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                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

                            JOINT MEETING OF

 

                  THE ARTHRITIS ADVISORY COMMITTEE AND

 

                  THE DRUG SAFETY AND RISK MANAGEMENT

 

                           ADVISORY COMMITTEE

 

 

                                VOLUME I

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                      Wednesday, February 16, 2005

 

                               8:00 a.m.

 

 

 

 

 

 

 

                          Hilton Gaithersburg

                           620 Perry Parkway

                         Gaithersburg, Maryland

                                                                 2

 

                        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

                                                                 3

 

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

 

      National Institutes of Health Participants

      (Voting):

 

      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

      Secretary

                                                                 4

 

                            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

 

      Welcome:

                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

      Celecoxib

                 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

        Celecoxib)

                   Ernest Hawk, M.D.                           402

                                                                 5

 

                      C O N T E N T S (Continued)

 

      NIH Investigator Presentation: The PreSAP Trial

        (Prevention of Colorectal Sporadic Adenomatous

         Polyps)

                 Bernard Levin, M.D.                           422

 

      Committee Questions to Speakers                          427

 

      Sponsor Presentation: Cardiovascular Safety and

         Risk/Benefit Assessment of Valdecoxib and

         Parecoxib

                Kenneth M. Verburg, Ph.D.                      443

 

      Concluding Comments

                Joseph M. Feczko, M.D.                         465

 

      FDA Presentation: COX-2 CV Safety:

      Valdecoxib-Parecoxib,

                   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

                                                                 6

 

                         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

 

      discussions.

 

                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

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      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

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      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,

                                                                 9

 

      and I have struggled with rheumatoid arthritis and

 

      osteoarthritis for 35 years.

 

                DR. BATHON:  Joan Bathon, Johns Hopkins

 

      University, Department of Medicine, Division of

 

      Rheumatology.

 

                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

 

      Committee.

 

                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

 

      Committee.

 

                DR. HOLMBOE:  I am Eric Holmboe, Vice

 

      President for Evaluation Research at the American

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      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

 

      Health.

 

                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

                                                                11

 

      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,

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      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

 

      FDA.

 

                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

                                                                13

 

                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

                                                                14

 

      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

                                                                15

 

      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

                                                                16

 

      speaker, who is Steve Galson.  Steve?

 

                                Welcome

 

                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

                                                                17

 

      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

 

      deliberations.

 

                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

                                                                18

 

      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

 

      meetings.

 

                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

                                                                19

 

      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

                                                                20

 

      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

                                                                21

 

      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

 

      approval.

 

                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

                                                                22

 

      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

                                                                23

 

      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

 

      questions.

 

                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

 

      first.

 

                DR. TEMPLE:  I am Bob Temple.  I am

                                                                24

 

      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

 

      Committee.

 

                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

                                                                25

 

      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

                                                                26

 

      paragraph and databases were discussed at that

 

      time.

 

                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

 

      claim.

 

                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

                                                                27

 

      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

 

      changes?

 

                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

                                                                28

 

      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

 

      safety.

 

                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

                                                                29

 

      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

 

      naproxen.

 

                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

                                                                30

 

      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

                                                                31

 

      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

                                                                32

 

      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

 

      effects.

 

                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

                                                                33

 

      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,

                                                                34

 

      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

 

      tract.

 

                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

                                                                35

 

      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

 

      obstruction.

 

                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

                                                                36

 

      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

 

      relevant.

 

                With respect to incidences of asymptomatic

 

      endoscopic ulcers, gastric ulcers happen two to

 

      three times more commonly than the duodenal ulcers,

                                                                37

 

      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

 

      inhibitors.

 

                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

                                                                38

 

      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

                                                                39

 

      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

                                                                40

 

      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

 

      complications.

 

                From the perspective of the PPI outcome

 

      trials, there have been fewer evaluations but there

 

      have been, in fact, some evaluations for clinically

                                                                41

 

      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

                                                                42

 

      was a 76 percent reduction in the subsequent

 

      incidence of upper gastrointestinal bleeding in the

 

      group that had received the proton pump inhibitor

 

      approach.

 

                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

                                                                43

 

      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

                                                                44

 

      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

                                                                45

 

      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

                                                                46

 

      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

                                                                47

 

      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

                                                                48

 

      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

 

      trials.

 

                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

                                                                49

 

      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

 

      doubled.

 

                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

                                                                50

 

      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,

                                                                51

 

      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

                                                                52

 

      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

 

      aspirin.

 

                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

                                                                53

 

      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

                                                                54

 

      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

 

      effects.

 

                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

                                                                55

 

      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

                                                                56

 

      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

                                                                57

 

      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

                                                                58

 

      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

 

      developed.

 

                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

                                                                59

 

      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

 

      population.

 

                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

                                                                60

 

      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

 

      benefit.

 

                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. 

                                                                61

 

      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

                                                                62

 

      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

                                                                63

 

      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

 

      aspirin.

 

                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

                                                                64

 

      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

 

      risk?

 

                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

                                                                65

 

      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

                                                                66

 

      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

                                                                67

 

      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

                                                                68

 

      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

                                                                69

 

      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

                                                                70

 

      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

 

      data?

 

                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

                                                                71

 

      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,

                                                                72

 

      Byron, if you would, to be available this

 

      afternoon.

 

                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

 

      next?

 

                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

                                                                73

 

      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

                                                                74

 

      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

 

      there.

 

                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

                                                                75

 

      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

                                                                76

 

      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

                                                                77

 

      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

 

      understand.

 

                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

                                                                78

 

      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?

 

      Peter?

 

                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

 

      COX-2?

 

                DR. CRYER:  Sure.  Your point is very well

                                                                79

 

      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

 

      approach.

 

                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

                                                                80

 

      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!

 

                (Laughter)

 

                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.

 

                (Laughter)

 

                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

                                                                81

 

      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

                                                                82

 

      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

                                                                83

 

      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,

                                                                84

 

      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

 

      COX-2.

 

                Well, that raised a question rather than

 

      answered a question even though it anteceded the

 

      approval of the first of these drugs.  The first

                                                                85

 

      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

                                                                86

 

      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

                                                                87

 

      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,

 

      aggregation.

 

                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

                                                                88

 

      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

 

      COX-2.

 

                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

                                                                89

 

      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

                                                                90

 

      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

 

      condition.

 

                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

                                                                91

 

      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

                                                                92

 

      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

                                                                93

 

      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

                                                                94

 

      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

 

      atherosclerosis.

 

                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

 

      here.

 

                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

 

      mice.

 

                So, here we see the atheroprotection in

                                                                95

 

      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

                                                                96

 

      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

                                                                97

 

      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.

                                                                98

 

      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

                                                                99

 

      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

 

      function.

 

                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

                                                               100

 

      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

                                                               101

 

      potency, celecoxib and diclofenac look remarkably

 

      similar.

 

                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

                                                               102

 

      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

                                                               103

 

      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

 

      individually.

 

                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

                                                               104

 

      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

 

      duck--

 

                (Laughter)

 

                --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

                                                               105

 

      is not the full explanation of VIGOR.

 

                Here is another one that needs to be

 

      chopped down, hypertension is not a different

 

      mechanism.

 

                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

 

      inflammation.

 

                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

                                                               106

 

      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

 

      questionable.

 

                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

 

      plaque.

 

                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.

                                                               107

 

      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

 

      misleading.

 

                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

 

      established.

 

                I mentioned interindividual variability,

 

      and these are log scales but they illustrate

                                                               108

 

      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,

                                                               109

 

      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

                                                               110

 

      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

                                                               111

 

      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

                                                               112

 

      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

 

      10:15.

 

                (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

                                                               113

 

      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

                                                               114

 

      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

                                                               115

 

      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

                                                               116

 

      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!

 

                (Laughter)

 

                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?

 

                (Laughter)

 

                DR. FITZGERALD:  You have such a way with

 

      words!

 

                DR. WOOD:  Because I am a Scot.

 

                (Laughter)

 

                DR. FITZGERALD:  You are very economical

 

      with them.

 

                DR. WOOD:  Exactly.

                                                               117

 

                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. 

                                                               118

 

      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

                                                               119

 

      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

 

      seen.

 

                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

                                                               120

 

      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

                                                               121

 

      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. 

                                                               122

 

      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

                                                               123

 

      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

 

      table.

 

                The reason I made the comparison between

 

      retention of approval and gaining approval is that,

                                                               124

 

      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

                                                               125

 

      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

                                                               126

 

      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

                                                               127

 

      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

                                                               128

 

      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.

 

      Gibofsky.

 

                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

                                                               129

 

      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

                                                               130

 

      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

                                                               131

 

      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,

                                                               132

 

      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

                                                               133

 

      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

 

      studies.

 

                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

                                                               134

 

      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

                                                               135

 

      clinical upper GI events is consistently seen with

 

      rofecoxib versus diclofenac, ibuprofen and

 

      naproxen.

 

                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

                                                               136

 

      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

                                                               137

 

      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

                                                               138

 

      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

                                                               139

 

      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. 

                                                               140

 

      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

 

      production.

 

                In addition to that hypothesis, there were

 

      other hypotheses being discussed in the clinical

                                                               141

 

      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

                                                               142

 

      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

 

      procedure.

 

                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

                                                               143

 

      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,

                                                               144

 

      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

                                                               145

 

      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

 

      excluded.

 

                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