it fosters


      platelet and neutrophil activation and vascular


      interactions of these cells, and removes the


      constraint on attendant oxidant stress.


                Now, we know that hypertension, which is


      also a consequence of inhibition of this pathway,


      itself accelerates atherogenesis.  So, one could


      imagine that the direct and indirect effect could


      converge to transform cardiovascular risk.


      Finally, again COX-1 is playing a modulatory role.


                There is a lot of speculation, which will


      no doubt be addressed in this meeting, as to



      whether in the APPROVe study we actually saw a


      delayed appearance of augmented cardiovascular


      risk.  I think, for me, the answer is we are not so


      sure but, if we did, this mechanism would explain


      not only early events but also the delayed


      emergence of cardiovascular phenotype.


                The other thing that is often trotted out


      is, well, but people on aspirin have had some of


      these events.  Well, of course, people on aspirin


      also have myocardial infarctions.  But I think it


      is worthwhile remembering as we consider that


      prostacyclin will buffer effects of thromboxane on


      blood pressure, atherogenesis, hemostasis and,


      indeed, cardiac damage, which I haven't gotten into


      today.  It acts as a general constraint on any


      agonist that acts harmfully on these systems.  So,


      one would expect aspirin, in a perfect world, to


      damp rather than abolish the signal.


                So, I think, if you will pardon me just


      for a moment to muse, one could relate the ability


      to detect a signal, expressed here as maybe numbers


      needed to treat or trial duration, as a function of



      the underlying cardiovascular risk of the patients


      involved.  The higher the risk, the more you would


      be able to detect it easily.  The lower the risk,


      it may require that you either perform a very large


      study or go on for a very long time because we are


      all mindful of the fact that clinical trials, even


      randomized clinical trials, are very crude detector


      systems for uncommon risk.


                Additionally, other elements will impact


      on this, including elements related to drug


      exposure and the degree of selectivity that is


      actually attained in vivo.  So, I think in some of


      the efforts to dismiss this idea of a class-based


      effect some have lost sight of the fact that one


      would expect not only the underlying substrate to


      be relevant, but elements of drug exposure like


      dose, duration of dosing, duration of drug action


      and, indeed, concomitant therapy to be relevant to


      the ability to detect a risk.  So, one is looking


      for a needle in the haystack and, to some extent,


      when one finds the needle it doesn't really matter


      how long it has been in the haystack.


                So, let's consider the extreme phenotypes


      of cardiovascular benefit and hazard in this


      pathway.  First of all, let's consider aspirin.



      Here we have a sustained mechanism of action that


      leads to complete and sustained inhibition of


      COX-1.  Even low dose aspirin inhibits prostacyclin


      to a minor degree.  But one would expect, and one


      sees, a cardiovascular benefit from aspirin, at


      least in the secondary prevention of stroke and


      myocardial infarction.


                In the case of COX-2 inhibitors one sees a


      reversible inhibition of COX-2.  One also sees


      variable degrees of inhibition of COX-1 but,


      because of that non-linearity that I mentioned to


      you in the relationship, effectively this makes


      these drugs selective for COX-2 because you have no


      inhibition of COX-1 dependent platelet function.


                That brings me to the last topic that I


      would like to address, and that is what about the


      traditional NSAIDs?  Well, here is one way of


      comparing aspirin to a prototypic NSAID, ibuprofen.


      You take healthy volunteers, you administer them



      low dose aspirin to stead-state efficacy, or


      ibuprofen 3 times a day to a steady-state effect,


      and you look at the offset of effect on enzyme


      inhibition and inhibition of function.


                With aspirin you see sustained inhibition


      over the 24 hours after stopping the drug.  As you


      would expect, with stopping ibuprofen you see


      offset of this reversible inhibitor on the enzyme.


      From whatever I have told you about that


      non-linearity in the relationship, you are not


      surprised to see a steeper offset of inhibition of




                Well, of course, we have no randomized,


      placebo-controlled trials of traditional NSAIDs.


      We have various overviews of the epidemiological


      experience, with all the limitations of that


      approach and we can see that ibuprofen looks like


      it is not really altering cardiovascular hazard.


      There seems to be a sort of 10 percent or so


      reduction with naproxen, particularly 500 mg twice


      a day which was the most commonly used dosage in


      these studies.


                Now, this would be like a dilute aspirin


      effect and, obviously, has relevance to the


      interpretation of studies like VIGOR and some of



      the experience with the etoricoxib that you will


      hear about as to whether naproxen is actually


      behaving like aspirin.


                Well, I think actually the epidemiology is


      entirely consistent with the clinical pharmacology


      of naproxen.  This elegant study was performed by


      Patrignani.  Again we are looking at the offset


      action of aspirin and naproxen 500 mg per day


      administered to steady state.  We are looking at


      inhibition of enzyme function, and we see with


      aspirin exactly what we would have expected,


      sustained inhibition.  However, at the end of a


      typical dosing interval for naproxen we see


      heterogeneity of response.  In fact, everybody is


      at 95 percent or lower, suggesting that within the


      dosing interval there is a variable degree of


      cardioprotection afforded through this mechanism,


      which would be consistent with the dilute aspirin


      effect from the epidemiology.


                This is a plot of the IC-50 for inhibition


      of COX-2.  This is inhibition of COX-1 in whole


      human blood.  As we move in this direction we are


      getting more selective for COX-2.  It brings us


      back to a point that arose in Byron's study, and


      that is that although there is a difference in



      potency, celecoxib and diclofenac look remarkably




                I would also remind you that naproxen,


      bearing in mind the Aleve study fiasco, is on the


      other side of the line, just like ibuprofen is, and


      exhibits preference for inhibition of COX-1.


                Well, you have had a nice job giving you a


      full data set, demonstrating that actually in whole


      human blood diclofenac and celecoxib are


      superimposable.  So, I would contend that through


      various lines of evidence diclofenac is probably a


      selective COX-2 inhibitor like Celebrex.


                Consistent with that is a pharmacodynamic


      interaction where we showed that prior occupancy of


      the COX-1 site by a typical mixed inhibitor like


      ibuprofen would block access of aspirin to its



      target acetylation site.  If we give aspirin and


      ibuprofen chronically we actually see a pattern


      that looks just like giving ibuprofen alone, an


      onset of action and a steep offset of function.


      However, if we substitute diclofenac for aspirin it


      looks like giving aspirin alone, which is


      consistent with the type of information you get


      with a selective COX-2 inhibitor like rofecoxib or


      celecoxib in this assay.


                So, I think we can start thinking of


      diclofenac as Celebrex with hepatic side effects.


      It has the same selectivity in whole blood in


      vitro.  It has no pharmacodynamic interaction with


      aspirin.  It has no clinical interaction with


      aspirin in the one epidemiological study which has


      addressed this interaction with the two drugs.


      Also, it is consistent with the superimposition of


      the GI and cardiovascular events in the


      retrospective look at CLASS in non-aspirin users.


                So, I would suggest the two trials that


      you will hear about, EDGE and the ongoing MEDAL,


      are actually the first trials that are a comparison



      within the class.


                Well, let's come back to this


      relationship.  I would remind you that while we


      have very strong evidence for this being true, we


      have almost no evidence that this is true.  The


      conjecture of this discordance underlies the


      argument for the fact that we have a problem with


      selective COX-2 inhibitors but, you know something,


      we have a problem with all of these drugs which


      clearly obscures the message.  We have no evidence


      for that and you will hear people parsing in


      meta-analyses naproxen versus non-naproxen NSAIDs.


                Well, I don't think that is a legitimate


      lumping of non-naproxen NSAIDs, which is really


      diclofenac plus ibuprofen in most instances.  I


      think it is as legitimate to consider them all


      individually as it is to consider naproxen




                So, could there be a hazard from a


      non-naproxen NSAID like ibuprofen where there is


      coincident inhibition of COX-1 and COX-2 over


      typical multiple dosing interval?  If there is a



      discordance in the relationship between inhibition


      of enzyme function and inhibition of enzyme


      product, then there might be a narrow part of the


      dosing interval where there could be a potential


      exposure to risk.  But the likelihood of detecting


      this notional risk would be much less than the


      likelihood of detecting the clear evidence-based


      risk of selective inhibitors of COX-2.


                So, there is some suggestion that naproxen


      achieves sustained platelet inhibition in some


      individuals.  I like to think of it as a dilute


      aspirin.  There is evidence that diclofenac is


      Celebrex.  There is evidence that ibuprofen may


      undermine the benefit from aspirin, although that


      is not yet answered one way or the other with a


      controlled trial.  And, I would say quite


      forcefully there is no rationale for lumping


      diclofenac and ibuprofen as non-naproxen NSAIDs in


      meta-analyses and the like.


                I am not sure when a canard becomes a dead






                --so I decided to dismiss some of the


      things that I think are worth dismissing and call


      them dead dragons.  First of all, naproxen clearly



      is not the full explanation of VIGOR.


                Here is another one that needs to be


      chopped down, hypertension is not a different




                There are a lot of off-target fantasies


      being touted around at the moment, strange chemical


      interactions that haven't actually been shown to


      occur in vivo yet but are postulated as the


      explanation for a drug-related rather than a


      class-based effect.


                Oddly, we never heard any of this


      conjecture when we were considering how all the


      drugs in this class afforded relief from pain and




                Here is another nice notion that makes


      clinical pharmacologists squirm in their seat, it


      is just a matter of reducing the dose.  Well, there


      is a lot of interindividual variability in response


      to COX-2 inhibitors and we all have our own



      dose-response curves.  It has been an approach in


      the past when a hazard emerges to suggest that in a


      population sense one just cuts the dose--perhaps in


      a population sense but it certainly does not


      obviate the possibility of individual hazard.


                Finally, if there ever was one, I think we


      have certainly moved beyond the need for a trial of


      a COX-2 inhibitor in patients with acute coronary


      syndrome.  Indeed, I feel that the evidence that


      supports a trial in patients at high cardiovascular


      risk to detect protection is scientific quite weak,


      and in the face of an emergent hazard is ethically




                Indeed, in the case of mice if one


      combines a thromboxane antagonist as a surrogate


      for the suppression of thromboxane by low dose


      aspirin with a COX-2 inhibitor, one doesn't see any


      benefit in terms of atheroprotection, but what one


      does see is the loss of the fibrous cap in the


      combination and necrosis of the atherosclerotic


      core, consistent with destabilization of the




                Finally, and you will be glad to know it


      is finally, I would just like to mention a couple


      of things relating to where we might go from here.



      Well, I think clearly an easy thing to write down


      and perhaps a more tricky thing to do is to exclude


      patients at high intrinsic risk of thrombosis, and


      you have heard my views on that.  Dose reduction


      alone is a simple message.  It has a political and


      legal appeal but in pharmacological terms it is




                I think we are likely to subject new drugs


      that might be approved from this class to


      significant hurdles before they are approved.  It


      seems logical to me that existing drugs in this


      class should be subject to the same hurdles to


      retain approval, particularly for extended dosing.


      And, I think that frankly one should logically


      restrict the duration of dosing until the


      parameters of safety for extended dosing have been




                I mentioned interindividual variability,


      and these are log scales but they illustrate



      looking at inhibition of COX-2 either in the


      typical ex vivo assay or by excretion of


      prostacyclin metabolite or inhibition of COX-1,


      that with this sort of display of the data to


      highlight it, there is considerable interindividual


      variability of response.  This is no surprise.  It


      is true of all drugs.


                But perhaps we can exploit the biochemical


      variability, the physiological response variability


      and, indeed, perhaps some genetic markers such as


      these polymorphisms associated with metabolism of


      drug or these polymorphisms in cyclooxygenase-1 to


      try and identify those patients at emerging


      cardiovascular risk before they culminate in


      events.  So, you might say that the future of these


      drugs or the challenge to the future of these drugs


      is that if their value--and I believe they have


      value as a class--is to be harvested, then to


      manage the risk we have to actually move to an


      example of personalized medicine.


                One would want to obviously restrict these


      drugs in some way to people who really needed them,



      for GI reasons.  We need to determine whether risk


      transformation actually occurs during chronic


      dosing and, if so, whether we can detect it.  And,


      it is likely, because we have so few events in any


      one trial, we can only do this by a combined


      analysis across the class in relevant trials.


      Then, obviously, we would have to validate


      prospectively such an index of emergent risk in a


      prospective trial.


                So, I really thank you for your patience


      and I would like to conclude.  Selective inhibitors


      of COX-2 depress prostacyclin without a concomitant


      inhibition of


      thromboxane-A2.  This can result in an augmented


      response to thrombotic and hypertensive stimuli and


      acceleration of atherogenesis in mice.  Indeed, the


      terrible beauty of this unfolding drama is how


      faithfully the emerging clinical information has


      fitted the predictable science, and that should


      reassure us in terms of the likelihood that the


      science can predict a way to conserve the value of


      these drugs while managing the risk.


                An increase in MI and/or stroke has been


      seen at last count, as of yesterday, in 5


      placebo-controlled trials with 3 structurally



      distinct COX-2 inhibitors.  Given the bulk of


      evidence, the mechanism-based evidence from mice


      and people, the pharmacopeidemiology and this, it


      seems to be that most rational people would accept


      a class-based mechanism as they did for efficacy.


                Finally, hazard would be expected to


      relate at the individual level to the drug


      selectivity attained in vivo, dose and duration of


      exposure and to interindividual differences in drug


      response.  Thank you.


                DR. WOOD:  Thank you.  Just before you sit


      down, one thing you seemed to be saying is that we


      should exclude patients at high risk.  The point


      estimate in the APPROVe trial for people with no


      symptomatic history of heart disease is 1.6 so that


      would be one way you would exclude people, I guess,


      but the point estimate remains 1.6.  Does that


      bother you?


                DR. FITZGERALD:  No, as I alluded to, I



      think the nature of the information we have in the


      APPROVe trial so far remains to be played out.


      Clearly, there was an attempt to exclude people at


      high cardiovascular risk but we all know that


      people who are at risk slip through any exclusion


      criteria.  So, one question is, is all that we are


      seeing people who, for one reason or another, are


      predisposed to thrombosis and they are the people


      that are having events?  Or, are we seeing people


      who through atherogenesis transform their risk?


      Or, are we seeing some combination of the two?  I


      don't think we know the answer to that.


                DR. WOOD:  We are running behind time so


      we will call a break right now and give everybody a


      moment or two to get out.  Before we do that, Dr.


      Galson wants to say some things and then, whenever


      he is finished, we will take a break and we will


      reconvene at 10:15.  So, those of you who don't


      want to hear what Dr. Galson has to say can get out


      now and the rest--


                DR. GALSON:  No, no, just a very brief


      announcement, and that is we have a space problem



      in this facility.  There are more people than we


      have seats for.  So, we have established a live


      video feed in our advisors and consultants


      conference room on the FDA campus at 5630 Fishers


      Lane, designed for FDA employees only.  So, FDA


      employees who may be sitting in the public section,


      I strongly urge you to please move to that area to


      make more room for the public and, of course, you


      will need your FDA ID badge to get into that space.


      But it is ready now and if you could move at the


      break, it would be great.  Thanks.


                DR. WOOD:  Okay, we start promptly at




                (Brief recess)


                    Committee Questions to Speakers


                DR. WOOD:  Let's get started and get the


      two previous speakers up for questions, Dr. Cryer


      and Dr. FitzGerald.  Yes, Susan?


                DR. MANZI:  I have a question for Dr.


      FitzGerald.  This is really in reference to your


      suggestion that we exclude people with high


      thrombotic potential.  I think there is clearly



      evidence that the natural aging process is


      associated with less effective fibrinolytic system,


      really increased thrombogenic potential with high


      levels of fibrinogen, PI-1 platelet aggregation,


      and considering that the elderly population is a


      huge target for non-steroidals, would you consider


      age as a risk?


                DR. FITZGERALD:  Well, I think, as you


      indicate, lots of things happen as we get older


      including the complexity of administering drugs and


      it ultimately culminates in death.  But I think the


      issue of determining cardiovascular risk is


      actually a very challenging one because it includes


      continuous and discontinuous variables.  It is easy


      to say if you have had a heart attack or a stroke


      you are statistically at greater risk of having


      another one.  It is harder to say that at an


      individual level, somebody who hasn't had a heart


      attack or a stroke has a cluster of variables that,


      in the eyes of their physician, determines their


      cardiovascular risk.


                With some of the discontinuous variables



      like some of the genetic mutations we can have an


      attributable risk that we can measure but, again,


      that can play geometrically into other small but


      absolute risks.  So, unfortunately, I think it is


      where the art and science of medicine intersect.


                DR. WOOD:  Richard Cannon?


                DR. CANNON:  You asked my question.


                DR. WOOD:  Joan Bathon?


                DR. BATHON:  We know that patients with


      rheumatoid arthritis and other inflammatory


      conditions are at higher risk for developing acute


      MIs and strokes, and these are the very patients


      who are taking NSAIDs chronically.  This is a big,


      confounding problem in interpreting some of the


      data and I am wondering if you have any thoughts.


      The reigning theory is that there is more


      atherosclerosis and RA due to vascular inflammation


      but I am wondering if you have any thoughts about


      whether the NSAIDs might be the sole contributor to


      increased events in these folks.


                DR. FITZGERALD:  Right.  As I indicated,


      through a COX-2 inhibitory mechanism one would



      anticipate that the clinical substrate of


      underlying cardiovascular risk would be one of the


      modulators of either individual hazard or the ease


      of detecting hazard with this crude detector system


      we call clinical trials.


                As you know, the relative risk of heart


      attack or stroke and RA is increased by about 50


      percent on average compared to RA or no arthritis.


      As a population that would be one of the


      ingredients predisposing towards emergence of a


      hazard.  Of course, within that population there is


      a very substantial interindividual variability


      conditioned by many other factors that impinge on


      cardiovascular risk.  So, at the time when we were


      naval gazing, looking at the contrast between CLASS


      and VIGOR, amongst the many things that were


      discussed was whether the preponderance of RA


      patients in VIGOR versus the preponderance of OA


      patients in CLASS may have been a factor.  I think


      it is reasonable to say it may have been a factor


      but I don't think we can really take it beyond


      conjecture in light of any current evidence that I



      am aware of.


                DR. WOOD:  Garret, let's cut to the chase.


      Is what you are saying--that was such a long


      answer, I am not sure what it meant!




                Is what you are saying that you think that


      COX-2 inhibitors have an effect here that the most


      selective, so-called non-selective like diclofenac


      and naproxen may also have an effect, and the


      non-selective, non-steroidals do not have an


      effect, or at least have not been shown to have an


      effect?  Is that your position?  If it is not,


      correct that.


                DR. FITZGERALD:  No, I think that is


      pretty true.


                DR. WOOD:  So, that is what you wanted us


      to take away from all the mice and stuff, is it?




                DR. FITZGERALD:  You have such a way with




                DR. WOOD:  Because I am a Scot.




                DR. FITZGERALD:  You are very economical


      with them.


                DR. WOOD:  Exactly.



                DR. FITZGERALD:  Unfortunately, reality is


      conditioned by a lot of different factors.  I think


      one of the things, both in terms of benefit and


      hazard, we have paid insufficient attention to is


      variability in drug response between individuals,


      and I think actually one of the things that has got


      us to today is not paying enough attention to that.


      But I think one of the ways out of the challenge


      that faces us today if we are to conserve the value


      is to exploit that variability in imaginative ways.


      So, I think that that is a tractable issue.


                DR. WOOD:  Okay.  Dr. Abramson?


                DR. ABRAMSON:  Yes, Garret, even though


      you are under the weather I wanted to follow-up


      with Dr. Wood's question and put you on the spot a


      little bit.  It is partly definitions because we


      use the word NSAIDs which we elect by inhibiting


      COX-2s.  Based on your presentation, it is clearly


      a continuum and there are highly selective drugs. 



      There is a cluster of five or six drugs, like


      diclofenac, that are in vitro at least comparably


      COX-2 selected.  Then you have these very complex


      stories of what one might call functional COX-2


      selectivity, which is based on the fact that the


      COX-1 inhibition may be more transient effectively


      than a more prolonged COX-2, which would give you


      imbalance.  So, I guess the "put on the spot"


      question is what do you define as the class?  How


      do you propose we should think about this continuum


      and personalize medicine?


                DR. FITZGERALD:  I think you are right.  I


      would remind all of us that COX-2 inhibitors are


      NSAIDs; they were never anything else.  They are


      NSAIDs that are selective for COX-2 and, as you are


      rightly pointing out, this is a continuous variable


      and within each drug, as I tried to point out,


      there is the same continuous variable between


      individuals.  So, my 800 mg of Celebrex may be your


      200 mg of Celebrex for example.


                So, I think all I am trying to raise is


      that there is clearly a mechanism which reflects



      the selective inhibition of COX-2.  That selective


      inhibition of COX-2, in terms of hazard, is


      modulated by COX-1 inhibition that occurs at the


      same time if it is sufficient to inhibit platelet


      activation for example.  So, I can't simplify that


      because I believe there is that complexity, but


      within the class--and I am referring to the class


      as the mechanism by which selective inhibition of


      COX-2 is attained--I think there is clearly a


      mechanism that explains everything that we have




                At the individual level this issue of a


      continuum comes into play because not only is there


      a continuum in terms of drug action and the degree


      of selectivity attained in an individual, but also


      many other factors impinging on cardiovascular risk


      that condition the emergence of that hazard at the


      individual level.


                DR. WOOD:  Steve?


                DR. NISSEN:  Yes, I have two quick


      questions.  You know, I want to talk with you a


      little bit more about this issue of dose



      dependency.  I want to make sure we didn't


      misunderstand you.  What you are saying I believe


      is that there is sufficient overlap in the


      biological effects that a low dose in one patient


      may be equivalent to a high dose in another.  But


      you didn't mean to suggest that we don't see


      evidence, as I think we do see from the trials,


      that the higher the dose of the drug on a


      population basis, the more we see--


                DR. FITZGERALD:  No, no, clearly there is


      evidence of a dose-related effect in populations.


      I am talking more at the individual level, that the


      assurance to a population based on population type


      evidence that all you need to do is reduce the dose


      and you, as an individual, will be protected from


      hazard is a false one.


                DR. NISSEN:  Yes, but it is quite relevant


      obviously to our discussions on Friday because one


      of the strategies to limit risk with this class of


      drugs is to limit dose--


                DR. FITZGERALD:  Sure.


                DR. NISSEN:  --and it may not make the



      hazard go away but it may make it smaller, and we


      are going to have to explore that in some detail


      before we finish.


                DR. FITZGERALD:  Well, I think that


      distinction between reducing it as opposed to


      making it go away and the distinction between


      population hazard and individual hazard is an


      important one.  It is the reason that I raised that


      particular point because I think that had not


      received sufficient attention.


                DR. NISSEN:  The second question I have


      is, you know, we have very few direct head-to-head


      trials amongst the so-called COX-2 inhibitors, but


      we do have for hypertension and there seemed to be


      really pretty striking differences in the


      hypertensive response between rofecoxib and


      celecoxib.  Would your point of view be that those


      differences are strictly a matter of COX-2


      selectivity of the two drugs, or do you think that


      it is possible that there is some dissociation in


      the hypertension response?


                DR. FITZGERALD:  I would make two points. 



      I would say, first of all, that in that particular


      comparison, again on average, we would anticipate


      that selectivity and duration of action would be


      confounded and it would be impossible to really


      segregate the two.


                The second is that, in a sense you pressed


      my button, I believe we have not performed the


      studies in hypertension that let us address the key


      questions that are on the table, and that is


      standardizing for the degree of selectivity


      attained or the degree of COX-2 inhibition attained


      do drugs come apart?  That question has been on the


      table since the mouse studies of Breyer and


      Kaufman, and perhaps the first signal of that is


      the epidemiological overview analysis from


      Australia.  But, in fact, we have never performed a


      study to address the hypothesis and I think it is


      timely that we do.


                DR. WOOD:  I see Dr. Cryer.  Did you want


      to say something?


                DR. CRYER:  Dr. Cryer has a question.


                DR. WOOD:  Go ahead.


                DR. CRYER:  Garret, you clearly made the


      point that diclofenac appears to have some COX-2


      selectivity.  In fact, I think you called it



      celecoxib with hepatic side effects.  You also made


      the point that we should subject drugs already


      approved to the same requirements.  So, the


      specific question I have for you is are you


      suggesting that we should evaluate diclofenac as


      well for its potential cardiac effects?


                DR. FITZGERALD:  Yes, I think there are


      quite a few unanswered questions on the table.  I


      think clearly the diclofenac question is one of


      them.  I think there are other drugs that fall into


      potentially the same situation, like meloxicam and


      nimesulide which, again, based on the IC-50


      comparisons look awfully similar to diclofenac and


      Celebrex but we just don't have the information


      even at a more fundamental level than outcome


      studies.  So, I think those questions are on the




                The reason I made the comparison between


      retention of approval and gaining approval is that,



      to me, if we do actually have to address some


      questions to determine the parameters within which


      drugs in this class can be administered safely and


      that would be a hurdle that any new drug would be


      required to overcome, in logic to me, it would be


      sensible to apply the sam standard to the extended


      dosing of drugs that already are on the market as a


      condition of their retention of approval.


                DR. WOOD:  Dr. Shafer?


                DR. SHAFER:  Yes, this is the question we


      just talked about briefly at the break, but as you


      pointed out, low dose aspirin gives you 100 percent


      inhibition of COX-1.  One might think then that low


      dose aspirin plus a COX-2 selective antagonist


      might give you the same risks as a non-selective


      NSAID.  Yet, in all the studies where they had


      aspirin present and they showed a CV risk, when


      they stratified by aspirin, among aspirin users the


      hazard didn't go away.  Now, what did happen is


      that some statistically significant hazards became


      non-statistically significant hazards but the


      actual magnitude of the hazard, at least as far as



      I can tell in all the studies that I looked at,


      didn't change.  I am having trouble understanding


      how that is consistent with the whole thing being


      the COX-2 imbalance.


                DR. FITZGERALD:  Right.  So, one important


      missing dimension in your question is time.  One of


      the key ingredients of aspirin's ability to afford


      cardioprotection is that while it inhibits COX-1


      like a ibuprofen does, it does it molecularly in a


      quite distinct fashion.  This results in sustained


      maximal inhibition throughout the dosing interval.


      By contrast, in the typical non-steroidal you are


      in the red zone for platelet inhibition transiently


      in the dosing interval.  Therefore, one would not


      expect the combination of, say, ibuprofen with a


      COX-2 inhibitor to be similar to aspirin with a


      COX-2 inhibitor in terms of cardiac protection.


                DR. SHAFER:  Doesn't that head in the


      opposite direction?


                DR. FITZGERALD:  In terms of which?


                DR. SHAFER:  The fact that the aspirin's


      effect is sustained because, you know, it is



      covalently bonded there--the fact that you are


      having a sustained aspirin effect means that you


      should absolutely--I mean, it would seem to me that


      that would really try to make the COX-2s look--


                DR. FITZGERALD:  Well, I will come back to


      what I said during my talk, and that is that I


      think a real mistake is to think of this as a yin


      and yang type of seesaw arrangement between


      thromboxane and prostacyclin.  We know that


      prostacyclin acts as a general biological


      constraint on anything that will activate


      platelets, elevate blood pressure, accelerate


      atherogenesis, and so on.  So, a priori we would


      expect that aspirin would damp rather than abolish


      the signal.


                Now, I would contend that, first of all,


      we have never formally addressed this and, in terms


      of the trials that have events, although we have


      attempted to look at the relationship to aspirin


      the numbers are so vanishingly small that it is


      really conjecture.  But one would expect a signal


      to be damped.  Indeed, from some of the



      epidemiology that is sort of what we are seeing,


      you know, a signal goes away at 25 mg of rofecoxib


      if they are on aspirin but not at 50, that sort of


      stuff.  But I would be the first to agree that this


      is really a crude stab at the issue that you are


      trying to get at.


                DR. WOOD:  Yes, and these studies did not


      stratify by aspirin use.  They were post hoc


      analyses in the majority of cases.  Dr. D'Agostino?


                DR. D'AGOSTINO:  I would like to go back


      to the question that was asked right after the


      break about the age.  If you tried to say, well,


      the perfect way of doing this is to make sure that


      people at high cardiovascular risk aren't going to


      take the drug, then males over 60, for example, are


      almost certain to be excluded.  How realistic--


                DR. FITZGERALD:  Certainly I am not trying


      to be dictatorial--


                DR. D'AGOSTINO:  No, no, your suggestion


      is fine, it is just how do you implement it?


                DR. FITZGERALD:  Yes, so I think all one


      can really hope to do is set the bar at some low



      level and then signal it in a way that is explicit


      and leave it to the patient-doctor relationship to


      divine the individual behavior.  I would love to


      say there is a different way of doing it but, yes,


      as we get older our cardiovascular risk goes up and


      multiple other things.  But that is where the


      balance against value comes into play.  As we get


      older with get arthritis; as we get older we get


      more GI bleeds on non-steroidals.


                DR. WOOD:  Okay, we got it.  Let's not go


      too far there.  One more question from Dr.




                DR. GIBOFSKY:  Dr. FitzGerald, in response


      to Dr. Nissen, I believe, you raised the notion and


      asked us to think about population variation as a


      factor in addition to individual variation.  One of


      the things that I am struggling with is exactly


      that, and one of the concerns I have is to what


      extent then can one extrapolate observations in


      populations of patients who may have Alzheimer's


      disease or who may have taken a drug for polyp


      prevention to the population of patients who are



      taking the drug for their arthritis?


                DR. FITZGERALD:  Well, I think in a way


      this whole cathartic experience is a cardinal point


      in the way that we look at drug development.  You


      know, we have talked about individualized medicine


      for a long time and never really had to care, and


      here is a situation where we actually do have to


      care and it is at the forefront of how we may or


      may not be able to find a way out of this.  You are


      absolutely right, there may be factors associated


      with an incident disease which is under study which


      modulates the importance or non-importance of the


      signal; modulates the way that drugs are


      metabolized; may be associated with genetic


      variance that influence outcome as well.


                DR. WOOD:  Any other questions for the


      last two speakers?


                (No response)


                In that case, let's move on to the


      sponsor's presentation.  I understand Dr. Kim is


      going to present first.


                Sponsor Presentation: Vioxx (Rofecoxib)


                DR. KIM:  Mr. Chairman, members of the


      advisory committee and FDA and ladies and


      gentlemen, my name is Peter Kim and I am President



      of Merck Research Laboratories.  My colleagues and


      I welcome the opportunity to present information at


      this advisory committee meeting, and I would like


      to begin with just a few introductory comments.


                As you will hear, to determine both its


      risks and its benefits, Merck extensively studied


      Vioxx before seeking regulatory approval to market


      it, and we continued to conduct clinical trials


      after the FDA approved Vioxx.


                As Merck continued to monitor the


      cardiovascular safety of Vioxx, we recognized the


      value and interest in obtaining additional


      cardiovascular safety data on this medicine.  After


      deliberations with numerous outside advisors, Merck


      developed and discussed with FDA a plan to


      prospectively analyze cardiovascular event rates


      from 3 large placebo-controlled trials.


                It was preliminary information from one of


      these long-term trials, the APPROVe trial, that led



      to Merck's decision to voluntarily withdraw Vioxx.


      When Merck made the decision to voluntarily


      withdraw Vioxx from the market, we stated that we


      believed that it would have been possible to


      continue to market Vioxx with labeling that would


      incorporate the data from the APPROVe trial.  We


      concluded, however, based on the science available


      at that time, that a voluntary withdrawal of the


      medicine was the responsible course to take given


      the availability of alternative therapies and the


      questions raised by the data.


                Since that time new cardiovascular safety


      data for other COX-2 inhibitors have become


      available and were reported on just this week in


      the New England Journal of Medicine.  We look


      forward to hearing and seeing presentations of


      these data and to hearing discussions and


      interpretation of them during this advisory


      committee meeting.  Thank you, and now I would like


      to turn the podium over to Dr. Ned Braunstein.


                DR. BRAUNSTEIN:  Good morning,  Dr.


      Chairman, members of the availability committee,



      FDA, I am Dr. Ned Braunstein, Senior Director of


      Merck Research Labs.


                Millions of patients suffer with painful


      arthritis and need effective therapies.  The recent


      data that have come to light on NSAIDs and


      selective COX-2 inhibitors raise many questions.


      Patients and physicians need information and


      guidance on the use of these effective medicines


      that we know are not without risk.  We recognize


      that the cardiovascular safety of the NSAID and


      coxib classes is an important public health issue


      and we welcome the opportunity to present this


      advisory committee information that we believe will


      help the FDA and the committee in their work in


      developing recommendations in the best interest of


      patients.                To assist us today, we have


      brought along as consultants Dr. Marc Hochberg from


      the University of Maryland School of Medicine, Dr.


      Marvin Konstam from Tufts University School of


      Medicine, and Dr. Loren Laine from the University


      of Southern California School of Medicine.  They


      are here to help answer your questions and



      otherwise assist the committee.


                Merck's objective today is to provide you


      with data on rofecoxib and review how those data


      affected our assessment of risk/benefit over time.


      The presentation will focus on GI and


      cardiovascular data or rofecoxib, starting with the


      data in the original NDA and proceeding through the


      voluntary withdrawal of Vioxx and the APPROVe data.


                In talking about the data, I will try to


      highlight some of the methodology we used to


      obtain, adjudicate and analyze cardiovascular data,


      and I will spend some time discussing the


      considerations that went into designing a study of


      cardiovascular outcomes with rofecoxib as the


      information may be useful in considering similar




                The presentation of data will end with a


      presentation of new exploratory analyses that we


      have performed and I will follow with a


      risk/benefit assessment, the review the major


      outstanding questions of the day, and the next


      steps we are taking and/or propose.


                I will start with an overview of the


      issues we face today.  Starting with the GI tract,


      as you have already heard, NSAID gastropathy has



      been the most common cause of drug-related


      morbidity and mortality in industrialized nations.


      The development of rofecoxib was based on the


      desire to limit and reduce this problem.


                You have also heard already about the


      COX-2 hypothesis.  I just want to emphasize two


      points.  First, all NSAIDs inhibit COX-2 in a


      dose-dependent manner and selective COX-2


      inhibitors do not inhibit COX-1 at clinical doses.


                The rofecoxib develop program confirmed


      the COX-2 hypothesis and demonstrated a reduction


      in clinical upper GI events, that is, actual GI


      outcomes with rofecoxib versus non-selective


      NSAIDs.  This was shown for rofecoxib in the VIGOR


      study and, based on that, rofecoxib was the only


      selective COX-2 inhibitor with a modified GI


      warning.  Since that time we have accrued


      additional information that extend the GI benefit


      of rofecoxib and have shown that the reduction in



      clinical upper GI events is consistently seen with


      rofecoxib versus diclofenac, ibuprofen and




                Although rofecoxib is associated with a


      reduced rate of upper GI events compared to these


      NSAIDs, rofecoxib is not placebo.  In addition to


      the upper GI findings, we have also observed a


      reduced incidence of lower GI events compared to


      naproxen in VIGOR,  So, although there remain some


      unanswered questions, for example for aspirin


      users, the GI benefit for rofecoxib is clear.


                As we have also learned, there are


      important cardiovascular findings with these drugs


      and perhaps with the larger class of NSAIDs.  In


      1998 Merck had implemented an adjudication standard


      operating procedure to methodically study the


      cardiovascular effects of its COX-2 selective


      inhibitor drugs in clinical trials.  Clinical data


      on thrombotic cardiovascular events with rofecoxib


      show an increased risk of events relative to


      placebo.  This was seen in APPROVe with


      long-standing use.


                In contrast to the difference seen from


      placebo, we have not observed a difference in


      cardiovascular event rates between rofecoxib and



      NSAIDs other than naproxen.  Long-term data,


      however, are limited.  In contrast to what had been


      observed versus the placebo, the increased risk


      compared to naproxen appears after short-term use.


                I think it is worth noting that similar


      observations have now been made with other


      selective COX-2 inhibitors.  We believe that these


      new data on rofecoxib and COX-2 inhibitors raise


      several questions about these drugs important to


      the public health.


                First, based on the data available, how do


      we currently assess the relative risks or benefits


      of selective COX-2 agents?  I cannot speak to the


      data on all of these drugs but I can talk about


      rofecoxib.  Clearly, there are risks versus


      placebo, and not just cardiovascular risks.


      however, placebo is not a choice for patients with


      chronic arthritis and pain who require chronic


      NSAID therapy.  For these patients the question is



      the risk and benefit of selective COX-2 agents


      versus non-selective NSAIDs.  I will present data


      on this question related to the GI and


      cardiovascular safety of these drugs.


                Second, can we identify factors associated


      with the observed increased risk for thrombotic


      cardiovascular events with these drugs?  Although


      we do not have definitive answers, I will present


      the data that we have.


                Finally, is the increased thrombotic


      cardiovascular risk that we have observed with


      rofecoxib indicative of a larger class effect of


      COX-2 inhibitor?  If so, how big is the class?


      That is perhaps the central question of this


      meeting.  At present we do not know the long-term


      cardiovascular effects of traditional NSAIDs.


      Other than aspirin, these agents have not been


      studied long term versus placebo.  We believe that


      long-term studies are needed and, in particular,


      comparator studies between selective COX-2 agents


      and non-selective agents to better understand the


      relative risk/benefit profiles.


                I will now turn to a presentation of the


      data, and will do so chronologically as it


      highlights the magnitude of data that were



      ultimately needed to dine the long-term


      cardiovascular risks of selective inhibitors.  This


      information may be useful regarding the development


      of future COX-2 inhibitors and in informing this


      committee on its decisions.


                I would like to start by reviewing the


      initial GI and cardiovascular data that were in the


      new drug application.  There were two main clinical


      components of the GI safety program in the original


      rofecoxib NDA, the GI endoscopy studies, which are


      described in your background package, and a pooled


      analysis of clinical upper GI events, shown here.


      Investigator reports of suspected upper GI


      perforations, ulcers or bleeds or PUBs were


      adjudicated by an external committee of blinded


      adjudicators, and the confirmed events formed the


      basis of this prespecified analysis.


                The Kaplan-Meier plot of the data is shown


      on this slide.  Throughout my presentation I will



      be showing several of these so I would like to take


      some time to walk through this first one.  Time is


      shown on the X axis, and below that the number of


      patients remaining in the studies at the different


      time points.  Cumulative incidence is shown on the


      Y axis and also shown are summary statistics,


      relative risk confidence interval and a p value.


                At the time of the original NDA a


      significant difference was demonstrated between


      rofecoxib and the combined NSAID comparators,


      mostly data on ibuprofen and diclofenac.  The


      relative risk of 0.45 corresponded to a 55 percent


      risk reduction with rofecoxib and, thus, we believe


      that we had established a GI safety advantage over


      these older NSAIDs.


                These are the cardiovascular safety data


      from the OA development program.  Rates per 100


      patient years of investigator reports or cardiac,


      cerebrovascular and peripheral arterial and venous


      serious thrombotic events were examined both in


      aggregate, as shown on this slide, and also in


      individually, as shown in your background package. 



      As you can see, then rates were similar for


      rofecoxib compared to the NSAIDs diclofenac,


      ibuprofen and nabumetone and for rofecoxib compared


      to placebo.


                These cardiovascular and GI data, along


      with our other data, were submitted to FDA in 1998


      as part of the new drug application for rofecoxib.


      They were discussed at the April, 1999 Arthritis


      Advisory Committee and the FDA concluded that there


      was a favorable risk/benefit profile for rofecoxib,


      and rofecoxib was approved in May of 1999.


                Around that time we were completing our


      Phase III osteoarthritis studies.  The results of


      studies that we were doing in collaboration with


      Dr. Garret FitzGerald became available, and he has


      already told you about those and the hypothesis


      that selective COX-2 inhibitors could be


      prothrombotic by inhibiting systemic prostacyclin


      production without inhibiting thromboxane




                In addition to that hypothesis, there were


      other hypotheses being discussed in the clinical



      literature and in the basic science literature at


      that time, including the possibility that NSAIDs,


      through their effects on COX-1, might decrease the


      risk of cardiovascular events.  Another was that


      perhaps by inhibiting COX-2 there may be a


      beneficial effect by inhibiting the enzyme in


      atherosclerotic plaques.


                Merck recognized that it would be


      important to continue to acquire cardiovascular


      data with its selective COX-2 inhibitors.  To


      address these hypotheses, in 1998 Merck initiated a


      vascular event adjudication standard operating


      procedure to standardize the evaluation of


      cardiovascular events in all of its COX-2 inhibitor


      studies.  Adjudication of events was based on


      predefined criteria.  Under the standard operating


      procedure all source documentation on events was


      collected and the data were then reviewed by


      blinded, external adjudication committees.  With


      this procedure, over 92 percent of cases had


      sufficient data for definitive determination and


      adjudication.  Thus, we can be confident in the



      quality of the data.  By eliminating questionable


      events, we would amplify and improve the clarity of


      any signal if present.  The standard operating


      procedure called for a pooled analysis of events


      across all studies to improve the precision of what


      would be obtained from individual studies.


                In order to obtain more data on the effect


      of rofecoxib on GI outcomes Merck initiated the


      Vioxx GI Outcomes Research, or VIGOR, study in


      January, 1999.  GI events would be adjudicated


      using the same approach as had been done for the


      osteoarthritis studies.  The cardiovascular events


      in VIGOR fell under the new standard operating




                VIGOR was designed to definitely assess


      the GI components of the COX-2 hypothesis.  It was


      conducted exclusively in rheumatoid arthritis


      patients because Merck believed that a GI benefit


      had already been established in osteoarthritis


      patients.  Rofecoxib of 50 mg, 2-4 times the


      recommended chronic dose, was chosen to provide a


      rigorous assessment of safety.  We chose as a



      comparator naproxen 500 mg twice a day to extend


      the GI findings to an additional NSAID and because


      that was the most commonly prescribed NSAID regimen


      in rheumatoid arthritis.  Patients using aspirin


      were excluded to avoid COX-1 inhibition as this


      could confound the ability to rigorously assess the


      COX-2 hypothesis.


                The primary endpoint was reduction


      confirmed clinical upper GI events.  There were 56


      events on rofecoxib and 121 on naproxen.  The time


      to event curve separated early and they continued


      to separate, and the relative risk of 0.46


      corresponds to a 54 percent risk reduction with


      rofecoxib.  The p value, as you can see, was highly


      significant.  A similar GI benefit was seen with


      confirmed complicated events, and in a post hoc


      analysis for lower GI events.


                A second finding in VIGOR was the


      difference in the rates of thrombotic


      cardiovascular events between the two treatment


      groups.  There was a relative risk of 2.4 for the


      confirmed events, as shown here.  The p value,



      again, was highly significant.


                Examination of the individual types of


      events broken down by vascular bed, cardia,


      cerebrovascular and peripheral shows that the


      difference between treatment groups was largely


      driven by the difference in myocardial infarction,


      20 on rofecoxib and 4 on naproxen.  Of note, there


      were similar numbers of patients with strokes in


      the two groups.


                Additional exploratory analyses were


      undertaken to better understand these


      cardiovascular findings.  I will focus on the types


      of analyses that I will show later for APPROVe.  In


      VIGOR the use of 50 mg, a dose 2-4 times the


      recommended approved chronic doses, was associated


      with a higher incidence of hypertension adverse


      experiences than with naproxen.  In analyses


      described in the background package the relative


      risk of events was similar in patients with or


      without increases in blood pressure during the


      study.  The relative risk of events was also


      similar in patients with or without baseline risk



      factors for cardiovascular risk.


                Finally, multiple analyses were performed


      to examine the patterns of risk and relative risk


      over time, both by Merck and the FDA.  Merck's


      interpretation was that there was no significant


      increase in relative risk over time for rofecoxib


      versus naproxen.  However, the FDA felt that a


      change in relative risk over time could not be




                Because VIGOR did not have a placebo


      control, we turned to other data from other studies


      to better understand these results.  Merck had


      initiated a program to assess the ability of


      rofecoxib to delay the onset of Alzheimer's disease


      in patients with minimal cognitive impairment or to