1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

              PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

 

                    WITH THE PEDIATRIC SUBCOMMITTEE

 

             OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

 

 

 

 

 

                        Monday, February 2, 2004

 

                               8:00 a.m.

 

 

 

                          Holiday Inn Bethesda

                          Versailles I and II

                         8120 Wisconsin Avenue

                           Bethesda, Maryland

 

                                                                 2

 

                              PARTICIPANTS

 

      Matthew Rudorfer, M.D., Chair

      Anuja M. Patel, M.P.H., Executive Secretary

 

      PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE

           MEMBERS

                Tana Grady-Weliky, M.D.

                Irene E. Ortiz, M.D.

                Richard P. Malone, M.D

                Wayne K. Goodman, M.D.

                James J. McGough, M.D.

                Jean E. Bronstein, R.N., M.S.

                  (Consumer Rep)

                Andrew C. Leon, Ph.D.

                Philip S. Wang, M.D. M.P.H., Dr. P.H.

                Dilip J. Mehta, M.D., Ph.D.,

                  (Industry Rep)

 

      ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

           MEMBERS

 

                Steven C. Ebert, Pharm. D. (Consumer Rep)

                Mary P. Glode, M.D.

                Samuel D. Maldonado, M.D., M.P.H.

                  (Industry Rep)

 

      PEDIATRIC SUBCOMMITTEE OF THE ANTI-INFECTIVE DRUGS

      ADVISORY COMMITTEE MEMBERS

 

                P. Joan Chesney, M.D.

                Mary Glode, M.D.

                Steven Ebert, Pharm. D. (Consumer Rep)

                Robert Nelson, M.D., Ph.D.

                Richard Gorman, M.D., FAAP

                Robert J. Fink, M.D.

                Susan Fuchs, M.D.

                David Danford, M.D.

                Victor Santana, M.D.

                Mark Hudak, M.D.

                Judith R. O'Fallon, Ph.D.

 

      SGE CONSULTANTS (VOTING)

 

                Elizabeth B. Andrews, Ph.D.

                Norman Fost, M.D., M.P.H.

                Charles E. Irwin, Jr., M.D.

                Lauren K. Leslie, M.D., FAAP

                James M. Perrin, M.D.

                Cynthia R. Pfeffer, M.D.

 

      SGE PATIENT REPRESENTATIVE (VOTING)

 

                Gail W. Griffith

 

                                                                 3

 

                        PARTICIPANTS (Continued)

 

      GOVERNMENT EMPLOYEE (non-voting)

 

                Daniel S. Pine, M.D.

 

      FDA

 

                Robert Temple, M.D.

                Russell G. Katz, M.D.

                Thomas Laughren, M.D.

                M. Dianne Murphy, M.D.

                Susan Cummins, M.D., MPH

                Anne Trontell, M.D., MPH

 

                                                                 4

 

                            C O N T E N T S

                                                              PAGE

      Call to Order and Opening Remarks:

                Matthew Rudorfer, M.D.                           6

 

      Introductions                                              8

 

      Conflict of Interest Statement:

                Anuja M. Patel, MPH                             15

 

      Overview of Issues:

                Russell Katz, M.D.                              19

 

      Pediatric Drug Development Program:

                Dianne Murphy, M.D.                             26

 

      Pediatric Depression and Its Treatment:

                Cynthia R. Pfeffer, M.D.                        39

 

      Suicide and Related Problems in Adolescents:

                David Shaffer, FRCP (Lond) FRC Psych            60

 

      Open Public Hearing

                Irving Kirsch and David Antonuccio              79

                Lisa Van Syckel                                 82

                Ann Blake Tracy, Ph.D.                          83

                Tom Woodward                                    85

                Mark Miller                                     87

                Corey and Jay Baadsgaard                        90

                Joyce Storey                                    91

                Jame Tierney                                    93

                Donna and Mark Taylor                           95

                Shannon Baker                                   97

                Dawn Rider                                      98

                Sara Bostock                                   100

                Vera Hassner Sharav                            103

                Cynthia Brockman                               104

                Todd and Eileen Shivak                         107

                Andy Vickery                                   109

                Rosie Carr Meysenburg                          111

                Rachel Adler                                   112

                Pepper Draper                                  115

                Donald Marks, M.D., Ph.D.                      117

                Leah Harris                                    119

                Donald Farber                                  121

                Lorraine Slater                                123

                Matthew Piepenberg                             125

                Terri Williams                                 127

                Glenn McIntosh                                 129

                Delnora Duprey                                 132

                Joe Pittman                                    133

                Richard Mack                                   135

                Noah Wright Smith                              137

                Marion Goff                                    139

 

                                                                 5

 

                      C O N T E N T S (Continued)

 

                                                              PAGE

      Open Public Hearing (Continued)

                Gary Cheslek, M.D.                             142

                Sherri Walton                                  144

                Peter R. Breggin, M.D.                         146

                Robert Fritz                                   148

                Lawrence Greenhill, M.D.                       151

                Suzanne Vogel-Scibilia, M.D.                   152

                Dennis Winter                                  155

                Steve Cole                                     157

                Allan Routhier                                 158

                Daniel J. Safer, M.D.                          161

                Julie Magno Zito, M.D.                         163

                Joseph Glenmullen, M.D.                        164

                Linda Cheslek                                  165

                Jeff Avery                                     167

                Harry Skigis                                   169

                Pamela Wild                                    170

                Karen Barth Menzies                            172

                Amy Coburn                                     174

                Sharon McBride                                 175

                Thomas Moore, M.D.                             178

 

      Pediatric and Adolescent Antidepressant Drug Use

      in the U.S.:

                Gianna C. Rigoni, Pharm.D., M.S.               181

 

      One-Year Post-Exclusivity-Mandated Adverse Event

      Review for Paroxetine and Citalopram:

                Solomon Iyasu, M.D., MPH                       195

 

      Office of Drug Safety Data Resources

      for the Study of Suicidal Events:

                Andrew D. Mosholder, M.D., MPH                 215

 

      Open Public Hearing

                David Fassler, M.D.                            225

                Lawrence Diller                                227

 

      Regulatory History on Antidepressants and

      Suicidality and Update on Current Plans for

      Analysis of Pediatric Suicidality Data:

                Thomas Laughren, M.D.                          230

 

      Suicidality Classification Project:

                Kelly Posner, Ph.D.                            265

 

      Plans for Analysis of Patient Level Data

      for Pediatric Studies:

                Tarek Hammad, M.D., Ph.D., M.Sc., M.S.         273

 

      Open Committee Discussion                                291

 

                                                                 6

 

  1                Call to Order and Opening Remarks

 

  2             DR. RUDORFER:  I am Dr. Matthew Rudorfer,

 

  3   a research psychiatrist at the National Institute

 

  4   of Mental Health, today wearing my hat as Chair of

 

  5   the Advisory Committee.

 

  6             As you settle in, please take this

 

  7   opportunity to put into silent mode your cell

 

  8   phones and any other devices that ring, beep, or

 

  9   play show tunes.

 

 10             I have some official language to read.

 

 11   All committee members and consultants have been

 

 12   provided with copies of background materials from

 

 13   the FDA and with copies of letters from the public

 

 14   that were received by the January 26th deadline.

 

 15   The background materials have been posted on the

 

 16   FDA web site.  Copies of all these materials are

 

 17   available for viewing at the FDA desk outside this

 

 18   room.

 

 19             We have a large table and a full house as

 

 20   you can see and a very important and exciting topic

 

 21   to discuss, so we would like to start with a few

 

 22   rules of order.  FDA relies on its advisory

 

 23   committees to provide the best possible scientific

 

 24   advice available to assist us in a discussion of

 

 25   complex topics.  We understand that issues raised

 

                                                                 7

 

  1   during the meeting may well lead to conversations

 

  2   over breaks or during lunch.

 

  3             However, one of the benefits of an

 

  4   advisory committee meeting is that discussions take

 

  5   place in an open and public forum.  To that end, we

 

  6   request that members of the committees not engage

 

  7   in off-record conversations on today's topic during

 

  8   the breaks and lunch.

 

  9             Whenever there is an important topic to be

 

 10   discussed, there are a variety of opinions.  One of

 

 11   our goals today is for this meeting to be conducted

 

 12   in a fair and open way where every participant is

 

 13   listened to carefully and treated with dignity,

 

 14   courtesy, and respect. Anyone whose behavior is

 

 15   disruptive to the meeting will be asked to leave.

 

 16             We are confident that everyone here is

 

 17   sensitive to these issues and can appreciate that

 

 18   these comments are intended as a gentle reminder.

 

 19   We look forward to a productive and interesting

 

 20   meeting.

 

 21             Just to reiterate a couple of points.

 

 22   This is an unusual meeting in that we have two

 

 23   advisory committees represented here,

 

 24   Psychopharmacologic Drugs and a subcommittee that

 

 25   is equivalent of a Pediatric Drugs Advisory

 

                                                                 8

 

  1   Committee chaired by Dr. Joan Chesney here to my

 

  2   left.

 

  3             Suppose we begin by going around the table

 

  4   for introductions.  Can we start at that end,

 

  5   please.

 

  6                          Introductions

 

  7             DR. TEMPLE:  I am Bob Temple.  I am the

 

  8   Office Director for Office of Drug Evaluation I.

 

  9             DR. KATZ:  Russ Katz, Division Director of

 

 10   the Division of Neuropharmacological Drug Products,

 

 11   FDA.

 

 12             DR. LAUGHREN:  Tom Laughren, Psychopharm

 

 13   Team Leader in the Neuropharm Division.

 

 14             DR. MURPHY:  Dianne Murphy, Office

 

 15   Director, Office of Counterterrorism and Pediatric

 

 16   Drug Development.

 

 17             DR. CUMMINS:  Susan Cummins, Medical Team

 

 18   Leader with the Division of Pediatric Drug

 

 19   Development.

 

 20             DR. TRONTELL:  Anne Trontell, Deputy

 

 21   Director, Office of Drug Safety.

 

 22             DR. FUCHS:  Susan Fuchs, member of the

 

 23   Pediatric Subcommittee of the Anti-Infective Drugs

 

 24   Advisory Committee.

 

 25             DR. FINK:  Bob Fink, pediatric

 

                                                                 9

 

  1   pulmonologist, Dayton, Ohio.

 

  2             DR. ORTIZ:  Irene Ortiz, geriatric

 

  3   psychiatrist, Albuquerque VA and the University of

 

  4   New Mexico.

 

  5             DR. LESLIE:  Lauren  Leslie, behavioral

 

  6   and developmental pediatrician and health services

 

  7   researcher in San Diego.

 

  8             DR. LEON:   Andrew Leon, Professor of

 

  9   Biostatistics and Psychiatry at Cornell Medical

 

 10   College.

 

 11             DR. GOODMAN:  Wayne Goodman, Professor and

 

 12   Chairman, Department of Psychiatry at the

 

 13   University of Florida.

 

 14             DR. PFEFFER:  Cynthia Pfeffer, Adolescent

 

 15   Psychiatrist and Professor of Psychiatry at Weill

 

 16   Medical College of Cornell University.

 

 17             DR. GORMAN:  Rich Gorman, pediatrician in

 

 18   private practice in Ellicott City and member of the

 

 19   Pediatric Advisory Subcommittee.

 

 20             DR. GLODE:  Mary Glode, Professor of

 

 21   Pediatrics, Pediatric Infectious Disease Specialist

 

 22   at Children's Hospital, University of Colorado at

 

 23   Denver.

 

 24             DR. HUDAK:  Mark Hudak, neonatologist and

 

 25   Professor of Pediatrics, University of Florida at

 

                                                                10

 

  1   Jacksonville, and member of the Pediatric

 

  2   Subcommittee.

 

  3             DR. MALONE:  Richard Malone, child

 

  4   psychiatrist, Drexel University, College of

 

  5   Medicine, and I am a member of the Psychopharm

 

  6   Advisory Committee.

 

  7             DR. SANTANA:  Victor Santana, pediatric

 

  8   hematologist/oncologist, St. Jude's Children's

 

  9   Research Hospital and University of Tennessee at

 

 10   Memphis, Tennessee.

 

 11             MS. PATEL:  Anuja Patel, Executive

 

 12   Secretary, Advisors and Consultants Staff.

 

 13             DR. RUDORFER:  Dr. Matthew  Rudorfer,

 

 14   Acting Chief, Adult Interventions Branch, National

 

 15   Institute of Mental Health and Chair of the

 

 16   Psychopharmacologic Drugs Advisory Committee.

 

 17             DR. CHESNEY:  Joan Chesney, Professor of

 

 18   Pediatrics at the University of Tennessee in

 

 19   Memphis, and at St. Jude's Children Research

 

 20   Hospital, and the Pediatric Subcommittee.

 

 21             DR. McGOUGH:  Jim McGough, Associate

 

 22   Professor in Child and Adolescent Psychiatry at

 

 23   UCLA and member of the Psychopharm Drugs Advisory

 

 24   Committee.                                DR.

 

 25   GRADY-WELIKY:  Tana Grady-Weliky, Associate

 

                                                                11

 

  1   Professor of Psychiatry at the University of

 

  2   Rochester, School of Medicine and Dentistry, and

 

  3   member of the Psychopharm Advisory Committee.

 

  4             DR. WANG:  Philip Wang, psychiatrist and

 

  5   epidemiologist, Harvard Medical School.

 

  6             DR. O'FALLON:  Judith O'Fallon, recently

 

  7   retired from the Cancer Center Statistics Unit of

 

  8   the Mayo Clinic.  I am a member of the Pediatric

 

  9   Subcommittee.

 

 10             DR. NELSON:  Robert Nelson, Pediatric

 

 11   Critical Care Medicine at the Children's Hospital,

 

 12   Philadelphia.

 

 13             DR. ANDREWS:  Elizabeth Andrews,

 

 14   pharmaco-epidemiologist at Research Triangle

 

 15   Institute and the University of North Carolina

 

 16   Centers for Educational Research and Therapeutics,

 

 17   and I am a consultant.

 

 18             MS. GRIFFITH:  Gail Griffith.  I am a

 

 19   writer.  I live in Washington.  I am the Patient

 

 20   Representative, a parent of a child suffering from

 

 21   MDD, and a patient who suffers from MDD.

 

 22             DR. FOST:  Norm Fost, Professor of

 

 23   Pediatrics and Director of the Bioethics Program at

 

 24   the University of Wisconsin.

 

 25             MS. BRONSTEIN:  Jean Bronstein, nurse with

 

                                                                12

 

  1   a background in psychiatry, retired, and I am the

 

  2   Consumer Representative for Psychopharm.

 

  3             DR. EBERT:  Steve Ebert, pharmacist and

 

  4   infectious diseases, Professor of Pharmacy at the

 

  5   University of Wisconsin/Madison, member of the

 

  6   Pediatric Subcommittee.

 

  7             DR. DANFORD:  David Danford, Professor of

 

  8   Pediatrics and cardiologist in the Joint Section of

 

  9   Pediatric Cardiology, University of Nebraska,

 

 10   Creighton University, member of the Pediatric

 

 11   Subcommittee.

 

 12             DR. PINE:  Daniel Pine, child

 

 13   psychiatrist, National Institute of Mental Health,

 

 14   Intramural Research Program.

 

 15             DR. MALDONADO:  Samuel Maldonado, Chair of

 

 16   the Pediatric Working Group at PhRMA  and member of

 

 17   the Pediatric Subcommittee.

 

 18             DR. MEHTA:  Dilip Mehta from New York.  I

 

 19   am the Industry Representative on the

 

 20   Psychopharmacologic Advisory Committee.       

 

 21                                         DR. RUDORFER:

 

 22   Thank you.  Our session today is actually the first

 

 23   of two planned advisory committee meetings convened

 

 24   to address recent concerns about reports of

 

 25   suicidal ideas and behavior developing in some

 

                                                                13

 

  1   children and adolescents during treatment of

 

  2   depression with an SSRI or similar newer

 

  3   antidepressants.

 

  4             Our goal is to gather information from a

 

  5   variety of sources and perspectives to help us

 

  6   understand this complex situation and ultimately to

 

  7   offer the best possible recommendations to the FDA.

 

  8             I would like to thank the many groups,

 

  9   individuals, and families that submitted written

 

 10   statements in advance of this meeting, many of

 

 11   which were quite informative as well as moving.

 

 12             Much of today's meeting will be devoted to

 

 13   a two-part open public hearing during which dozens

 

 14   of people from around and even beyond the country

 

 15   will have the opportunity to present their own

 

 16   personal or professional experiences and ideas

 

 17   about the relative risks and benefits of

 

 18   antidepressant medications in children and

 

 19   adolescents.

 

 20             Although the necessary consideration of

 

 21   the clock will permit only a short time at the

 

 22   microphone for each speaker, I can assure you that

 

 23   the committee welcomes and values input from all

 

 24   viewpoints and feels it essential to our work that

 

 25   all voices be heard.

 

                                                                14

 

  1             Major depression remains an

 

  2   underdiagnosed, understudied, and undertreated

 

  3   serious and even life-threatening mental disorder

 

  4   among thousands of our nation's youth, leading to

 

  5   considerable dysfunction, disability, and

 

  6   heartbreak in many families.

 

  7             I am hopeful that with a fair and

 

  8   open-minded review of the evidence in hand and that

 

  9   still emerging, this advisory committee can

 

 10   constructively address the challenges we all share

 

 11   to assure that interventions for this deadly

 

 12   disorder are available for those young people who

 

 13   desperately need them and that those treatments

 

 14   meet high standards for both effectiveness and

 

 15   safety.

 

 16             Now, I will ask Anuja Patel, of the FDA

 

 17   Center for Drug Evaluation and Research, to review

 

 18   some of the ground rules for the open public

 

 19   hearing.

 

 20             MS. PATEL:  Good morning.  As you know, we

 

 21   have a very full open public hearing today and in

 

 22   the interest of both fairness and efficiency, we

 

 23   are running it by some strict rules.

 

 24             Due to the vast majority of requests by

 

 25   registered speakers to speak in the morning

 

                                                                15

 

  1   session, we will lengthen the morning session of

 

  2   open public hearing and shorten the afternoon

 

  3   session accordingly.

 

  4             To make the transitions between speakers

 

  5   more efficient, all speakers will be using the

 

  6   podium in front of the audience.  Each speaker has

 

  7   been given their number and the order of

 

  8   presentation, and when the person ahead of you is

 

  9   speaking, we ask that you move to the nearby next

 

 10   speaker chair.

 

 11             Individual presenters and families have

 

 12   been allotted two minutes for their presentations.

 

 13   The three combined groups' presentations have been

 

 14   allotted three minutes.  We will be using a timer

 

 15   and speakers who run over their time limit will

 

 16   find that the microphone is no longer working.

 

 17             We apologize for the need for the strict

 

 18   rules, but we wanted to give as many people as

 

 19   possible an opportunity to participate.  Thank you

 

 20   for your cooperation.

 

 21             I will now state the Conflict of Interest

 

 22   Statement for the record.

 

 23                  Conflict of Interest Statement

 

 24             The following announcement addresses the

 

 25   issue of conflict of interest with respect to this

 

                                                                16

 

  1   meeting and is made a part of the record to

 

  2   preclude even the appearance of such at this

 

  3   meeting.

 

  4             Based on the agenda, it has been

 

  5   determined that the topics of today's meeting are

 

  6   issues of broad applicability and there are no

 

  7   products being approved at this meeting.  Unlike

 

  8   issues before a committee in which a particular

 

  9   product is discussed, issues of broader

 

 10   applicability involve many industrial sponsors and

 

 11   academic institutions.

 

 12             All Special Government Employees have been

 

 13   screened for their financial interests as they may

 

 14   apply to the general topics at hand.  To determine

 

 15   if any conflict of interest existed, the Agency has

 

 16   reviewed the agenda and all relevant financial

 

 17   interests reported by the meeting participants.

 

 18             The Food and Drug Administration has

 

 19   granted general matter waivers to the Special

 

 20   Government Employees participating in this meeting

 

 21   who require a waiver under Title 18, United States

 

 22   Code, Section 208.

 

 23             A copy of the waiver statements may be

 

 24   obtained by submitting a written request to the

 

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

 

                                                                17

 

  1   of the Parklawn Building.

 

  2             Because general topics impact so many

 

  3   entities, it is not prudent to recite all potential

 

  4   conflict of interests as they apply to each member

 

  5   and consultant and guest speaker.

 

  6             FDA acknowledges that there may be

 

  7   potential conflicts of interest, but because of the

 

  8   general nature of the discussion before the

 

  9   committee, these potential conflicts are mitigated.

 

 10             With respect to FDA's invited industry

 

 11   representatives, we would like to disclose that Dr.

 

 12   Dilip Mehta and Dr. Samuel Maldonado are

 

 13   participating in this meeting as industry

 

 14   representatives acting on behalf of regulated

 

 15   industry.  Dr. Mehta is retired from Pfizer and Dr.

 

 16   Maldonado is employed by Johnson & Johnson.

 

 17             In addition, FDA would also like to note

 

 18   that one member of the Psychopharmacologic Drugs

 

 19   Advisory Committee, Andrew Leon, and an FDA

 

 20   speaker, David Shaffer, were members of the

 

 21   American College of Neuropsychopharmacology ACMP

 

 22   Task Force that has recently issued a preliminary

 

 23   report on SSRIs and suicidal behavior in youth.

 

 24             This task force reviewed published and

 

 25   unpublished data from controlled trials in youth,

 

                                                                18

 

  1   data from epidemiological studies, and data from

 

  2   autopsy studies.

 

  3             Based on their preliminary review, they

 

  4   concluded that the available evidence does not

 

  5   suggest that SSRIs increase the risk of suicidal

 

  6   behavior in youth and with depression, however,

 

  7   they acknowledge that their conclusions are

 

  8   preliminary and they recommend that the pertinent

 

  9   data available to pharmaceutical companies and FDA

 

 10   be rapidly made available to ACMP and others, so

 

 11   that they may be independently evaluated.

 

 12             In the event that the discussions involve

 

 13   any other products or firms not already on the

 

 14   agenda for which FDA participants have a financial

 

 15   interest, the participants' involvement and their

 

 16   exclusion will be noted for the record.

 

 17             With respect to all other participants, we

 

 18   ask in the interest of fairness that they address

 

 19   any current or previous financial involvement with

 

 20   any firm whose product they may wish to comment

 

 21   upon.

 

 22             Thank you.

 

 23             DR. RUDORFER:  Thank you.

 

 24             To put the meeting in context, I would now

 

 25   like to turn to Dr. Russell Katz, Director of the

 

                                                                19

 

  1   FDA Division of Neuropharmacologic Drug Products,

 

  2   who will provide a brief overview of the background

 

  3   leading to today's deliberations and the likely

 

  4   next steps.

 

  5                        Overview of Issues

 

  6             DR. KATZ:  Thank you, Dr. Rudorfer, and

 

  7   good morning.  I would like to also add my welcome

 

  8   to all of you here for this joint meeting of the

 

  9   Pediatric Subcommittee of the Anti-Infective Drugs

 

 10   Advisory Committee and the Psychopharmacologic

 

 11   Drugs Advisory Committee.

 

 12             In particular, I would like to welcome our

 

 13   invited guests who are not members of the

 

 14   committee, but who have graciously agreed to help

 

 15   us grapple with the difficult problem that we bring

 

 16   to you today.

 

 17             As you know, we are here to discuss with

 

 18   you an issue of enormous importance and interest,

 

 19   namely, the relationship, if any, between treatment

 

 20   of pediatric patients with antidepressant drugs and

 

 21   suicidal behavior.

 

 22             This has been an issue of extreme

 

 23   complexity and we are here both to inform you of

 

 24   our efforts to date to examine the question and our

 

 25   plans for further examination of the data, as well

 

                                                                20

 

  1   as to ask for your comments and advice about these

 

  2   plans.

 

  3             We come to you at this time for several

 

  4   reasons. Under current law, the Agency is required

 

  5   to present postmarketing adverse event data to the

 

  6   Pediatric Subcommittee for the first year of

 

  7   marketing for those drugs granted market

 

  8   exclusivity under the pediatric exclusivity

 

  9   provisions of the Act.

 

 10             At this time, therefore, the Agency is

 

 11   meeting its obligation under the law to present

 

 12   this data for Paxil and Celexa.  More importantly,

 

 13   however, given the intense interest in the Agency's

 

 14   efforts to examine the question of antidepressant

 

 15   use in pediatric patients and suicidal behavior, we

 

 16   concluded that it would be appropriate to inform

 

 17   you about these latter efforts at this time, as

 

 18   well.

 

 19             As you know, we most recently became aware

 

 20   of a potential signal of concern during the review

 

 21   of the controlled trial data for Paxil.  In the

 

 22   course of that review, we became aware that the

 

 23   sponsor had categorized some events that could have

 

 24   represented suicidal behavior or suicidal thinking

 

 25   using a description that seemed somewhat

 

                                                                21

 

  1   inappropriate.

 

  2             We asked them to clarify their

 

  3   presentation of the data, and their response raised

 

  4   a concern that such a signal existed.  Based on

 

  5   these concerns, the Agency issued a public

 

  6   statement in June of last year recommending that

 

  7   this drug not be used to treat pediatric patients

 

  8   with depression, but based on the Paxil data and

 

  9   the problem of idiosyncratic characterization of

 

 10   events of potential concern identified in that

 

 11   application, we asked the sponsors of the other

 

 12   antidepressant drugs to search their controlled

 

 13   trial databases in a more formal way to identify

 

 14   potential cases of suicidal behavior.

 

 15             Our review of their responses resulted in

 

 16   a second Agency statement that alerted

 

 17   practitioners to a similar potential signal for

 

 18   other drugs in this class, and recommended that

 

 19   these drugs be used with caution in these patients.

 

 20             Our continued review of these data,

 

 21   however, convinced us that the data submitted from

 

 22   the various companies involved may not have been

 

 23   collected or reported to us in a form that would

 

 24   permit us to adequately evaluate the potential

 

 25   relationship between these drugs and suicidal

 

                                                                22

 

  1   behavior.

 

  2             Indeed, we became convinced that with the

 

  3   data before us at that time, we could not

 

  4   adequately answer the question of whether there was

 

  5   such a relationship for any specific drug or

 

  6   whether there were any differences between drugs.

 

  7             You will hear in greater detail later the

 

  8   deficiencies with these data as previously

 

  9   submitted and why we have therefore continued to

 

 10   work with the sponsors involved to submit to us

 

 11   data in the form that will permit us to adequately

 

 12   and comprehensively address the critical question

 

 13   before us.

 

 14             It is because we are not yet able to do

 

 15   this that we could not present definitive analyses

 

 16   at this time.  It is absolutely critical, in our

 

 17   view, that we make every effort to provide the best

 

 18   answer possible to this question. The wrong answer

 

 19   in either direction, prematurely arrived at, could

 

 20   have profound negative consequences for the public

 

 21   health.

 

 22             However, we now believe that we have

 

 23   obtained from the sponsors all of the relevant data

 

 24   collected during the trials, presented in a

 

 25   standardized manner that will permit us to perform

 

                                                                23

 

  1   analyses that will give us the best possible chance

 

  2   to address this question.

 

  3             Before we embark upon these analyses,

 

  4   however, we are taking this opportunity to inform

 

  5   you and the public about the problems we have

 

  6   encountered in trying to answer this question, how

 

  7   we have attempted to address those problems, and to

 

  8   describe our plans for analyzing the data.

 

  9             We are primarily interested in your views

 

 10   about our proposed approaches to the data and are

 

 11   eager to hear if you believe we should request

 

 12   additional data from the sponsors and whether you

 

 13   believe we should perform additional analyses

 

 14   beyond those we will describe to you later today.

 

 15             In our efforts to further evaluate the

 

 16   data, we have enlisted the help of outside experts

 

 17   with particular expertise in the issue of pediatric

 

 18   depression and suicide, and in particular, we have

 

 19   enlisted a group from Columbia University, who will

 

 20   objectively reclassify potential cases of

 

 21   suicidality from all the drug development programs,

 

 22   so that we may move forward with our more

 

 23   definitive analyses.  You will hear about this from

 

 24   Dr. Kelly Posner in more detail later.

 

 25             We will also present the postmarketing

 

                                                                24

 

  1   adverse event data for the drugs in question, but

 

  2   as you will hear, and for the reasons you will

 

  3   hear, we do not believe that this data can

 

  4   reasonably inform our judgment about any

 

  5   relationship between these drugs and suicidal

 

  6   behavior.

 

  7             It is the controlled trial data that we

 

  8   believe is best able to help us provide an adequate

 

  9   answer to this question, but as you have heard, and

 

 10   you will hear throughout today's presentations, we

 

 11   do not believe that this data until now has been

 

 12   provided to us in a way that would permit us to

 

 13   interpret it fully.

 

 14             It should be noted that this view of the

 

 15   data has not been a unanimous one among Agency

 

 16   staff.  Some within the Agency have examined the

 

 17   data and concluded that the data, as currently

 

 18   submitted, do permit definitive analyses and that

 

 19   these analyses support the conclusion that this

 

 20   class of drugs is associated with a risk of

 

 21   suicidal behavior in pediatric patients.

 

 22             However, the staff of the

 

 23   Neuropharmacological Drugs Division has examined

 

 24   the individual cases reported by the sponsors that

 

 25   allegedly represent suicidal behavior, and we are

 

                                                                25

 

  1   convinced that the categorization of these events,

 

  2   as performed idiosyncratically by the individual

 

  3   sponsors, is not entirely reliable.

 

  4             Examples of these categorizations will be

 

  5   presented to you later today, and we are confident

 

  6   that this conclusion will become clear to you.

 

  7             Further, the pattern of these potential

 

  8   signals is also difficult to understand, for

 

  9   example, arising from one single study out of

 

 10   several similarly size studies for a given drug.

 

 11   This unusual pattern gives us further reason to

 

 12   more closely examine the data.

 

 13             We are, of course, aware that there is

 

 14   great concern among the families of children and

 

 15   adolescents with depression about whether or not

 

 16   these drugs can be used safely.  For them, I am

 

 17   sure answering this question has already taken too

 

 18   long.

 

 19             We, too, are frustrated with the time it

 

 20   has taken to come to a definitive answer to this

 

 21   question.  Indeed, we had originally hoped to be

 

 22   able to present to you today more definitive

 

 23   analyses and conclusions, however, as I have

 

 24   described, closer examination of the data at each

 

 25   step of our analyses convinced us that it would be

 

                                                                26

 

  1   premature to arrive at a conclusion without

 

  2   additional work, the plans for which we will

 

  3   present to you later today.

 

  4             We are firmly convinced that we serve no

 

  5   one's goals or needs by rushing to a judgment that

 

  6   has not considered all reasonable sides to the

 

  7   question.  We are committed to, and fully expect

 

  8   to, come back to the committee in late summer with

 

  9   the results of the analyses we will discuss today.

 

 10             At that time, we expect to be able to

 

 11   present the best possible answer that the current

 

 12   data can provide to the question of whether or not

 

 13   any of these drugs, all of these drugs, or none of

 

 14   these drugs increase the risk of suicidality in

 

 15   pediatric patients.

 

 16             With that as an introduction, I will turn

 

 17   it back to Dr. Rudorfer.

 

 18             DR. RUDORFER:  Thank you, Dr. Katz.

 

 19             We will now hear from Dr. Dianne Murphy,

 

 20   Director of FDA's Office of Counterterrorism and

 

 21   Drug Development, who will speak about the

 

 22   Pediatric Drug Development Program.

 

 23                Pediatric Drug Development Program

 

 24             DR. MURPHY:  Welcome.  Thank you very much

 

 25   for taking time to make this endeavor an important

 

                                                                27

 

  1   part of your scientific and academic life.  We hold

 

  2   your advice very important and look very much

 

  3   forward to your discussion.

 

  4             [Slide.]

 

  5             I am going to ask you to step back for a

 

  6   moment. My comments are not going to focus directly

 

  7   on the topic of depression or the therapies for

 

  8   that.  The goal of my presentation is to provide

 

  9   you some background on pediatric drug development

 

 10   because I think you will see that is the process

 

 11   that has brought us some of this data and we need

 

 12   to make sure everybody understands how this

 

 13   evolved.

 

 14             It is also an example of watch out what

 

 15   you ask for because we now finally, in the last few

 

 16   years, are beginning to get the kind of information

 

 17   that we wanted for a long time to be able to

 

 18   understand how we could better treat children with

 

 19   the therapies that we have.

 

 20             Of course, we will be reviewing FDA's

 

 21   specific responsibilities during these activities.

 

 22             [Slide.]

 

 23             Acronyms.  Throughout the day, you will be

 

 24   hearing these potentially.  You have FDAMA.  That

 

 25   is the Food and Drug Administration Modernization

 

                                                                28

 

  1   Act.  This is important because this is the

 

  2   legislative initiative that provided the Agency

 

  3   with the ability to provide an incentive that has

 

  4   been a tremendous -- I call it the engine that has

 

  5   really been driving this process for being able to

 

  6   develop information on how to use these products in

 

  7   children.

 

  8             Remember, before this, most children, if

 

  9   it was not a pediatric disease like otitis media,

 

 10   these products were not being studied in children,

 

 11   and each child was an n of 1 in which we did not

 

 12   learn anything, and that was not an approach we

 

 13   thought useful.  That's FDAMA.

 

 14             Best Pharmaceuticals for Children, renewal

 

 15   of the legislation basically expanding not only the

 

 16   legislative mandate to look at products that have

 

 17   patents remaining where the incentive will work,

 

 18   but a process which mandates FDA and NIH to work

 

 19   together to develop the same sort of data for

 

 20   products that are older and would not benefit

 

 21   because that was an area that was not being

 

 22   developed.

 

 23             The way that is done is important to

 

 24   understand because it is done via what is called

 

 25   the written request in which FDA -- and this is

 

                                                                29

 

  1   distinctive from most other drug development -- FDA

 

  2   determines what the public health need is and

 

  3   issues a written request defining the studies that

 

  4   they think need to be done, so that we can better

 

  5   understand how to dose children or if it works in

 

  6   children, or what are the distinctive adverse

 

  7   events that occur in children, because as we all

 

  8   know, the variability between a preemie and a

 

  9   fullback is tremendous, and we have that in

 

 10   children, and evolving developmental processes.

 

 11             PREA was the recently legislation that in

 

 12   essence said yes, FDA, you have the authority to

 

 13   require that if a sponsor submits an application

 

 14   for a disease -- I am going to call it indication

 

 15   throughout the rest of this -- for an indication

 

 16   that exists in children for which this product will

 

 17   likely be used, you are to study it in children

 

 18   also.  You are not just to market it for adults.

 

 19             This proposed pediatric study is a process

 

 20   that applies to the written request, which if

 

 21   industry is interested in studying a product, they

 

 22   can submit it to FDA, and we can look at that.

 

 23             That is important because what you need to

 

 24   understand is that this whole exclusivity process

 

 25   is voluntary, so it is up to the sponsor whether

 

                                                                30

 

  1   they want to participate or not.  This process is

 

  2   not.

 

  3             [Slide.]

 

  4             The interesting thing about pediatric drug

 

  5   development is that many of the legislation that

 

  6   has developed has developed because of misfortunes

 

  7   and severe tragedies that have happened in

 

  8   children, and yet every time new legislation would

 

  9   be mandated, it would apply to adults, and not to

 

 10   children.

 

 11             Many of you have heard this talk, so I am

 

 12   just quickly putting these up here to remind

 

 13   everybody.

 

 14             [Slide.]

 

 15             We have for decades been trying to have

 

 16   products that are being used in children studied,

 

 17   and this is just to give you really the benchmarks,

 

 18   starting in the '70s, in which the Academy of

 

 19   Pediatrics issued a statement saying we ought to be

 

 20   studying these products we are using in children,

 

 21   why do we think that children are going to be less

 

 22   variable than adults.  All reason and information

 

 23   would say they are going to be more variable, and

 

 24   we need to.

 

 25             The Agency actually issued a statement

 

                                                                31

 

  1   saying we think children should be studied, and we

 

  2   would like you to conduct two adequate trials also

 

  3   for children, to evaluate the safety and efficacy

 

  4   in children.

 

  5             What happened was not much, and as

 

  6   everybody has heard, the majority of products were

 

  7   not studied in children until really here.

 

  8             In 1994, FDA published a regulation which

 

  9   basically said we understand that there are times

 

 10   in which you can extrapolate efficacy only.  If the

 

 11   disease is similar enough, the pathophysiology, and

 

 12   the expected response have been defined well

 

 13   enough, that you might be able to extrapolate

 

 14   efficacy, hoping to incentivize in a way the

 

 15   interest in developing information and conducting

 

 16   trials in children.  Safety and dose finding were

 

 17   still trials that you would need to conduct in

 

 18   children.

 

 19             Again, minimal response.  So, bottom line,

 

 20   the first incentive program was the major push.

 

 21   The FDA published a regulation, which was then

 

 22   enjoined by a court saying we didn't have the

 

 23   authority to require it, so Congress came back in

 

 24   2003 and said, yes, FDA, you do.

 

 25             So, right now here are the two things that

 

                                                                32

 

  1   are driving pediatric drug development, so that we

 

  2   can better understand how to use these products in

 

  3   children.

 

  4             [Slide.]

 

  5             It has been a tremendous response.  This

 

  6   is just simulated to exclusivity.  We have received

 

  7   over 300 proposals.  You could have counted the

 

  8   number of products developed on your fingers and

 

  9   toes before this that weren't primarily pediatric

 

 10   diseases.

 

 11             We have issued over 283 written requests

 

 12   where FDA has determined what needs to be developed

 

 13   in the way of studies, and has issued sponsors'

 

 14   requests. This is updated from your handout, by the

 

 15   way, these numbers are slightly different because

 

 16   we updated it for the slides.

 

 17             The important thing about exclusivity

 

 18   determinations, it means that over 100 products

 

 19   have been brought in with the studies that have

 

 20   been requested, and you are discussing some of

 

 21   those today, with the type of information that

 

 22   helps us better understand.

 

 23             We have an entire one-hour talk on some of

 

 24   the very significant findings that have been

 

 25   developed, that we have discovered in this process.

 

                                                                33

 

  1   Today is another example of we are finding out what

 

  2   more information we need if we are going to

 

  3   properly use these products.

 

  4             I only put these numbers up because once

 

  5   exclusivity is granted, you can see some were

 

  6   denied, even though it may have been denied, it

 

  7   still could have been approved.  It just meant that

 

  8   they didn't meet the terms completely that we asked

 

  9   for.

 

 10             There are now 63 new labels, so products

 

 11   that are being used in children, there are now 63

 

 12   of them that have new labels, new important dosing

 

 13   and safety information in them including

 

 14   information that says they don't work in kids with

 

 15   these studies.

 

 16             [Slide.]

 

 17             These are the products that were mandated,

 

 18   not the individual products, but the process that

 

 19   was mandated by the Best Pharmaceuticals, the BPCA.

 

 20   I point this out because one of these, our set of

 

 21   data you are going to hear today is the result of

 

 22   BPCA saying FDA, one year after a product has been

 

 23   granted exclusivity, you will follow all of the

 

 24   adverse events that are reported for that product,

 

 25   and you will present it to the Pediatric Advisory

 

                                                                34

 

  1   Subcommittee that will soon be a full committee,

 

  2   and that this is an area which BPCA wanted to make

 

  3   sure that additional attention was paid to the

 

  4   process of reviewing what happens.

 

  5             The thing to understand about that is that

 

  6   a product could be approved way back 10 years ago,

 

  7   and it could then be studied later in its life for

 

  8   pediatrics, so that the one-year post-safety

 

  9   assessment is at varying stages of these different

 

 10   products, they are not all the same, and the

 

 11   Division has tried to standardize that for you

 

 12   today in looking at the safety assessments at more

 

 13   standardized times because each product is coming

 

 14   in at a different time.

 

 15             [Slide.]

 

 16             The only other thing I really wanted to

 

 17   point out to everybody, to bring us back to the

 

 18   topic at hand today, is that this drug development

 

 19   process that has begun to occur really since 1998,

 

 20   five, six years, has brought forth not only new

 

 21   information that challenges some of our

 

 22   preconceived thoughts about safety and how children

 

 23   respond, it has been a tremendous bounty of

 

 24   information because children are finally getting

 

 25   studied.

 

                                                                35

 

  1             We are beginning to have to figure out how

 

  2   do you measure that endpoint in children.  That

 

  3   type of science was not being developed.  We are

 

  4   also dealing with the ethical issues that come up,

 

  5   that are different for kids who cannot consent, so

 

  6   this is a whole different process, and I just want

 

  7   to make sure that you all knew that we have brought

 

  8   various ethical issues to the committees, and we

 

  9   have a wonderful cadre of ethicists who are Special

 

 10   Government Employees, who work with the Pediatric

 

 11   Advisory Subcommittee, who attended these meetings

 

 12   and advised us on such topics as should children be

 

 13   enrolled in trials in which they are not going to

 

 14   receive direct benefit, should children be enrolled

 

 15   in placebo-controlled trials, should children who

 

 16   are especially vulnerable -- most people think of

 

 17   children as a vulnerable population, but in truth,

 

 18   there are subsets, subpopulations that are even

 

 19   more vulnerable, and this was a population of

 

 20   children with CP, how do you develop a product in

 

 21   that population.  These are difficult issues.

 

 22             [Slide.]

 

 23             This is, quickly, and I am not going to go

 

 24   over every one of these, but to give you an idea of

 

 25   the broad array of products that are being

 

                                                                36

 

  1   developed in children and the questions that have

 

  2   come up.

 

  3             Actually, Neuropharm, the Division of

 

  4   Neuropharmacological Drug Products, has brought a

 

  5   number of these issues to the committee, including

 

  6   how do we develop pediatric products -- NIMH also

 

  7   participated in this meeting -- from such issues as

 

  8   -- also, this was another Neuropharm Advisory

 

  9   Committee meeting with the Pediatric Committee --

 

 10   chronic hepatitis, reflux in infants, HIV drugs,

 

 11   how do you approach the whole field of developing a

 

 12   product that may be put in almost every newborn who

 

 13   develops hyperbilirubinemia, tremendous issues,

 

 14   long term study issues.

 

 15             Again, more, what do you do about some of

 

 16   these products.  Most of our products' safety

 

 17   databases are collected on weeks, usually, maybe

 

 18   months, but certainly not years, what do you do

 

 19   with products that we know can potentially suppress

 

 20   your adrenal axis or products that we know can be

 

 21   oncogenic, but have to be used.

 

 22             [Slide.]

 

 23             Some of the ongoing lessons that we have

 

 24   learned during this process -- which we think is a

 

 25   positive process, it is much better than ignorance

 

                                                                37

 

  1   -- it is that children are even more variable than

 

  2   we really thought.

 

  3             We are finding, for certain classes, you

 

  4   may have to have dosing based on clearance in three

 

  5   different age groups that is very different, and it

 

  6   is not just the preemies, it is not just the

 

  7   neonates.  It is actually children of all ages,

 

  8   from adolescence, preschool, et cetera.

 

  9             Adverse reactions that are

 

 10   pediatric-specific are being defined.  Clearly,

 

 11   growth is one everybody would expect would be

 

 12   defined, that we are finding that products, and

 

 13   Prozac was an example of that, are having an effect

 

 14   on growth.  But there are many other products that

 

 15   we are beginning to look now, and beginning to look

 

 16   in a more systematic way, that we are finding that

 

 17   they do have an effect on growth.

 

 18             But there are other issues - school

 

 19   behavior problem, other products where aggression

 

 20   and behavioral changes have been seen.  So, this is

 

 21   a very important area that we are trying to look at

 

 22   as we develop these products.

 

 23             Trial designs are being modified as we

 

 24   learn, and I think that is probably why we are here

 

 25   today.  We are learning.  We take the best

 

                                                                38

 

  1   knowledge we have, we get the best experts, we

 

  2   issue the type of study we think will be the best,

 

  3   and sometimes something happens in the meantime,

 

  4   more data becomes available, we need to update

 

  5   that, or what we thought we were going to be able

 

  6   to evaluate didn't turn out to be as valuable as

 

  7   something else in the study.

 

  8             We learn from these studies.  Remember,

 

  9   there is a huge amount of science that has not been

 

 10   developed, that is now being developed for

 

 11   children, and, as I said, the ethical issues have

 

 12   to be reassessed from the pediatric perspective.

 

 13             [Slide.]

 

 14             I just got the signal that my time is up,

 

 15   so I will leave you with the general principles

 

 16   that we have developed from the International

 

 17   Conference on Harmonization on how one should

 

 18   approach the whole process involving children in

 

 19   trials, and this is a group that involves European

 

 20   nations, Japan and the United States, and I think

 

 21   that it is a shared responsibility.  That is why we

 

 22   thank you for being here today.  Thank you.

 

 23             [Slide.]

 

 24             This is where you can go onto the web.

 

 25   There is a tremendous amount of information posted

 

                                                                39

 

  1   on pediatric numbers, stats, and studies.

 

  2             Thank you.

 

  3             DR. RUDORFER:  Thank you, Dr. Murphy.

 

  4             As Dr. Katz pointed out, an important way

 

  5   to put issues of drug safety in context is to

 

  6   understand more about the disorder being treated,

 

  7   so we are pleased to have a couple of experts in

 

  8   the area of depression in young people to address

 

  9   us on the latest understanding of this complicated

 

 10   disorder.

 

 11             First, from Weill Medical College of

 

 12   Cornell University, we are pleased to have Dr.

 

 13   Cynthia Pfeffer, who will address Pediatric

 

 14   Depression and its Treatment.

 

 15              Pediatric Depression and its Treatment

 

 16             DR. PFEFFER:  I want especially to provide

 

 17   an overview of pediatric depression, which in fact

 

 18   is a major mental health problem in the United

 

 19   States and probably worldwide.

 

 20             [Slide.]

 

 21             There is a tremendous need to develop

 

 22   treatments for these problems and also prevention

 

 23   efforts primarily because these disorders,

 

 24   particularly major depressive disorder, dysthymic

 

 25   disorder, and for that matter, other mood disorders

 

                                                                40

 

  1   are very prevalent and recurrent, they have high

 

  2   rates of morbidity and comorbidity, they are often

 

  3   accompanied by very poor psychosocial outcomes for

 

  4   children and adolescents.  They are associated with

 

  5   high risk for suicide and also for substance abuse.

 

  6             [Slide.]

 

  7             There are a number of problems which I

 

  8   will touch on in my talk in reducing major

 

  9   depressive disorder in children and adolescents,

 

 10   and these include problems in actually diagnosing

 

 11   children and adolescents.  There are developmental

 

 12   variations that need to be considered.

 

 13             There is a complexity of factors that are

 

 14   associated with the clinical course of children who

 

 15   have such mood disorders and a need for specificity

 

 16   of treatments.

 

 17             [Slide.]

 

 18             Epidemiologically, we know that the

 

 19   prevalence of major depressive disorder in children

 

 20   who are prepubertal is approximately 2 percent, and

 

 21   it increases in adolescents to a rate of between 4

 

 22   and approximately 8 percent.

 

 23             The male-to-female ratio for younger

 

 24   people, prepubertal children, is about equal, but

 

 25   in adolescents, females outnumber males who have

 

                                                                41

 

  1   major depression 2 to 1.

 

  2             By the time a youngster reaches the age of

 

  3   18, there is approximately a 20 percent prevalence

 

  4   rate of those who are depressed, who show major

 

  5   depression, and since prior to World War II, each

 

  6   successive generation seems to have a higher risk

 

  7   for major depressive disorder.

 

  8             If we look at dysthymia, the prevalence

 

  9   rate is somewhat lower although something to be

 

 10   concerned about, with the highest rate of

 

 11   approximately 2 percent in children, and in

 

 12   adolescents, ranging from almost 2 to 8 percent.

 

 13   Dysthymia is a condition that is often

 

 14   under-recognized.

 

 15             [Slide.]

 

 16             There are a number of complexities in

 

 17   diagnosing major depression in children and

 

 18   adolescents.  These include an overlap of a variety

 

 19   of the mood symptoms, and in addition, the symptoms

 

 20   often overlap with comorbid disorders.

 

 21             There are developmental variations in the

 

 22   symptoms and how they are manifest.  There are

 

 23   etiological variations of mood disorders that do

 

 24   involve gene and environmental interactions, and

 

 25   there is a question of whether some of these issues

 

                                                                42

 

  1   are actually spectrum related or categorical

 

  2   disorders.

 

  3             Finally, the effects of medical conditions

 

  4   on the prevalence and incidence of major depression

 

  5   and other mood disorders needs to be considered.

 

  6             [Slide.]

 

  7             The DSM criteria for major depressive

 

  8   disorder involves a pervasive change in mood, which

 

  9   is manifest for at least two weeks by either being

 

 10   depressed or irritable or having a loss of interest

 

 11   in pleasure.

 

 12             There are other symptoms that are

 

 13   necessary in making the diagnosis, that include

 

 14   changes in appetite, weight, sleep, activity

 

 15   levels, concentration, and sometimes

 

 16   indecisiveness, changes in energy level,

 

 17   self-esteem, including worthlessness and excessive

 

 18   guilt, changes in motivation, and recurrent

 

 19   suicidal ideation and acts.

 

 20             These symptoms should represent a change

 

 21   from the child or adolescent's previous functioning

 

 22   and produce impairment.  These symptoms are not

 

 23   attributable to substance abuse, medications, or

 

 24   other psychiatric illness, bereavement, and medical

 

 25   illness.

 

                                                                43

 

  1             [Slide.]

 

  2             There are developmental variations which

 

  3   have been identified.  For example, in children,

 

  4   they tend to have a greater number of symptoms of

 

  5   anxiety, including phobias and separation anxiety,

 

  6   more somatic complaints, and if they do occur,

 

  7   auditory hallucinations.

 

  8             They express irritability with temper

 

  9   tantrums and behavioral problems, and the children

 

 10   tend to have fewer delusions and fewer serious

 

 11   suicide attempts, however, adolescents tend to show

 

 12   more sleep and appetite disturbances, if they

 

 13   occur, delusional thinking, greater degrees of

 

 14   suicidal ideation and acts, and greater impairment

 

 15   of functioning.

 

 16             Compared to adults, however, adolescents

 

 17   have more behavioral problems and fewer

 

 18   neurovegetative symptoms.

 

 19             [Slide.]

 

 20             The diagnostic criteria for dysthymia

 

 21   involves a persistent long-term change in mood

 

 22   which is less intense, but more chronic than major

 

 23   depressive disorder.  These children in adolescence

 

 24   have extensive psychosocial impairment.

 

 25             The depressed mood or irritability occurs

 

                                                                44

 

  1   most of the time during the day for at least one

 

  2   year, and there are at least two other symptoms

 

  3   that are associated in making the diagnosis.  These

 

  4   include again changes in appetite, sleep, lowered

 

  5   self-esteem, problems with concentration, problems

 

  6   with decisionmaking, changes in energy level, and a

 

  7   sense of hopelessness.

 

  8             People who have no symptoms for more than

 

  9   two months at a time, and do not have a major

 

 10   depressive disorder in the first year of

 

 11   disturbance, may be considered to have dysthymic

 

 12   disorder, and these are also youngsters who never

 

 13   had manic or hypomanic episodes.

 

 14             [Slide.]

 

 15             Other symptoms tend to go along with

 

 16   dysthymic disorder.  These include feelings of

 

 17   being unloved, angry outbursts, self-depreciation,

 

 18   somatic complaints, anxiety, and often

 

 19   disobedience.

 

 20             [Slide.]

 

 21             There are a variety of variations that the

 

 22   symptoms of major depressive disorder involve.  For

 

 23   example, psychotic depression, bipolar depressive

 

 24   states, atypical depression, seasonal affective

 

 25   disorder, subclinical or subsyndromal depression,

 

                                                                45

 

  1   and treatment-resistant depression.

 

  2             [Slide.]

 

  3             I will touch on some of these variants now

 

  4   more specifically.  Psychotic depression includes

 

  5   major depressive disorder symptoms that are

 

  6   associated with mood-congruent or incongruent

 

  7   hallucinations and/or delusions, and unlike

 

  8   adolescents, children tend to manifest more

 

  9   hallucinations.

 

 10             Psychotic depression occurs in up to about

 

 11   30 percent of those youngsters with major

 

 12   depressive disorder. It is associated with more

 

 13   severe depression, greater long-term morbidity,

 

 14   resistance to antidepressant monotherapy, a low

 

 15   placebo response, increased risk for bipolar

 

 16   disorder, and a family history of bipolar and

 

 17   psychotic depression.

 

 18             [Slide.]

 

 19             Bipolar depression presents similarly to

 

 20   unipolar depressive disorder.  The risks for

 

 21   bipolar disorder is indicated by psychosis,

 

 22   psychomotor retardation, psychopharmacologically

 

 23   induced hypomania, and a family history of bipolar

 

 24   disorder.

 

 25             Adolescents are likely to have rapid

 

                                                                46

 

  1   cycling or mixed episodes, and an increased suicide

 

  2   risk and difficulty in treatment compliance.  There

 

  3   is a need to rule out bipolar II disorder, which is

 

  4   more prevalent in adolescents and often overlooked

 

  5   and misdiagnosed.

 

  6             [Slide.]

 

  7             Atypical depression has not yet been

 

  8   studied in children and adolescents, and it usually

 

  9   has an onset in adolescence, and it is manifest by

 

 10   increased lethargy, appetite and weight changes,

 

 11   and reactivity to rejection.

 

 12             There is hypersomnia and often

 

 13   carbohydrate craving.  In adults, it tends to be

 

 14   genetically distinct from major depressive

 

 15   disorder.

 

 16             [Slide.]

 

 17             Seasonal affective disorder usually has

 

 18   its onset in adolescence in those living in regions

 

 19   with distinct seasons. The symptoms are similar to

 

 20   those of atypical depression, but are more

 

 21   episodic.  They do not include increase reactivity

 

 22   to rejection.

 

 23             This disorder should be differentiated

 

 24   from depression precipitated by school problems and

 

 25   school stress since it usually overlaps with the

 

                                                                47

 

  1   school calendar.

 

  2             [Slide.]

 

  3             Treatment-resistant depression is not

 

  4   clearly defined for children and adolescents.  It

 

  5   occurs in approximately 6 to 10 percent of

 

  6   depressed children and adolescents who suffer

 

  7   chronic depression.

 

  8             In adults, treatment resistance is defined

 

  9   as patients who have had at least two trials with

 

 10   two different classes of antidepressants which are

 

 11   administered at approximately similar doses for at

 

 12   least six weeks each.

 

 13             [Slide.]

 

 14             Another issue that needs to be thought

 

 15   about in understanding the mood disorders and

 

 16   especially major depression is that they may be

 

 17   affected by the complexity of comorbid disorders

 

 18   which may affect the recognition and diagnosis of

 

 19   major depression, the types and efficacy of

 

 20   treatments, and various psychosocial outcomes.

 

 21             [Slide.]

 

 22             Comorbidity tends to be present in 40 to

 

 23   90 percent of youth with major depression.  Two or

 

 24   more comorbid disorders tend to be present in

 

 25   approximately 20 to 50 percent of youth with major

 

                                                                48

 

  1   depression.

 

  2             Comorbidity in youth with major depression

 

  3   involves dysthymia or anxiety disorders with a rate

 

  4   of approximately 30 to 80 percent, disruptive

 

  5   disorders with a rate of approximately 10 to 80

 

  6   percent, and substance abuse disorders with a rate

 

  7   of approximately 20 to 30 percent.

 

  8             Major depressive onset is usually after

 

  9   the comorbid disorders except for substance abuse

 

 10   in which major depression tends to antedate

 

 11   substance abuse disorders. Conduct problems may be

 

 12   a complication of major depression and may persist

 

 13   after the major depressive episode resolves.

 

 14             Children may manifest separation anxiety

 

 15   comorbid disorders, while adolescents may tend to

 

 16   manifest social phobia, generalized anxiety

 

 17   disorder, conduct disorder, and substance abuse.

 

 18             [Slide.]

 

 19             In terms of differential diagnosis of

 

 20   major depressive disorder, the complexities tend to

 

 21   be with an overlap of symptoms with other

 

 22   nonaffective disorders, such as anxiety states,

 

 23   learning problems, disruptive disorders, and

 

 24   personality disorders and eating disorders.

 

 25             The overlapping symptoms may include poor

 

                                                                49

 

  1   self-esteem, demoralization, poor concentration,

 

  2   irritability, dysphoria, poor sleep, appetite

 

  3   problems, suicidal thoughts, and being overwhelmed.

 

  4             [Slide.]

 

  5             One should consider in the differential

 

  6   diagnosis the nonaffective psychiatric disorders,

 

  7   which include anxiety disorders especially

 

  8   separation anxiety, generalized anxiety, and other

 

  9   anxiety states, disruptive and attention deficit

 

 10   disorders, learning problems, substance abuse,

 

 11   eating disorders especially anorexia nervosa,

 

 12   personality disorders, and premenstrual dysphoric

 

 13   disorder.

 

 14             [Slide.]

 

 15             Another disorder that needs to be

 

 16   considered and understood is an adjustment disorder

 

 17   with depressed mood. This includes a mood change

 

 18   and impairment of functioning within about three

 

 19   months of a stressor, and this does not meet the

 

 20   criteria for major depressive disorder.

 

 21             Adjustment disorder with depressed mood

 

 22   tends to be self-limited, there are less mood

 

 23   disturbances associated with it, fewer symptoms,

 

 24   and no relapse, which is an important issue.

 

 25             Consider other disorders if the symptoms

 

                                                                50

 

  1   last more than six months or meet the criteria for

 

  2   other disorders, for example, dysthymia.

 

  3             [Slide.]

 

  4             General medical conditions may be another

 

  5   complexity in understanding and diagnosing major

 

  6   depressive disorder.  These medical conditions may

 

  7   be accompanied by symptoms of depression.  They may

 

  8   also impact the course of major depressive

 

  9   disorder.

 

 10             Major depression can be diagnosed if the

 

 11   depressive symptoms preceded or are not solely due

 

 12   to the medical condition or to medications used to

 

 13   treat the medical condition.

 

 14             The incidence of major depression tends to

 

 15   be higher in certain medical illnesses.  Chronic

 

 16   illness may affect sleep, appetite, and energy.

 

 17   Guilt, worthlessness, hopelessness, and suicidal

 

 18   ideation are usually not attributed to the medical

 

 19   illness, but do suggest the symptoms of major

 

 20   depressive disorder.

 

 21             Medical conditions that are often

 

 22   associated with major depressive disorder include

 

 23   cancer, hypothyroidism, lupus erythematosus, AIDS,

 

 24   anemia, diabetes, and epilepsy.

 

 25             Chronic fatigue syndrome is another

 

                                                                51

 

  1   disorder that needs to be considered, but its

 

  2   symptoms are similar to major depression, but there

 

  3   tends to be more somatic symptoms, less mood,

 

  4   cognitive, and social symptoms.

 

  5             Medication-induced symptoms involve those

 

  6   induced by stimulants, neuroleptics, cortical

 

  7   steroids, and contraceptives.

 

  8             [Slide.]

 

  9             Bereavement is another issue that needs to

 

 10   be considered because there are a similarity of

 

 11   symptoms with major depressive disorder.  The

 

 12   diagnosis of major depression can be made if the

 

 13   bereaved child or adolescent has moderate or severe

 

 14   functional impairment, psychosis, suicidal thoughts

 

 15   or acts, and a prolonged course.

 

 16             Following bereavement, a predisposition to

 

 17   major depression may be related to prior major

 

 18   depression or a  family history of major depressive

 

 19   disorder.  In general, uncomplicated bereavement

 

 20   often remits in 6 to 12 months after a death.

 

 21             [Slide.]

 

 22             I would like to focus now on some issues

 

 23   of clinical course for major depressive disorder.

 

 24   The median duration for clinically referred

 

 25   children and adolescents tends to be 7 to 9 months,

 

                                                                52

 

  1   and in community samples it has been reported to be

 

  2   shorter, approximately 1 to 2 months.

 

  3             Predictors of a longer course or duration

 

  4   involve the severity of depression, the degree of

 

  5   comorbidity, the presence of negative life events,

 

  6   parental psychiatric disorders, and poor social

 

  7   functioning.

 

  8             Remission of major depression is defined

 

  9   as a period of 2 weeks to 2 months in which there

 

 10   is one clinically significant symptom only.  Ninety

 

 11   percent of children and adolescents with major

 

 12   depression remit in 1 to 2 years after the onset of

 

 13   the major depressive episode.

 

 14             [Slide.]

 

 15             Approximately 6 to 10 percent of those

 

 16   with major depression have a protracted course.  A

 

 17   relapse is an episode of major depression during

 

 18   the period of remission, and predictors of relapse

 

 19   include the natural course of major depression,

 

 20   namely, the nature of the way it manifests, lack of

 

 21   compliance with interventions, negative life

 

 22   events, rapid decrease, or discontinuation of

 

 23   therapy.

 

 24             Forty to 60 percent of youth with major

 

 25   depression tend to have a relapse after successful

 

                                                                53

 

  1   acute therapy, it's a high rate.  This indicates

 

  2   the need for continuous treatment.

 

  3             [Slide.]

 

  4             Recurrences occur also, and this is an

 

  5   emergence of major depressive symptoms during a

 

  6   period of recovery, which is an asymptomatic period

 

  7   of more than two months. Clinical and non-clinical

 

  8   samples have a probability of recurrence of

 

  9   approximately 20 to 60 percent within one or two

 

 10   years after recovery, and 70 percent after five

 

 11   years of recovery.  So, this is a chronic disorder.

 

 12             Predictors of recurrence include the

 

 13   earlier age of onset of major depressive symptoms,

 

 14   increased number of prior episodes of major

 

 15   depression, the severity of an initial episode, the

 

 16   presence of psychosis, the degree of psychosocial

 

 17   stressors, the presence of dysthymia and other

 

 18   comorbidities, and the lack of compliance with

 

 19   therapy.

 

 20             [Slide.]

 

 21             In terms of the clinical course, children

 

 22   with major depression, 20 to 40 percent develop

 

 23   bipolar disorder in 5 years after the onset of

 

 24   major depressive disorder, and predictors for the

 

 25   bipolar disorder onset would be early onset of

 

                                                                54

 

  1   major depression, the presence of psychomotor

 

  2   retardation, psychosis, a family history of

 

  3   psychotic depression, a heavy family loading for

 

  4   mood disorders, and psychopharmacologically-induced

 

  5   hypomania.

 

  6             [Slide.]

 

  7             Other factors that affect the clinical

 

  8   course of major depression is that the risk for

 

  9   depression increases 2- to 4-fold after puberty, a

 

 10   very important developmental issue, and that

 

 11   various genetic, as well as environmental, factors

 

 12   influence the pathogenesis of major depression.

 

 13             For example, shared family environmental

 

 14   or not extra-environmental non-shared issues tend

 

 15   to be very important in affecting the course, as

 

 16   well as those youngsters who have high genetic risk

 

 17   are more sensitive to  various environmental

 

 18   stressors.

 

 19             Children with depressed parents are three

 

 20   times more likely to have a lifetime episode of a

 

 21   major depressive disorder.

 

 22             [Slide.]

 

 23             The prevalence of children's first-degree

 

 24   relatives when children have major depression tends

 

 25   to be 30 to 50 percent.  In addition, parents also

 

                                                                55

 

  1   may have major depression and anxiety disorders,

 

  2   substance abuse, as well  as personality disorders.

 

  3             [Slide.]

 

  4             The clinical course of children with major

 

  5   depression is also associated with poor school

 

  6   success, low parental satisfaction with the child,

 

  7   a very important parent-child problem, learning

 

  8   problems, other psychiatric disorders that

 

  9   interfere with the child's learning.

 

 10             The course may also be affected by various

 

 11   personality traits, such as the child being

 

 12   judgmental, having angry outbursts frequently, poor

 

 13   self-esteem, and dependency.  Cognitive styles and

 

 14   temperament, such as negative attributional styles,

 

 15   may affect the course of major depressive disorder.

 

 16             Early adverse experiences, such as

 

 17   parental separation or death, may affect the

 

 18   course.  Recent adverse events may affect the

 

 19   course, family conflicts, neglect, and abuse,

 

 20   biological factors, such as inability to regulate

 

 21   emotions, and/or distress.

 

 22             [Slide.]

 

 23             The relation of dysthymia in major

 

 24   depression is quite important because dysthymia is

 

 25   associated with an increased risk for major

 

                                                                56

 

  1   depressive disorder.  Seventy percent of youth with

 

  2   dysthymia tend to have major depressive disorders.

 

  3             Dysthymia has a mean episode of

 

  4   approximately 3  to 4 years for both clinical and

 

  5   non-clinical in community samples.  A first major

 

  6   depressive episode usually occurs 2 to 3 years

 

  7   after the onset of dysthymia, which may be

 

  8   considered a gateway to the developing recurrent

 

  9   major depressive disorder.

 

 10             The risk for dysthymia is associated with

 

 11   chaotic families, high family loading for mood

 

 12   disorders particularly dysthymia.

 

 13             [Slide.]

 

 14             Another important issue in terms of course

 

 15   of children with major depression is that they are

 

 16   at very high risk for suicidal tendencies.  There

 

 17   are a few studies, some of which I will highlight,

 

 18   one by Marika Kovacs, which is a 9-year follow-up

 

 19   of prepubertal children.  She had various groups

 

 20   that she studied.

 

 21             At the time of follow-up, children who had

 

 22   major depression had a 74 percent rate of suicidal

 

 23   thinking and a 28 percent rate of suicide attempts.

 

 24   Those who initially had dysthymia, also had a 78

 

 25   percent rate of suicidal thinking, and close to 20

 

                                                                57

 

  1   percent rate of suicide attempts.

 

  2             Compared to children with adjustment

 

  3   disorder or other types of psychiatric disorders

 

  4   that are not mood disorders, these rates for

 

  5   children with mood disorders, namely, major

 

  6   depression and dysthymia, are significantly greater

 

  7   for suicidal thinking and suicidal attempts.

 

  8             Our own follow-up study of 6 to 8 years

 

  9   for prepubertal inpatients indicated that there is

 

 10   a 5 times risk for suicide attempt when the

 

 11   prepubertal children reach adolescence if they had

 

 12   a prepubertal mood disorder.

 

 13             [Slide.]

 

 14             A community sample study indicated that

 

 15   the 1-year incidence of suicide attempts in

 

 16   adolescence was associated with a 12 to 15 times

 

 17   greater risk if the youngster had major depressive

 

 18   disorder.

 

 19             [Slide.]

 

 20             There are various concerns about treating

 

 21   major depressive disorder.  The treatment research,

 

 22   first of all, is relatively sparse in children and

 

 23   adolescents.  There are varied opinions about

 

 24   whether psychotherapy or pharmacotherapy, or a

 

 25   combination should be the first-line treatment.

 

                                                                58

 

  1             The initial acute treatment often depends

 

  2   on the severity of symptoms of major depression,

 

  3   the number of prior episodes, the chronicity, the

 

  4   age, contextual issues in the family, school, and

 

  5   other environmental features, the degree of

 

  6   negative life events, the compliance with

 

  7   treatment, prior treatment responses, and the

 

  8   motivation for treatment.

 

  9             [Slide.]

 

 10             Some general principles that clinicians

 

 11   have thought about is that psychotherapy may be

 

 12   considered for the more mild or moderate major

 

 13   depressive symptoms.  Empirical effect of

 

 14   psychotherapies that we now know of include

 

 15   cognitive behavioral therapy and ITP, interpersonal

 

 16   psychotherapy.

 

 17             Antidepressants may be used for youngsters

 

 18   who have symptoms of major depressive disorder,

 

 19   nonrapid cycling by polar states, psychotic

 

 20   depression, depression with severe symptoms that

 

 21   prevent effective psychotherapy or that fail to

 

 22   respond to psychotherapy.

 

 23             Also, due to the psychosocial context,

 

 24   frequently pharmacotherapy alone may not be

 

 25   effective.

 

                                                                59

 

  1             [Slide.]

 

  2             The treatment of children with major

 

  3   depression, there are very few studies of acute

 

  4   treatment using medication.  There are few

 

  5   pharmacokinetic or dose-range studies with children

 

  6   and adolescents.

 

  7             The SSRIs are thought to perhaps induce

 

  8   mania, hypomania, behavioral activation, which

 

  9   might include impulsive behavior, silly or agitated

 

 10   daring, and there are no long-term studies for the

 

 11   treatment of major depression.

 

 12             I am going to actually conclude, and not

 

 13   go over some of these studies, which you will hear

 

 14   about I am sure today, and to say again that major

 

 15   depressive disorder in children and adolescents is

 

 16   complex and heterogeneous regarding its clinical

 

 17   course, comorbidities, predictors, of course, need

 

 18   for specificity of treatment, and the developmental

 

 19   variations.

 

 20             It is a chronic condition that recurs with

 

 21   serious morbidity including suicidal tendencies.

 

 22   There are few treatment studies, which limit our

 

 23   knowledge of the methods to reduce these symptoms

 

 24   and the morbidities.

 

 25             There is a need to clarify the indications

 

                                                                60

 

  1   for pharmacotherapy, as well as psychotherapy

 

  2   whether alone or used in combination, as well as

 

  3   that to maintain youngsters who have already

 

  4   exhibited major depressive disorder.

 

  5             Thank you.

 

  6             DR. RUDORFER:  Thank you, Dr. Pfeffer.

 

  7             We will now turn to Dr. David Shaffer of

 

  8   Columbia University who will speak on the topic of

 

  9   Suicide and Related Problems in Adolescents.

 

 10           Suicide and Related Problems in Adolescents

 

 11             DR. SHAFFER:  Good morning.

 

 12             [Slide.]

 

 13             I am going to review the epidemiology of

 

 14   youth suicide and also some of its phenomenology as

 

 15   it may be relevant to the discussion that you are

 

 16   going to be having for the rest of the day.  It is

 

 17   a topic that I have been involved in for a number

 

 18   of years, and I hope that it is helpful.

 

 19             [Slide.]

 

 20             In the United States, in 2001, the last

 

 21   year for which we have statistics of this kind,

 

 22   about 1,600 15- to 19-year-olds committed suicide.

 

 23   You will see that that is the third leading cause

 

 24   of death in the United States, and in most

 

 25   countries, it is the second leading cause of death,

 

                                                                61

 

  1   but in the United States and a few other countries,

 

  2   homicide comes between that.

 

  3             You can also see that suicide accounted

 

  4   for more deaths, over twice as many deaths as from

 

  5   cancer, in fact, more deaths than all of the other

 

  6   major physical conditions combined.

 

  7             [Slide.]

 

  8             The methods by which children commit

 

  9   suicide are, by and large, very similar to those --

 

 10   with children, young people -- are very similar to

 

 11   those which are used by adults.  The main

 

 12   difference is that hanging is somewhat more common

 

 13   in young people, and the figures that I have got

 

 14   here on the left are the 5- to 19-year-olds, on the

 

 15   right, over the rest of the population.

 

 16             You will see a few other things of

 

 17   interest.  Ingestion is primarily a cause of death

 

 18   in females, firearms  are more common in males than

 

 19   in females, and carbon monoxide poisoning is one of

 

 20   the few conditions where there have been any

 

 21   changes in causes of death, so that the proportion

 

 22   of suicides attributable to carbon monoxide

 

 23   poisoning has declined since the introduction of

 

 24   catalytic converters.  The proportion of suicides

 

 25   attributable to firearms, even though there has

 

                                                                62

 

  1   been a general decline in access and use of

 

  2   firearms, has not declined.

 

  3             You can also see from this slide that

 

  4   cutting, which there is often a lot of debate about

 

  5   cutting, whether that is or is not a form of

 

  6   suicide, in fact, accounts for a very negligible

 

  7   number of deaths.  I think most people would view

 

  8   cutting as not being part of the suicide syndrome.

 

  9             [Slide.]

 

 10             This is a chart which shows the

 

 11   distribution of suicide by different genders and

 

 12   ethnic groups across the life cycle, and the top

 

 13   line represents white males.  That is followed by

 

 14   African-American males, then white females and

 

 15   black females.  Where the vertical arrow is, is the

 

 16   rate for adolescents.

 

 17             You can see several things from this

 

 18   chart.  First of all, I should say that this chart

 

 19   is remarkably similar in one country to another, so

 

 20   there is something about this pattern of mortality

 

 21   which seems to be almost independent of cultural

 

 22   influence.

 

 23             You do get very big differences in parts

 

 24   of Asia, but apart from that, it is remarkably

 

 25   similar.  That is to say that there are very, very

 

                                                                63

 

  1   few suicides that occur before puberty, that

 

  2   adolescents occupies an intermediate position

 

  3   between childhood and adulthood, and then one gets

 

  4   this very striking increase in the rate in elderly

 

  5   males and relatively little variation by age in

 

  6   females.

 

  7             [Slide.]

 

  8             If we deconstruct this a little more and

 

  9   thus look at adolescents, what you can see is that

 

 10   here, most 10- to 15-year-old suicides actually are

 

 11   occurring amongst 14- and 15-year-olds, and that

 

 12   suicide before puberty is very, very rare.

 

 13             Sometimes you will read about big

 

 14   increases or big changes in the young child rate,

 

 15   but the rates are very low and very unstable as a

 

 16   result of that, and I don't think that one can draw

 

 17   very many conclusions about suicide before puberty.

 

 18             That may also be relevant to the matters

 

 19   that you are considering today, because both

 

 20   suicide and depression are relatively uncommon,

 

 21   very uncommon before puberty, and that may mean

 

 22   that what we should be looking at is what are the

 

 23   differences between adolescents and adults.

 

 24             [Slide.]

 

 25             The United States ranks around about in

 

                                                                64

 

  1   the bottom of the top tier of rates in the world.

 

  2   Most countries with the highest rates of suicide

 

  3   are in Northern/Eastern Europe, but the United

 

  4   States is 16th as far as males are concerned, and

 

  5   ranks 22nd as far as females.

 

  6             There are quite big differences in gender

 

  7   mainly in China, where suicide is the 7th country

 

  8   for female deaths, but much lower for male deaths,

 

  9   but, in general, the United States is not

 

 10   distinguished by having a particularly high or a

 

 11   particularly low rate.

 

 12             [Slide.]

 

 13             We know quite a lot about the frequency of

 

 14   suicidal ideation and attempts from large community

 

 15   studies, particularly the Youth Risk Behavior

 

 16   Study, which is a study that is carried out by the

 

 17   National Center for Health Statistics every two

 

 18   years, for which different states volunteer, and a

 

 19   broad population of between 15- and 20,000 high

 

 20   school students are interviewed using self-report

 

 21   measures every two years.

 

 22             [Slide.]

 

 23             What one has been able to see from that

 

 24   really was a big eye-opener.  That is to say, that

 

 25   suicidal ideation in high school students is

 

                                                                65

 

  1   extraordinarily common.  Almost 20 percent of

 

  2   American high school students will think about

 

  3   suicide during the past year.

 

  4             Suicide attempts are also very common, so

 

  5   that the overall rate is about 9 percent, and if

 

  6   you track these YRBS results, they don't show an

 

  7   awful lot of variation from one year to another.

 

  8             I have highlighted by color the difference

 

  9   between the self-reported attempts and attempts

 

 10   that received medical attention, because only about

 

 11   a quarter of attempts do receive medical attention

 

 12   or are brought to medical attention.

 

 13             I think what is important about this is

 

 14   that adolescents may not disclose even suicidal

 

 15   attempt behavior, let alone suicide ideation, and

 

 16   that is frequently not known to either their

 

 17   parents or to others, and that also has to be a

 

 18   consideration, I think, in what you are

 

 19   considering.

 

 20             Both ideation and attempts, and attempts

 

 21   which receive medical attention, are far, far more

 

 22   common than completed suicide, and if you were to

 

 23   array these out by gender, we estimate that there

 

 24   are about 4,000 suicide attempts for every female

 

 25   suicide death, but about 400 male attempts for

 

                                                                66

 

  1   every male death, so that you do get these big

 

  2   gender discrepancies with attempts being more

 

  3   common in females and deaths being more common in

 

  4   males, but you can see that the ratio of attempts

 

  5   to deaths is extreme particularly in females.

 

  6             [Slide.]

 

  7             Not only do many adolescents attempt and

 

  8   think about suicide, but they do it quite often, so

 

  9   that from the studies that we have, about half of

 

 10   suicide attempters will  make only one attempt a

 

 11   year, and nearly a half will make two or more, in

 

 12   many instances, four or more deaths per year.

 

 13             We get similar findings in clinical or

 

 14   community studies, and we do know from follow-up

 

 15   studies that having made one attempt will increase

 

 16   the probability of another 15-fold, so that can be

 

 17   quite an important consideration if you are

 

 18   planning a medication study or any other kind of

 

 19   therapeutic study, because maybe what you need to

 

 20   find out about is not so much the state of

 

 21   suicidality at the time of inception into the

 

 22   study, but the history of suicidality as well

 

 23   because that could be an important factor in either

 

 24   stratifying for suicide risk or for filtering it

 

 25   out or filtering it in.

 

                                                                67

 

  1             The episodes of ideation, again, you can

 

  2   see that most youngsters who think about suicide do

 

  3   so more than once a year, and in many instances, it

 

  4   is several times a year.

 

  5             [Slide.]

 

  6             With respect to how suicidal adolescents

 

  7   are excluded from psychopharm studies, because in

 

  8   general, the studies of depression have excluded

 

  9   suicidal instances, there have been variations in

 

 10   the techniques that have been used, there has been

 

 11   no uniform approach, and that may be a

 

 12   consideration that the committee would want to look

 

 13   at in weighing up different studies and trying to

 

 14   compare them.

 

 15             [Slide.]

 

 16             Finally, with epidemiology, I just want to

 

 17   show you how the suicide rate has changed over the

 

 18   last century. This is the 20th century youth

 

 19   suicide profile.

 

 20             What you can see is that starting I guess

 

 21   in the late '50s, the top line are males and the

 

 22   bottom are females, the male youth suicide rate

 

 23   started to increase, and it increased and increased

 

 24   3-fold, finally, reaching some sort of asymptote

 

 25   around in the late '80s, peaked a little bit more

 

                                                                68

 

  1   towards the end, and then started to decline.

 

  2             So, starting in 1994, we have had an

 

  3   extraordinary decline in the youth suicide rate,

 

  4   which is very interesting.  It has been parallel

 

  5   twice before, once coinciding with World War I and

 

  6   once with World War II.  We don't know what this

 

  7   could be due to, and that will be something that I

 

  8   am going to return to in a second or two.

 

  9             [Slide.]

 

 10             As far as the causes of suicide, far and

 

 11   away the most common finding in psychological

 

 12   autopsy studies, which interview friends and family

 

 13   after a death has taken place, are the very high

 

 14   rates of diagnosable psychiatric illness that are

 

 15   present, and in studies done in a variety of

 

 16   locations, 90 percent of completed suicides were

 

 17   diagnosable with a DSM diagnosis prior to their

 

 18   death, and the rates are  extraordinarily similar

 

 19   from location to location.

 

 20             [Slide.]

 

 21             The most common diagnoses are depression,

 

 22   antisocial behavior, substance abuse, and some form

 

 23   of anxiety, and most teen suicides occur in 16- to

 

 24   19-year-olds, and in that group, in 16- to

 

 25   19-year-old male suicides, it is important to know

 

                                                                69

 

  1   that two-thirds meet the criteria for substance or

 

  2   alcohol abuse.

 

  3             So, the occurrence of completed suicide is

 

  4   very closely linked to the occurrence of

 

  5   particularly alcohol abuse.

 

  6             [Slide.]

 

  7             As Cynthia Pfeffer outlined, and I won't

 

  8   repeat this, suicidality is extraordinarily common

 

  9   in depressed children and teens, both at the time

 

 10   of diagnosis -- and this is a meta-analysis from

 

 11   six studies -- ideation was present in about 60

 

 12   percent, a previous attempt in 30 percent, and

 

 13   during the follow-up period, attempts also occurred

 

 14   frequently, so that when you find ideation and

 

 15   attempts during the course of treatment of

 

 16   depression, as I say, this is a well-reported

 

 17   phenomenon.

 

 18             [Slide.]

 

 19             There are other factors that predispose to

 

 20   suicide.  Imitation is one that is particularly

 

 21   worrying because it means that public information

 

 22   campaigns may have a double-edged sword, because we

 

 23   do know that you do get suicide epidemics in the

 

 24   young.

 

 25             There is a contagion factor, and the

 

                                                                70

 

  1   Centers for Disease Control are very actively

 

  2   engaged in trying to find ways of reducing this,

 

  3   and there are now a host of studies in adults, but

 

  4   not yet in children or adolescents, that show that

 

  5   biological abnormalities may predispose to

 

  6   impulsive responses to stress and a family history

 

  7   of suicide.

 

  8             [Slide.]

 

  9             We can devise a schema, which you have got

 

 10   in your handout, which can show the route from any

 

 11   of these disorders to suicide ideation and from

 

 12   there to suicide, but  I don't think that there is

 

 13   time to get into that model in this presentation.

 

 14             [Slide.]

 

 15             I just want to go back to changing rates,

 

 16   because they may be very relevant to today's

 

 17   discussion.

 

 18             [Slide.]

 

 19             As I showed you, there has been this very

 

 20   striking and encouraging reduction in male suicide

 

 21   males amongst young males 15 to 24.  It is even

 

 22   more striking actually if you look at 15- to

 

 23   19-year-olds.

 

 24             What is important is that this has not

 

 25   been a United States phenomenon only.  It has been

 

                                                                71

 

  1   reported in a large number of other industrialized

 

  2   nations.

 

  3             In the list that I have given here, three

 

  4   nations, Austria, Germany, and Switzerland, have

 

  5   been experiencing a decline which well predated the

 

  6   introduction of any of the newer groups of

 

  7   antidepressants, but in all of the other countries,

 

  8   the decline started sometime after 1988.

 

  9             There is only one country which seems to

 

 10   have a stable or rising rate, which is Scotland,

 

 11   and there are a number of possible reasons that

 

 12   have been debated to explain these reductions.

 

 13             One is that during the '90s, at least in

 

 14   the United States, there was economic prosperity, a

 

 15   decline in unemployment, and other social indices

 

 16   tended to improve, but rates also started to

 

 17   decline in high youth unemployment countries in

 

 18   Europe, and the relationship between SES and

 

 19   suicide is not strong, and, in fact, it hasn't

 

 20   really been established.

 

 21             The first thought was if so many suicides

 

 22   are associated with drug and alcohol abuse, maybe

 

 23   exposure to drugs and alcohol would have been

 

 24   reduced during this time, and this is certainly my

 

 25   first guess.  However, use and abuse rates have not

 

                                                                72

 

  1   changed, if anything, they have continued to inch

 

  2   up.

 

  3             [Slide.]

 

  4             Reduced firearm availability, the Brady

 

  5   Act was introduced in 1994, and there is evidence

 

  6   from tracking studies that ownership and use of

 

  7   firearms started to decline around about 1980, but

 

  8   the proportion of suicides by firearm has gone

 

  9   unchanged, and although there have been very

 

 10   striking declines in accidents attributable to

 

 11   firearms, it is not clear that we can point to the

 

 12   reduction in suicides as being caused by that.

 

 13             Also, the declines have been noted in

 

 14   countries in which there are almost no firearm

 

 15   suicides, so this doesn't seem to be a very

 

 16   plausible explanation.

 

 17             [Slide.]

 

 18             More psychotherapeutic treatment is a

 

 19   possibility, but, in fact, the data seem to suggest

 

 20   that visits for psychotherapy have declined

 

 21   consistently over the past 10 to 12 years, more

 

 22   psychopharmacologic treatment, and you will have

 

 23   heard that there has been an enormous increase in

 

 24   exposure to antidepressants during this period in

 

 25   many countries, or it could be a nonspecific

 

                                                                73

 

  1   finding, a better recognition of adolescent suicide

 

  2   with some nonspecific interventions or some

 

  3   combination of the above.

 

  4             [Slide.]

 

  5             A word or two about treatment.  There have

 

  6   been some useful Cochrane analyses looking at

 

  7   effective treatments for suicide attempts.  These

 

  8   have mainly been done in adults, and only two

 

  9   treatments emerged as being successful.

 

 10             One is dialectical behavior therapy, which

 

 11   is a  very specific form of therapy which is hard

 

 12   to come by because very few people are trained in

 

 13   it, and one study looking at flupenthixol, which is

 

 14   an antipsychotic or neuroleptic, in multiple

 

 15   attempters.

 

 16             There have also been studies showing

 

 17   lithium or at least discontinuation of lithium

 

 18   results in an increase in the suicidality, and

 

 19   Clozaril seems to have a specific suicide sparing

 

 20   effect in schizophrenia.

 

 21             But apart from that, we don't have much to

 

 22   guide us, and there is nothing out there which

 

 23   tells the clinician what to do with this very

 

 24   common problem.

 

 25             [Slide.]

 

                                                                74

 

  1             Maybe that is why, but, in general, teens

 

  2   who do commit suicide tend to be relatively

 

  3   undertreated compared to adults, so that, for

 

  4   example, the top three lines show that between 30

 

  5   and 60 percent of adults who commit suicide will

 

  6   have had mental health treatment, but in

 

  7   adolescents, very few have had that, so it is

 

  8   getting between 7 and 21 percent, they are an

 

  9   undertreated group.

 

 10             [Slide.]

 

 11             Furthermore, one of the things that has

 

 12   been interesting to epidemiologists over this

 

 13   current debate is do you find antidepressants in

 

 14   toxicologic studies of completed suicides, and Exen

 

 15   [ph] in Sweden has done a study showing that the

 

 16   findings in autopsy studies suggest that suicides

 

 17   are significantly undertreated with SSRIs compared

 

 18   to the rest of the population.

 

 19             There has only been one study in youth,

 

 20   and that is from the Utah Youth Suicide Study by

 

 21   Dr. Gray, and he has looked at 50 psychological

 

 22   autopsies, all of whom had careful toxicology

 

 23   investigations.

 

 24             A quarter of those had been prescribed

 

 25   antidepressants, but in none of those cases were

 

                                                                75

 

  1   antidepressants found at autopsy, so we know that

 

  2   teenagers often don't take their medication, and

 

  3   certainly they didn't seem to be taking it in this

 

  4   case.

 

  5             [Slide.]

 

  6             So, I would just like to conclude with

 

  7   some cautions and considerations.  Ideation and

 

  8   attempts are very common in depressed teens, and

 

  9   they recur frequently, so finding them in

 

 10   youngsters being treated for depression is, of

 

 11   course, not surprising.   That doesn't address any

 

 12   treatment effect that might be found.

 

 13             A methodological point.  Teenagers often

 

 14   conceal ideation and attempts unless they are asked

 

 15   about them directly.  Self-report facilitates

 

 16   disclosure.  It is my understanding that we are

 

 17   heavily dependent upon event reports in these data,

 

 18   and event reports may be influenced by the mode of

 

 19   elicitation.

 

 20             They are not used with a glossary which

 

 21   precisely defines how things should be classified,

 

 22   so misclassifications can occur.

 

 23             Self-harm is a term that is used by some,

 

 24   but not others in the mental health profession.  It

 

 25   is a very heterogeneous descriptor and not all

 

                                                                76

 

  1   types of self-harm are associated with suicidal

 

  2   intent.

 

  3             There have been no direct studies with

 

  4   frequent and careful measurement examining whether

 

  5   SSRIs increase, decrease, or have no effect on

 

  6   suicidal ideation and behavior, so that we are

 

  7   dependent very much on inference, but maybe that is

 

  8   always the case.

 

  9             I just would like to conclude with the

 

 10   following. After increasing for 35 years, teen

 

 11   suicide rates have been declining consistently in

 

 12   many countries.  During this period, there has been

 

 13   a marked increase in exposure of teens to SSRI

 

 14   antidepressants.

 

 15             These trends could be related.  This is

 

 16   ecologic, and we don't know whether they are

 

 17   related, but at the moment we don't have a better

 

 18   explanation for the turnabout of a condition that

 

 19   led to the death of tens of thousands of young

 

 20   people.

 

 21             I would like to stop at that point.

 

 22             DR. RUDORFER:  Thank you very much.

 

 23             At this time, just before our break, I

 

 24   have one announcement to make.  Any open public

 

 25   hearing speakers who have not yet signed in, please

 

                                                                77

 

  1   do so immediately.  We will only be able to call

 

  2   upon speakers who have formally signed in, so we

 

  3   wouldn't want you to miss your chance.

 

  4             We have time for a 15-second break, but I

 

  5   am told that may not work, so why don't we take 5

 

  6   minutes or as close to that as we can work, and we

 

  7   will come back for our open public hearing.

 

  8   Thanks.

 

  9             [Break.]

 

 10                       Open Public Hearing

 

 11             DR. RUDORFER:  There is specific guidance

 

 12   from the FDA that I would like to read.  This

 

 13   applies to all meetings or considered general

 

 14   matters meetings, and as we heard earlier from

 

 15   Anuja, since we are not focusing on one specific

 

 16   product here, that encompasses this joint meeting.

 

 17             Both the Food and Drug Administration, or

 

 18   FDA, and the public believe in a transparent

 

 19   process for information gathering and

 

 20   decisionmaking.  To ensure such transparency at the

 

 21   open public hearing sessions of the Advisory

 

 22   Committee meeting, FDA believes that it is

 

 23   important to understand the context of an

 

 24   individual's presentation.

 

 25             For this reason -- and I am addressing the

 

                                                                78

 

  1   speakers this morning -- FDA encourages you, the

 

  2   open public hearing speaker, at the beginning of

 

  3   your oral statement to advise the committee of any

 

  4   financial relationship you may have with any

 

  5   company or any group that is likely to be impacted

 

  6   by the topic of this meeting.  For example, the

 

  7   financial information may include a company's or a

 

  8   group's payment of your travel, lodging, or other

 

  9   expenses in connection with your attendance at the

 

 10   meeting.

 

 11             Likewise, FDA encourages you at the

 

 12   beginning of your statement to advise the committee

 

 13   if you do not have any such financial

 

 14   relationships.  If you choose not to address the

 

 15   issue of financial relationships at the beginning

 

 16   of your statement, it will not preclude you from

 

 17   speaking.

 

 18             As I mentioned earlier, the clock dictates

 

 19   only a limited amount of time for each speaker.  I

 

 20   would like to run all night, but I hear an ice

 

 21   storm is coming, so in the interest of time, we

 

 22   have a light warning system, and each speaker,

 

 23   please be advised, when you see the yellow light,

 

 24   you have 30 seconds remaining, so please start to

 

 25   wrap up.

 

                                                                79

 

  1             The flashing red light means you are out

 

  2   of time and the microphone will go off.  I have

 

  3   asked them to let you finish your sentence for

 

  4   three or four words, but it is out of our hands.

 

  5             We have two speaker-ready chairs, so I am

 

  6   asked to remind you that when your two away from

 

  7   your number, please be sure you are in one of

 

  8   those.

 

  9             Speakers are assigned by number and we

 

 10   will begin with Number 1.

 

 11                Irving Kirsch and David Antonuccio

 

 12             DR. KIRSCH:  My name is Irving Kirsch.

 

 13   Baum, Hedlund has paid for my air tickets.  I

 

 14   decided to come before knowing that.

 

 15             Dr. David Antonuccio, Amanda Drews, and I

 

 16   are reviewing the published literature evaluating

 

 17   the efficacy of antidepressants in depressed

 

 18   children.  A total of 12 randomized, controlled

 

 19   clinical trials have been published.

 

 20             Two-thirds of these trials failed to find

 

 21   any significant benefit of medication over inert

 

 22   placebo.  Only 4 trials reported significant

 

 23   differences, and these did so only on

 

 24   clinician-rated measures, not on patient-rated

 

 25   measures.

 

                                                                80

 

  1             When the data from these trials are

 

  2   combined, the placebo response is found to be 87

 

  3   percent of the drug response.  This means that the

 

  4   drug effect is only 13 percent of the drug

 

  5   response.  This is not a clinically significant

 

  6   effect.

 

  7             Many children get better when given

 

  8   antidepressants, but the data indicate that this is

 

  9   largely a placebo effect.  These conclusions are

 

 10   consistent with those found in 7 previous published

 

 11   reviews.

 

 12             To summarize, the published clinical trial

 

 13   data show that the therapeutic benefits of

 

 14   antidepressants for children is negligible at best.

 

 15             David.

 

 16             DR. ANTONUCCIO:  These results were drawn

 

 17   from studies with design flaws that typically favor

 

 18   the study drug.  For example, they frequently

 

 19   exclude placebo responders before random

 

 20   assignment, rely on ratings by clinicians who have

 

 21   a vested interest in the outcome, and are likely to

 

 22   be unblinded by medication side effects.

 

 23             Furthermore, these results are drawn from

 

 24   the published literature which is subject to

 

 25   publication bias and file drawer problems meaning

 

                                                                81

 

  1   that many studies with negative results do not get

 

  2   published.  Adding unpublished studies, most of

 

  3   which have negative results, will surely shrink the

 

  4   difference between antidepressants and placebo even

 

  5   further.

 

  6             In order to evaluate the cost

 

  7   effectiveness of antidepressant use in children,

 

  8   the committee must consider the benefits, as well

 

  9   as the risks.  Clinically meaningful benefits have

 

 10   not been adequately demonstrated in depressed

 

 11   children, therefore, no extra risk is warranted.

 

 12             An increased risk of suicidal behavior is

 

 13   certainly not justified by these minimal benefits.

 

 14   Neither are the established increased risks of

 

 15   other commonly reported side effects, which include

 

 16   agitation, insomnia, and gastrointestinal problems.

 

 17             The highest possible standard should be

 

 18   applied to scientific data involving drug treatment

 

 19   of children, because children are essentially

 

 20   involuntary patients.  Those of you on the

 

 21   committee who are parents know this to be true

 

 22   because when your children have prescription

 

 23   medication for something that ails them, you make

 

 24   them take it as prescribed whether they want to or

 

 25   not.

 

                                                                82

 

  1             Children given antidepressant medication

 

  2   often do get better, but so do children given

 

  3   placebo.  Thus, the clinical data suggest the

 

  4   improvement is due primarily, if not entirely, with

 

  5   placebo effect.

 

  6             Please be careful to ensure that our

 

  7   children are not exposed to risk without

 

  8   commensurate benefit.

 

  9             DR. RUDORFER:  Thank you.

 

 10             May we have the next speaker, Number 2.

 

 11                         Lisa Van Syckel

 

 12             MS. SYCKEL:  Good morning, ladies and

 

 13   gentlemen. My name is Lisa Van Syckel, and my

 

 14   daughter, Michelle, at the age of 15, was placed on

 

 15   Paxil.  She was diagnosed with depression and

 

 16   anorexia nervosa.  It turned out that that

 

 17   diagnosis was wrong, she actually had Lyme Disease.

 

 18             My daughter self-mutilated, became

 

 19   psychotic, became violent, attempted suicide twice.

 

 20   My daughter survived those two suicide attempts,

 

 21   not because of the drug, because of the police

 

 22   officers who were summoned to my home.

 

 23             Michelle has suffered severe withdrawal.

 

 24   She is constantly ill with flu-like symptoms.  She

 

 25   has had rectal bleeding, she has vomited blood. 

 

                                                                83

 

  1   She has had her friends at school call her

 

  2   "Psycho," all because she was misdiagnosed and all

 

  3   because everyone has withheld from the public the

 

  4   adverse effects of Paxil.

 

  5             I am a parent.  It is my right to make an

 

  6   informed decision on behalf of my daughter.  You

 

  7   did not allow me to make that informed decision and

 

  8   she was harmed.  We are blessed because Michelle

 

  9   did not die, and Michelle is now attending

 

 10   university and doing beautifully.

 

 11             Please, have respect for our children,

 

 12   make sure that you put proper warnings on these

 

 13   medications.  Our children's lives are at stake

 

 14   here, because not only does it cause suicide, it

 

 15   also causes them to become violent, very, very

 

 16   violent.

 

 17             Thank you.

 

 18             DR. RUDORFER:  Thank you.

 

 19             May we have the next speaker, Number 3.

 

 20                      Ann Blake Tracy, Ph.D.

 

 21             DR. TRACY:  I would like to say, first of

 

 22   all, that this is a meeting that should not be

 

 23   taking place today.  I testified at an FDA hearing

 

 24   similar to this in 1991, and these drugs should

 

 25   have been banned at that time in my opinion.

 

                                                                84

 

  1             I am Dr. Ann Blake Tracy, a Ph.D. in

 

  2   health sciences with emphasis on psychology.  I

 

  3   have spent the last 14 years researching the SSRIs

 

  4   and working with patients who are having adverse

 

  5   reactions to these medications.  I am also the

 

  6   author of Prozac: Panacea or Pandora, Our Serotonin

 

  7   Nightmare.

 

  8             I have testified in criminal and civil

 

  9   cases for 12 years concerning these medications,

 

 10   and I am greatly concerned about the use of these

 

 11   drugs among children, with developing brains, who

 

 12   have far more reactions than the general public

 

 13   would, as I am the elderly who are having severe

 

 14   adverse reactions.

 

 15             What I presented to the FDA in 1991, I

 

 16   would like to present again.  Each of you will get

 

 17   a copy of this.  This is a 31-year-old patient on

 

 18   Prozac for six months, shows the patient, although

 

 19   appearing alert and functioning, in a total

 

 20   anesthetic sleep state while dreaming.  I believe

 

 21   technically, you could call that a REM sleep

 

 22   behavior disorder.

 

 23             The research now shows, this many years

 

 24   later, that 86 percent of the cases being diagnosed

 

 25   with this REM sleep behavior disorder are patients

 

                                                                85

 

  1   on antidepressants, 80 percent of those on SSRI

 

  2   antidepressants.

 

  3             There are some very famous cases that I

 

  4   believe manifest that very clearly, and in

 

  5   representing those families today, I would give you

 

  6   Andrea Yates, who drowned her five children while

 

  7   taking Effexor and Remeron.

 

  8             DR. RUDORFER:  Thank you.  I am afraid we

 

  9   are out of time now.

 

 10             DR. RUDORFER:  Thank you.

 

 11             Number 4, please.

 

 12                           Tom Woodward

 

 13             MR. WOODWARD:  My name is Tom Woodward.

 

 14   My wife Kathy and I have been married for 19 years

 

 15   and until 6 months ago had 4 children.  Our oldest

 

 16   child, Julie, hung herself after 7 days on Zoloft,

 

 17   and she was only 17, was a cautious child, and had

 

 18   no history of self-harm or suicide, nor was there

 

 19   any history of depression or suicide in our family.

 

 20             The doctors we spoke with stressed that

 

 21   Zoloft was safe and had very few side effects.  The

 

 22   possibility of violence, self-harm, or suicidal

 

 23   acts was never raised.  The two and a half pages we

 

 24   received with the Zoloft never mentioned self-harm

 

 25   or suicide.

 

                                                                86

 

  1             Julie began experiencing akathisia almost

 

  2   immediately.  We now know from a blood test from

 

  3   the coroner's office that she was not metabolizing

 

  4   the drug.

 

  5             We are 100 percent convinced that Zoloft

 

  6   killed our daughter.  We are here because we

 

  7   believe the system we have in place is flawed.  It

 

  8   is clear that the FDA is a political entity and its

 

  9   leadership has protected the economic interests of

 

 10   the drug industry.  Under the Bush administration,

 

 11   the FDA has placed the interests of the drug

 

 12   industry over protecting the American public.

 

 13             Dr. McClellan understands how important

 

 14   political contributions are particularly since his

 

 15   mother has headed up the Republican fund-raising in

 

 16   Texas.  Eighty-six percent of the $14 million in

 

 17   political contributions given by drug companies has

 

 18   gone to the Bush administration Republican

 

 19   candidates - what did Pfizer, Eli Lilly, and

 

 20   GlaxoSmithKline Beecham buy?

 

 21             The FDA should be a jealous advocate in

 

 22   protecting the American people.  Those in

 

 23   leadership positions within the FDA must be beyond

 

 24   reproach.  FDA's chief counsel Daniel Troy has

 

 25   spent his career defending the drug industry. 

 

                                                                87

 

  1   Suppressing unfavorable data may be legal, but is

 

  2   it ethical?

 

  3             If the trials don't favor a drug, the

 

  4   public never hears of them.  Legal maneuverings

 

  5   have thrown out the scientific method.  The drug

 

  6   industry must be compelled to produce all of their

 

  7   findings and studies.  I also believe public

 

  8   funding of these trials is warranted.

 

  9             Our daughter, Julie, had been excited

 

 10   about college and scored 1,300 in her SATs several

 

 11   weeks before her death. Instead of picking out

 

 12   colleges with our daughter, my wife and I had to

 

 13   pick out a cemetery plot for her.

 

 14             Instead of looking forward to visiting

 

 15   Julie at school, we now visit her grave.  The loss

 

 16   we have experienced is horrific.  We don't want

 

 17   another innocent child or family to suffer this

 

 18   tragedy.

 

 19             DR. RUDORFER:  Thank you, Mr. Woodward.

 

 20             May we have the next speaker, please.

 

 21                           Mark  Miller

 

 22             MR. MILLER:  My wife Cheryl and I

 

 23   desperately hope that our story, along with others

 

 24   that you will hear today, and I so proud of the

 

 25   teens and the young adults who you will hear from

 

                                                                88

 

  1   today, that they have the courage to come forward

 

  2   and talk with you personally.  I wish our son

 

  3   could, he cannot.

 

  4             There is a serious problem with the way

 

  5   SSRI medications are being prescribed today and

 

  6   how, in many cases, they can directly cause

 

  7   violence and suicidal behavior in those we love and

 

  8   treasure the most, our children.

 

  9             You see, we lost our 13-year-old son,

 

 10   Matt, in the summer of 1997.  He died after a

 

 11   psychiatrist we did not know gave him three sample

 

 12   bottles of a pill we had never heard of, for a

 

 13   perceived illness that his doctor could only guess

 

 14   at.

 

 15             We were advised with great authority that

 

 16   Matt was suffering from a chemical imbalance that

 

 17   could be helped by a new, wonderful medication

 

 18   called Zoloft.  It was safe, effective, only two

 

 19   minor side effects were cautioned with us -

 

 20   insomnia, indigestion.

 

 21             Now, I don't know if Matt had a chemical

 

 22   imbalance.  I do know this.  We had moved into to a

 

 23   new neighborhood a year before, a new school

 

 24   setting, he was uneasy.  He didn't have the friends

 

 25   he had grown up with in our old neighborhood.  Yes,

 

                                                                89

 

  1   our son was unhappy.

 

  2             So, Matt's doctor, a man we know through

 

  3   court testimony to have been a well-paid spokesman

 

  4   for Pfizer, gave us Zoloft.  He said, "Take these

 

  5   for a week, call me back when you know how Matt is

 

  6   doing."

 

  7             Matt didn't have a week.  He became

 

  8   agitated on the pills.  He did not sleep.  He did

 

  9   not eat.  He could not sit still.  That night, a

 

 10   Sunday, before leaving on vacation, after taking

 

 11   his 7th Zoloft tablet, he took his own life.

 

 12             This is important for you to know.  Matt

 

 13   hung himself from a bedroom closet hook, barely

 

 14   higher than he was tall.  To commit this

 

 15   unthinkable act, something he had never attempted

 

 16   before, never threatened to any family member,

 

 17   never talked about, he was actually able to pull

 

 18   his legs up off the floor and hold himself that way

 

 19   until he lost consciousness and forced himself to

 

 20   leave us.

 

 21             Matt's autopsy showed the levels of

 

 22   sertraline in his blood were three times the

 

 23   therapeutic minimum levels.

 

 24             You have an obligation today, this panel,

 

 25   to prevent this tragic story from being repeated

 

                                                                90

 

  1   over and over and over again.  I hope you will do

 

  2   the right thing.

 

  3             DR. RUDORFER:  Thank you, Mr. Miller.

 

  4             If we could have the next speaker, please.

 

  5                     Corey and Jay Baadsgaard

 

  6             MR. COREY BAADSGAARD:  Good morning.  My

 

  7   name is Corey Baadsgaard.  Four years ago I was

 

  8   diagnosed with having social anxiety disorder, and

 

  9   my family practitioner doctor, he prescribed Paxil

 

 10   20 milligrams.

 

 11             After about 8 1/2 months, I started taking

 

 12   40 milligrams of Paxil because it was not working

 

 13   at 20 milligrams.  A few months after that, I went

 

 14   back.  The same problem, it wasn't working, and he

 

 15   suggested I start taking a new medication called

 

 16   Effexor.

 

 17             He abruptly discontinued the Paxil and put

 

 18   me immediately on Effexor at 75 milligrams, and I

 

 19   was supposed to work up to 300 milligrams over a

 

 20   3-week period.  The day that I took the 300

 

 21   milligrams, I didn't feel very well and I stayed

 

 22   home from school.

 

 23             I went back to sleep and that evening I

 

 24   woke up in a juvenile detention center.  Unaware of

 

 25   what I had actually done, I asked one of the

 

                                                                91

 

  1   members of the juvenile detention center, and I

 

  2   found out that I had taken my high-powered rifle

 

  3   that I use for hunting to my third period class,

 

  4   took 23 of my classmates hostage and 1 teacher

 

  5   hostage.

 

  6             I spent 14 months in jail, not really

 

  7   knowing why I had been there, not really

 

  8   remembering anything that I had done.

 

  9             This whole thing has changed my whole

 

 10   family, it changed me, myself.  We were forced to

 

 11   move.  I cannot even go back to the same town that

 

 12   I lived in, I have to stay at least 25 miles away

 

 13   from city limits.

 

 14             These drugs are ridiculous.  They should

 

 15   not be prescribed unless it's absolutely last

 

 16   resort.

 

 17             MR. JAY BAADSGAARD:  These drugs are hell.

 

 18   Look at what they have done to my son.

 

 19             DR. RUDORFER:  Thank you.

 

 20             May we have the next speaker, please.

 

 21                           Joyce Storey

 

 22             MS. STOREY:  My son, Brian Storey, was 17

 

 23   years old in 1997.  Our family doctor diagnosed him

 

 24   with severe  depression.  He took blood, checked

 

 25   for drugs or any medical condition.  He found

 

                                                                92

 

  1   neither.  He gave me 14 Zoloft pills and said come

 

  2   back in two weeks.  He never told me they had side

 

  3   effects and he even said if a person is drinking or

 

  4   doing drugs, that Zoloft works well with them.

 

  5             Five days later, my son killed a woman.

 

  6   When they arrested him, he was drug-tested.  They

 

  7   found no illegal drugs, he was only on Zoloft.

 

  8   During his trial, the kids that testified with him

 

  9   and against him said he did no drugs or alcohol.

 

 10             The psychiatrist that examined him was Dr.

 

 11   James Merkangis from Connecticut.  He is also a

 

 12   Doctor of Neurology and is on the faculty at Yale

 

 13   University.  He said Brian had a manic reaction to

 

 14   Zoloft.  He testified Brian told him it was like

 

 15   being in a dream.

 

 16             The news media called my son the

 

 17   All-American boy, and he was.  He is now serving

 

 18   life without parole.  Six months later, another boy

 

 19   at my son's high school, Jeff Franklin, 17 years

 

 20   old, on Prozac, took an ax to both his parents and

 

 21   three of his brothers and sisters.  Both of his

 

 22   parents died.  He is serving two life sentences.

 

 23             This is not a coincidence.  There is a

 

 24   common denominator, teenager, severely depressed,

 

 25   on an SSRI antidepressant.  What is scary is that

 

                                                                93

 

  1   you are only hearing from a few of us that this has

 

  2   happened to, and there are a lot more out there.

 

  3             I am praying you will look at these drugs

 

  4   very closely and, at the very least, take them out

 

  5   of the hands of pediatricians and GPs.  These

 

  6   doctors are not psychiatrists, and they do not have

 

  7   the knowledge and experience in treating mentally

 

  8   ill children.

 

  9             My son never had a chance.  There are 13

 

 10   million people on these drugs, 6 to 8 million are

 

 11   children.  The question is why are we handing these

 

 12   drugs out like candy, and the answer is $17 billion

 

 13   a year business.  It is always about money.  Please

 

 14   help before more families are destroyed.

 

 15             Thank you.

 

 16             DR. RUDORFER:  Thank you.

 

 17             Next speaker, please.

 

 18                           Jame Tierney

 

 19             MS. JAME TIERNEY:  Good morning.  My name

 

 20   is Jame Tierney.  I was 14 years old when I was

 

 21   prescribed 75 milligrams of Effexor for migraine

 

 22   headaches.  I took this for about a year.  At the

 

 23   time, the drug lost its effectiveness and my doctor

 

 24   doubled the dose.

 

 25             For the next 9 months, my life as I had

 

                                                                94

 

  1   known it was gone.  I thought daily about suicide

 

  2   and hurting myself. I felt void of normal emotions.

 

  3   I was so belligerent, agitated, and filled with

 

  4   hate - hate for my family, my friends, and most of

 

  5   all myself.  Rage consumed me.  I felt trapped.

 

  6             I said and did things I had never done

 

  7   before and never would do now.  I had little

 

  8   control and little inhibition.  It was as if I was

 

  9   watching a movie and some villain was destroying

 

 10   all the relationships around me.  I spent my time

 

 11   alone and viciously fighting with my parents. They

 

 12   would ask what was wrong and what had happened to

 

 13   me.  I could not answer them because I did not know

 

 14   or understand myself.  I was terrified.

 

 15             I thank God my parents knew that wasn't

 

 16   really me and continued to search for answers.

 

 17   They found the answer to my uncharacteristic

 

 18   behavior.  It was the Effexor that my neurologist

 

 19   had prescribed for my migraine headaches.  I was

 

 20   not, repeat not, prescribed this drug for

 

 21   depression.  I have had no history of depression

 

 22   prior to or after I was off the Effexor.  For me,

 

 23   this drug caused the very symptoms it's supposed to

 

 24   alleviate.

 

 25             Due to the severe withdrawal symptoms,

 

                                                                95

 

  1   Prozac was used to get me off Effexor.  It worked,

 

  2   but the same personality and behavior problems

 

  3   reemerged.  Effexor and Prozac affected me the same

 

  4   way.  I had never had these feelings before I took

 

  5   Effexor, I have never had these feelings since I

 

  6   stopped taking the Effexor and Prozac.

 

  7             Effexor took three years from me and I

 

  8   will never get them back.  The horror of what these

 

  9   drugs did to me is ineffable.  These drugs are

 

 10   destroying lives everywhere.

 

 11             I implore you to please protect the

 

 12   children from these drugs.

 

 13             DR. RUDORFER:  Thank you very much.

 

 14             If we can have speaker Number 9, please.

 

 15                   Donna Taylor and Mark Taylor

 

 16             MS. TAYLOR:  Hi.  My name is Donna Taylor.

 

 17   My son was shot at Columbine.  He took 7 to 13

 

 18   bullets though his chest and nearly died.  I also

 

 19   have other members of the family that have died

 

 20   since then on these drugs, but we can't get into

 

 21   that right now, and many, many people that we know,

 

 22   that families have been divided and separated, and

 

 23   there is just all kinds of divorces and all that

 

 24   going on from these drugs.

 

 25             I will let Mark speak.

 

                                                                96

 

  1             MR. TAYLOR:  First of all, I would thank

 

  2   you for allowing me to come and speak on behalf of

 

  3   the thousands of innocent Americans that have died

 

  4   as a result of these drugs.

 

  5             I would like to start with an opening,

 

  6   very famous statement, and it says, "The measure of

 

  7   a man is not his strength or how much money he has,

 

  8   or how good he looks or how strong he is, or how

 

  9   powerful he is.  The measure of the man is how

 

 10   noble he is."

 

 11             I want to ask you guys, are you really

 

 12   being noble with your choices, or are you just

 

 13   allowing the drug companies to squeeze by you just

 

 14   because they have a big pocketbook.  This is

 

 15   ridiculous.

 

 16             Do you people have children, do you, do

 

 17   any of you?  Have any of you had anyone that has

 

 18   died on these drugs?  If you have, I am amazed that

 

 19   you guys are even standing here supporting these

 

 20   drug companies.

 

 21             I mean this has never happened in the

 

 22   history of America.  This is a shame and it ought

 

 23   to be stopped today, not next week.

 

 24             MS. TAYLOR:  And God says the same thing.

 

 25   It's in the Bible, Revelations 18, 19 through 24

 

                                                                97

 

  1   makes it clear, sorcery means anarchy in the last

 

  2   days and blood will be running all over the

 

  3   streets.

 

  4             MR. TAYLOR:  Say yes to America's health

 

  5   and no to the drug companies.

 

  6             DR. RUDORFER:  Thank you both.

 

  7             We are going to move on to speaker Number

 

  8   11, Shannon Baker.

 

  9                          Shannon Baker

 

 10             MS. BAKER:  My name is Shannon Baker and I

 

 11   have no financial ties to the pharmaceutical

 

 12   industries, nor am I here to complain about my

 

 13   daughter's side effects, adverse reactions, or

 

 14   withdrawal symptoms.  I am here because she is no

 

 15   longer alive.

 

 16             I know you have all got pictures.  I am

 

 17   here because today, I am representing the love that

 

 18   my daughter had for life and to be her voice and

 

 19   the voice of all the other children who their

 

 20   voices have been silenced by these drugs.

 

 21             Their deaths have been so senseless and

 

 22   needless.  I am here speaking in front of you,

 

 23   hoping that you will go the right direction and ban

 

 24   these drugs for children.  There needs to be no

 

 25   more senseless and needless deaths because of these

 

                                                                98

 

  1   drugs.

 

  2             Thank you.

 

  3             DR. RUDORFER:  Thank you.

 

  4             Our next speaker, Number 12, please.

 

  5                            Dawn Rider

 

  6             MS. RIDER:  My name is Dawn Rider and I am

 

  7   here to tell you my story, and I represent, as

 

  8   president of ASPIRE, more than 11,000 persons who

 

  9   are all named on the Eli Lilly and Prozac petition,

 

 10   which a copy has been given to the panel.

 

 11             We have been educated to believe that

 

 12   mental, emotional, and behavioral disorders are

 

 13   caused by chemical imbalances in the brain.  The

 

 14   fact is that this is only theory, and this theory

 

 15   is pushed on us as if it were the absolute truth.

 

 16             The reality is that the best of scientists

 

 17   do not completely understand the complex inner

 

 18   actions of the myriad chemicals in our brains.

 

 19   Those of us who elect to believe this theory and

 

 20   subject ourselves to treatment become guinea pigs

 

 21   in an ongoing experiment.

 

 22             I know this from personal experience.  I

 

 23   trusted our family doctor when he explained that

 

 24   depression is caused by a chemical imbalance.  We

 

 25   trusted him when he determined that Paxil was right

 

                                                                99

 

  1   for my husband, and Prozac for my son.

 

  2             We weren't educated enough at that time to

 

  3   ask him to provide us with the test results that

 

  4   proved which chemicals were being balanced.

 

  5             I am not going to go into details of what

 

  6   happened to our family.  I have given you all

 

  7   documentation, it's very painful.  Suffice it to

 

  8   say that my beautiful 14-year-old son is now dead,

 

  9   and when we discovered the problems with these

 

 10   drugs, we decided it would be better for my husband

 

 11   to suffer through depression than end up dead like

 

 12   our son, and we found out that he could not get off

 

 13   of Paxil.

 

 14             He went through over a year of hell before

 

 15   he was able to finally withdraw from the drug, and

 

 16   in the process it destroyed our marriage of over 20

 

 17   years.

 

 18             I say with no apology whatsoever that

 

 19   these SSRI drugs destroyed what was once a loving

 

 20   and vibrant family. Why do we believe that street

 

 21   drugs like heroin and LSD can lead to outcomes such

 

 22   as this, yet, we won't accept that legally

 

 23   prescribed drugs, working on the same

 

 24   neurochemicals, can result in horrific crimes

 

 25   against persons and property?

 

                                                               100

 

  1             Why do we accept that a drug like

 

  2   penicillin, beneficial as it is for some, can prove

 

  3   fatal for others?  We fail to accept that these

 

  4   drugs can have paradoxical effects.  These drugs

 

  5   are not safe for everyone.

 

  6             They should be labeled with the strongest

 

  7   of precautions and dispensed only by trained

 

  8   physicians who have time to adequately monitor the

 

  9   patient.  Most doctors do not have time for this

 

 10   level of care.

 

 11             Also, patients should be required to sign

 

 12   letters of informed consent.  Please carefully

 

 13   consider the documentation that I have left with

 

 14   you and look at the faces of those that are here

 

 15   today and the faces that out in the hall, those

 

 16   children who cannot speak for themselves because

 

 17   they are dead.  They are not merely anecdotal

 

 18   evidences.

 

 19             There is a preponderance of evidence that

 

 20   will be presented before you today.  Please

 

 21   consider it carefully and do the right thing.

 

 22             Thank you.

 

 23             DR. RUDORFER:  Thank you.

 

 24             We are up to Number 13.

 

 25                           Sara Bostock

 

                                                               101

 

  1             MS. BOSTOCK:  I have slides, so please

 

  2   look at the screen.

 

  3             My daughter Cecily had only been taking

 

  4   Paxil for two weeks before she died, during which

 

  5   time her condition greatly worsened.

 

  6             By the day of her death, was pale, unable

 

  7   to sleep, almost unable to converse, and in a

 

  8   frightened, agitated state, jumping at the

 

  9   slightest noise.  That night she got up and without

 

 10   turning on any lights, went into our kitchen only

 

 11   40 feet from where I was half asleep.  She stabbed

 

 12   herself twice in the chest with a large chef's

 

 13   knife.  The only noise was a slight yelp and a

 

 14   thump when she fell on the floor.

 

 15             This was a young woman who had everything

 

 16   to live for.  She had just completed applications

 

 17   to grad school and received a large pay increase

 

 18   the month before.

 

 19             She had a boyfriend who loved her and

 

 20   scores of wonderful friends.  She had never been

 

 21   suicidal.  To die in this violent, unusual fashion

 

 22   without making a sound after  the marked worsening

 

 23   of her condition led me to believe that Paxil must

 

 24   have put her over the edge.

 

 25             Her autopsy revealed she had a very high

 

                                                               102

 

  1   blood level of Paxil, which reflects poor

 

  2   metabolization and is a feature common to many of

 

  3   these suicides.  I believe this induced an

 

  4   intensely dissociative state, perhaps even

 

  5   sleepwalking.  SSRIs suppress rapid eye movement

 

  6   and block the muscle paralysis which occurs in this

 

  7   stage of sleep.

 

  8             The whole regulation of waking, sleeping,

 

  9   dreaming occurs in the brain stem where the

 

 10   serotonin neurons are clustered and where SSRIs are

 

 11   having their impact.  Patients taking SSRIs had

 

 12   rapid eye movement during non-REM sleep and while

 

 13   awake when they were not paralyzed.  This atypical

 

 14   REM is often associated with strange behaviors

 

 15   including hallucinations.

 

 16             The effects of SSRIs on sleeping, waking,

 

 17   unconsciousness itself are ill understood.  From

 

 18   accounts of people under the influence of these

 

 19   drugs, I believe SSRIs can alter consciousness in

 

 20   some mysterious and frightening way that is not

 

 21   normally seen even in mental illness.  I am certain

 

 22   this is what happened to my daughter.

 

 23             Untold thousands have died because of the

 

 24   drug companies and the FDA's failure to heed the

 

 25   evidence over the past 17 years.

 

                                                               103

 

  1             DR. RUDORFER:  Thank you.

 

  2             Again, I apologize for the short time.

 

  3             Number 14, please.

 

  4                       Vera Hassner Sharav

 

  5             MS. SHARAV:  I am Vera Sharav and I am

 

  6   president of the Alliance for Human Research

 

  7   Protection.

 

  8             The family testimonies that you are

 

  9   hearing today are not anecdotes.  They are

 

 10   corroborated by a Harvard review of children's

 

 11   medical charts, which found that within three

 

 12   months of treatment on an SSRI, 22 percent suffered

 

 13   drug-induced adverse psychiatric effects, and

 

 14   overall, 74 percent of children suffered adverse

 

 15   events during the course of treatment.

 

 16             The FDA has known for years, but failed to

 

 17   reveal that antidepressants consistently fail to

 

 18   demonstrate a benefit in children.  At least 12 of

 

 19   15 trials failed.  The FDA has known and failed to

 

 20   warn physicians and the public that SSRIs increase

 

 21   the risk of suicide and hostility in children.

 

 22             FDA's 1996 Zoloft review found "7-fold

 

 23   greater incidence of suicidality in children

 

 24   treated with Zoloft than adults."  The British Drug

 

 25   Regulatory Authority reviewed the evidence, which

 

                                                               104

 

  1   is not being shown in this meeting, and they

 

  2   determined that the risks far outweigh any

 

  3   benefits.  They took action to protect children.

 

  4   When is the FDA going to take action?

 

  5             The FDA is foot dragging, equivocating,

 

  6   and tinkering with definitions while children are

 

  7   dying.  The San Francisco Chronicle reports that

 

  8   the FDA has barred its own medical reviewer who

 

  9   reviewed more than 20 trials involving 4,000

 

 10   children, and his findings confirmed the British

 

 11   finding, which is that SSRIs increase the risk of

 

 12   suicide.

 

 13             DR. RUDORFER:  Thank you.

 

 14             If we could have speaker 16, please.

 

 15                         Cynthia Brockman

 

 16             MS. BROCKMAN:  Thank you for allowing me

 

 17   to address you about the 1999 Zoloft-induced drug

 

 18   reactions that my son Chris had at 16, resulting in

 

 19   a woman's death and a life sentence for him.

 

 20             My son and I want to express sincere

 

 21   sorrow for that death.  Our sympathies also extend

 

 22   to all victims of SSRI's deadly mind-altering

 

 23   effects.

 

 24             The medical community has tolerated mental

 

 25   health care in which patients are worse off after

 

                                                               105

 

  1   treatment than before with the worst cases ending

 

  2   in death.

 

  3             I urge you to ban SSRI use in children,

 

  4   and not to let another life be destroyed by lack of

 

  5   adequate SSRI regulation.

 

  6             Chris took Zoloft or Adderall,

 

  7   deteriorated from drug-induced akathisia, could not

 

  8   bear adverse symptoms of inner turmoil, loss of

 

  9   conscious behavior.  He described overpowering drug

 

 10   effects, his uncontrollable fits of anger, pitches

 

 11   and voices setting him off, not wanting to be

 

 12   touched, feeling horrible all over his body, not

 

 13   being in reality.

 

 14             After his offense, his drug reactions

 

 15   stopped, went off all SSRIs for about a year, but

 

 16   restarted when depressed and put on Zoloft again.

 

 17   Prison doctors ignored warnings, forced him to take

 

 18   harmful drugs drugging him into hallucinating,

 

 19   irrational, suicidal state.

 

 20             May 2002, I met with the Texas House

 

 21   Committee on Corrections who ordered prison doctors

 

 22   to correct this health crisis caused by these

 

 23   drugs.  Various drugs had triggered severe

 

 24   suicidal, homicidal symptoms for about two years in

 

 25   a clinical setting of doctors starting and stopping

 

                                                               106

 

  1   his meds.

 

  2             When doctors stopped all drugs, all

 

  3   symptoms disappeared.  Doctors released Chris as

 

  4   recovered from the prison psych hospital to a

 

  5   regular unit May 2003.  Chris has not had any psych

 

  6   drugs since.

 

  7             These clinical events show dangerous

 

  8   reactions caused by SSRI-induced psychosis through

 

  9   challenge, de-challenge, re-challenge.  Medical

 

 10   experts said Chris would not have been suicidal,

 

 11   homicidal had he not been reacting to SSRI drugs.

 

 12             Dr. O'Donnell concluded Chris' offense was

 

 13   from combined toxic drug effects which altered

 

 14   behavior, enhanced violent thoughts and actions,

 

 15   impaired judgment, was unable to form intent.

 

 16             Citizens Commission on Human Rights

 

 17   confirmed SSRIs caused his symptoms.  Now Chris

 

 18   take omega-3 fatty acids and fish oil to restore

 

 19   his mental health that was damaged from SSRIs.  He

 

 20   is doing well without medications, and I thank

 

 21   Jesus Christ for that.

 

 22             Please ban these drugs and their use in

 

 23   children.

 

 24             Thank you.

 

 25             DR. RUDORFER:  Thank you.

 

                                                               107

 

  1             We will move on now to Number 18, please.

 

  2                           Todd Shivak

 

  3             MR. SHIVAK:  Good morning.  We are Todd

 

  4   and Eileen Shivak.  We do not have any financial

 

  5   relationship to anyone here.

 

  6             Our story is much like the cases everyone

 

  7   else here today is bringing forward to you.

 

  8             Our son Michael was 11 when he was

 

  9   prescribed Paxil for what was diagnosed as

 

 10   depression.  The consequences of this still live

 

 11   with us today.  Thank God he is alive and with us

 

 12   today, but Michael is afraid of his doctors, how

 

 13   can he trust what they will give him next.

 

 14             He is afraid of the police.  He has been

 

 15   wrestled down, handcuffed and taken to jail.  The

 

 16   police are supposed to protect us and look what

 

 17   they have done to him.

 

 18             It is difficult for him to trust his

 

 19   teachers. They still look at Michael as a

 

 20   troublemaker even though he currently is an A/B

 

 21   student with much improving grades.  His peers

 

 22   still think of him as a freak, the kid who tried to

 

 23   slash his wrists while in class.

 

 24             As parents, our most important job is to

 

 25   protect our kids.  We thought we were doing the

 

                                                               108

 

  1   right thing.  The doctors convinced us that taking

 

  2   these drugs was the only thing that we could do for

 

  3   Michael.  Now, Michael wonders whether we are going

 

  4   to have him arrested, sentenced, physically

 

  5   restrained and punished again.  If he can't trust

 

  6   his parents, who can he trust?

 

  7             Our daughter, Catherine, was 5 years old

 

  8   at the time.  She witnessed firsthand some of the

 

  9   most terrifying sights that I have ever had to deal

 

 10   with.  Our family is finally getting back to the

 

 11   loving family we once were, but the fear of what

 

 12   happened still haunts us.

 

 13             Worse yet, how could all the doctors not

 

 14   recognize what was happening?  Michael saw three

 

 15   different social workers, two different

 

 16   psychiatrists, and went through at least four

 

 17   different emergency room psychological evaluations

 

 18   in two different hospitals.

 

 19             We are here to plead that you do something

 

 20   to stop the prescriptions of these drugs, so that

 

 21   no one else has to go what we are all going

 

 22   through.  It is impossible to describe the pain and

 

 23   utter helplessness we all felt watching Michael

 

 24   suffer, watch him cry, take up weapons against us,

 

 25   and beg us to let him die.  How do you erase the

 

                                                               109

 

  1   picture of your child trying to run in front of a

 

  2   moving car?

 

  3             Please save our children from this drug.

 

  4             DR. RUDORFER:  Thank you.

 

  5             If we can have speaker 19, please.

 

  6                           Andy Vickery

 

  7             MR. VICKERY:  Good morning.  My name is

 

  8   Andy Vickery and I am a trial lawyer from Houston,

 

  9   Texas.  For the last eight years, I have

 

 10   represented parents who lost their children to

 

 11   suicide induced by these drugs.  You have heard

 

 12   from two of my clients this morning already and

 

 13   will hear from another.

 

 14             I only have two minutes and I can tell you

 

 15   a lot more than two minutes.  The title of the

 

 16   paper that I filed with you is "Needle in the

 

 17   Haystack."  I applaud your desire to look at the

 

 18   randomized clinical trials comprehensively to see

 

 19   if they confirm the signal that Dr. Katz

 

 20   acknowledged exists.

 

 21             I applaud that, however, I am concerned as

 

 22   Lilly was told in 1990 that you are looking for a

 

 23   needle in a haystack, you are off on a wild goose

 

 24   chase.  These trials were not designed to detect

 

 25   suicidality, they did not use the Beck Suicide

 

                                                               110

 

  1   Ideation Scale which would make the kind of refined

 

  2   measurements that the epidemiologist gentleman who

 

  3   spoke earlier said are needed.  They did not use

 

  4   the Barnes Scale, as Dr. Mann himself had

 

  5   recommended in a '91 article to measure treatment

 

  6   emergent akathisia.

 

  7             They weren't designed to answer the

 

  8   problem, and in 1990 or '91, when Lilly met -- and

 

  9   you have the handwritten notes of this in the

 

 10   materials I gave you -- when they met with outside

 

 11   consultants including Dr. Jerold Rosenbaum, he

 

 12   said, "There is a data problem, you are looking for

 

 13   a needle in a haystack."

 

 14             Find these vulnerable people and

 

 15   rechallenge them. Please look at the way Lilly

 

 16   sought to study this issue in 1990.  They followed

 

 17   a protocol by Charles Beasley that said don't use

 

 18   RCTs, don't use epi studies, find these people and

 

 19   rechallenge them.  That was done by Anthony

 

 20   Rothschild who said these patients need to be

 

 21   reassured it's not them.

 

 22             In the meantime, because the signal is

 

 23   there, please issue warnings; while you look at the

 

 24   data, issue warnings.

 

 25             DR. RUDORFER:  Thank you.

 

                                                               111

 

  1             We are up to speaker 20.

 

  2                      Rosie Carr Meysenburg

 

  3             MS. MEYSENBURG:  My name is Rosie Carr

 

  4   Meysenburg. I am from Dallas, Texas.  I have no

 

  5   financial ties with anybody but my husband of 40

 

  6   years.

 

  7             In my handout, I have highlighted what I

 

  8   am speaking about here.

 

  9             The first paper is a personal letter from

 

 10   Dr. Peter S. Jensen.  At that time, he was the head

 

 11   of Child & Adolescent Disorders Research Branch of

 

 12   the NIMH, the National Institute of Mental Health.

 

 13   He said that research indicates that

 

 14   antidepressants for depressed adolescents are not

 

 15   very effective.

 

 16             The second paper is a personal letter from

 

 17   Dr. Larry S. Goldman, Director of the AMA, the

 

 18   American Medical Association.  He writes physicians

 

 19   have known for many years the dangers of giving any

 

 20   antidepressant to patients with certain disorders.

 

 21   There is a substantial risk of precipitating mania

 

 22   or psychosis.

 

 23             The last item is a journal article from

 

 24   the Journal of Clinical Psychiatry researched at

 

 25   Yale University.  It states that 11 percent of all

 

                                                               112

 

  1   psychiatric hospital admissions were from

 

  2   antidepressant-induced mania and psychosis.

 

  3             It also states another area of research

 

  4   that would be relevant to this issue is the work of

 

  5   Winter and colleagues showing that Prozac and other

 

  6   SSRIs can simulate the effects of LSD.  In other

 

  7   words, this is saying for some people, taking an

 

  8   SSRI is the same as taking LSD.

 

  9             About two million people enter a

 

 10   psychiatric hospital every year, 11 percent then is

 

 11   over 200,000 people a year who have an

 

 12   antidepressant-induced psychosis and who are

 

 13   hospitalized.  Not all are hospitalized.  Some of

 

 14   them have either committed suicide, a homicide, or

 

 15   a murder/suicide.

 

 16             DR. RUDORFER:  Thank you.

 

 17             Number 21, please.

 

 18                           Rachel Adler

 

 19             MS. ADLER:  Mr. Chairman, I respectfully

 

 20   request that my entire remarks be entered in the

 

 21   record.  My name is Rachel Adler.  I am on the

 

 22   board of directors of the Child and Adolescent

 

 23   Bipolar Foundation, CABF, a parent-led,

 

 24   not-for-profit organization, that is the leading

 

 25   source of public information for pediatric bipolar

 

                                                               113

 

  1   disorder.

 

  2             Board members Sheila McDonald and John

 

  3   Adler are here with me, as well.

 

  4             Bipolar disorder may emerge with an

 

  5   episode of major depression, an illness which often

 

  6   causes suicidality even in preschoolers.  Children

 

  7   with depression are at a high risk to switch to

 

  8   bipolar disorder.

 

  9             We surveyed 17,000 members last month and

 

 10   received a 15 percent response rate over a 5-day

 

 11   period.  Eighty-nine percent of the respondents

 

 12   report that their child had been treated with an

 

 13   antidepressant.

 

 14             We have received favorable comments, but

 

 15   some responses indicate that in some subgroups of

 

 16   children, suicidal ideation and behavior may emerge

 

 17   for the first time or worsen when a child is given

 

 18   an antidepressant.  Some of these children perhaps

 

 19   have a vulnerability to a bipolar disorder.

 

 20             For these reason, CABF urges the FDA to

 

 21   require manufacturers to add a black box warning on

 

 22   the labeling for antidepressants to alert

 

 23   clinicians and parents to the possibility that

 

 24   antidepressants can trigger and worsen suicidality,

 

 25   as well as mania or rapid cycling bipolar disorder

 

                                                               114

 

  1   in some children.

 

  2             CABF opposes any ban on the off-label use

 

  3   of these or other psychiatric medications in

 

  4   children because many of our members report them to

 

  5   be necessary and even lifesaving for their children

 

  6   with mood disorders especially when used in

 

  7   combination with a mood stabilizer.

 

  8             CABF also urges the pharmaceutical

 

  9   industry and the Federal Government to fund

 

 10   research to analyze what factors are shared by

 

 11   those children who, according to parent reports,

 

 12   became suicidal shortly after taking an

 

 13   antidepressant.

 

 14             Finally, CABF calls upon the

 

 15   pharmaceutical industry and the National Institutes

 

 16   of Health to make public all safety and efficacy

 

 17   data from unpublished studies in children.

 

 18             I would also like to say that what I am

 

 19   hearing is a lot of people blaming a medication for

 

 20   what happened to their children, and have a direct

 

 21   blame.  What I would sort of like to see is more

 

 22   trained psychiatrists who actually know the side

 

 23   effects as well themselves and who are talking to

 

 24   the parents, telling them about the possibility of

 

 25   side effects, about that depression inherently, you

 

                                                               115

 

  1   know, can result in suicidality and that the

 

  2   medication might increase that.

 

  3             But to blame the medication itself that

 

  4   has helped so many people and has also prevented so

 

  5   many suicides, I don't think is the right way, but

 

  6   we do need to have much more clinicians guiding our

 

  7   patients and parents, so that they know what kind

 

  8   of side effects are possible.

 

  9             Thank you.

 

 10             DR. RUDORFER:  Thank you.

 

 11             We are going to move on to Number 23.

 

 12                          Pepper Draper

 

 13             MS. DRAPER:  Good morning.  My name is

 

 14   Pepper Draper.  I am a Director of the

 

 15   International Coalition for Drug Awareness.  I have

 

 16   absolutely no financial gain.  I do this completely

 

 17   100 percent voluntary, and the reason for that is

 

 18   because of my own son's problems.

 

 19             My child was prescribed Ritalin, which

 

 20   became very depressed, and we bought into the whole

 

 21   serotonin theory, so we were naturally raising that

 

 22   serotonin, which unfortunately started causing him

 

 23   to become severely depressed and suicidal.

 

 24             Unfortunately or fortunately I should say

 

 25   is that we were able to finally understand the

 

                                                               116

 

  1   truth about serotonin, that raising serotonin and

 

  2   stopping the metabolism of it has caused suicide

 

  3   and aggression, and that is well documented.

 

  4             Unfortunately, Dr. Tracy was not able to

 

  5   talk about that, but what I want to share with you

 

  6   is that there is going to be others here from

 

  7   Arizona who are going to share with you how

 

  8   wonderful these drugs have been for the State of

 

  9   Arizona, but I am here to tell you that I deal with

 

 10   these people every day who are tired of their

 

 11   mental health workers putting them on another

 

 12   medication and another medication and another

 

 13   medication, until these children are now being put

 

 14   in mental hospitals at an enormous rate.

 

 15             They are being given electric shock

 

 16   therapy and it is very tragic what I am seeing, and

 

 17   I just want to share with you that I know that if

 

 18   we will teach them the right ways to take care of

 

 19   their bodies and cut out the things that are

 

 20   addictive, like these medications are, that we can

 

 21   help our youth learn to deal with what is going on

 

 22   in their lives, and I just want to share with you

 

 23   one last thing.

 

 24             I am really saddened that the fact that

 

 25   every single parent cannot share what has happened

 

                                                               117

 

  1   to their child because if they could, my mother

 

  2   would be here, standing up here, sharing what has

 

  3   happened to her adult son.

 

  4             DR. RUDORFER:  Thank you.

 

  5             If we could have speaker 24, please, Dr.

 

  6   Marks.

 

  7                    Donald Marks, M.D., Ph.D.

 

  8             DR. MARKS:  Good morning.  My name is Dr.

 

  9   Donald Marks and I address your subcommittee as a

 

 10   prescribing physician, as a father, and as a former

 

 11   associate director and director for clinical

 

 12   research for two multinational pharmaceutical

 

 13   companies.  I am here at my own expense because I

 

 14   believe in the importance of these issues.

 

 15             SSRI manufacturing and sales is serious

 

 16   business with tens of millions of patients in the

 

 17   U.S. and a market in the tens of billions of

 

 18   dollars.

 

 19             My experience working for pharmaceutical

 

 20   companies is that any attempt to decrease sales by

 

 21   increasing warnings will be met with severe

 

 22   organized resistance.  SSRI drugs are mostly

 

 23   prescribed by primary care physicians who have

 

 24   limited time with patients, limited training in

 

 25   childhood and adolescent neuropsychiatry and

 

                                                               118

 

  1   neuropsychopharmacology, and minimal time to

 

  2   evaluate properly patient suitability and response

 

  3   to pharmacologic versus non-pharmacologic

 

  4   interventions.

 

  5             The seriousness and severe adverse event

 

  6   effects of SSRI drugs make their use hardly

 

  7   justified in the majority of cases because SSRIs

 

  8   are well known to have limited efficacy over

 

  9   placebo and against non-pharmacologic treatments.

 

 10             There are many studies in the peer

 

 11   reviewed medical literature supporting the causal

 

 12   role of serotonin in disinhibition and violence.

 

 13   My own prescribing experience with SSRI drugs and

 

 14   evaluation of numerous cases referred to me has

 

 15   revealed significant agitation and aggression,

 

 16   akathisia, activation of mania and hypomania,

 

 17   increased depression, serious dependency and

 

 18   withdrawal difficulties, suicidal ideation, and

 

 19   toxic interactions with other drugs.

 

 20             It is important to be aware that these

 

 21   symptoms of SSRI toxicity can be mistaken for the

 

 22   progression of the underlying mental state being

 

 23   treated, leading to use of more of the same and

 

 24   other offending SSRI drugs rather than to

 

 25   withdrawal of the causative SSRI agent.

 

                                                               119

 

  1             This creates coding problems for

 

  2   physicians, coding problems by clinical researchers

 

  3   and sponsoring companies reporting adverse events

 

  4   in SSRIs.

 

  5             SSRI manufacturers, such as Glaxo and

 

  6   Pfizer, have conducted clinical trials in depressed

 

  7   children, many of which show no efficacy against

 

  8   placebo, and this has led to an increased warning

 

  9   in England that Paxil should not be prescribed as

 

 10   new therapy for depressed children under the age of

 

 11   18.

 

 12             DR. RUDORFER:  Thanks.  I am sorry we are

 

 13   out of time, but thank you, Dr. Marks.

 

 14             We are going to move on to speaker 25.

 

 15                           Leah Harris

 

 16             MS. HARRIS:  Good morning.  My name is

 

 17   Leah Harris and I am here at my own expense.

 

 18             The two minutes I have to speak will not

 

 19   permit me to go into the details of what I suffered

 

 20   while taking Prozac, Paxil, and Zoloft from age 12

 

 21   to 18.  I provided additional information in my

 

 22   submitted written statement.

 

 23             I went from being a shy and mildly

 

 24   depressed, but never suicidal kid to being overcome

 

 25   with thoughts of hurting and killing myself while

 

                                                               120

 

  1   on the SSRI drugs, thoughts which I acted on.

 

  2             Since quitting SSRIs over a decade ago, I

 

  3   have never again self-mutilated or had suicidal

 

  4   thoughts.  All other things being equal, the

 

  5   suicidality simply vanished. For me, this is clear

 

  6   proof that the drugs must have played a role, and I

 

  7   am one of the lucky ones, I have survived to tell

 

  8   the tale.

 

  9             I am not an anecdote and my story is not

 

 10   anecdotal evidence.  As a tax-paying American

 

 11   citizen who was hurt by these drugs throughout my

 

 12   childhood, I demand that the FDA take seriously the

 

 13   British decision of December 2003 banning all SSRIs

 

 14   except Prozac for use in children.

 

 15             Please consider all the evidence

 

 16   especially that which the pharmaceutical industry

 

 17   does not want you to see. The FDA must take action

 

 18   now regarding this grave issue of public health.

 

 19             Yes, many people claim to be helped by

 

 20   these drugs, and that is wonderful, but what about

 

 21   those of us who are harmed?  Medical professionals

 

 22   and the public must be informed of the very serious

 

 23   risks that are associated with SSRIs.

 

 24             In light of these risks, at the very

 

 25   least, isn't it time for the FDA to require that

 

                                                               121

 

  1   the drugs be labeled with clear warnings that might

 

  2   save lives?  Such warnings may negatively affect

 

  3   sales, as Dr. Marks referred, which may not please

 

  4   the pharmaceutical industry, but the FDA was

 

  5   created as an independent regulatory agency to

 

  6   serve the interests of the American public, not Big

 

  7   Pharma.

 

  8             American children are no less precious

 

  9   than British children, and they are in need of our

 

 10   protection, too.

 

 11             Thank you.

 

 12             DR. RUDORFER:  Thank you.

 

 13             We are up to speaker 26.

 

 14                          Donald Farber

 

 15               MR. FARBER:  I am Donald Farber of Marin

 

 16   County, California.  I am a plaintiff's attorney.

 

 17   I have represented antidepressant victims for five

 

 18   years.

 

 19             As a lawyer, I look at the evidence, too.

 

 20   I hear the emotional stories, but I look at the

 

 21   evidence.

 

 22             On January 27th, six days ago, I got a

 

 23   writing that I have been waiting for the FDA for 15

 

 24   years, from GlaxoSmithKline.  Attempted suicides on

 

 25   Paxil during all premarketing testing were

 

                                                               122

 

  1   frequent, placebo, it was actually rare, but due to

 

  2   the fact they manipulated the figures in the

 

  3   re-analysis of the data, it was infrequent.  So,

 

  4   even by this standard, we should have had a warning

 

  5   12 years ago.  What do we have to do to get a

 

  6   warning?

 

  7             Dr. Katz mentioned the re-analysis of the

 

  8   data.  I call it tinkering with the data.

 

  9             Here is what happened to Paxil to get it

 

 10   approved. Dr. Laughren knows about these figures.

 

 11   Here is what happened with the tinkering of the

 

 12   data before and after.

 

 13             Look at the difference.  These are not

 

 14   lawyer figures, these are their figures.  They

 

 15   manipulated the data, Paxil suicides went down,

 

 16   placebo suicides, which is the key figure here for

 

 17   you mathematicians, went way up, so that the result

 

 18   was statistical insignificance by the time the PDAC

 

 19   met in October of '92.

 

 20             Whether the drugs go on the market or not,

 

 21   they have to be given a warning.  I am for full

 

 22   disclosure.  I am not for banning these drugs, but

 

 23   I want full disclosure, and the FDA doesn't need a

 

 24   citizens' petition to do their job.

 

 25             Finally, I do object to this entire

 

                                                               123

 

  1   meeting.  I would venture that 95 percent of you

 

  2   are pro-industry and it is time for people like Joe

 

  3   Glenmullen and Peter Breggin to sit on this

 

  4   committee as well as you distinguished people.

 

  5             Thank you.

 

  6             DR. RUDORFER:  Thank you, sir.

 

  7             Could we have speaker 27, please.

 

  8                         Lorraine Slater

 

  9             MS. SLATER:  Informed parental consent is

 

 10   only possible as long as full disclosure is made by

 

 11   the pharmaceutical companies, the FDA, and the

 

 12   medical community.

 

 13             How can you imagine I feel as Dominique's

 

 14   mother knowing now that I was slowly poisoning my

 

 15   daughter every day as I was dispensing her

 

 16   antidepressant medication including Celexa and

 

 17   which she made her first suicide attempt after

 

 18   being on it for almost one month, and effects of

 

 19   the last medication she was on when she did commit

 

 20   suicide?

 

 21             Yes, Dominique's mind and behavior were

 

 22   slowly being altered to the point that she became

 

 23   very agitated, irrational, ultimately suicidal,

 

 24   because none of the so-called medical professionals

 

 25   acknowledged the drug's role in her irrational and

 

                                                               124

 

  1   suicidal behavior or properly withdrew her from

 

  2   their suicidal effects.

 

  3             Our lovely 14-year-old daughter is dead.

 

  4   Dominique has been denied the unalienable right by

 

  5   her creator of the pursuit of life, liberty, and

 

  6   happiness.  She will no longer be able to pursue

 

  7   her dreams of becoming either a computer software

 

  8   engineer, computer graphics engineer, or marine

 

  9   biologist, and someday an entrepreneur, she had

 

 10   hoped.

 

 11             Gone, too, is the ability to be able to

 

 12   watch Dominique blossom into womanhood, as well as

 

 13   motherhood, as she expressed the desire to someday

 

 14   have five kids.  Now, we will never have the

 

 15   opportunity to continue sharing our lives with

 

 16   Dominique, whom we loved and cherished so much.

 

 17             She was not only very intelligent,

 

 18   humorous, delightful, insightful, and innovative,

 

 19   she was also very caring and thoughtful.  Dominique

 

 20   had a way of making others feel special and loved.

 

 21   She touched so many lives.  For example, Dominique

 

 22   made 1,000 paper origami cranes and sent them to

 

 23   Governor George Pataki of New York for the first

 

 24   anniversary of 9/11.

 

 25             It was because of Dominique's very loving

 

                                                               125

 

  1   and genuine nature that around 300 people showed up

 

  2   to her memorial service.  They couldn't believe

 

  3   that for someone who was so loving and caring, she

 

  4   would herself take her own life.

 

  5             I submit to you today, ladies and

 

  6   gentlemen, that Dominique's life was taken from her

 

  7   as a result of drug-induced psychosis and suicidal

 

  8   ideations, not to mention the probability of

 

  9   experiencing akathisia, extreme agitation.  As a

 

 10   14-year-old adolescent, her brain was experiencing

 

 11   the second largest growth period, and her hormones

 

 12   were unbalanced.

 

 13             How can teenagers be allowed to be given

 

 14   antidepressants that were never approved for

 

 15   adolescent consumption, only for adults?  How come

 

 16   the medical profession doesn't fully disclose the

 

 17   possible harmful and fatal effects of medication as

 

 18   well as watch carefully for diverse effects on its

 

 19   adolescent population?

 

 20             DR. RUDORFER:  I am sorry that we are out

 

 21   of time, but thank you very much.

 

 22             If we could have speaker 28, please.

 

 23                        Matthew Piepenburg

 

 24             MR. PIEPENBURG:  Well, there are very

 

 25   impressive credentials around this room and

 

                                                               126

 

  1   certainly at this panel, and impressive schools and

 

  2   qualifications and professorial positions at very

 

  3   elite institutions.

 

  4             There are also a number of impressive

 

  5   terms of art tossed around - morbidity,

 

  6   idiosyncratic.  I like Mr. Katz's term controlled

 

  7   data or controlled trial data.

 

  8             What I would like to suggest is behind me

 

  9   is a number of things that do not show up in

 

 10   controlled trial data that need to be heard, that

 

 11   are as important as what can be achieved

 

 12   statistically.

 

 13             I don't think for parents who spend a

 

 14   great deal of time in cemeteries, controlled trial

 

 15   data is as pervasive or persuasive.

 

 16             I do not suggest or believe that everyone

 

 17   here has a negative or a grotesque motive or is all

 

 18   greedy.  I do think there are legitimate motives

 

 19   here, and I think these things do need to be

 

 20   discussed without being incendiary.

 

 21             Nevertheless, it is important to recognize

 

 22   the human dimension here.  We had prepared a

 

 23   two-page speech full of FDA talk papers, adverse

 

 24   reporting events on Paxil in particular, my family

 

 25   friend, Paul Domb, has suffered as a victim of

 

                                                               127

 

  1   Paxil.  It is just very hard to go over that when

 

  2   you hear these stories.

 

  3             Last night, we were at a restaurant.  We

 

  4   gave the waiter our speech to print out for us off

 

  5   of a disk.  He came back.  He had suffered Paxil

 

  6   side effects that led to suicidal thoughts, violent

 

  7   thoughts after a 40-year marriage, and he saw our

 

  8   speech and sat down for 20 minutes and basically

 

  9   cried before us.

 

 10             It is a pattern and epidemic that is

 

 11   pervasive and has more importance to me than the

 

 12   statistics we were going to read.  Let me just

 

 13   suggest also that this individual had been to

 

 14   Vietnam, lost most of his platoon and most of his

 

 15   body in Vietnam, crawled for two and a half days

 

 16   through the jungle to survive.

 

 17             None of that caused him the depression or

 

 18   the desire to jump off a bridge like Paxil did.  If

 

 19   he could handle Vietnam with poise, how are 13- and

 

 20   12-year-old kids supposed to handle Paxil?

 

 21             Thank you very much.

 

 22             DR. RUDORFER:  Thank you.

 

 23             Could we have speaker 29, please.

 

 24                          Terri Williams

 

 25             MS. WILLIAMS:  My son, Jacob Williams, was

 

                                                               128

 

  1   born on October the 15th, 1986.  Jacob was an

 

  2   exceptional athlete who participated in football on

 

  3   both the varsity and junior varsity football teams

 

  4   in his school.

 

  5             In September of 2000, Jacob experienced a

 

  6   loss of interest in his school activities.  He

 

  7   maintained his interest in football, however, there

 

  8   was a conflict with his grades and his attendance.

 

  9             As a result of this issue, his father and

 

 10   I attended a conference at his school on October

 

 11   the 11th, 2000 with various representatives from

 

 12   the school.  The school administrator suggested

 

 13   that Jacob may be depressed and that we should seek

 

 14   medical help.

 

 15             I contacted Jacob's pediatrician and made

 

 16   an appointment for 3:45 that afternoon.  On October

 

 17   the 11th, 2000, his pediatrician prescribed 10

 

 18   milligrams of Prozac, which was increased to 20

 

 19   milligrams three weeks later.

 

 20             Shortly after starting the initial dose,

 

 21   Jacob began to complain of having strange dreams,

 

 22   which he had said were bad.  Shortly after the

 

 23   dosage was increased, I began to  notice an

 

 24   aggressive behavior, which had not been there

 

 25   before.  Jacob also became destructive and

 

                                                               129

 

  1   destroyed some of his favorite things.

 

  2             His friends would later tell me they had

 

  3   noticed the same behavioral change.  He also showed

 

  4   a verbal aggression and short temper, which had not

 

  5   been present before.

 

  6             When questioned about this behavior, he

 

  7   stated I don't know what is making me do this.  At

 

  8   this time, I thought this could be a part of normal

 

  9   adolescent behavior and did not pursue the matter

 

 10   any further.

 

 11             On December the 5th, 2000, I discovered

 

 12   Jacob's body hanging from the rafter in our attic.

 

 13   He had hung himself with his own belt.  A letter

 

 14   was placed on the ladder leading up to our attic

 

 15   thanking us for giving him 14 years of a happy

 

 16   life.

 

 17             Something had to have gone wrong in the

 

 18   thinking process to have brought this about.  Had I

 

 19   know that this was a potential side effect,

 

 20   suicide, I would have never allowed my son to take

 

 21   the drug Prozac.

 

 22             Thank you.

 

 23             DR. RUDORFER:  We are now going to go to

 

 24   speaker 32, please.

 

 25                          Glenn McIntosh

 

                                                               130

 

  1             MR. McINTOSH:  I would like to introduce

 

  2   you to my daughter, Caitlin Elizabeth McIntosh.

 

  3   Well, it is actually only a 2-dimensional image of

 

  4   her, but it is all I have left.  She died of

 

  5   suicide at age 12 years, 3 months, just 8 weeks

 

  6   after being put on Paxil, and then Zoloft.

 

  7             Caitlin was a straight "A" student in the

 

  8   fifth grade, a talented musician, artist, and poet,

 

  9   who loved animals and wanted to be a veterinarian.

 

 10   The sixth grade began, and that, combined with the

 

 11   onset of puberty, this bright, sensitive girl who

 

 12   had once loved going to school, started having some

 

 13   trouble coping, as many kids do in the sixth grade,

 

 14   it's a tough adjustment.

 

 15             She was also having some problems sleeping

 

 16   due to a mild seizure disorder.  We wanted to help,

 

 17   of course, so we took her to our family physician,

 

 18   who prescribed her Paxil.  He said it would help

 

 19   with her coping and her sleep.

 

 20             She didn't do well on it at all, so he

 

 21   took her off it cold turkey, which you are not

 

 22   supposed to do.  When we saw a psychiatrist a week

 

 23   later, he put her on Zoloft.  She then started

 

 24   having strong suicidal ideations, along with severe

 

 25   agitation known as akathisia and hallucinations,

 

                                                               131

 

  1   and she was put in the adolescent ward of a mental

 

  2   hospital to "balance her meds."

 

  3             Well, there, things only got worse, as she

 

  4   was put on other strong psychotropic drugs to treat

 

  5   the symptoms that we now know were actually caused

 

  6   by the SSRIs, and let me be very clear about

 

  7   something.  The dramatic and severe symptoms that

 

  8   led to my daughter's suicide manifested only after

 

  9   she started taking antidepressant drugs.

 

 10             The downward spiral continued until

 

 11   January 5th, 2000, when she hung herself with her

 

 12   shoelaces in the girl's bathroom in the middle

 

 13   school she was attending.

 

 14             We were told that antidepressants like

 

 15   Paxil and Zoloft were wonder drugs, that they were

 

 16   safe and effective for children.  We were lied to.

 

 17   The pharmaceutical companies have known for years

 

 18   that these drugs could cause suicide in some

 

 19   patients.  Why didn't we?

 

 20             I implore you, ban the use of

 

 21   antidepressants here in the United States so that

 

 22   other parents will not have to endure the pain I

 

 23   felt and other children might be saved.

 

 24             DR. RUDORFER:  Thank you.

 

 25             Speaker 33, please.

 

                                                               132

 

  1                          Delnora Duprey

 

  2             MS. DUPREY:  My name is Delnora Duprey,

 

  3   and it has been well over two years since I have

 

  4   seen my grandson play ball, ride a bike, talk on

 

  5   the phone, or run in to say, "Hey, grandma, what's

 

  6   for dinner?"

 

  7             All the normal everyday things in his life

 

  8   are lost.  He is not here to get his restricted

 

  9   license in April, see his little sister start

 

 10   school, to ride with his big sister when she

 

 11   started driving, or just to go out and have pizza

 

 12   and see a movie.

 

 13             A tall, thin boy, quiet and well liked and

 

 14   respectful to everyone, a big heart and a smile

 

 15   that made you ask what are you up to, a boy who

 

 16   loved his family dearly, had hopes and dreams for a

 

 17   future.  A future of uncertainty now - he is locked

 

 18   away in a detention center awaiting trial for the

 

 19   murder of two people who he loved most in the

 

 20   world.

 

 21             A nightmare that started with a diagnosis

 

 22   of depression and placed on medication that was

 

 23   never tested on children and never meant for their

 

 24   use.  He had no say in this.  We, as adults, trust

 

 25   our doctors and the FDA to know what they are

 

                                                               133

 

  1   doing.  Even when we get complaints, we say the

 

  2   doctor said it will help you.

 

  3             A sweet boy who never hurt himself or

 

  4   anyone else went to live with his grandparents.

 

  5   His medication was changed from Paxil, which he had

 

  6   been on a very short time, to Zoloft.

 

  7             From a family physician, this medication

 

  8   was increased to 200 milligrams for an 80-pound

 

  9   child.  Within 48 hours, his grandparents were

 

 10   dead, and he is sitting, facing a life of

 

 11   uncertainty, a life of maybe total incarceration

 

 12   for the rest of his life, a child that does not

 

 13   even know what has happened to him.

 

 14             I don't want to see any more families go

 

 15   through this nightmare that we have all endured.

 

 16   The child's life changed forever.  Next time it

 

 17   might be one of your own family.  We must stop

 

 18   these drugs for children and strengthen our

 

 19   restrictions on the doctors who prescribe them.

 

 20             DR. RUDORFER:  Thank you.

 

 21             Number 34, please.

 

 22                           Joe Pittman

 

 23             MR. PITTMAN:  Hello.  My name is Joe

 

 24   Pittman.

 

 25             My son, at the tender age of 12, killed my

 

                                                               134

 

  1   parents.  I am going to read you a letter he wrote

 

  2   to me to you all.

 

  3             "Dear FDA:  My name is Chris Pittman.  I

 

  4   am now 14 years old.  I would like to tell you what

 

  5   happened to me, what the medication did to me and

 

  6   how it made me feel.

 

  7             "When I was taking Zoloft, I took the

 

  8   lives of two people that I loved more than

 

  9   anything, my grandparents.  I went to the doctor

 

 10   and he gave me a sample pack of Zoloft. He told me

 

 11   to take 50 milligrams once in the morning and

 

 12   another 50 at night.

 

 13             "I didn't notice a change in my behavior

 

 14   until I was completely off the medication.  It made

 

 15   me hate everyone.  The smallest things made me blow

 

 16   up, and I started getting into fights, which was

 

 17   not me.  I would usually avoid fights.  Before the

 

 18   medication, I had only been in two fights my whole

 

 19   life.  I just hated the whole world for no apparent

 

 20   reason.

 

 21             "A week after the doctor gave me the

 

 22   sample packs, he increased my dosage to 200

 

 23   milligrams a day.  Everything just kept getting

 

 24   worse.  Then, I snapped.  I took everything out on

 

 25   my grandparents who I loved so very much.

 

                                                               135

 

  1             "When I was lying in my bed that night, I

 

  2   couldn't sleep because my voice in my head kept

 

  3   echoing through my mind telling me to kill them

 

  4   until I got up, got the gun, and I went upstairs

 

  5   and I pulled the trigger.  Through the whole thing

 

  6   it was like watching your favorite TV show.  You

 

  7   know what is going to happen, but you can't do

 

  8   anything to stop it.  All you can do is just watch

 

  9   it in fright.

 

 10             "Because of my own personal experience on

 

 11   the medication, I would not want anyone to go

 

 12   through what I have then and now, losing the lives

 

 13   of my loved ones for the effects of homicide or

 

 14   suicide, or both, due to the medication.

 

 15             "Thank you.  Christopher Pittman."

 

 16             DR. RUDORFER:  Thank you.

 

 17             Number 35, please.

 

 18                           Richard Mack

 

 19             MR. MACK:  My name is Richard Mack.  I am

 

 20   a retired law enforcement officer and sheriff from

 

 21   Arizona.

 

 22             My expertise in that field was juvenile

 

 23   delinquency, school violence, and narcotics

 

 24   investigations.

 

 25             My first experience with SSRIs was when I

 

                                                               136

 

  1   was a parent of a second grader, my wife and I were

 

  2   called into the school, our son had a problem

 

  3   staying in his chair.  What was the government

 

  4   school's answer?  Drug your son into submission, so

 

  5   he will stay in his chair.

 

  6             We refused and we thank God now that we

 

  7   did.  Our son turned out just fine, played

 

  8   basketball, baseball, and excelled at school and

 

  9   sports.

 

 10             I was a sheriff of a small community in

 

 11   Arizona. We had an abnormal amount of high rate of

 

 12   suicide and teen violence.  I am just an

 

 13   investigator, I just present the facts.  One thing

 

 14   that we could not ignore was the circumstantial

 

 15   evidence that the common denominator in all of

 

 16   these cases was the victims or perpetrators were on

 

 17   SSRIs.

 

 18             In investigating these events, it became

 

 19   quite commonplace for all of us to ask the same

 

 20   question as we got to the next event of horrified

 

 21   and traumatized people and families.  You have

 

 22   heard from many of them today.

 

 23             Some people don't have the adverse

 

 24   reaction to these drugs, some do.  I learned the

 

 25   same with LSD when I investigated that as an

 

                                                               137

 

  1   undercover narcotics officer.  I can only say that

 

  2   the evidence is mounting over and over as did our

 

  3   investigations.

 

  4             We cannot, as law enforcement officials,

 

  5   ignore such circumstantial evidence.  I doubt very

 

  6   seriously if you could either.  I am an advocate

 

  7   for state's rights and I do believe that if the FDA

 

  8   fails to take action, the state and local

 

  9   authorities will have to.

 

 10             Thank you.

 

 11             DR. RUDORFER:  Thank you.

 

 12             Speaker 36.

 

 13                        Noah Wright Smith

 

 14             MS. SMITH:  My name is Noah Wright Smith

 

 15   and I am a 15-year-old victim of legalized drug

 

 16   abuse.  My mother had me put on Ritalin when I was

 

 17   5.  I felt sick all the time on Ritalin and it was

 

 18   just the beginning of bad things happening to me

 

 19   because of drugs.

 

 20             My grandparents won custody of me last

 

 21   year.  When they won, they got upset because I was

 

 22   in bad shape and on a lot of drugs.  They picked me

 

 23   up at Broughton Mental Hospital in Morganton, North

 

 24   Carolina, and learned I was on 1,000 milligrams of

 

 25   drugs a day.  In my lifetime, I have been on 16

 

                                                               138

 

  1   psychotropic drugs including Zoloft, Paxil, and

 

  2   Effexor, and all of them made me feel sick and do

 

  3   very bad things.

 

  4             I wasn't a bad kid.  I was a badly abused

 

  5   kid, abused by my mother and my stepfather.  The

 

  6   Department of Social Services knew I was being

 

  7   abused, but they didn't do anything except put me

 

  8   on more drugs.

 

  9             The drugs made me sick and do bad things

 

 10   like trying to stab my teacher with scissors.

 

 11   Sometimes it made me want to kill my parents, and I

 

 12   told them that, and was put in a mental hospital.

 

 13             Some drugs made me have bad nightmares, so

 

 14   I tried very hard not to sleep every night, so they

 

 15   gave me drugs to make me sleep.  Some of the drugs

 

 16   made me want to kill myself.  I couldn't stop

 

 17   thinking about killing myself.  When I told the

 

 18   doctors, they sent me to still another mental

 

 19   hospital.

 

 20             One day I tried to jump off a very high

 

 21   railing to kill myself.  I was put in a mental

 

 22   hospital again for doing that, but I really wanted

 

 23   to die.  I really did want to, and I was so scared

 

 24   and mad, too.  In those mental hospitals, they kept

 

 25   giving me more drugs, and I got depressed.  I got

 

                                                               139

 

  1   diabetes and high blood pressure.

 

  2             My grandparents won my custody and took me

 

  3   to a new psychiatrist.  We have worked hard

 

  4   together and he found I really don't need any

 

  5   drugs.  Last year he took me off all of them, one

 

  6   at a time.  No more nightmares or wanting to hurt

 

  7   or kill other people, and I don't want to kill

 

  8   myself anymore.

 

  9             Drugs almost ruined my life and almost

 

 10   killed me. What about the kids that have to take

 

 11   these drugs?  I don't want kids to kill themselves.

 

 12   Who is taking care of them? Who really cares about

 

 13   us kids?  I don't even know if you care, do you?

 

 14   Somebody had better listen to kids who say the

 

 15   medicines make them want to kill themselves, and

 

 16   make them sick, and do bad things, because they are

 

 17   telling you the truth.

 

 18             Thank you for listening to me.  Now,

 

 19   please, help the other kids, so that they don't get

 

 20   hurt by drugs, and so they don't kill themselves.

 

 21   I almost killed myself and I am glad I am alive.

 

 22             DR. RUDORFER:  Number 37, please.

 

 23                           Marion Goff

 

 24             MS. GOFF:  I do not have any financial

 

 25   ties.  I am her with my daughter, Alex.  We are

 

                                                               140

 

  1   here to tell you about her twin sister, Devon, when

 

  2   she was 9 years old.  We are also joined by Senator

 

  3   Lincoln Chafee's wife Stephanie who is a friend of

 

  4   ours.

 

  5             In 2002, Devon developed an

 

  6   obsessive-compulsive disorder very suddenly and

 

  7   very severely.  In a three-month period, she lost

 

  8   10 pounds.  We consulted a specialist who

 

  9   prescribed Zoloft on her second visit with him.

 

 10   Soon thereafter, he increased the Zoloft to 50

 

 11   milligrams or more, but it didn't help, so he

 

 12   changed her prescription to Paxil.

 

 13             She was hospitalized and Devon's medical

 

 14   condition was compromised in that she had developed

 

 15   a cardiac arrhythmia and had to be placed on a

 

 16   heart monitor.  She was in the hospital for one

 

 17   month, and she was on the heart monitor and bed

 

 18   rest for the entire time.

 

 19              During this time, her Paxil was increased

 

 20   to 20 milligrams.  A few days later she was started

 

 21   on Zyprexa also.  Devon was not getting any better,

 

 22   in fact, her behaviors grew worse.  She began

 

 23   hitting her head against the metal hospital bed.

 

 24   She threatened to jump out of the window on two

 

 25   occasions.

 

                                                               141

 

  1             On two other occasions, we found a pair of

 

  2   sharp scissors in her bed.  Our child was never

 

  3   suicidal before these medications.  At one point,

 

  4   my 9-year-old child, who weighed little more than

 

  5   60 pounds, was on 30 milligrams of Paxil and 10

 

  6   milligrams of Zyprexa.

 

  7             Our gentle daughter would now fly into a

 

  8   rage several times each day.  It became part of our

 

  9   life to have my husband and myself restrain Devon

 

 10   at times for fear that she would truly hurt

 

 11   herself.

 

 12             During these times, she would try to

 

 13   inflict injury upon herself by banging her head on

 

 14   walls, beds, floors.  She would punch herself in

 

 15   the legs and arms.  She grew extremely violent

 

 16   toward us.  She would run to the silverware drawer

 

 17   and get a knife and attempt to stab herself.

 

 18             The worst moment happened when I looked in

 

 19   on her, in her room one night, to find her by her

 

 20   open second floor bedroom window with one leg out

 

 21   the window in a position as if she appeared she

 

 22   would jump.

 

 23             Devon is presently being treated for Lyme

 

 24   Disease.  In summary, our experience has been one

 

 25   of absolute terror to watch your 9-year-old

 

                                                               142

 

  1   daughter suffer so much, so suddenly, and to be so

 

  2   lost in helping her.

 

  3             So often we would ask why this was

 

  4   happening, and we were told to forget about the

 

  5   etiology.

 

  6             DR. RUDORFER:  I am sorry, we are out of

 

  7   time. Thank you very much.

 

  8             Number 38, please.

 

  9                        Gary Cheslek, M.D.

 

 10             DR. CHESLEK:  Actually, my wife is

 

 11   speaking later.

 

 12             My name is Gary Cheslek, and I am a

 

 13   practicing dentist from Vicksburg, Mississippi, and

 

 14   I am speaking today, not just as a health care

 

 15   professional, but also as a parent.

 

 16             I am here today to tell you an anecdote.

 

 17   Webster defines an anecdote as a short narrative of

 

 18   an interesting or amusing biographical event, an

 

 19   anecdote or anecdotal.  That is the euphemism the

 

 20   manufacturers of Prozac, Paxil, Effexor, and Zoloft

 

 21   use to describe the thousands of reported out of

 

 22   character, violent, homicidal, suicidal events that

 

 23   occur in a vulnerable subset of patients who ingest

 

 24   their SSRI antidepressants.  They would have us

 

 25   believe that these are mere coincidences and don't

 

                                                               143

 

  1   prove anything.

 

  2             My son, Justin, was a 20-year-sophomore at

 

  3   the University of Southern Mississippi when he went

 

  4   to the Student Health Clinic complaining of

 

  5   insomnia.  He was given a thorough examination

 

  6   including bloodwork.  Significant in the doctor's

 

  7   note at that initial visit is the notation, "No

 

  8   suicidal ideation."

 

  9             Complaining that the sleep medication he

 

 10   was prescribed made him feel sedated and depressed,

 

 11   he was put on Paxil for two weeks.  During those

 

 12   two weeks, he repeatedly told his doctor he didn't

 

 13   like the way the Paxil made him feel, so he was

 

 14   switched to Effexor.

 

 15             Within 24 hours of the switch to Effexor,

 

 16   he had a seizure.  Five days later he hung himself

 

 17   in his apartment.  He didn't leave a note.  Beneath

 

 18   him was his laptop computer and a glass of Coke.

 

 19   It was as if some sudden impulse had made him do

 

 20   this.

 

 21             We grilled his girlfriend about his mood

 

 22   and behavior in the months prior to his death.  She

 

 23   said his demeanor changed dramatically around her

 

 24   birthday, February 22.  Justin started taking Paxil

 

 25   February 21.

 

                                                               144

 

  1             Last June, regulators in the UK and Canada

 

  2   banned Effexor and Paxil for use in children and

 

  3   adolescents, and recently expanded that ban to all

 

  4   SSRIs except Prozac.  Last August, Wyeth issued a

 

  5   Dear Doctor letter alerting the health care

 

  6   professionals that the clinical trials had not

 

  7   established the safety and effectiveness of Effexor

 

  8   in children, and revealed an increased risk of

 

  9   suicidal ideation and self-harm.

 

 10             The letter does not, however, indicate

 

 11   that some of these trials were done seven years

 

 12   ago.

 

 13             DR. RUDORFER:  Thank you very much.

 

 14                          Sherri Walton

 

 15             MS. WALTON:  My name is Sherri Walton and

 

 16   I am here as a volunteer advocate.  This is my

 

 17   14-year-old daughter, Jordan.  We have traveled

 

 18   here from Arizona at our own expense because we

 

 19   know that public forums, such as this, usually only

 

 20   hear from those who have had negative experiences.

 

 21   We felt it was important for us to share our story.

 

 22             Jordan was diagnosed with Tourette's

 

 23   syndrome when she was 7 years old.  As is typical

 

 24   of Tourette's syndrome, she also has OCD and ADHD.

 

 25   She was originally prescribed an SSRI medication to

 

                                                               145

 

  1   relieve the anxiety that consumed her because she

 

  2   could not control her thoughts or behaviors.

 

  3             This medication allowed her to participate

 

  4   in, and understand, the cognitive behavior therapy

 

  5   that gave her some semblance of normalcy.  In

 

  6   fourth grade, Jordan was still being hampered by

 

  7   the obsessive thoughts caused by her OCD.  In the

 

  8   classroom, this was overwhelming and extremely

 

  9   frightening for her.

 

 10             Her medication was changed to a different

 

 11   SSRI and within a few months, her obsessive

 

 12   thoughts became less and less intense.  They were

 

 13   still there, but now she was able to recognize what

 

 14   they were and usually work through them.

 

 15             Dance is Jordan's passion.  It is what she

 

 16   wants to do with her life.  In November of 2002,

 

 17   she announced she wanted to quit dance.  As she

 

 18   burst into tears, she said that she wanted to die,

 

 19   she wanted to kill herself.

 

 20             She was diagnosed with clinical depression

 

 21   and her medication was changed from the SSRI she

 

 22   had taken for four years to a different SSRI to

 

 23   treat both her OCD and depression.

 

 24             As Jordan has struggled to find success in

 

 25   school and in her relationships with peers, her

 

                                                               146

 

  1   meds were sometimes the only thing she could count

 

  2   on to help her.  The daughter I have here now

 

  3   standing next to me is a happy, healthy, successful

 

  4   teenager.  There is no doubt in my mind that the

 

  5   SSRI medication saved her life, and like the other

 

  6   SSRI antidepressants she is taking gave her a

 

  7   chance for a full and complete life.

 

  8             With the greatest sympathy for any

 

  9   families who have lost children to suicide, I ask

 

 10   that you identify and fix any breakdown in the

 

 11   system that could lead to such tragedy.  At the

 

 12   same time, I ask that you appreciate and take into

 

 13   account the enormous benefits that these

 

 14   medications have had for children and their

 

 15   families.

 

 16             Please urge the FDA not to take away the

 

 17   tools that have allowed my daughter and millions of

 

 18   other sons and daughters out there to be successful

 

 19   in life, and, in fact, to have lives.

 

 20             As a parent, I call on the FDA to take no

 

 21   action that would harm my child.

 

 22             DR. RUDORFER:  Thank you.

 

 23             We are up to speaker 40.

 

 24                      Peter R. Breggin, M.D.

 

 25             DR. BREGGIN:  Hello.  I am Dr. Peter

 

                                                               147

 

  1   Breggin.  I am a psychiatrist and one of the few

 

  2   experts in the world on medications who isn't

 

  3   involved in any way with the drug industry.  I

 

  4   think there are handful of us.

 

  5             I have given you a peer-reviewed article

 

  6   that came out just a few weeks ago that I wrote,

 

  7   which is the most extensive review to date on

 

  8   violence, suicide, and mania caused by the SSRIs,

 

  9   and it has just, I don't know, maybe hundreds of

 

 10   citations.

 

 11             Back in the 1980s when Prozac was being

 

 12   approved, Richard Kapit, the chief medical officer

 

 13   at the FDA, identified a stimulant syndrome in

 

 14   association with Prozac, and he repeatedly warned

 

 15   in in-house documents that this stimulant effect

 

 16   would turn depression into agitated depression and

 

 17   cause a deterioration in the individual.

 

 18             Since then, we have been able to identify

 

 19   a continuum of stimulation that has at least four

 

 20   syndromes involved, that I have now seen produce

 

 21   violence and suicide in dozens of patients in my

 

 22   clinical consultations and in my medical/legal

 

 23   work.

 

 24             The syndrome, first and foremost, includes

 

 25   manic-like behavior.  We know that Luvox, for

 

                                                               148

 

  1   example, just in its label has a 4 percent rate of

 

  2   mania.  From Emslie's study,  hidden in the fine

 

  3   print, we know that Prozac, controlled clinical

 

  4   trials, 6 percent rate of mania.

 

  5             The second syndrome is the agitated

 

  6   depression, it is hard to tell often clinically

 

  7   from mania.

 

  8             The third syndrome is this obsessive

 

  9   suicidality and violence, and the fourth syndrome

 

 10   is akathisia, which we now know, and is even in the

 

 11   old DSM, can produce psychosis and agitation, and a

 

 12   variety of other problems leading to suicide and to

 

 13   violence.

 

 14             The literature is extensive.  You have got

 

 15   to go beyond the needle in the haystack.  Please

 

 16   look at my review.

 

 17             DR. RUDORFER:  Thank you, Dr. Breggin.

 

 18             Speaker 41.

 

 19                           Robert Fritz

 

 20             MR. FRITZ:  People have been pleading with

 

 21   the FDA for 11-plus years to put warnings on

 

 22   prescriptions for antidepression medication to no

 

 23   avail.  The FDA has had people present information

 

 24   about suicidal tendency increase and numerous

 

 25   completed suicides, and still no warnings of

 

                                                               149

 

  1   increased risk of suicide were issued.

 

  2             The people of the United States have a

 

  3   right to know what risks are associated with taking

 

  4   these drugs.  I have a right to know what risks are

 

  5   associated with taking these drugs, so I can make

 

  6   an informed decision as to whether or not I want my

 

  7   children to take these drugs.

 

  8             The need for a warning is compounded by

 

  9   the fact that doctors are prescribing these

 

 10   medications off label.  My daughter, Stephanie Raye

 

 11   Fritz was taking Zoloft.  We weren't told of any

 

 12   risk of increased suicidal tendencies or increased

 

 13   suicide attempts.

 

 14             She hung herself on the evening of

 

 15   November 11th in her bedroom after finishing her

 

 16   homework.  She showed no signs of increased

 

 17   depression or imminent suicidal thoughts, and, in

 

 18   fact, was still recruiting people to see her sing

 

 19   the following month.

 

 20             We had no warning of what Zoloft could do

 

 21   to our daughter, but you people, the FDA, certainly

 

 22   did.  On October 27th, two weeks before she took

 

 23   her life, you put out a Public Health Advisory and

 

 24   notified physicians about preliminary data from

 

 25   studies suggesting an excess of reported suicidal

 

                                                               150

 

  1   ideation and suicide attempts for pediatric

 

  2   patients receiving certain of these antidepressant

 

  3   drugs.

 

  4             Why weren't we, the parents of the kids

 

  5   taking Zoloft, notified with this advisory?  It is

 

  6   too late for my daughter, but for the FDA to

 

  7   continue to sit on this information and not let the

 

  8   public know the risks associated with these drugs

 

  9   is a gross misuse of power.

 

 10             I am not asking that these drugs be taken

 

 11   off the market.  I don't know enough about their

 

 12   safety to recommend that.  What I am seeking is

 

 13   that when the drugs are prescribed off label, or

 

 14   when drugs are prescribed after an advisory is

 

 15   issued suggesting new adverse side effects, that

 

 16   the FDA make it mandatory that the physicians

 

 17   prescribing such drugs explain in plain English

 

 18   what the risks are and that an informed written

 

 19   consent be received from the parents or the

 

 20   patient's guardian.

 

 21             I hope that you will agree that all

 

 22   Americans deserve to know what risks they are

 

 23   assuming when they take medication.  I believe that

 

 24   most Americans, including most elected officials,

 

 25   agree with that.

 

                                                               151

 

  1             How many more people have to die before a

 

  2   warning gets issued?

 

  3             DR. RUDORFER:  Thank you.

 

  4             We are going to move ahead to speaker 43.

 

  5                     Lawrence Greenhill, M.D.

 

  6             DR. GREENHILL:  My name is Lawrence

 

  7   Greenhill.  I am a child psychiatrist, Professor of

 

  8   Child Psychiatry and Pharmacology at Columbia.  I

 

  9   am speaking today on behalf of the American Academy

 

 10   of Child and Adolescent Psychiatry where I serve as

 

 11   Chairman of the Program Committee and as Chair of

 

 12   the Pediatric Psychopharmacology Initiative

 

 13   Committee.

 

 14             First, I want to extend my sympathy to all

 

 15   the families who spoke so moving here today about

 

 16   their losses. I think similarly, the membership,

 

 17   who are comprised of 7,000 child psychiatrists at

 

 18   the American Academy of Child and Adolescent

 

 19   Psychiatry, are concerned about these families, and

 

 20   they want to get the results of this review to help

 

 21   their patients with safe and effective treatments.

 

 22             In that regard, the American Academy of

 

 23   Child and Adolescent Psychiatry supports the review

 

 24   that is going on and it specifically supports the

 

 25   reclassification of suicidal events using patient

 

                                                               152

 

  1   charts, that is, patient level analysis, as the

 

  2   category that turned up in Dr. Laughren's report of

 

  3   possible suicide-related events was one most

 

  4   subject to possible methodological bias that might

 

  5   be addressed by patient level analyses and

 

  6   reclassification.

 

  7             Furthermore, I support the mandatory

 

  8   registration of all clinical trials as advocated in

 

  9   JAMA by Dickerson and Rennie in July of 2003.  That

 

 10   is because one of the greatest roadblocks to

 

 11   understanding the safety and efficacy of trials is

 

 12   the lack of public access and its disclosure of

 

 13   these data sets due to laws that treat some of the

 

 14   data as proprietary trade secrets.

 

 15             I join my colleagues at Columbia in

 

 16   encouraging the field to carry out further

 

 17   prospective placebo-controlled trials using methods

 

 18   such as we have heard today, the randomized

 

 19   withdrawal discontinuation or challenge,

 

 20   de-challenge --.

 

 21             DR. RUDORFER:  Thank you, Dr. Greenhill.

 

 22             Number 46, please.

 

 23                   Suzanne Vogel-Scibilia, M.D.

 

 24             DR. VOGEL-SCIBILIA:  I would like to have

 

 25   my remarks into the written record, and I want to

 

                                                               153

 

  1   let you know I am here at my own expense.

 

  2             Good morning.  My name is Dr. Suzanne

 

  3   Vogel-Scibilia.  I a member of the NAMI board of

 

  4   directors.  As a person diagnosed with bipolar

 

  5   disorder, I am proud to serve on the NAMI Board and

 

  6   proud that NAMI is the nation's voice on mental

 

  7   illness representing both consumers and family

 

  8   members.  I am also proud to be the mother of five

 

  9   children, two who are diagnosed with mental

 

 10   illnesses and one who is currently being treated

 

 11   with an SSRI.

 

 12             I am also a practicing clinical

 

 13   psychiatrist with no financial ties to the

 

 14   pharmaceutical industry.  I represent thousands of

 

 15   families across the country.

 

 16             My son, Anthony, had a very severe mental

 

 17   illness primarily depression and attention deficit

 

 18   disorder as a manifestation of his bipolar

 

 19   disorder, and another son has had treatment with

 

 20   numerous antidepressant medications including

 

 21   several SSRIs.

 

 22             My children have had tremendous

 

 23   improvement with their illnesses and lead very full

 

 24   and functional lives because of SSRI medication,

 

 25   along with other psychotropic medications.  I

 

                                                               154

 

  1   shudder to think of their plight if these

 

  2   medications were not available.

 

  3             One of my sons has had suicide attempts

 

  4   and violent incidents with knives.  He has also run

 

  5   out of our house - in a fit of terror --in subzero

 

  6   weather only to be found freezing and hypothermic

 

  7   by our local police department in the next town.

 

  8   These incidents all occurred while his illness was

 

  9   not adequately treated with an antidepressant

 

 10   medication.

 

 11             My other son suffers from disabling

 

 12   obsessive- compulsive disorder symptoms and

 

 13   depression, and has had his life dramatically

 

 14   improve from treatment with SSRIs.

 

 15             I want to talk and speak about suicide and

 

 16   the consequences of untreated mental illnesses.

 

 17             We are pleased that the FDA is looking

 

 18   closely at the data related to SSRI use and

 

 19   suicidality.  NAMI is deeply concerned with the

 

 20   public health crisis and the number of youths who

 

 21   commit suicide.  The U.S. Surgeon General reports

 

 22   that up to 80 percent of our youth who need mental

 

 23   health treatment receive none at all.

 

 24             In summary, I would like to thank the

 

 25   committee for allowing 200,000 members of NAMI to

 

                                                               155

 

  1   share our views on this critically important issue.

 

  2   I hope and pray that this committee will render a

 

  3   decision based, not on emotion-filled pleas of

 

  4   individuals whose experience are not supported by

 

  5   adequate research.

 

  6             Thank you very much.

 

  7             DR. RUDORFER:  Thank you.

 

  8             If we could have speaker 48, please.

 

  9                          Dennis Winter

 

 10             MR. WINTER:  I am Dennis Winter.  I am

 

 11   here today with Karine Winter and Mary Lou Winter,

 

 12   Beth's mom.

 

 13             Four months ago or less than four months

 

 14   ago, Beth, a 22-year-old recent graduate from the

 

 15   University of Rhode Island, she graduated summa cum

 

 16   laude, she was a child who was loving, from a very

 

 17   tight, close family, never any instance of alcohol

 

 18   or drug abuse, never any problems, a wonderful

 

 19   student, a wonderful girl, a loving sister to her

 

 20   brothers and sisters, committed suicide after being

 

 21   on Paxil for seven days.

 

 22             Now, what I think is critical here is the

 

 23   fact that she can go to her general practitioner on

 

 24   the first visit and be prescribed Paxil.  I think

 

 25   it is clear that you need to come out with warning

 

                                                               156

 

  1   labels for practitioners and doctors, so the

 

  2   lawyers in this room, when those labels are out

 

  3   there, if the doctors continue to do it, will be

 

  4   able to bring actions.  If you bring out the

 

  5   warning labels, there is enough legal community in

 

  6   this world that will police itself.

 

  7             Let me go on.  As we are sitting here

 

  8   today, we heard a lot about idiosyncratic data, all

 

  9   permitted data, requested data available, data we

 

 10   are permitted to evaluate fully, and it comes down

 

 11   to this data stream that we don't know that

 

 12   happened 15, 20 years ago, the data stream you are

 

 13   trying to analyze.

 

 14             I don't know, like Mr. Farber said, if you

 

 15   are going to be analyze all that data and come out

 

 16   with that data.  You should put out warning labels

 

 17   because you are not going to get a clear answer.

 

 18             I am running out of time, but Dr. Healy

 

 19   provided testimony in federal court on May 22nd,

 

 20   2001.  Everybody needs to be read that testimony.

 

 21   He gave it under oath, under threat of perjury, and

 

 22   that is very enlightening to anybody involved here,

 

 23   and you really need to read it.

 

 24             Also, you need to look at confidentiality

 

 25   agreements.  A lot of families of people who commit

 

                                                               157

 

  1   suicide are embarrassed.  When the lawyers come,

 

  2   they sign confidentiality agreements, and you don't

 

  3   hear about what is really happening out there.

 

  4             DR. RUDORFER:  Thank you very much.

 

  5             We are going to move along to speaker 51.

 

  6                            Steve Cole

 

  7             MR. COLE:  I am Steve Cole.  I am here at

 

  8   my own expense.

 

  9             My father committed suicide after 13 days

 

 10   on Prozac.  He has absolutely no history of mental

 

 11   illness, in fact, quite the contrary.  He and my

 

 12   mom had just built a new house, a lot of the work

 

 13   he did himself.  He and I and a friend built a

 

 14   cabin out of raw lumber.

 

 15             These are not the type of things that you

 

 16   do if you are planning on dying.  Let me repeat

 

 17   that.  You do not do that.

 

 18             He was looking forward to his new house.

 

 19   He was planning many activities.  He was upbeat, he

 

 20   didn't drink or gamble, and he did not have any

 

 21   recognized prerequisites for suicide unless you

 

 22   want to consider all 70-year-old men suicidal, and

 

 23   I just don't buy that.  Generally, he was in very

 

 24   good health.

 

 25             Next slide.

 

                                                               158

 

  1             He experienced some chest pains about a

 

  2   month and a half after moving into the new house.

 

  3   As a precaution,  he went to his cardiologist.  His

 

  4   heart tested perfectly well.  He was upbeat and had

 

  5   a new grandbaby on the way.

 

  6             He was prescribed Prozac off label for the

 

  7   chest pain.  The doctor, who is an outstanding,

 

  8   wonderful man, stood behind us on this, and stated

 

  9   that he has no doubt that it was Prozac induced.

 

 10   Eleven days after he started, he demonstrated

 

 11   symptoms of akathisia, he was jittery.  His fingers

 

 12   and his skin felt odd, he was easily agitated.

 

 13             He told me, "I cannot stand the way this

 

 14   drug makes me feel."  Two days later he committed

 

 15   suicide.

 

 16             Growing up, he watched a lot of westerns.

 

 17   He loved westerns, but he would turn the channel if

 

 18   a man was hung or lynched.  This is the way my

 

 19   father died.  He hung himself.  It was completely

 

 20   out of character.  He died by means of his own

 

 21   nightmare.

 

 22             Thank you very much.

 

 23             DR. RUDORFER:  Thank you.

 

 24             Number 52, please.

 

 25                          Allan Routhier

 

                                                               159

 

  1             MR. ROUTHIER:  I am here to request that

 

  2   Wellbutrin be recognized as another dangerous drug.

 

  3   Information was sent to this committee by some

 

  4   researchers and myself as to the reasons for

 

  5   inclusion.  There are too many cases of suicide and

 

  6   deaths caused by this drug.  It is known to cause

 

  7   akathisia, depression, psychosis, serotonin

 

  8   syndrome, seizures, hallucinations, and many other

 

  9   serious adverse effects.

 

 10             One suicide while on Wellbutrin for ADHD

 

 11   was 9-year-old Carey Brooks, who had to kneel down

 

 12   to hang himself with his shoelace.  There are many

 

 13   reasons these drugs are prescribed, and they can

 

 14   cause suicide in non-depressed people.

 

 15             Do not blame acts of drug-induced

 

 16   psychosis on depression especially when this is

 

 17   happening to people given these drugs for other

 

 18   purposes.  It is not only SSRIs.  SSRI is a

 

 19   misnomer.  None of them are selective to serotonin.

 

 20   When you affect one neurotransmitter, you affect

 

 21   others.

 

 22             Remeron, Serzone, Effexor are not SSRIs.

 

 23   Effexor works on serotonin, norepinephrine, and

 

 24   dopamine, as does Wellbutrin.  FDA Med Watch

 

 25   reports hundreds of suicides on Wellbutrin. 

 

                                                               160

 

  1   Wellbutrin is structurally similar to amphetamine

 

  2   and overstimulates many people.

 

  3             Six months ago my wife went to the doctor

 

  4   sick and was sent home with Wellbutrin.  After six

 

  5   days of serious adverse reactions and insomnia, she

 

  6   shot herself.  This was not her. Forty years old,

 

  7   beautiful, with two boys, she was a perfect wife

 

  8   and mother, married for 18 years, almost 25 years

 

  9   working in the Welfare Office.

 

 10             She was never depressed.  She was the most

 

 11   loving, unselfish person anyone could know.

 

 12   Immediately after starting Wellbutrin, she was not

 

 13   herself.  This was an act of psychosis.  This has

 

 14   been happening for too long.  People are worth more

 

 15   than profits.

 

 16             How many more have to die before something

 

 17   is done?  Don't be fooled by manipulated studies.

 

 18   This was whitewashed in 1991, now they are trying

 

 19   to do it again. This happens to adults, as well as

 

 20   children, prescribed for any reason, not just MDD.

 

 21             My wife was murdered.  The FDA is supposed

 

 22   to protect us from these pill pushers.

 

 23             Thank you.

 

 24             DR. RUDORFER:  Thank you.

 

 25             Number 53, please.

 

                                                               161

 

  1                      Daniel J. Safer, M.D.

 

  2             DR. SAFER:  I am Daniel Safer.  I am a

 

  3   child psychiatrist, and I have no conflict of

 

  4   interest in coming here.

 

  5             I think the major finding of the British

 

  6   Committee on the Safety of Medicines was that most

 

  7   of the data that they got were unavailable to them

 

  8   prior to the company coming in for an indication,

 

  9   so when they found the data, they were surprised to

 

 10   see that most of the studies were negative or

 

 11   failed for the treatment of depression in children

 

 12   using SSRIs.  So, that was I think the major

 

 13   finding as far as I am concerned of the British

 

 14   Committee.

 

 15             The second finding indeed was that most of

 

 16   the studies, the vast majority of the studies they

 

 17   looked at were either failed or negative for the

 

 18   treatment of depression in children.

 

 19             The third finding had to do with the side

 

 20   effects of particularly the suicidality issue,

 

 21   which I consider a minor finding of the British

 

 22   report.  It was about 1 and a quarter percent rate

 

 23   for placebo and about 3.5 percent for the active

 

 24   medication.

 

 25             I think that is fairly understandable

 

                                                               162

 

  1   because the medication, the SSRIs are known, and

 

  2   have been known, to increase the risk of agitation

 

  3   and activation and children. In fact, the rate is

 

  4   about 15 to 20 percent when you look over about 40

 

  5   or 50 studies on SSRIs.

 

  6             It is a high rate, so you would expect

 

  7   that children who were depressed might have an

 

  8   increased rate of suicidality if they are agitated

 

  9   or anxious or activated under medication.

 

 10             Now, there is a lot of concern about the

 

 11   fact that a lot of these studies are not published,

 

 12   they simply are put in a file drawer.  I think that

 

 13   is a big concern, it's a big concern for Eric Kahn

 

 14   [ph] and Michael Thase and Norman Sussman, some of

 

 15   the major people in the field of psychiatry.

 

 16             So, I think the focus of the meeting is

 

 17   sort of unfortunate by focusing on suicidality

 

 18   because I think the big issue here is that we don't

 

 19   have access to the data that we need from the

 

 20   controlled trials, that are simply put in a file

 

 21   drawer by the companies.

 

 22             So, I would like to close by quoting

 

 23   Daniel Conner in the American Journal of American

 

 24   Academy of Child and Adolescent Psychiatry this

 

 25   month.  Oh, I will leave the quote out.

 

                                                               163

 

  1             DR. RUDORFER:  We will look it up.  Thank

 

  2   you.

 

  3             Speaker 54, please.

 

  4                        Julie Zito, Ph.D.

 

  5             DR. ZITO:  I am Julie Zito from the

 

  6   University of Maryland/Baltimore, and I bring to my

 

  7   comments this morning 20 years' experience in

 

  8   psychiatric pharmacoepidemiology.

 

  9             I would like the committee to consider the

 

 10   following drug safety issues in making their

 

 11   recommendations.

 

 12             First, symptoms like activation and

 

 13   agitation are reported very inconsistently,

 

 14   anywhere from no incidence in a clinical trial to

 

 15   as many as 55 percent of the children in an SSRI

 

 16   trial.  This information suggests a lack of

 

 17   standardization of measurements and methods with

 

 18   which to assess these events.

 

 19             Second, we need research on behavioral

 

 20   toxicity in order to separate symptoms associated

 

 21   with drug from those associated with the underlying

 

 22   psychiatric disorder.  I don't think we can just

 

 23   assume it.

 

 24             Third, because suicide is a very rare

 

 25   event, we need research that requires active

 

                                                               164

 

  1   surveillance, not passive surveillance, active

 

  2   surveillance in large, well-defined populations.

 

  3   We have the capacity to do that with research

 

  4   methods in pharmacoepi, but as yet, there is no

 

  5   federal mandate to go beyond Med Watch.

 

  6             Thank you.

 

  7             DR. RUDORFER:  Thank you.

 

  8             Speaker 55, please.

 

  9                     Joseph Glenmullen, M.D.

 

 10             DR. GLENMULLEN:  I am Joe Glenmullen.  I

 

 11   am a psychiatrist and clinical instructor in

 

 12   Psychiatry at Harvard Medical School and the author

 

 13   of Prozac Backlash, which describes my experience

 

 14   seeing patients become suicidal on SSRIs.

 

 15             I am here at my own expense because there

 

 16   is a specific side effect of SSRIs called akathisia

 

 17   that can make some patients so agitated that they

 

 18   feel death would be a welcome relief.

 

 19             This side effect is so well established

 

 20   that it is clearly described with SSRIs in the

 

 21   Diagnostic and Statistical Manual, the DSM, the

 

 22   American Psychiatric Association's official

 

 23   diagnostic manual.

 

 24             If you look at the transcript of the FDA

 

 25   hearing on this very side effect 10 years ago, you

 

                                                               165

 

  1   will see the FDA saying repeatedly we don't know

 

  2   what to do, we need more research.  It is a tragedy

 

  3   to be here 10 years later and hear the FDA saying

 

  4   the same thing.

 

  5             The industry's response to this side

 

  6   effect has been to blame the underlying psychiatric

 

  7   conditions of patients, to dismiss legitimate

 

  8   medical case reports as anecdotes, and to scare the

 

  9   media away from the subject, claiming that it would

 

 10   frighten patients away from treatment.

 

 11             Indeed, there is a prevailing

 

 12   authoritarian attitude don't warn patients, you

 

 13   might scare them.

 

 14             Well, I prescribe SSRIs and I warn

 

 15   patients, and they are not frightened away from

 

 16   treatment.  Let's stop blaming patient's underlying

 

 17   psychiatric conditions.  Let's stop blaming the

 

 18   victims and deal with this very real side effect.

 

 19             Thank you.

 

 20             DR. RUDORFER:  Thank you.

 

 21             Speaker 56, please.

 

 22                          Linda Cheslek

 

 23             MS. CHESLEK:  Hello.  My name is Linda

 

 24   Cheslek.  I am a pediatric nurse practitioner and I

 

 25   have prescribed medications for pediatric patients

 

                                                               166

 

  1   for 25 years.

 

  2             In the past, I thought that when an FDA

 

  3   drug was approved, that it had gone through a

 

  4   rigorous battery of independent tests and trials

 

  5   under the auspices of the FDA, but I can longer

 

  6   believe this.

 

  7             Why?  Well, this summer I received this

 

  8   letter from Wyeth.  It is a Dear Doctor letter.  It

 

  9   goes to all health care professionals, and it told

 

 10   me an update on Effexor, that the safety and

 

 11   effectiveness in pediatric patients had not been

 

 12   established, but there were reports of increased

 

 13   hostility, suicide, adverse events, suicidal

 

 14   ideation, and self-harm.

 

 15             This letter that came to my home confirmed

 

 16   what I already knew, that my son, who had a

 

 17   three-week trial of Paxil and Effexor became very

 

 18   much worse.  He developed the akathisia you have

 

 19   been hearing about.  He developed serotonin

 

 20   syndrome symptoms and a seizure.

 

 21             Wyeth had this information for almost

 

 22   seven years. Why did not the FDA require this trial

 

 23   data to be submitted along with the other data?

 

 24   The FDA allows the drug sponsors to manipulate and

 

 25   massage the data, to present it in a way that they

 

                                                               167

 

  1   feel is promoting their drug, and not the truth.

 

  2             I ask you to require them to submit all

 

  3   the data and to give a warning about these

 

  4   medications.  When you go to bed tonight, I hope

 

  5   you will see my face, the face of my son, and maybe

 

  6   of other faces of these people, and give a warning.

 

  7             Thank you.

 

  8             DR. RUDORFER:  Thank you.

 

  9             We are to speaker 57.

 

 10                            Jeff Avery

 

 11             MR. AVERY:  Hello.  My name is Jeff Avery.

 

 12             My 16-year-old stepson, Brandon Ferris,

 

 13   committed suicide on July 22nd, 2001, about three

 

 14   weeks after he began taking Zoloft.  Brandon was a

 

 15   bright and socially outgoing teen who got along

 

 16   well with others.  He was a black-belt instructor

 

 17   in Tai Kwon Do, active in the church's youth group,

 

 18   and held a part-time job.

 

 19             His mother home-schooled Brandon and

 

 20   worked at the Tai Kwon Do School, so she was very

 

 21   active in Brandon's activities.

 

 22             In June of 2001, Brandon expressed that he

 

 23   was feeling down, and not his usual energetic self.

 

 24   It was decided that he should take some time off

 

 25   and see a counselor.

 

                                                               168

 

  1             The counselor suggested that he see a

 

  2   doctor.  The doctor, who found no physical

 

  3   problems, prescribed Zoloft.

 

  4             Sunday, July 22nd, Brandon and I went to

 

  5   church.  On the way home Brandon volunteered to

 

  6   make a cake for his mother's birthday.  He asked

 

  7   permission to go on a boating trip.  He spent the

 

  8   rest of the day with his friends and an older

 

  9   brother Randy.

 

 10             When he came home from his youth group

 

 11   meeting at 9:15, he seemed fine.  At 9:45 he asked

 

 12   his mother about the boating trip.  At 10:30 he

 

 13   went to check his e-mail, but his brother was using

 

 14   the computer.  At 11 o'clock, he was found in his

 

 15   room hung by the neck from a belt in his closet.

 

 16   We called 911, we performed CPR to no avail.  He

 

 17   was pronounced dead at the hospital.

 

 18             Reflecting on the day's events, I could

 

 19   not detect any indication of forethought to

 

 20   suicide.  However, later conversations with others

 

 21   close to Brandon inferred that he may have been

 

 22   having problems with the medication.

 

 23             The obvious question is what happened in

 

 24   Brandon's mind between 10:30 and 10:45.

 

 25             This was not the end of unspeakable

 

                                                               169

 

  1   tragedy.  Five months later, Barbara, unable to

 

  2   cope with the loss of her youngest son, took her

 

  3   life.

 

  4             Since then I have collaborated with

 

  5   Brandon's biological father, Dan Ferris, to obtain

 

  6   information that would point to the cause of

 

  7   Brandon's death.  We believe, after having done

 

  8   much research, that the drug Zoloft had a causal

 

  9   effect in Brandon's final actions.

 

 10             Thank you.

 

 11             DR. RUDORFER:  Speaker 58, please.

 

 12                           Harry Skigis

 

 13             MR. SKIGIS:  What can I say that hasn't

 

 14   really already been said, but I had a speech

 

 15   prepared and decided to revamp it while sitting

 

 16   here in the audience.

 

 17             I tried to kill myself and luckily didn't

 

 18   succeed. I am still on Paxil because I am hooked on

 

 19   a nonhabit-forming drug.  I don't know if I will

 

 20   live long enough to see how this thing ends up, but

 

 21   I am going to try.

 

 22             I have always believed that do unto others

 

 23   as you would have done to yourself.  Would you

 

 24   people put your children on this drug?  Would you

 

 25   take it yourselves?  I doubt it.

 

                                                               170

 

  1             Probably not all the statistics in the

 

  2   world can't bring back the people that are dead

 

  3   because of the irresponsibility of the FDA.  How

 

  4   can I put in any faith in a government that still

 

  5   somewhat denies that cigarettes are addictive?

 

  6             I wonder if you people can sleep at night

 

  7   while your decisions are killing innocent people

 

  8   every day.  I leave my life in your hands and hope

 

  9   that you will apologize to all the people here for

 

 10   your decision and ignorance in this matter and how

 

 11   it has shattered so many people's lives.

 

 12             I really hope you guys can do something

 

 13   about this or at least tell us who will help us,

 

 14   because a lot of people are dead here today, and

 

 15   it's all in your hands.  So good luck.

 

 16             DR. RUDORFER:  Thank you.

 

 17             Speaker 59, please.

 

 18                           Pamela Wild

 

 19             MS. WILD:  On September 9, 2001, in a

 

 20   state of confusion and hopelessness, I put a.38

 

 21   Special, Smith & Wesson revolver under my chin and

 

 22   pulled the trigger.

 

 23             In going through withdrawal from Paxil, I

 

 24   lost all ability to cope and reason and without

 

 25   realizing it, became suicidal.  I suffered from

 

                                                               171

 

  1   sleeplessness, night sweats, light and sound

 

  2   sensitivity, irritability, and dizziness.

 

  3             I was in a constant state of terrible

 

  4   anxiety and felt as though the only thing holding

 

  5   me together was my skin.  I couldn't understand why

 

  6   others weren't seeing things my way, as though I

 

  7   was speaking in another language. I was told by my

 

  8   therapist that I had drifted into a fantasyland.

 

  9             She said it was though my system had been

 

 10   poisoned somehow, I was told not to worry, the only

 

 11   way to die from this drug was to fill a tub with

 

 12   Paxil and water and drown in it.

 

 13             The side effects I experienced on Paxil,

 

 14   even though I reported them to my doctor, were

 

 15   dismissed because no one was warned that Paxil

 

 16   could cause what I was experiencing.

 

 17             If I, at 41 years old, could not

 

 18   articulate what was happening, how do you expect a

 

 19   child to?

 

 20             There is no real medical explanation for

 

 21   my survival.  The front of my face was blown away,

 

 22   leaving a hole large enough  to encompass a man's

 

 23   fist.  The bullet miraculously only took two-thirds

 

 24   of my tongue, most of my mandible and my cheek

 

 25   bones.  The maxilla was shattered.

 

                                                               172

 

  1             The orbit of my left eye was broken and

 

  2   forced the eyeball out onto what remained of my

 

  3   left cheek.  It completely destroyed my hard and

 

  4   soft palate along with my nose and sinus cavity.

 

  5             I was blessed, though.  I may not able to

 

  6   taste or smell, but at least I lived.  I can see,

 

  7   talk, and I can hear.  But more surprising than any

 

  8   of those, I have brain function.  I truly believe

 

  9   my life was spared for a reason. That reason is so

 

 10   I can prevent others from experiencing what I

 

 11   experienced.

 

 12             DR. RUDORFER:  Thank you very much.

 

 13             We are up to speaker 60.  Thank you.

 

 14                       Karen Barth Menzies

 

 15             MS. MENZIES:  Good morning.  My name is

 

 16   Karen Barth Menzies and I am an attorney for Baum,

 

 17   Hedlund.  We represent several thousand SSRI

 

 18   victims.  We have been doing this for 12 years.

 

 19             The U.S. Code of Federal Regulations

 

 20   201.57 mandates that you require the drug companies

 

 21   to warn when there is reasonable evidence, not

 

 22   causation, reasonable evidence of an association of

 

 23   a serious risk.

 

 24             The clinical researchers who did these

 

 25   trials on kids and the drug companies themselves

 

                                                               173

 

  1   confirmed that there are multiple events of

 

  2   suicidality caused by the drug.  The methodology

 

  3   that you are going to be using is designed to

 

  4   explain away those events.

 

  5             Even Dr. Laughren admits in the memo he

 

  6   gave you for this hearing today that there is

 

  7   evidence in these trials of an increased risk of

 

  8   suicidality, reasonable evidence is there.  If

 

  9   there is reasonable evidence, you must make them

 

 10   warn.

 

 11             Serious risk, we certainly have that.

 

 12   Akathisia, psychosis, mania.  When you are looking

 

 13   at this data, you are not just looking at the

 

 14   suicide, also look for signs of akathisia and

 

 15   psychosis and mania.  These aren't as easily

 

 16   explained away by the drug companies, by blaming

 

 17   the disease, by blaming the victims.

 

 18             When you take the potentially fatal risk

 

 19   and couple that with lack of efficacy of these

 

 20   cases, why take that risk especially when it comes

 

 21   to our kids.

 

 22             Paul Leber [ph] predicted this day when he

 

 23   said that the FDA would come under attack because

 

 24   they weren't as demanding as they ought to have

 

 25   been when they were looking at the efficacy of the

 

                                                               174

 

  1   antidepressant products.

 

  2             Put me out of business for the right

 

  3   reasons, warn about these drugs and disclose.

 

  4             DR. RUDORFER:  Thank you.

 

  5             Speaker 61, please.

 

  6                            Amy Coburn

 

  7             MS. COBURN:  Hi.  My name is Amy Coburn.

 

  8   I have flown here from Salt Lake City, Utah, at my

 

  9   own expense.

 

 10             I am here on behalf of my father, myself,

 

 11   and my family.  My father's name was Wayne Coburn.

 

 12   Most people remember him as a man full of life and

 

 13   willing to help anyone in need.

 

 14             I remember my dad as a man who loved his

 

 15   family very much and was very loved in return, a

 

 16   man full of ideas and hope for the future, but like

 

 17   many people, he found he got a little down in the

 

 18   wintertime.  He was diagnosed with seasonal

 

 19   depression without suicidal tendencies.

 

 20             When I was 13 years old, he was put on

 

 21   Paxil.  Three weeks later he pulled his car into an

 

 22   old factory garage, started his engine, and there

 

 23   waited until he died of carbon monoxide poisoning.

 

 24             This naturally shocked me and my family

 

 25   and we all had a hard time coping with his death. 

 

                                                               175

 

  1   I started going to a counselor to work through my

 

  2   grief, and I was put on Paxil, the same drug my

 

  3   father was on.

 

  4             I started acting differently, then very

 

  5   soon after I started having suicidal thoughts, mood

 

  6   swings, I was fighting with my friends, and the one

 

  7   thing my mom noticed is that I wouldn't talk about

 

  8   how I was feeling.  The only thing she could get

 

  9   out of me was "I am fine, leave me alone."

 

 10             Six weeks after I was put on the drug, I

 

 11   stayed home from school, wrote my good-bye letters,

 

 12   and swallowed a cupful of poisonous bathroom

 

 13   cleaner.  I immediately got scared and ran to my

 

 14   neighbor's house.  She called 911 and luckily I

 

 15   survived and I am standing here today.

 

 16             We soon found out that we weren't the only

 

 17   ones who had problems with these drugs.  Hundreds

 

 18   of families have lost people they love because they

 

 19   had no idea of the effect they could have on a

 

 20   person's mind.  All me and my family want are

 

 21   warnings on these drugs.

 

 22             DR. RUDORFER:  Thank you.  I am sorry, we

 

 23   are out of time.  Thanks.

 

 24             Speaker 62, please.

 

 25                          Sharon McBride

 

                                                               176

 

  1             MS. McBRIDE:  I am here as a mother and I

 

  2   am here at my own expense.

 

  3             When our daughter was 13 years old, she

 

  4   came to me and said that something was wrong with

 

  5   her.  After discussion, I took her to the emergency

 

  6   room where she was diagnosed with depression.

 

  7             After three years of intense psychotherapy

 

  8   to discover and help the cause, she experienced her

 

  9   first manic episode.  She was hospitalized and

 

 10   given lithium and a mild dose of antipsychotic

 

 11   medication for a brief period of time.

 

 12             The resulting acne and weight gain caused

 

 13   her further depression thereafter.  Due to my

 

 14   inability to accept the diagnosis, we took her to a

 

 15   psychologist rather than a psychiatrist to get a

 

 16   middle-of-the-road opinion.

 

 17             Because she was so depressed, we did

 

 18   eventually see a psychiatrist again, and she was

 

 19   prescribed one of the SSRI medication, Zoloft.

 

 20   Shortly after beginning this treatment, she had a

 

 21   serious suicide attempt.  The doctor at the

 

 22   hospital first thought that it was just another

 

 23   attempt trying to get attention, but after he

 

 24   interviewed her, his opinion changed.

 

 25             While she had been depressed, she had

 

                                                               177

 

  1   never attempted suicide before this time.

 

  2   Eventually, she was prescribed three medications,

 

  3   one of which was Paxil.  Three different times in

 

  4   her life she abruptly stopped taking the

 

  5   medications including Paxil, which resulted in

 

  6   manic episodes.

 

  7             Before her last episode, she had been

 

  8   stable for five years.  Then, during a very

 

  9   stressful time with her grandmother dying, she

 

 10   abruptly stopped the Paxil and experienced her

 

 11   worst manic episode with hallucinations and other

 

 12   health problems.

 

 13             She finally had to be court-ordered into

 

 14   the hospital and it devastated her life.  She lost

 

 15   her job as a security assistant at a hospital, and

 

 16   her roommates could no longer live with her because

 

 17   this was not the person that they had known and

 

 18   loved.

 

 19             That was two years ago and she is just

 

 20   beginning to put her life back together.  I would

 

 21   encourage the committee to look very closely at the

 

 22   suicide attempt ratio for children and teenagers

 

 23   taking these SSRI medications.

 

 24             Thank you.

 

 25             DR. RUDORFER:  We are up to I believe our

 

                                                               178

 

  1   final speaker of the morning session, and that is

 

  2   Dr. Thomas Moore.

 

  3                        Thomas Moore, M.D.

 

  4             DR. MOORE:  Good afternoon.  I represent

 

  5   Drug Safety Research.  I have completed two studies

 

  6   that raise additional questions about the safety of

 

  7   antidepressant drugs, and both of those studies

 

  8   should be in your binders.

 

  9             The first of those concerns the medical

 

 10   use of these drugs, who are taking them, and the

 

 11   headline finding is that in the four-period 1998 to

 

 12   2001, use of antidepressant drugs in children

 

 13   doubled.

 

 14             The second finding is that less than 10

 

 15   percent of these cases were these drugs being

 

 16   prescribed for FDA-approved use, and the remaining

 

 17   90 percent of the cases, they were for unapproved

 

 18   use or ones that raised safety concerns.  Let me

 

 19   give you some examples of what I found.

 

 20             Among boys 6 to 12 years old, 52 percent

 

 21   of the use was for treating attention deficit or

 

 22   conduct disorders typically in combination with an

 

 23   antipsychotic or a stimulant, such as Ritalin.

 

 24             Now, I know of no scientific evidence that

 

 25   says that combination therapy is effective in these

 

                                                               179

 

  1   disorders, and I know of no evidence that it is

 

  2   safe either.

 

  3             As you go on, combination therapy was very

 

  4   common in the real world.  Twenty-two percent were

 

  5   taking two antidepressant drugs, 17 percent were

 

  6   taking drugs that were ineffective in clinical

 

  7   trials, 42 percent were taking two of more

 

  8   antidepressant drugs.

 

  9             So, what we are seeing is when drugs are

 

 10   ineffective, rather than abandoning them or trying

 

 11   alternatives, doctors increase the dose or combine

 

 12   the drugs in ways, the safety of which we are not

 

 13   aware.

 

 14             The second major study that I submitted to

 

 15   you today is of the adverse event experience,

 

 16   largely the same data set, but different criteria

 

 17   from what the FDA has conducted.

 

 18             The two key findings there are, number

 

 19   one, it appears based on the medical use of these

 

 20   drugs that these drugs cause suicidal and related

 

 21   behaviors at double the expected rate compared to

 

 22   adults.  So, they seem to be being reported more

 

 23   frequently in children.

 

 24             The second finding is there appeared to be

 

 25   no difference in adverse event reports between the

 

                                                               180

 

  1   two drugs for which there were warnings, and those

 

  2   four drugs for which we do not have warnings.

 

  3             DR. RUDORFER:  Thank you, Dr. Moore.

 

  4             We will now end our morning session.  I

 

  5   want to thank all our open public hearing speakers

 

  6   for raising very important issues for the

 

  7   committee.  I believe we will have two additional

 

  8   public speakers during the afternoon session, but

 

  9   we are now going to take our lunch break.

 

 10             We will reconvene at 1 o'clock.

 

 11             [Whereupon, at 11:59 a.m., the proceedings

 

 12   were recessed, to be resumed at 1:00 p.m.

 

                                                               181

 

  1             A F T E R N O O N  P R O C E E D I N G S

 

  2                                                    [1:10 p.m.]

 

  3             DR. RUDORFER:  Good afternoon.

 

  4             We are going to begin this afternoon's

 

  5   session with several speakers from the FDA.  What

 

  6   we are going to do is hear a total of six speakers

 

  7   from the FDA, as well as our two remaining public

 

  8   speakers.  There will be a break along the way.

 

  9             I am going to ask the committee to save

 

 10   your questions until the end.  We will have a lot

 

 11   of time for discussion later this afternoon.

 

 12             First, I would like to introduce Dr.

 

 13   Gianna Rigoni from the Office of Drug Safety of the

 

 14   FDA.

 

 15             Pediatric and Adolescent Antidepressant

 

 16                       Drug Use in the U.S.

 

 17             DR. RIGONI:  Thank you, Dr. Rudorfer, and

 

 18   good afternoon.

 

 19             [Slide.]

 

 20             Today, I would like to describe for you

 

 21   antidepressant drug use trends in children and

 

 22   adolescents in outpatient settings to provide a

 

 23   context for further discussions this afternoon.

 

 24             [Slide.]

 

 25             First, I will describe the use of selected

 

                                                               182

 

  1   antidepressant products by prescriptions dispense

 

  2   in the United States, followed by the proportion of

 

  3   those prescriptions dispensed to 1- to

 

  4   17-year-olds.

 

  5             Next, I will examine the specialties of

 

  6   the physicians responsible for prescribing these

 

  7   products to children and adolescents.

 

  8             Finally, I will identify the primary

 

  9   diagnoses for which these products are used in

 

 10   these populations.

 

 11             [Slide.]

 

 12             The antidepressants examined in this

 

 13   analysis include the selective serotonin reuptake

 

 14   inhibitors, or SSRIs, as we refer to today, and the

 

 15   atypical antidepressants seen on this list here.

 

 16   Atypical include nefazodone, venlafaxine, and

 

 17   mirtazapine.

 

 18             These products will be presented at the

 

 19   molecule level, therefore, fluoxetine will refer to

 

 20   Prozac, Prozac Weekly, Sarafem, and all generic

 

 21   fluoxetine equivalents, and so on, for each

 

 22   product.

 

 23             All references to the term

 

 24   "antidepressants" in this talk will refer only to

 

 25   these 10 products.  Tricyclic antidepressants,

 

                                                               183

 

  1   MAOIs, and other products used to treat depression

 

  2   were not examined for this analysis.

 

  3             [Slide.]

 

  4             At this time, only three SSRI products

 

  5   have FDA-approved labeling for use in pediatric

 

  6   population.  Fluoxetine is the only product

 

  7   approved for the treatment of pediatric major

 

  8   depressive disorder at this time, while fluoxetine,

 

  9   sertraline, and fluvoxamine are approved for the

 

 10   treatment of obsessive-compulsive disorder in this

 

 11   population.

 

 12             Although only three products have

 

 13   FDA-approved labeling for the treatment of MDD and

 

 14   OCD, use of SSRIs and atypical antidepressants

 

 15   outside of current FDA labeling in pediatrics is

 

 16   endorsed by many in the medical community through

 

 17   various clinical practice guidelines.

 

 18             [Slide.]

 

 19             I will now describe the methods that were

 

 20   used in this analysis.

 

 21             [Slide.]

 

 22             Since data for 2003 was not complete in

 

 23   time for this presentation, we will look at drug

 

 24   use trends from 1988, the year fluoxetine was

 

 25   launched, through 2002.

 

                                                               184

 

  1             When examining trends and prescriber

 

  2   specialties and diagnoses related to prescribing

 

  3   these products, trends over a five-year period of

 

  4   time, from 1998 to 2002, were used.  Data on drug

 

  5   utilization will be presented from sources FDA has

 

  6   available under various contracts.  For this

 

  7   analysis, outpatient data was obtained from two

 

  8          IMS Health audits.

 

  9             IMS is a source of marketing data commonly

 

 10   used by the pharmaceutical industry and government

 

 11   agencies, and is used to obtain numbers of

 

 12   prescriptions dispensed, as well as diagnoses

 

 13   related to the recommendation of pharmaceutical

 

 14   products in physicians' offices in the U.S.

 

 15             [Slide.]

 

 16             The first IMS Health Audit examined the

 

 17   National Prescription Audit Plus, or NPA Plus, as I

 

 18   will refer from now on, measures dispensed

 

 19   prescriptions from the outpatient pharmacy settings

 

 20   seen here.  We have chain, independent, mass

 

 21   merchandisers, food stores with pharmacies, mail

 

 22   order and long-term care pharmacies.

 

 23             The number of estimated prescriptions

 

 24   dispensed are obtained from a sample of

 

 25   approximately 22,000 pharmacies in the U.S., and

 

                                                               185

 

  1   are projected nationally.

 

  2             [Slide.]

 

  3             Next, we examined data from the National

 

  4   Disease and Therapeutic Index Audit, or NDTI, from

 

  5   IMS Health.  NDTI collects data on drug products

 

  6   and diagnoses mentioned during office-based

 

  7   physician visits.

 

  8             A mention is a physician's treatment

 

  9   intention where they believe one of the selected

 

 10   antidepressants is appropriate, and important to

 

 11   remember is it could result in either a

 

 12   prescription, a refill authorization, or samples

 

 13   given to the patient.

 

 14             Information on trends of diagnoses,

 

 15   patients, and treatment patterns occurring during

 

 16   these visits are linked to each drug.  NDTI data

 

 17   are obtained from a sample of 2,000 to 3,000

 

 18   physicians representing approximately 100

 

 19   specialties in the U.S., and are projected

 

 20   nationally to reflect national prescribing

 

 21   patterns.

 

 22             The exact distribution of the specialties

 

 23   participating in the sample each year is

 

 24   unavailable at this time, but is roughly

 

 25   proportional to the distribution of office-based

 

                                                               186

 

  1   practice specialties in the United States.

 

  2             [Slide.]

 

  3             We will now examine antidepressant

 

  4   prescription trends, prescriber specialties, and

 

  5   diagnoses from 1988 through 2002.  I will first

 

  6   describe antidepressant use in the U.S. for all

 

  7   ages and then zoom in more specifically on the

 

  8   younger pediatric and adolescent age groups.

 

  9             [Slide.]

 

 10             It was estimated that over 157 million

 

 11   prescriptions for SSRIs and atypical

 

 12   antidepressants were dispensed in the United States

 

 13   for all ages in 2002.  The market leaders among

 

 14   these 10 products were sertraline, accounting for

 

 15   over 31 million prescriptions, followed closely by

 

 16   paroxetine, with 30.5 million.

 

 17             [Slide.]

 

 18             I will now graphically show you the use

 

 19   trends of these products since the launch of

 

 20   fluoxetine.  This graph has a lot of information on

 

 21   it, but it displays the national estimates of

 

 22   antidepressant use in the U.S. in millions of

 

 23   prescriptions dispensed for all ages, so this y

 

 24   axis here is in millions, and each product is

 

 25   represented by a different color line.

 

                                                               187

 

  1             Here, we see how the four products on the

 

  2   previous slide make up the highest volumes

 

  3   dispensed.  Here, you see paroxetine, sertraline,

 

  4   fluoxetine, and citalopram.  But more importantly,

 

  5   we see that for the past 15 years, there is an

 

  6   increasing and substantial number of prescriptions

 

  7   dispensed in outpatient pharmacy settings for these

 

  8   products.

 

  9             We will now examine the estimated use of

 

 10   these products in the younger pediatric and

 

 11   adolescent populations.

 

 12             [Slide.]

 

 13             First, I must describe how we estimated

 

 14   these numbers.  Since NPA Plus data does not

 

 15   include the demographic information about the

 

 16   patients receiving each prescription, we used NDTI

 

 17   to estimate the number of prescriptions dispensed

 

 18   to 1- to 17-year-olds.

 

 19             NPA Plus and NDTI were designed by IMS to

 

 20   be comparable in terms of volume of prescriptions

 

 21   dispensed and the proportion of office visits

 

 22   mentioning products dispensed in larger volumes.

 

 23             So, to estimate the number of SSRI and

 

 24   atypical antidepressant prescriptions dispensed to

 

 25   1- to 17-year-olds, the proportion of office visits

 

                                                               188

 

  1   in that population that involved the mention of one

 

  2   of these products were applied to the total number

 

  3   of prescriptions dispensed for that year.

 

  4             [Slide.]

 

  5             Applying the proportion of office visits

 

  6   to the national prescription estimates for 2002, I

 

  7   present to you the top five selected

 

  8   antidepressants in thousands of prescriptions

 

  9   dispensed to 1- to 17-year-olds.

 

 10             Approximately, 10.8 million total

 

 11   prescriptions were dispensed for all SSRIs and

 

 12   atypicals in this population, representing a

 

 13   substantial 7 percent of the market in 2002.

 

 14             Sertraline accounted for the highest

 

 15   volume of prescriptions dispensed, at 2.9 million,

 

 16   and paroxetine followed closely with approximately

 

 17   2.2 million, and this is for 2002.

 

 18             Next, I will more closely examine these

 

 19   patterns by breaking the 1- to 17-year age group

 

 20   into the younger pediatric population, which will

 

 21   represent 1- to 11-year-olds, and the adolescent

 

 22   population, which will represent 12- to

 

 23   17-year-olds.

 

 24             [Slide.]

 

 25             When we examined use in these

 

                                                               189

 

  1   subpopulations, we can still see substantial use of

 

  2   these products in both groups.  The younger

 

  3   pediatric population accounted for approximately

 

  4   2.7 million prescriptions dispensed in 2002.

 

  5   Sertraline again was the most commonly prescribed

 

  6   product, accounting for about 31 percent of

 

  7   dispensed antidepressants, followed by paroxetine

 

  8   and then fluoxetine.

 

  9             The adolescent population accounted for

 

 10   approximately 8.1 million prescriptions dispensed

 

 11   in 2002, and this is close to about 5 percent of

 

 12   all antidepressants dispensed in that year.

 

 13             Again, sertraline was the most commonly

 

 14   prescribed, accounting for 26 percent, but this

 

 15   time followed closely by paroxetine, with 22

 

 16   percent.

 

 17             [Slide.]

 

 18             Now that we better understand the trends

 

 19   in prescriptions dispensed for these products to

 

 20   children and adolescents, we need to better

 

 21   understand the specialties of the physicians most

 

 22   often prescribing these products.

 

 23             The top prescribers of SSRIs and atypical

 

 24   antidepressants in 1998 were compared to those of

 

 25   2002, and the top ranked specialties are listed

 

                                                               190

 

  1   here by age group and by year.

 

  2             Here, it makes sense to see psychiatry as

 

  3   the top prescribing specialty over time since it is

 

  4   hard to diagnose mental illness in younger

 

  5   populations.  There does appear to be some shifting

 

  6   in prescribers over time, though, as the pediatric

 

  7   specialty becomes responsible for a more

 

  8   substantial proportion of mentions of these

 

  9   products in 2002.

 

 10             As you can see, the proportion of

 

 11   pediatricians prescribing doubles over that

 

 12   five-year period in both populations, or nearly

 

 13   doubles in adolescents.

 

 14             [Slide.]

 

 15             Now, we will examine the diagnoses most

 

 16   commonly associated with these products in

 

 17   office-based practices. All diagnoses naturally

 

 18   fell into the following four categories:

 

 19             Mood disorders, represented here by the

 

 20   blue portion of the bar, include bipolar affective

 

 21   disorders and all depressive disorders; anxiety

 

 22   disorders are represented by the red portion of the

 

 23   bar, and they include anxiety, obsessive-compulsive

 

 24   disorder, and phobias.

 

 25             Attention-deficit disorder is represented

 

                                                               191

 

  1   by the yellow portion of the bar, and Other

 

  2   disorders are represented by the green portion.

 

  3             Now, these Other disorders include other

 

  4   diagnoses for psychiatric illnesses, such as

 

  5   adjustment disorder, personality disorder, and

 

  6   psychotic disorders, as well as including diagnoses

 

  7   for autism, migraine, convulsions, menstrual

 

  8   symptoms, eating disorders, and drug and alcohol

 

  9   dependency.

 

 10             We see nearly 900,000 physician office

 

 11   visits involved the mention of an antidepressant in

 

 12   the younger pediatric population in 2002.  This

 

 13   represents approximately 1.6 percent of all visits

 

 14   in the U.S. for these products across all ages.

 

 15             We also see that anxiety and mood

 

 16   disorders were the most common diagnoses in 2002,

 

 17   accounting for 30 percent and 26 percent,

 

 18   respectively, in this population.

 

 19             Office visits involving the mention of one

 

 20   of these products in adolescents is much higher, at

 

 21   2.6 million visits for 2002, and that represents

 

 22   about 5 percent of the visits in the U.S.  Mood

 

 23   disorders were the most common diagnoses treated

 

 24   with this product, accounting for nearly 60

 

 25   percent.

 

                                                               192

 

  1             Next, we will look at these bars more in

 

  2   depth as we examine diagnoses trends for specific

 

  3   drugs in younger pediatric and adolescent

 

  4   populations.

 

  5             [Slide.]

 

  6             This slide contains a lot of information,

 

  7   but I believe it is important to show that not all

 

  8   of these products are used in the same way in the

 

  9   younger pediatric population.

 

 10             The following graph displays the

 

 11   distribution of diagnoses for the top five

 

 12   antidepressants mentioned in 2002 to this

 

 13   population.  Notice here the percent scale on the y

 

 14   axis.  Each bar represents all mentions for these

 

 15   products to this age group, and the percent is what

 

 16   percent of the mentions for that drug were for each

 

 17   disorder.

 

 18             In the younger pediatric population, we

 

 19   see some variation in how these products are being

 

 20   used, and from the previous slide, we saw that both

 

 21   anxiety and depression or mood disorders were

 

 22   primarily treated with these products. It is seen

 

 23   right here in the graph.

 

 24             When we look at the top five, we also see

 

 25   that bupropion has the distinctive use in treating

 

                                                               193

 

  1   attention deficit disorders in this population, so

 

  2   that middle bar signifies bupropion, and the yellow

 

  3   portion is ADD.

 

  4             [Slide.]

 

  5             In the adolescent population, we see there

 

  6   is not much variation in prescribing of these

 

  7   products.  Mood disorders were the primary

 

  8   diagnosis being treated with all five products, but

 

  9   we do, however, once again see this distinctive use

 

 10   of bupropion for attention deficit disorders.

 

 11             [Slide.]

 

 12             Next, we wanted to determine if

 

 13   prescribing trends for these products has changed

 

 14   over the last five years.  In the younger pediatric

 

 15   population, we saw a shift in prescribing from 1998

 

 16   to 2002, from these antidepressants being used

 

 17   primarily to treat mood disorders, which were

 

 18   identified before as bipolar and other depressive

 

 19   disorders, to being used more to treat anxiety

 

 20   disorders, such as OCD and other anxiety or phobia

 

 21   disorders.

 

 22             We saw that in the adult population, there

 

 23   was no change in prescribing from 1998 to 2002, and

 

 24   that continuously over this time period, these

 

 25   products were used to treat mood disorders in this

 

                                                               194

 

  1   population.

 

  2             [Slide.]

 

  3             Some limitations of our drug use data

 

  4   analysis are, first, data on prescriptions

 

  5   dispensed include prescriptions filled in

 

  6   outpatient pharmacies only.  Inpatient and

 

  7   institutional use of these products was not

 

  8   included in this analysis.

 

  9             Secondly, prescriptions dispensed to 1- to

 

 10   17-year-olds were extrapolated from the proportion

 

 11   of these populations visiting a physician and

 

 12   receiving a prescription sample or refill

 

 13   authorization for one of these products, and this

 

 14   methodology has not yet been fully validated.

 

 15             Finally, data on diagnoses related to the

 

 16   use of these antidepressants reflects office-based

 

 17   physicians prescribing based on a small sample of

 

 18   physicians.  The small sample size may make these

 

 19   numbers unstable and could underestimate the

 

 20   prescribing patterns of certain subspecialists.

 

 21             Also, since these patients are not

 

 22   followed into the pharmacy after their appointment,

 

 23   a patient may not actually fill the antidepressant

 

 24   prescription.

 

 25             [Slide.]

 

                                                               195

 

  1             In conclusion, use of SSRIs and atypical

 

  2   antidepressants is substantial in children and

 

  3   adolescents, and appears to be increasing rapidly

 

  4   every year.  Pediatric specialists, pediatricians,

 

  5   and primary care providers continue to be the

 

  6   leading prescribers of these products, and over the

 

  7   past five years, the proportion of pediatricians

 

  8   prescribing these products has nearly doubled.

 

  9             Finally, diagnoses related to the use of

 

 10   these antidepressants are slightly different among

 

 11   the younger pediatric population who are being

 

 12   treated for mood and anxiety disorders, and the

 

 13   adolescent population who are being treated mostly

 

 14   for mood disorders.

 

 15             Thank you.

 

 16             DR. RUDORFER:  Thank you very much.

 

 17             This morning we heard from Dr. Murphy

 

 18   about the mandated adverse event review associated

 

 19   with one-year post-exclusivity for some

 

 20   medications.  Now, I am pleased to welcome Dr.

 

 21   Solomon Iyasu from the Division of Pediatric Drug

 

 22   Development who will give us a review of that

 

 23   information for paroxetine and citalopram.

 

 24            One-Year Post-Exclusivity Mandated Adverse

 

 25            Event Review for Paroxetine and Citalopram

 

                                                               196

 

  1             DR. IYASU:  Good afternoon.

 

  2             Today, I am going to be presenting adverse

 

  3   event reports that have been received by FDA and

 

  4   reviewed as mandated by the Best Pharmaceuticals

 

  5   for Children Act.

 

  6             [Slide.]

 

  7             The Best Pharmaceuticals for Children Act

 

  8   was enacted January 4, 2003, and Section 17

 

  9   mandates to FDA to review all adverse events for

 

 10   one year post-exclusivity determination, and then

 

 11   report to the Pediatric Advisory Subcommittee for

 

 12   their review.

 

 13             [Slide.]

 

 14             The data source for my presentation, as

 

 15   well as Dr. Mosholder's presentation following

 

 16   mine, is the FDA's Adverse Event Reporting System,

 

 17   which is a spontaneous and voluntary reporting

 

 18   system.

 

 19             FDA maintains an electronic database of

 

 20   postmarketing reports of adverse drug reactions,

 

 21   and reporters to this system include health care

 

 22   providers, pharmacies, consumers, and

 

 23   pharmaceutical manufacturers.  A large majority of

 

 24   these reports come from manufacturers.

 

 25             [Slide.]

 

                                                               197

 

  1             To make today's presentation relevant to

 

  2   today's topic, I will be focusing the later part of

 

  3   my presentation on the psychiatric adverse events

 

  4   that have been reported during this one-year

 

  5   post-exclusivity period.

 

  6             [Slide.]

 

  7             To give you some background about the drug

 

  8   that I will be talking about today, paroxetine is

 

  9   an antidepressant that belongs to the class of

 

 10   drugs which are called SSRIs, is marketed by

 

 11   GlaxoSmithKline.

 

 12             Adult indications that are approved by FDA

 

 13   include major depressive disorder,

 

 14   obsessive-compulsive disorder, panic disorder,

 

 15   social anxiety disorder, generalized anxiety

 

 16   disorder, and posttraumatic stress disorder.

 

 17             The typical adult dose, which are

 

 18   approved, are 20 to 60 milligrams per day.  There

 

 19   are no approved pediatric indications, and the

 

 20   exclusivity was granted January 27, 2002.

 

 21             I have to point out here that exclusivity

 

 22   to a sponsor can be granted without getting an

 

 23   approved indication as long as they do the study

 

 24   set that have been asked in the written request

 

 25   that FDA issues, and that they have met the

 

                                                               198

 

  1   criteria fairly as part of the written request.

 

  2             [Slide.]

 

  3             To give you some important information

 

  4   that is on the label already, paroxetine is

 

  5   Pregnancy Category C drug, which means that

 

  6   paroxetine has not been studied in pregnancy and

 

  7   therefore should be used only if potential benefit

 

  8   justifies the risk to the fetus.  It also should be

 

  9   used with caution in nursing mothers.

 

 10             There is also information on the

 

 11   Precautions section of the label, suicide risk is

 

 12   inherent in major depressive disorders especially

 

 13   before remission occurs, therefore, high-risk

 

 14   patients should be supervised very closely

 

 15   especially during the initial phases of therapy.

 

 16             There are also similar precautions about

 

 17   mania and also about seizures, and recommendations

 

 18   to use this medication with caution in patients who

 

 19   have a history of mania or seizures.

 

 20              There is also, on the same section,

 

 21   adverse events with abrupt discontinuation, which

 

 22   includes symptoms like agitation, anxiety,

 

 23   dizziness, sensory disturbance, that is related to

 

 24   withdrawal, and therefore, the recommendation is to

 

 25   taper it slowly.

 

                                                               199

 

  1             [Slide.]

 

  2             Now, I would just summarize the drug use

 

  3   trends for paroxetine, extensively discussed by

 

  4   Gianna before me, but paroxetine is the second most

 

  5   commonly used SSRI in children.  Both pediatric and

 

  6   adult prescriptions have steadily increased between

 

  7   1999 and 2003.

 

  8             The main diagnosis linked with its use

 

  9   include depression, anxiety, and

 

 10   obsessive-compulsive disorders in children.

 

 11             Pediatric patients account for

 

 12   approximately 3.5 percent of the total U.S.

 

 13   prescriptions of Paxil between July 2002 and June

 

 14   2003.

 

 15             [Slide.]

 

 16             To give you an overview of the adverse

 

 17   event reports that have been received by FDA since

 

 18   the original marketing for this medication, there

 

 19   were a total of 17,000 adult and pediatric reports

 

 20   including domestic and foreign that were received

 

 21   by FDA.  This included duplicates, as well, and 68

 

 22   percent of them were domestic.  Less than 5 percent

 

 23   of these reports were in pediatric patients

 

 24             Looking at the top 20 pediatric adverse

 

 25   events  for this entire period, the pediatric

 

                                                               200

 

  1   adverse event in the top 20 was similar to those

 

  2   reported in adults.  The majority were limited

 

  3   events related to mostly the events that resulted

 

  4   from maternal exposure, prenatal exposure.

 

  5             [Slide.]

 

  6             Looking at the annual reports of adverse

 

  7   events for this drug since 1992, there was

 

  8   distinctly an increase in 2002 compared to prior

 

  9   years.  These data, the bar graphs represent raw

 

 10   counts of adverse events that were received by FDA,

 

 11   and do not exclude the duplicate reports, and they

 

 12   are unadjusted for use.

 

 13             You will notice that the last bar graph,

 

 14   which is really representing the first half of the

 

 15   year, the numbers were 87, which seems to suggest

 

 16   that there is this continuing increase that was

 

 17   observed in 2002.

 

 18             [Slide.]

 

 19             Just to provide some context, I want to

 

 20   mention the timeline for some important events that

 

 21   may have some importance in this deliberation.

 

 22             First, the yellow line as you see here is

 

 23   the period of that inclusive post-exclusivity

 

 24   one-year period, and during that period, there was

 

 25   a BBC show, which is "The Secret of Seroxat," that

 

                                                               201

 

  1   was aired on October 2002 in the British TV, which

 

  2   subsequently got very widespread media coverage

 

  3   around the U.S. and other parts of the world.

 

  4             In 2003, the British Government warned

 

  5   against the use of Paxil, and FDA issued a talk

 

  6   paper on Paxil for its treatment of depression in

 

  7   June 2003.  Following the post-exclusivity period,

 

  8   in October 27, 2003, there was an FDA public

 

  9   advisory for antidepressants and suicide.

 

 10             The contents of this will be discussed

 

 11   more fully, I think when Dr. Laughren presents his

 

 12   talk.

 

 13             [Slide.]

 

 14             Now, focusing on the mandated period,

 

 15   which is a  one-year post-exclusivity determination

 

 16   period, after manual review of the reports, there

 

 17   were a total of 127 unduplicated pediatric adverse

 

 18   event reports.  The gender distribution was 61

 

 19   females and 59 males.

 

 20             The age distribution for these 127 reports

 

 21   were zero to 2, about 32, which mostly represented

 

 22   maternal exposures or prenatal exposures; 2 to 5,

 

 23   about 6, the majority were actually in the older

 

 24   kids.

 

 25             The outcomes for the 127, 10 percent of

 

                                                               202

 

  1   the reports included outcomes of death, which were

 

  2   13.  Approximately, a third of them also ended up

 

  3   in hospitals or at ER visits.

 

  4             [Slide.]

 

  5             The age distribution, to give you a flavor

 

  6   by type of exposure, is that in the

 

  7   maternal/breastfeeding exposure, the majority were

 

  8   in males, and in the direct pediatric exposure, the

 

  9   majority were females.

 

 10             The age distribution, as expected, in the

 

 11   maternal/breastfeeding group, 32 of them were less

 

 12   than 2 years of age, which actually most of them

 

 13   were in less than 1 month.  In the direct exposure,

 

 14   most of the reports came from older kids, mostly 12

 

 15   to 16, and 6 to 11.

 

 16             [Slide.]

 

 17             Looking at the pediatric exposures by

 

 18   reasons for exposure to paroxetine, looking at 127,

 

 19   33 of them were maternal exposure or breastfeeding

 

 20   exposure, and the rest of them are described in

 

 21   depression/dysthymia, 28; anxiety/panic or

 

 22   posttraumatic syndrome disorder, about 15; ADHD, 2;

 

 23   OCD, 1.  There were about 18 of them that had

 

 24   multiple diagnosis of psychiatric conditions, and

 

 25   then Others, which are a smattering of other

 

                                                               203

 

  1   conditions which occurred in single digit.  Unknown

 

  2   were in 21, we did not have any information in the

 

  3   reports about what the reason for exposure was.

 

  4             [Slide.]

 

  5             Looking again at the 127, concomitant

 

  6   medications were described in 55 out of the 127

 

  7   reports.  Specifically, paroxetine was mentioned as

 

  8   the only drug used in 5 cases. In most, it was

 

  9   actually not described whether there was

 

 10   concomitant medication or not.

 

 11             Reporters for this 127, looking at the

 

 12   type of reporter, one-third of the reports were

 

 13   actually from health professionals, two-thirds of

 

 14   them were from consumers, media, or litigation

 

 15   sources, which is really atypical in the sense that

 

 16   most of the reports that we get at FDA, two-thirds

 

 17   often come from health professionals.

 

 18             The dose range in the reports range from 5

 

 19   to 60 mg/day.  This excluded the

 

 20   maternal/breastfeeding exposure. This was really

 

 21   looking at the children that were exposed directly.

 

 22             [Slide.]

 

 23             The pediatric adverse events, looking at

 

 24   them from predominant events, there were about 68

 

 25   psychiatric adverse events, and discontinuation

 

                                                               204

 

  1   syndrome or decreasing dose was observed in 7,

 

  2   maternal exposure in 33 as previously described.

 

  3             Today, I am going to be focusing more on

 

  4   the psychiatric adverse events, which are 68

 

  5   reports that were received, and then the rest of

 

  6   the presentation in terms of describing the other

 

  7   events will be in tomorrow's presentation which I

 

  8   will be doing to the same committee.

 

  9             [Slide.]

 

 10             Looking at those 68 adverse events, and

 

 11   looking at labeled and unlabeled events, there were

 

 12   about 9 completed suicides reported, 17 suicide

 

 13   attempts, and suicidal ideation in 11 patients, and

 

 14   occurrence of other psychiatric symptoms that

 

 15   included mania, impulsivity, disinhibition, or

 

 16   obsessive behavior, and so forth.

 

 17             Then, unlabeled events were self-injurious

 

 18   behavior in about 10 patients, completed homicides

 

 19   in about 4, and then aggression, hostility,

 

 20   homicidal ideation in about 8 patients.

 

 21             [Slide.]

 

 22             Looking more closely at the psychiatric

 

 23   events, the gender distribution was 57 percent of

 

 24   them were in females.  The age distribution, most

 

 25   of them were in the older children 12 to 16 years

 

                                                               205

 

  1   of age, 60 percent of them, and 35 percent in 6 to

 

  2   11 years old.

 

  3             Concomitant medications were described

 

  4   only in 24 patients out of the 68, we did not have

 

  5   any information on the rest of them.  In 20 of the

 

  6   24 patients,  there were other psychotherapeutic

 

  7   agents being used, as well.

 

  8             Discontinuation or decrease in dose was

 

  9   noted in about 11 of the 68 patients that were

 

 10   reported.

 

 11             [Slide.]

 

 12             Going more in detail as to the

 

 13   discontinuation or decrease in dose with respect to

 

 14   psychiatric events, among the completed suicide, 1

 

 15   out of the 9, there was discontinuation or decrease

 

 16   in dose involved; suicidal attempts, 5 out of the

 

 17   17, and 2 out of the 4 for homicides, and then 3

 

 18   out of the 8 for the aggression/hostility/homicidal

 

 19   ideation.

 

 20             [Slide.]

 

 21             Looking closely at the suicide attempts,

 

 22   which were about 17, the majority of them were

 

 23   being treated for MDD or bipolar disorder.

 

 24   Concomitant medications were mentioned in

 

 25   approximately one-third of these patients, and

 

                                                               206

 

  1   discontinuation or decrease in dose in

 

  2   approximately one-fourth.

 

  3             [Slide.]

 

  4             Pediatric deaths, there were a total of 13

 

  5   as I mentioned before.  Because of the topic today,

 

  6   I will talk about the 9 completed suicides, and the

 

  7   rest of the patients will be discussed in

 

  8   tomorrow's presentation.

 

  9             [Slide.]

 

 10             Among the 9, the age distribution was 12

 

 11   to 16 years, and then the gender distribution of 5

 

 12   females and 4 males.  Initial diagnosis in these

 

 13   patients, 5 of them was major depressive disorder,

 

 14   1 explosive disorder, in 3 of them it was not

 

 15   known.

 

 16             Duration of treatment ranged from 14 days

 

 17   to 1 year.  Discontinuation was mentioned in 2

 

 18   patients.  Concomitant medications, that included

 

 19   also some psychotherapeutic agents, was mentioned

 

 20   in 4 patients, and there was possible substance

 

 21   abuse in 4 patients, and a history of prior

 

 22   attempts in 3 of them.

 

 23             [Slide.]

 

 24             In summary, the causality assessment was

 

 25   very difficult in many of the reviews that we have

 

                                                               207

 

  1   done with these reports, and many of the

 

  2   psychiatric events that were described in the

 

  3   reports occurred in patients with underlying

 

  4   psychiatric disorders, therefore, severity of

 

  5   illness/underlying disease may play a role, and it

 

  6   was very difficult to disentangle its effect from

 

  7   what might have been going on.

 

  8             There is also a prior history of suicide

 

  9   attempts in some of the patients, and in others,

 

 10   there was no negative history of this.  The other

 

 11   factors in terms of patient factors are concomitant

 

 12   medications that were mentioned in several of these

 

 13   patients, and also the lack in others.  So, there

 

 14   is the variability in terms of the type and the

 

 15   quality of the reports that we got.

 

 16             In terms of the reporting factors, there

 

 17   was inadequate detail in describing the event.

 

 18   They also varied in terms of descriptions that were

 

 19   in the reports.

 

 20             The timing of event in relationship to the

 

 21   medication was not always clear in many of these

 

 22   reports, and also ascertainment of reported events

 

 23   by medical professions was absent in many of these

 

 24   reports.  The lack of follow-up information also

 

 25   made it difficult to assess.

 

                                                               208

 

  1             [Slide.]

 

  2             I also want to mention the nature of the

 

  3   data system that we have, which is really a passive

 

  4   spontaneous and voluntary system, and it suffers

 

  5   from a number of limitations.

 

  6             Often there is underreporting of important

 

  7   events, and there may be also the reporting biases

 

  8   that are influenced by either media publicity, and

 

  9   also the well-known variability in terms of reports

 

 10   that we get or the frequency of report related to

 

 11   the length of time that a drug has been in the

 

 12   market.  In the early period of the marketing,

 

 13   there are more reports than later.

 

 14             The report quality, as I said, also may

 

 15   vary, missing details, example, concomitant

 

 16   medications is a common problem.  Also, because

 

 17   this is really enumerated data, we could not really

 

 18   estimate true incidence rate of events or exposure

 

 19   risk for many of these medications that we have

 

 20   reports for.

 

 21             So, the AERS database has some serious

 

 22   limitations in terms of interpreting the data that

 

 23   we have.

 

 24             [Slide.]

 

 25             In closing, the psychiatric events

 

                                                               209

 

  1   described in the adverse event reports may actually

 

  2   reflect to the underlying disease, because many of

 

  3   these events are also unexpected in other natural

 

  4   progression of the disease or part of the disease

 

  5   picture.

 

  6             It may also be a drug effect or other

 

  7   concomitant medication, or it may actually be lack

 

  8   of effectiveness of the drug, and it is very

 

  9   difficult from these reports to sort out what is

 

 10   going on.

 

 11             Therefore, evaluation of the controlled

 

 12   trials is necessary to sort out causality in terms

 

 13   of the observed adverse events.

 

 14             [Slide.]

 

 15             I am going to continue with the next drug,

 

 16   which is citalopram, but I would like to

 

 17   acknowledge the following individuals for their

 

 18   contribution for their review.

 

 19             [Slide.]

 

 20             Next, I will cover, as mandated by BPCA,

 

 21   citalopram, and will be talking about the adverse

 

 22   events in detail.

 

 23             [Slide.]

 

 24             To give you some background again about

 

 25   citalopram, it's an antidepressant belonging to

 

                                                               210

 

  1   SSRIs, and marketed by Forest Pharmaceuticals.

 

  2             Its current approved adult indication is

 

  3   for major depressive disorder.  The adult dose

 

  4   ranges from 20 to 40 mg/day.  There are no approved

 

  5   pediatric indications.

 

  6             The original market approval was July 17,

 

  7   1998, and exclusivity was granted July 9, 2002.

 

  8             [Slide.]

 

  9             Again, to mention some of the relevant

 

 10   safety labeling which already exists, Pregnancy

 

 11   Category C, as I mentioned before, and also a

 

 12   caution against the use in nursing mothers.

 

 13             There is also a Precaution section that

 

 14   mentions, similar to what is observed for Paxil,

 

 15   suicide risk inherent in depression and also the

 

 16   danger of activation of mania and hypomania.

 

 17             Also, additional events mentioned in the

 

 18   precautions, any psychoactive agent may impair

 

 19   intellectual or psychomotor functions, and

 

 20   therefore, care should be exercised in prescribing

 

 21   these medications when individuals have to operate

 

 22   machinery or other things that may require

 

 23   intellectual and motor functions.

 

 24             Seizures is another precaution that is

 

 25   mentioned especially in those with history of

 

                                                               211

 

  1   seizure.

 

  2             [Slide.]

 

  3             Additional safety information in the

 

  4   Adverse Reaction section is about agitation with

 

  5   the use of citalopram, and also additional

 

  6   premarketing reports which are frequent, impaired

 

  7   concentration, depression, suicide attempt, and

 

  8   confusion; and infrequently reported in premarket

 

  9   reports are aggressive reaction, psychotic

 

 10   reaction, delusion, paranoid reaction, emotional

 

 11   lability, and panic reaction.

 

 12             [Slide.]

 

 13             To give you just a summary of the drug use

 

 14   pattern, it is the fourth most commonly used SSRI

 

 15   in children.  Again, use had been increasing in

 

 16   recent years. Pediatric  patients account for

 

 17   approximately 3.3 percent of the total U.S.

 

 18   prescriptions of Celexa.

 

 19             Pediatric diagnoses most often linked with

 

 20   its use are depressive disorders,

 

 21   obsessive-compulsive disorder, and attention

 

 22   deficit order.

 

 23             [Slide.]

 

 24              Since marketing, there were over 6,000

 

 25   reports which included also duplicates that were

 

                                                               212

 

  1   reported to FDA, 79 percent of them were domestic.

 

  2   Less than 5 percent of the reports were in

 

  3   pediatric patients.

 

  4             The top 20 pediatric adverse events were,

 

  5   looking at that, all adverse events related to in

 

  6   utero exposure were unlabeled, which actually

 

  7   happened to be in the top 20 for pediatric adverse

 

  8   events.

 

  9             Adverse event reports for children

 

 10   involving direct exposure were generally similar to

 

 11   those reported for adults.

 

 12             [Slide.]

 

 13             After a manual review of the one-year

 

 14   post-exclusivity period, there were 42 unduplicated

 

 15   reports that were pediatric.  Sixteen of them were

 

 16   in utero exposures, and resulted in unlabeled

 

 17   events and one death.

 

 18             There were 26 children involving direct

 

 19   exposure, 8 unlabeled events, and no deaths in this

 

 20   group.

 

 21             Looking at the outcomes, there were 16

 

 22   serious outcomes, 10 hospitalizations, 4

 

 23   life-threatening, and 2 was disability.  For the

 

 24   direct exposure group, the dose range was typically

 

 25   5 to 60 mg/day.  The median dose was about 20

 

                                                               213

 

  1   mg/day in these reports.

 

  2             [Slide.]

 

  3             Again looking at the age distribution, in

 

  4   the in utero exposure, most of them female, as well

 

  5   as in the direct exposure group, and age

 

  6   distribution is 0 to 1 in 15 patients, and then

 

  7   most of the direct exposure group, in older

 

  8   children.

 

  9             [Slide.]

 

 10             Looking at the reasons for exposure to

 

 11   citalopram, there were 26 direct pediatric

 

 12   exposures and then 16 in utero exposures.  I am

 

 13   going to just focus on the adverse events

 

 14   pertaining to psychiatric, but these are the

 

 15   reasons for why they were exposed.

 

 16             [Slide.]

 

 17             There were only 5 psychiatric events, in 5

 

 18   patients where there were psychiatric events, and

 

 19   these are broken down by labeled and unlabeled

 

 20   events.

 

 21             In the labeled events are the cognitive

 

 22   impairment, aggression, agitation, mania, and

 

 23   delusions, suicidality, and psychotic reaction.

 

 24             Unlabeled events are the violent/homicidal

 

 25   behavior, which were observed in 2 of the patients.

 

                                                               214

 

  1             [Slide.]

 

  2             Looking at these 5 patients with

 

  3   psychiatric events, there were 4 males and 1

 

  4   female.  The age distribution as 6 to 11 years with

 

  5   2; 11 to 16, about 3 of them.  Diagnosis in 4 of

 

  6   them was MDD, and 1 case was oppositional defiant

 

  7   disorder, ODD.

 

  8             Concomitant medications were reported in 2

 

  9   patients, Prozac in 1, and another, Keppra and

 

 10   clonazepam. Symptom resolved once citalopram

 

 11   discontinued in 4 according to the reports.

 

 12             [Slide.]

 

 13             In closing, I would like to say there were

 

 14   few psychiatric events that were reported during

 

 15   this one-year post-exclusivity period, unable

 

 16   really to determine causality due to limitations of

 

 17   the AERS database, therefore, we will continue to

 

 18   monitor these adverse events in children.

 

 19             I would like to reiterate the same

 

 20   limitations that I mentioned before with respect to

 

 21   paroxetine when I talked about limitations of the

 

 22   AERS database.

 

 23             Thank you very much for your attention.

 

 24             DR. RUDORFER:  Thank you.

 

 25             Dr. Andrew Mosholder will now speak on the

 

                                                               215

 

  1   Office of Drug Safety Data Resources for the Study

 

  2   of Suicidal Events.

 

  3             Andy.

 

  4             Office of Drug Safety Data Resources for

 

  5                   the Study of Suicidal Events

 

  6             DR. MOSHOLDER:  Thank you very much.

 

  7             I am very pleased to be here this

 

  8   afternoon.  I am going to talk about how we looked

 

  9   at some of our Office of Drug Safety data resources

 

 10   to see if they would be relevant to exploration of

 

 11   this issue.

 

 12             [Slide.]

 

 13             It is very much a team effort and I want

 

 14   to start by acknowledging my colleagues who

 

 15   assisted me.

 

 16             [Slide.]

 

 17             The objective of my brief presentation

 

 18   will be to describe the data resources we have

 

 19   available in the Office of Drug Safety at FDA that

 

 20   are relevant to this issue, and, in particular,

 

 21   looked at two types of databases, the first being

 

 22   the postmarketing surveillance database that Dr.

 

 23   Iyasu just described, and also some

 

 24   population-based epidemiological databases.

 

 25             Also, I will be describing the context of 

 

                                                               216

 

  1         spontaneous postmarketing reports of these

 

  2   types of events    with newer antidepressants.

 

  3             [Slide.]

 

  4             Turning first to the postmarketing

 

  5   surveillance data from the AERS system as you have

 

  6   just heard about.

 

  7             [Slide.]

 

  8             We did a special search for these events,

 

  9   and I will describe the methods.  The list of drugs

 

 10   is shown here, and it is the same drugs we have

 

 11   been discussing throughout the day.  We limited the

 

 12   age on the report to patients 17  years or younger,

 

 13   and we looked at U.S. reports only.

 

 14             [Slide.]

 

 15             In the AERS database, the events are

 

 16   classified under particular adverse event terms

 

 17   according to the so-called MedDRA dictionary.  We

 

 18   chose a list of event terms that we thought would

 

 19   capture suicidal behaviors and ideation.  I will

 

 20   let you read for yourselves the list, but that was

 

 21   the list of terms that we searched in the AERS data

 

 22   base for those events.

 

 23             [Slide.]

 

 24             The results showed for all those drugs

 

 25   over their full marketing history, there was a

 

                                                               217

 

  1   total of 524 case reports, of which 110 were death

 

  2   reports.  I should add that these are raw counts,

 

  3   which means there was no hands-on review for

 

  4   duplicate reports.

 

  5             Occasionally, the same case will be

 

  6   reported by more than one health professional or

 

  7   the health professional and the consumer, and those

 

  8   are referred to as duplicate reports.  So, these

 

  9   are just the raw counts.

 

 10             [Slide.]

 

 11             Here they are broken down by drug, and you

 

 12   see they are ranked in order.  You see fluoxetine

 

 13   has the most, and, roughly speaking, the numbers of

 

 14   reports parallels the prevalence of their use in

 

 15   the pediatric population, so that is not too

 

 16   surprising.

 

 17             [Slide.]

 

 18             What this displays is the same totals

 

 19   broken down by year of reports.  So, we see the

 

 20   year the report was received down here on the x

 

 21   axis, and the number of reports.

 

 22             A couple of things to observe here.  First

 

 23   of all, for most of the drugs, we see that there is

 

 24   between, say, zero and 10 reports annually, and

 

 25   then, of course, there are these two sort of

 

                                                               218

 

  1   exceptions to that.  There is a peak over here in

 

  2   the early '90s, and that is for fluoxetine, and

 

  3   then in the last two to three years, there is

 

  4   another peak, and that is for paroxetine.

 

  5             The one thing to point out here relevant

 

  6   to the fluoxetine, as I am sure everyone is aware,

 

  7   this peak coincides with the controversy in the

 

  8   early '90s about whether fluoxetine can induce

 

  9   suicidality.  In fact, in 1991, there was an

 

 10   advisory committee about that topic.

 

 11             To understand this increase with the

 

 12   paroxetine reports, we looked at that in a little

 

 13   more detail, as I will show you.

 

 14             [Slide.]

 

 15             This shows the proportion of reports

 

 16   according to whether they were consumer or health

 

 17   professional, and the interesting thing here is

 

 18   that while the health professional reports have

 

 19   remained fairly constant over the years, what we

 

 20   see in the last two to three years is an increase

 

 21   in the proportion of reports that are coming from

 

 22   consumers, which, of course, doesn't mean that they

 

 23   are not legitimate reports, but it does illustrate

 

 24   that there is some influence on the spontaneous

 

 25   reporting that is encouraging consumers to report

 

                                                               219

 

  1   more of the these events in the last few years, and

 

  2   that seems to account for this increase.

 

  3             [Slide.]

 

  4             To go into things a little more in depth,

 

  5   we decided to look at reports from the first three

 

  6   years of marketing and do an in-depth review.

 

  7             We took reports for all 10 drugs from the

 

  8   first three years that they were marketed in the

 

  9   U.S.  This is a standard way in

 

 10   pharmacoepidemiology of comparing reports across

 

 11   drugs to account for the so-called Weber effect

 

 12   that applies during the first three years of a

 

 13   drug's marketing history.

 

 14             Even so, during this time period, there

 

 15   was limited pediatric use of these drugs, and

 

 16   because of secular trends, changes in reporting

 

 17   systems, and other variables, it is still very

 

 18   difficult to make quantitative comparisons between

 

 19   drugs.

 

 20             [Slide.]

 

 21             So, we looked at these reports, we

 

 22   eliminated duplicate reports, and we chose four

 

 23   suicide-related categories - suicidal ideation,

 

 24   suicide attempt, completed suicide, and

 

 25   self-mutilation, and classified the reports into

 

                                                               220

 

  1   one of those categories.

 

  2             [Slide.]

 

  3             This shows the results.  There were 94

 

  4   reports retrieved from the AERS system.  After

 

  5   review for duplicates, there were 78 unduplicated

 

  6   reports, which gives you an idea of the proportion

 

  7   of duplication.  It is something like 15 percent.

 

  8             This was for 9 drugs, no cases for

 

  9   nefazodone.  Out of these 78 reports, most were

 

 10   female, most were over 12 years of age, and that is

 

 11   consistent with what we know about the epidemiology

 

 12   of suicidal behavior in adolescents.  Most of the

 

 13   events were classified as suicide attempts.

 

 14             There were 7 completed suicides, 6 with

 

 15   fluoxetine, 1 paroxetine, 4 males, and 3 females.

 

 16   We found no reports of rechallenge with the same

 

 17   drug, which is sometimes used as an indication of

 

 18   evaluating the causality.

 

 19             [Slide.]

 

 20             This slide shows the numbers of reports by

 

 21   category here and by drug.  If you look at the

 

 22   total, you see that, as I already mentioned, 67 out

 

 23   of 78 were in the suicide attempt category.

 

 24             Again, these are ranked in terms of the

 

 25   totals.  You see that fluoxetine again has the

 

                                                               221

 

  1   most. Again, this sort of roughly parallels the

 

  2   prevalence of their pediatric use.

 

  3             [Slide.]

 

  4             So, interpreting these results, we would

 

  5   say that suicidality was reported with all drugs.

 

  6   The drugs with the largest numbers of reports

 

  7   coincided, roughly speaking, with the greatest

 

  8   amount of pediatric use.

 

  9             The reporting is variable and appears to

 

 10   be influenced by various events and also because of

 

 11   the quality and variability and low pediatric use,

 

 12   the data really do not support quantitative

 

 13   comparison between drugs.

 

 14             [Slide.]

 

 15             In general, AERS data are most useful for

 

 16   distinctive or rare adverse drug reactions, such as

 

 17   aplastic anemia.  The problem here, as Dr. Iyasu

 

 18   has already described, is that the outcome of

 

 19   interest that we are tracking, which is

 

 20   suicidality, is also an outcome of the indication

 

 21   for which the drug is prescribed, so that it is

 

 22   very difficult to sort out whether the drug played

 

 23   a role or whether it was the underlying disorder

 

 24   from evaluating data of this type.

 

 25             [Slide.]

 

                                                               222

 

  1             I want to move on to look at some other

 

  2   data resources that we have in ODS and tell you

 

  3   about that.

 

  4             [Slide.]

 

  5             We looked at four principal sources that

 

  6   could be used, one, the Tennessee Medicaid.  That

 

  7   is a health care claims database.  We have two

 

  8   surveillance databases.  I will let you read the

 

  9   descriptions, but they are maintained by CDC and

 

 10   the Consumer Products Safety Commission.

 

 11             This one applies to hospital emergency

 

 12   rooms, and this one applies to emergency rooms and

 

 13   also ambulatory care.

 

 14             Finally, there is the Oregon Adolescent

 

 15   Suicide Attempt Data System.  In the State of

 

 16   Oregon, adolescent suicides and suicide attempts

 

 17   are reportable conditions, so that the State Center

 

 18   for Health Statistics maintains a database on those

 

 19   reports.

 

 20             [Slide.]

 

 21             To summarize briefly, there are

 

 22   significant limitations in attempting to use these

 

 23   data sources to evaluate this issue.  One was

 

 24   rarity of completed suicide, difficulty in

 

 25   identifying individuals with outcome of completed

 

                                                               223

 

  1   suicide.  It may not generate a health care claim,

 

  2   for example.

 

  3             There is great difficulty in classifying

 

  4   non-fatal suicidal behavior, as we have already

 

  5   heard about, difficulty obtaining data on drug

 

  6   exposure prior to the event, lack of suitable

 

  7   control groups, confounding by indication, and

 

  8   privacy restrictions.

 

  9             [Slide.]

 

 10             In conclusion, for the study of this issue

 

 11   of pediatric suicidal behavior associated with

 

 12   antidepressant treatment, the available

 

 13   pharmacoepidemiological data and postmarketing

 

 14   surveillance data is of limited utility, and

 

 15   randomized, controlled trial data should be

 

 16   superior to these sources.

 

 17             Thank you very much.

 

 18             DR. RUDORFER:  Thank you.

 

 19                       Open Public Hearing

 

 20             DR. RUDORFER:  We will now turn to the

 

 21   afternoon portion of our open public hearing.

 

 22             I am mandated to read the ground rules for

 

 23   meetings of general matters, so if you will bear

 

 24   with me for a moment, I need to address our open

 

 25   public hearing speakers.

 

                                                               224

 

  1             Both the FDA and the public believe in a

 

  2   transparent process for information gathering and

 

  3   decisionmaking.  To ensure such transparency at

 

  4   this open public hearing session of the Advisory

 

  5   Committee meeting, FDA believes that it is

 

  6   important to understand the context of an

 

  7   individual's presentation.

 

  8             For this reason FDA encourages you, the

 

  9   open public hearing speaker, at the beginning of

 

 10   your oral statement to advise the committee of any

 

 11   financial relationship that you may have with any

 

 12   company or any group that is likely to be impacted

 

 13   by the topic of this meeting.  For example, the

 

 14   financial information may include a company's or a

 

 15   group's payment of your travel, lodging, or other

 

 16   expenses in connection with your attendance at the

 

 17   meeting.

 

 18             Likewise, FDA encourages you at the

 

 19   beginning of your statement to advise the committee

 

 20   if you do not have any such financial

 

 21   relationships.  If you choose not to address the

 

 22   issue of financial relationships at the beginning

 

 23   of your statement, it will not preclude you from

 

 24   speaking.

 

 25             With that, we will turn to our first

 

                                                               225

 

  1   afternoon speaker, David Fassler.

 

  2                       David Fassler, M.D.

 

  3             DR. FASSLER:  Thank you.  My name is David

 

  4   Fassler.  I am a child and adolescent psychiatrist

 

  5   practicing in Burlington, Vermont.  I am speaking

 

  6   today on behalf of the American Psychiatric

 

  7   Association where I serve on the board of trustees.

 

  8             The APA represents over 35,000 psychiatric

 

  9   physicians across the country.  The APA receives

 

 10   funding from a variety of sources including

 

 11   pharmaceutical companies, but no pharmaceutical

 

 12   funding was used in conjunction with my appearance

 

 13   today or the preparation of my comments.

 

 14             You have already heard lots of testimony

 

 15   today, so let me try and briefly highlight and

 

 16   underscore a few key issues.

 

 17             First, childhood and adolescent depression

 

 18   is a very real illness which will affect between 3

 

 19   and 5 percent of all young people.  The good news

 

 20   is that we can help most kids who suffer from this

 

 21   disorder.  Intervention is most effective when it

 

 22   begins early and when it involves a comprehensive

 

 23   treatment plan individualized to the needs of the

 

 24   child and family.

 

 25             Because we care deeply about children, we

 

                                                               226

 

  1   encourage parents to be advocates for their kids,

 

  2   to ask lots of questions about any proposed course

 

  3   of treatment.  We also encourage the FDA to develop

 

  4   mechanisms to enhance access to data from clinical

 

  5   trials including negative trials, as well as

 

  6   unpublished research.

 

  7             We believe that such access would

 

  8   facilitate scientific discussion and dialogue and

 

  9   help physicians and parents make fully informed

 

 10   decisions about treatment options.

 

 11             Second, with specific reference to

 

 12   suicidal ideation, it is important to emphasize

 

 13   that such thinking is always a very real concern,

 

 14   and as you have heard this morning, it is also not

 

 15   uncommon.

 

 16             From the Youth Risk Behavior Survey, we

 

 17   know that 1 adolescent in 5 thinks about suicide

 

 18   each year, and that by the end of high school, at

 

 19   least 1 in 10 has made an actual suicide attempt.

 

 20             Third, medications can be extremely

 

 21   helpful and even lifesaving for some children, but

 

 22   medication alone is rarely a sufficient treatment

 

 23   for complex child psychiatric disorders such as

 

 24   depression.

 

 25             Finally, we are concerned that the

 

                                                               227

 

  1   publicity surrounding this issue may frighten some

 

  2   parents and discourage them from seeking help for

 

  3   their children.  This would be a real tragedy since

 

  4   the reality is that we really can help most of

 

  5   these kids.

 

  6             DR. RUDORFER:  Thank you, Dr. Fassler.

 

  7             Our next speaker is Dr. Lawrence Diller.

 

  8                      Lawrence Diller, M.D.

 

  9             DR. DILLER:  Last but not least.  I am

 

 10   behavioral developmental pediatrician who has

 

 11   prescribed psychiatric drugs to children for 26

 

 12   years.  I have no financial connections to the

 

 13   industry.

 

 14             I am the author of Running on Ritalin and

 

 15   Should I Medicate My Child.

 

 16             As a front-line practitioner, I have lost

 

 17   faith in my research academic colleagues to provide

 

 18   me the data information, opinion, and conclusions

 

 19   in an objective and unbiased fashion.  I

 

 20   desperately need that information in order to

 

 21   validate and augment the clinical decisions I must

 

 22   make every day on who does and doesn't get

 

 23   medication.

 

 24             Unfortunately, in my quarter century of

 

 25   practice, I have seen child psychiatry's biologic

 

                                                               228

 

  1   revolution hijacked by a for-profit drug industry.

 

  2   Drug companies so pervasively influence academic

 

  3   research, professional education, now direct

 

  4   consumer information, ultimately determining the

 

  5   very way society views its own problems.

 

  6             I see top research leaders in the field of

 

  7   child psychiatry simultaneously publishing papers

 

  8   in scientific peer-reviewed journals while

 

  9   appearing in press conferences for corporations

 

 10   that have funded the research, which is then

 

 11   reported in the Wall Street Journal.

 

 12             We learn of nonpublication agreements of

 

 13   negative finding studies and limited access to raw

 

 14   data that potentially allows for completely

 

 15   different interpretations or conclusions based upon

 

 16   the published information.

 

 17             At this time, the conflict of interest

 

 18   between my academic colleagues and the drug

 

 19   industry rivals that of the stock analysts and the

 

 20   brokerage firms.  Doctors are at risk of being

 

 21   regulated by the government, but this is unlikely

 

 22   to happen soon since the public and the Congress

 

 23   have been similarly influenced or bought by these

 

 24   powerful corporations.

 

 25             Unfortunately, it will take children dying

 

                                                               229

 

  1   followed by trial lawyer class action suits to get

 

  2   changes either in the practice or the regulation of

 

  3   the SSRIs.  That is a heck of a costly way, both

 

  4   the individual families and the public, for what

 

  5   should be routine formal postmarketing drug

 

  6   surveillance funded by neutral third parties.

 

  7             Until then, I hope there is more

 

  8   government-funded research, but as long as I only

 

  9   have research funded or suppressed by drug

 

 10   companies, I will remain quite cautious and

 

 11   hypervigilant over what I prescribe the youth of

 

 12   America.

 

 13             Thank you.

 

 14             DR. RUDORFER:  Thank you, Dr. Diller.

 

 15             At this time we are going to take just a

 

 16   very quick break and return for further speakers

 

 17   from the FDA. Let's say five minutes if possible.

 

 18   Thanks.

 

 19             [Break.]

 

 20             DR. RUDORFER:  We have three additional

 

 21   speakers from the FDA who will address some of the

 

 22   important data at hand and that is still emerging.

 

 23             First, I am pleased to introduce Dr.

 

 24   Thomas Laughren, who is team leader of the Division

 

 25   of Neuropharmacologic Drug Products, who will

 

                                                               230

 

  1   discuss with us the regulatory history on

 

  2   antidepressants and suicidality, and give us an

 

  3   update on current plans for the analysis of

 

  4   pediatric suicidality data.

 

  5            Regulatory History on Antidepressants and

 

  6             Suicidality and Update on Current Plans

 

  7            for Analysis of Pediatric Suicidality Data

 

  8             DR. LAUGHREN:  Thank you, Matt.

 

  9             [Slide.]

 

 10             I am going to talk very briefly about the

 

 11   regulatory history of antidepressants and

 

 12   suicidality, and then spend most of my time talking

 

 13   about our current plans for looking at the

 

 14   pediatric suicidality data coming out of the

 

 15   controlled trials

 

 16             But first I would like to thank the

 

 17   families who came forward this morning to talk

 

 18   about their very personal stories, both the

 

 19   families that talked about tragic outcomes and

 

 20   those who talked about children who appear to have

 

 21   been helped by medications.

 

 22             It is very hard to do that, and I think it

 

 23   helps us to put all of this discussion in context,

 

 24   but a very important point, and this has been made

 

 25   several times, it is very difficult to assess

 

                                                               231

 

  1   causality based on individual cases.  That is true

 

  2   both of those cases where the outcome is tragic,

 

  3   but also true of the cases where the outcome is

 

  4   good.

 

  5             For either of those, we have to turn to

 

  6   controlled trials, so my focus is going to be on

 

  7   the controlled trials.

 

  8             [Slide.]

 

  9              What I have given you in this slide is

 

 10   the standard language which is in all

 

 11   antidepressant labeling, and has been in

 

 12   antidepressant labeling for decades.  This is in

 

 13   the Precaution section.  Essentially, it warns

 

 14   clinicians of the possibility of a suicide attempt

 

 15   in major depressive disorder, and advises

 

 16   clinicians especially early in treatment to watch

 

 17   patients very carefully.

 

 18             Now, this statement does not explicitly

 

 19   warn of the possible linkage between antidepressant

 

 20   use and the emergence of suicidality, but I think

 

 21   it allows for that interpretation and, in fact,

 

 22   this idea that antidepressants may be associated

 

 23   with the emergence of suicidality early in

 

 24   treatment has been around for a very long time in

 

 25   psychiatry.

 

                                                               232

 

  1             [Slide.]

 

  2             This is a statement from a textbook of

 

  3   psychiatry published in 1960.  This was the time at

 

  4   which the tricyclic antidepressants had just come

 

  5   on the scene.  Let me read it.

 

  6             It says, "With beginning convalescence,

 

  7   the risk of suicide once more becomes serious as

 

  8   retardation fades."

 

  9             [Slide.]

 

 10             What this statement is referring to is

 

 11   what is commonly known as the roll back phenomenon.

 

 12   This is the observation again of emergent

 

 13   suicidality early in treatment and the belief, the

 

 14   belief that that is in some way linked to the use

 

 15   of the drug, and the view, the mechanism proposed

 

 16   is that antidepressants give patients increased

 

 17   energy, particularly those with psychomotor

 

 18   retardation, that allows them to act on their

 

 19   suicidal ideas before the drug has had a chance to

 

 20   affect mood.

 

 21             So, this is one proposed mechanism for

 

 22   this observation.  In fact, it is only one of

 

 23   several proposed mechanisms.  When we met with the

 

 24   advisory committee in 1991, to talk at that time

 

 25   about Prozac and the possibility of suicidal

 

                                                               233

 

  1   induction, Dr. Martin Teicher from Harvard

 

  2   University reviewed a number of proposed mechanisms

 

  3   to explain this observation including the roll back

 

  4   phenomenon.

 

  5             But he also talked about the possibility

 

  6   of actually a paradoxical worsening of depression,

 

  7   in other words, the mood actually becoming worse

 

  8   rather than better.

 

  9             He talked about the possible role of

 

 10   akathisia, which is associated with many of these

 

 11   drugs, about the induction of anxiety and panic

 

 12   attacks by some of these drugs, about the idea that

 

 13   patients with bipolar depression may experience a

 

 14   stage shift, in other words, moving from depression

 

 15   to a mixed state, and finally, even the induction

 

 16   of insomnia.

 

 17             All of these ideas, the idea is that once

 

 18   these behaviors are induced, there is then a link

 

 19   from that behavior to suicidality, and all of these

 

 20   proposed mechanisms have some plausibility, but it

 

 21   is quite a different matter between proposing a

 

 22   mechanism and empirically establishing that there

 

 23   is, in fact, a link between the use of an

 

 24   antidepressant and the emergence of suicidality.

 

 25             [Slide.]

 

                                                               234

 

  1             That is really the question that we are

 

  2   dealing with here today and that is the question we

 

  3   hope to be able to address with these clinical

 

  4   trials data for these pediatric studies:  Is there

 

  5   a causal link between antidepressant drug use and

 

  6   suicidality in pediatric patients with major

 

  7   depressive disorder or with other psychiatric

 

  8   disorders?

 

  9             We agree that this is a critically

 

 10   important question to answer, but we also feel that

 

 11   it is important to answer it in a careful and

 

 12   thoughtful manner because to err in either

 

 13   direction has significant consequences.

 

 14             Clearly, we do not want to miss a signal

 

 15   of increased risk of suicidality, because that

 

 16   would give us greater comfort in the use of these

 

 17   drugs than would be warranted.

 

 18             On the other hand, we don't want to reach

 

 19   a premature decision on the strength of the signal

 

 20   because that could result either in the overly

 

 21   conservative use of these medications or in their

 

 22   lack of availability all together for treating

 

 23   pediatric depression.  So, it is important to get

 

 24   it right.

 

 25             [Slide.]

 

                                                               235

 

  1             In this slide, what I have done is to list

 

  2   the 9 drugs that are involved in our ongoing

 

  3   review.  You have seen this list before today.

 

  4   This involves a total of 25 studies in pediatrics,

 

  5   16 of them in major depression, the others in

 

  6   various other pediatric disorders, involving a

 

  7   total of over 4,000 patients.

 

  8             [Slide.]

 

  9             Right now let me talk a little bit about

 

 10   how the signal came onto our radar screen.  We had

 

 11   reviewed over the past three to four to five years

 

 12   pediatric supplements for 8 drugs, and we looked at

 

 13   the safety and efficacy data for these drugs.

 

 14             In the course of putting together a report

 

 15   for FDA, companies code their adverse event data,

 

 16   and they do this in their own ways.  We don't tell

 

 17   them how to code the data, they choose their own

 

 18   dictionaries and they set about coding the data

 

 19   before they send it in.

 

 20             This applied to any events suggestive of

 

 21   suicidality, as well as any other adverse events.

 

 22   We reviewed those supplements over this period of

 

 23   three to four years, and suicidality did not emerge

 

 24   as a matter of concern based on those reviews.

 

 25             However, the Paxil review did raise a

 

                                                               236

 

  1   question about data management in that events

 

  2   suggestive of suicidality were coded under the

 

  3   general preferred term "emotional lability."

 

  4             This struck the reviewer as rather odd,

 

  5   and so in responding to GSK, we asked them to

 

  6   separate out the verbatim terms suggestive of

 

  7   suicidality under a term specific to suicidality.

 

  8             [Slide.]

 

  9             That request to GlaxoSmithKline resulted

 

 10   in additional work and ultimately resulted in a

 

 11   report on paroxetine and pediatric suicidality.

 

 12   That report went first to the MHRA -- that is FDA's

 

 13   counterpart in the UK -- and shortly thereafter to

 

 14   FDA in May of last year.

 

 15             That report indeed suggested an increased

 

 16   risk of suicidality associated with paroxetine use

 

 17   in particular in one of the three studies done in

 

 18   pediatric depression.

 

 19             [Slide.]

 

 20             What I am going to do in the next two

 

 21   slides is to quickly walk you through a timeline of

 

 22   key events that occurred over the past eight months

 

 23   to try and give you a sense of how we got from the

 

 24   time of that initial report up to the present time.

 

 25             So, that report was issued in May.  In

 

                                                               237

 

  1   June, both FDA and MHRA issued regulatory

 

  2   responses.  As you heard earlier, the MHRA

 

  3   essentially contraindicated paroxetine in pediatric

 

  4   depression.  FDA came out with fairly strong

 

  5   language that recommended against its use in

 

  6   pediatric depression, but stopped short of a

 

  7   contraindication, and, in essence, we said that we

 

  8   were continuing to look at the data.

 

  9             In July, we issued a request to sponsors

 

 10   of the eight other antidepressant products asking

 

 11   them to look at the suicidality data in their

 

 12   databases using an approach similar to that, that

 

 13   had been used by GSK, and I will talk about that

 

 14   approach a little bit later.

 

 15             So, in essence, we wanted to look at

 

 16   summary data from the other programs, similar to

 

 17   what had been given to us for Paxil.  In August of

 

 18   last year, we went back and relooked at the

 

 19   suicidality data in the pediatric supplements.

 

 20             In August, Wyeth, the manufacturer of

 

 21   Effexor, having responded to our July request and

 

 22   having looked at their data, decided that they did

 

 23   have a signal and they made a labeling change which

 

 24   they are allowed to do under changes being effected

 

 25   without our prior approval, so they changed their

 

                                                               238

 

  1   labeling, adding information about that perceived

 

  2   signal, and they also sent a Dear Doctor letter

 

  3   which essentially recommended against the use of

 

  4   Effexor in pediatrics.

 

  5             Also, at that time, MHRA contraindicated

 

  6   Effexor in pediatric depression.

 

  7             In September of last year, we held an

 

  8   internal regulatory briefing at FDA.  We hold these

 

  9   briefings basically to update upper management on

 

 10   key issues that are before us, and this certainly

 

 11   was a key issue, and we have the briefing.

 

 12             There were a number of recommendations

 

 13   that came out of that briefing.  Two were of

 

 14   critical importance to our ongoing review.  One of

 

 15   those was the suggestion that we think about

 

 16   reclassifying the cases, because there was some

 

 17   uncertainty about what this diverse array of events

 

 18   coded under this broad term "possibly

 

 19   suicide-related" actually meant.  So, there was a

 

 20   suggestion that we do that.

 

 21             There was also a suggestion that we think

 

 22   about doing a more refined data analysis, allowing

 

 23   the use of adjustment for covariates.

 

 24             [Slide.]

 

 25             In September and October, we began to get

 

                                                               239

 

  1   responses to our July requests for summary data for

 

  2   other antidepressants, and it gave us some cause

 

  3   for concern, because we were seeing that sponsors

 

  4   had not used exactly the same approaches that we

 

  5   had suggested in our July request.

 

  6             In October, we issued an updated Public

 

  7   Health Advisory, at this time essentially

 

  8   broadening the concern to all antidepressants.  In

 

  9   essence, we advised clinicians to use caution when

 

 10   using these drugs in pediatric depression,

 

 11   essentially, to pay attention to the language that

 

 12   is already in labeling.

 

 13             In October, having thought more about a

 

 14   patient level data analysis allowing us to look at

 

 15   covariates, we issued a response to all

 

 16   antidepressant manufacturers asking them to give us

 

 17   patient level data sets to allow us to do this

 

 18   analysis.

 

 19             Also, in October, having thought more

 

 20   about the reclassification effort, we decided,

 

 21   instead of trying to do this inside FDA, we decided

 

 22   to go outside FDA and get an outside expert group

 

 23   to help us with this reclassification.

 

 24             In November and December, having thought

 

 25   more about this problem of case finding that I had

 

                                                               240

 

  1   alluded to earlier in response to our July request,

 

  2   we issued a second and actually then a third

 

  3   response to companies to give us cases to look at.

 

  4             Finally, in December, as was pointed out

 

  5   several times earlier today, MHRA, having completed

 

  6   its review of all the pediatric data, decided to go

 

  7   ahead and contraindicate all the other new

 

  8   generation antidepressants except for fluoxetine.

 

  9             So, as I understand it, fluoxetine is the

 

 10   only current generation antidepressant available

 

 11   for treating pediatric depression in the UK.

 

 12             [Slide.]

 

 13             I have used the terms summary data and

 

 14   patient level data several times, and I want to

 

 15   make sure that you understand what it is I am

 

 16   talking about.

 

 17             By "summary data," I am referring to data

 

 18   tables that are provided to us by sponsors based on

 

 19   their own analyses, that include only numbers of

 

 20   patients with events as the numerators and either

 

 21   total patients exposed or total accumulated

 

 22   person-time as the denominators.

 

 23             These are the data that we got from Glaxo

 

 24   back in May and that we have since gotten from all

 

 25   the other sponsors.  These are summary data.

 

                                                               241

 

  1             "Patient level data" are data sets that

 

  2   are provided by sponsors in response to a detailed

 

  3   request from FDA for electronic data sets that are

 

  4   structured to include one row per patient

 

  5   participating in each study, so that we have data

 

  6   for all patients participating in those trials, and

 

  7   we have multiple variable data for each patient.

 

  8             These data sets allow us to do adjustments

 

  9   for covariates that may be important for any

 

 10   particular event of interest, while summary data of

 

 11   course do not.

 

 12             In the next slide, I am going to summarize

 

 13   for you the suicidality risk data from the seven

 

 14   programs for the antidepressants that were studied

 

 15   in pediatric depression. Before I do that, I want

 

 16   to clarify what the two event categories are that

 

 17   we are dealing with.

 

 18             [Slide.]

 

 19             The first event category is an umbrella

 

 20   term, "possibly suicide related."  This is the term

 

 21   that Glaxo developed in looking at its own

 

 22   database, and it is the term that we asked other

 

 23   sponsors to look at in going through their data

 

 24   sets.

 

 25             Basically, it was intended to capture any

 

                                                               242

 

  1   event in their databases that included any thoughts

 

  2   or behaviors that the sponsor considered to

 

  3   represent possible suicidality, so it is a very

 

  4   broad term.

 

  5             The term "suicide attempt," as defined for

 

  6   these analyses, was the subset of that umbrella

 

  7   term, so a subset of these originally captured

 

  8   events that met the conditions of having any

 

  9   indication of self-harm.  So, this is how "suicide

 

 10   attempt" was defined in this analysis.

 

 11             So, the overall umbrella term "possibly

 

 12   suicide related" and then the subset of those

 

 13   events that had some indication of self-harm.

 

 14             [Slide.]

 

 15             This is, I am sorry, a very busy slide.

 

 16   These are the risk data coming out of these seven

 

 17   programs, and I am going to walk you through this.

 

 18             Again, there were seven programs -

 

 19   paroxetine, fluoxetine, sertraline, venlafaxine,

 

 20   citalopram, nefazodone, and mirtazapine.  I have

 

 21   divided these up into different colored rows so you

 

 22   can see the number of studies in each program, two

 

 23   of them involving three studies, the rest all

 

 24   two-study programs.

 

 25             This is risk data.  So, this is simply the

 

                                                               243

 

  1   number of patients having one or more of these

 

  2   events divided by the total number of patients

 

  3   exposed.  There is no adjustment for time here.

 

  4   This is crude risk.  In parentheses, I have got the

 

  5   percent.

 

  6             The way this is set up, first of all, the

 

  7   overall umbrella category "possibly suicide

 

  8   related," and then the subset of these events that

 

  9   met the criterion for "suicide attempt."  Again,

 

 10   that criterion was any indication of self-harm.

 

 11             Let's just walk through the individual

 

 12   programs. Again, paroxetine had three trials.  For

 

 13   the first trial,  329, you see a risk ratio of

 

 14   roughly 6, 6.5 percent for drug, 1.1 percent for

 

 15   placebo, so definitely a signal of something.

 

 16             However, if you look at the other two

 

 17   studies in this program, 377 and 701, these were

 

 18   also fairly large studies, in fact, this one was

 

 19   slightly larger, the risk ratio was around 1.  So,

 

 20   the signal for paroxetine is essentially coming out

 

 21   of one study, a big signal, but the other studies

 

 22   show essentially nothing.

 

 23             If you look at fluoxetine, there really

 

 24   isn't any signal coming out of the fluoxetine

 

 25   program, the risk ratios are all in the vicinity of

 

                                                               244

 

  1   1.

 

  2             For sertraline, again, you have one study

 

  3   which is suggestive of a signal, 4.1 percent versus

 

  4   zero, drug versus placebo, but for the other study,

 

  5   similarly sized, in fact, these were identically

 

  6   designed studies, there is no signal. It's 2.2

 

  7   percent for both.

 

  8             If you look at venlafaxine, there appears

 

  9   to be a signal coming out of both studies in that

 

 10   program.  For citalopram, again, you have two

 

 11   studies, both large studies. One study, no signal,

 

 12   in fact, if anything, it is slightly in favor of

 

 13   drug.  The other study, a weak signal, but many

 

 14   more events, many more events in this study, and a

 

 15   risk ratio of rough 1.6.

 

 16             The number of events in the nefazodone and

 

 17   mirtazapine programs is so small that it is hard to

 

 18   know what to make of that.

 

 19             There are two points that I want you to

 

 20   take away from this slide.  First of all, I think

 

 21   in looking at these data, there is enough of a

 

 22   suggestion of a signal of something that clearly it

 

 23   is worth pursuing this.

 

 24             Everyone at FDA concluded that there is

 

 25   obviously something going on here, we need to

 

                                                               245

 

  1   pursue this, but one troubling thing about this set

 

  2   of data is the inconsistency in the signal across

 

  3   studies within the programs.

 

  4             In most of these programs where there is a

 

  5   signal except for venlafaxine, it appears to be

 

  6   coming from one study.  So, that is something that

 

  7   we felt that we need to try and explore in some

 

  8   way.

 

  9             [Slide.]

 

 10             In the remaining time what I am going to

 

 11   do is talk about the concerns we have had in

 

 12   interpreting these suicidality data.

 

 13             I should have mentioned at the outset, I

 

 14   am sorry, I made a number of changes in my slides

 

 15   over the weekend, so I apologize.  I have had to

 

 16   delete some of the material.  I didn't talk about

 

 17   efficacy, and I am not planning on talking about

 

 18   efficacy here, you know, in the discussion section

 

 19   I am happy to do that.

 

 20             I thought it would be useful if I focused

 

 21   instead on the clinical cases because one of the

 

 22   concerns we have had is what these reported events

 

 23   that are captured under this broad term "possibly

 

 24   suicide related" actually represent.

 

 25             So, I put together a number of slides over

 

                                                               246

 

  1   the weekend to try and give you a better sense of

 

  2   that, and that is why the slide package you have is

 

  3   different than what I am presenting.

 

  4             In any case, there are three concerns that

 

  5   we have looked at.  One has to do with case

 

  6   finding, and that is the first bullet, and I

 

  7   alluded to that earlier.  In looking at the summary

 

  8   data that sponsors gave us, it appeared that

 

  9   somewhat different approaches were used to

 

 10   capturing and presenting these cases to us.  So, I

 

 11   will talk about how we explore that.

 

 12             Secondly, there is the issue I talked

 

 13   about of the question of how you classify these

 

 14   cases into meaningful categories for the purposes

 

 15   of analysis and regulatory decisionmaking.

 

 16             Finally, I have already alluded to the

 

 17   issue of the inconsistency in the signal across

 

 18   individual studies within the programs, and that

 

 19   was one of the findings that led us to want to do a

 

 20   more refined analysis looking at covariates.  It is

 

 21   one of several reasons, but that is one

 

 22   justification for that analysis.

 

 23             [Slide.]

 

 24             Let me first focus on the issue of case

 

 25   finding. This is a very busy slide, I apologize for

 

                                                               247

 

  1   that, but I will walk you through it.  This is the

 

  2   algorithm that was used initially by Glaxo and that

 

  3   we then asked the other companies to apply to their

 

  4   databases in finding cases.

 

  5             In essence, there were two components to

 

  6   this. There was an electronic string search, which

 

  7   I will talk about, and what they were to do is to

 

  8   apply this string search, and they were to blindly

 

  9   look at the events that were turned up with that

 

 10   search and decide whether or not those events were

 

 11   of interest from the standpoint of suicidality and

 

 12   then give us those data.

 

 13             So, the string search was one part of the

 

 14   search. The other part was to do a blinded review

 

 15   of narratives for any deaths or other serious

 

 16   adverse events in their databases.  Now, there were

 

 17   no deaths in any of these trials, so this part of

 

 18   the search focused on narratives for serious

 

 19   adverse events.

 

 20             So, let go back to the string search.

 

 21   There were two components to the string search.

 

 22   First of all, we asked companies to look at their

 

 23   preferred terms.  These are the dictionary terms

 

 24   that companies use in coding data.  We asked them

 

 25   to look at the text string "suic" and "overdos" to

 

                                                               248

 

  1   pick up any instances of events that were coded

 

  2   under either suicidality or overdose, or any

 

  3   variation of that.

 

  4             Now, the bullet underneath here suggests

 

  5   that we ask for a separate listing for events coded

 

  6   as accidental overdose.  Accidental overdose is

 

  7   usually, just to give you an example, where a

 

  8   patient misses a dose on one day and then on the

 

  9   next day thinks he should take two doses.  So, that

 

 10   would not be a suicide attempt, that is what is

 

 11   usually considered an accidental overdose.

 

 12             So, we didn't want those to be included

 

 13   among the events, but we wanted to be able to see

 

 14   them to see which ones were excluded.

 

 15             The second part of this was to do a string

 

 16   search for the actual verbatim investigator terms.

 

 17             Here we used -- again, this is the

 

 18   approach that was used by Glaxo, and we passed this

 

 19   on to the other sponsors -- a variety of terms

 

 20   suggestive of either self-harm or of overdose or

 

 21   suicidality.

 

 22             So, this was to go through the

 

 23   investigator terms and try and capture any events

 

 24   that were suggestive either of suicidality overdose

 

 25   or some type of self-harm.

 

                                                               249

 

  1             Again, we allowed exclusions from that

 

  2   list for what I am calling false positives.  A

 

  3   false positive, for example, would be when the text

 

  4   string inadvertently picks up a term that has

 

  5   nothing at all to do with suicidality, so, for

 

  6   example, the test string g-a-s, for gas, would pick

 

  7   up gastrointestinal, so we allowed companies to

 

  8   exclude those events from their lists.

 

  9             Once they came up with a list of events

 

 10   that they considered representative of suicidality,

 

 11   we asked them to go through and blindly select out

 

 12   from that overall group of possibly suicide-related

 

 13   events, the events that were suggestive of suicide

 

 14   attempt.

 

 15             Again, the definition of that was any

 

 16   indication of self-harm.  So, again, the overall

 

 17   umbrella term and then the subset of suicide

 

 18   attempts.

 

 19             We asked them then to provide us a

 

 20   narrative of all of those cases that had been

 

 21   turned up.  So, that was the algorithm for finding

 

 22   events.

 

 23             [Slide.]

 

 24             Now, we had hoped in doing that, that we

 

 25   would get a fairly complete accounting of the

 

                                                               250

 

  1   original list of events that had been turned up and

 

  2   the exclusions.  Unfortunately, we weren't explicit

 

  3   about that, and it is not what we got.

 

  4             Often, we got only the narratives for the

 

  5   events that the companies had already decided

 

  6   represented the suicidality set, and did not

 

  7   include the exclusions.  Often, there was little

 

  8   explanation for why certain events had been

 

  9   excluded or what the criteria had been in excluding

 

 10   events. So, that was one problem.

 

 11             [Slide.]

 

 12             Another problem was that we had failed to

 

 13   ask for narratives on accidental injuries.  I had

 

 14   mentioned earlier that we had asked for a listing

 

 15   of accidental overdose, but  not accidental

 

 16   injuries.  In talking to sponsors about this, and

 

 17   asking them to give us some of the accidental

 

 18   injuries, we turned up a couple of events that

 

 19   caused us some concern.

 

 20             This was one particular example.  This was

 

 21   a child who had been excluded, this event had been

 

 22   excluded from the list.  It was a patient who

 

 23   stabbed himself in the neck with a pencil while

 

 24   taking a test.

 

 25             Now, this probably was an accident, but it

 

                                                               251

 

  1   occurred to us that we wanted to see all of these.

 

  2   We wanted to see all of the events that had been

 

  3   excluded as accidental injury, so that our experts

 

  4   -- because at this point, we had already decided to

 

  5   go outside and have an outside group look at these

 

  6   cases, we wanted to have a complete set of events

 

  7   for them to look at, so we asked for all the

 

  8   accidental injuries.

 

  9             [Slide.]

 

 10             Another thing that we discovered when we

 

 11   started talking to companies about the application

 

 12   of the search algorithm is that one company in

 

 13   particular acknowledged that it had not done the

 

 14   searching blindly of the narratives for serious

 

 15   adverse events, and this was a problem, because

 

 16   again this had to be done blindly to be done

 

 17   properly.

 

 18             Another issue that turned up when we

 

 19   started looking at these cases is that some

 

 20   companies had excluded events that were not

 

 21   "treatment emergent."

 

 22             Now, when looking at adverse event data,

 

 23   it is entirely appropriate to be interested in

 

 24   events that either occur for the first time on

 

 25   assigned treatment, or if present at baseline, are

 

                                                               252

 

  1   worse on treatment than at baseline.  That is what

 

  2   we mean by "treatment emergent."

 

  3             So, it is not that it was improper to do

 

  4   that.  The problem was that we wanted to see which

 

  5   events were excluded for that reason, so that we

 

  6   could assess ourselves whether or not it was an

 

  7   appropriate exclusion.  So, again, in going back,

 

  8   we have now asked for all the events excluded as

 

  9   treatment emergent.

 

 10             Finally, in looking and comparing the

 

 11   strength of the signal coming out of the pediatric

 

 12   supplement re-review and the signal coming out of

 

 13   the summary data, in one particular case we noted a

 

 14   fairly substantial discrepancy between the strength

 

 15   of the signal.  That again raised a question about

 

 16   case finding.

 

 17             [Slide.]

 

 18             So, the bottom line is that having looked

 

 19   at these initial summary reports from companies, we

 

 20   did not have complete confidence in the case

 

 21   finding, so we issued, as I mentioned, a second

 

 22   request for clarification both of how the search

 

 23   had been done and then a complete accounting of how

 

 24   the companies winnowed down to the list of events

 

 25   that they considered to represent the suicidality

 

                                                               253

 

  1   set, so that we could see what events had been

 

  2   excluded, for what reason, and so that we could be

 

  3   confident that we had a complete set of data to

 

  4   start with.

 

  5             In addition, we asked for narratives for

 

  6   all serious adverse events rather than just the

 

  7   ones that the companies decided represented

 

  8   suicidality, so again our outside experts could go

 

  9   through all of these data and independently and

 

 10   blindly themselves decide which were representative

 

 11   of suicidality.

 

 12             So, that is the case finding issue.

 

 13             [Slide.]

 

 14             Next, I want to talk about the issue of

 

 15   reclassification.  There were two issues that again

 

 16   caused us concern about the approach to classifying

 

 17   these cases.

 

 18             One was in looking at the events that got

 

 19   captured, we noticed that there was an extremely

 

 20   wide variability in the types of events that got

 

 21   included under either the broad umbrella category

 

 22   or also under the narrower term "suicide attempt."

 

 23             We also notice that companies appeared to

 

 24   have used very different approaches to capturing

 

 25   the subset of events labeled "suicide attempt."

 

                                                               254

 

  1             Some companies used a fairly conservative

 

  2   approach, others essentially labeled all of the

 

  3   events as suicide attempts even though there was

 

  4   nothing in the case report to suggest self-harm.

 

  5             [Slide.]

 

  6             So, what I have done, and these are the

 

  7   slides that I put together this weekend, I have

 

  8   gone back to look at the 109 patients having one or

 

  9   more possibly suicide-related events.  These were

 

 10   the patients who were included in the numerators

 

 11   for the table that I showed you earlier.

 

 12             So, these are the cases, and the

 

 13   collection of 109 patients goes across all studies,

 

 14   not just the depression studies.

 

 15             A couple of points to make.  First of all,

 

 16   the point about there were no completed suicides

 

 17   among these 109 cases.  As I mentioned, there was

 

 18   very wide variability in the types of verbal

 

 19   expressions and behaviors that were considered by

 

 20   companies to be representative of suicidality.

 

 21             Another problem with these cases is that

 

 22   the majority of them were not well described.  We

 

 23   did not have the level of detail in these cases

 

 24   that one would have liked to do a rational

 

 25   classification.

 

                                                               255

 

  1             My goal in doing this is to provide you

 

  2   with a sense of the range of events to consider.

 

  3   You know, this is not a formal classification.

 

  4   Again, we have contracted with an outside group to

 

  5   do the classification, but I wanted you to have a

 

  6   sense of the kind of variability in the case

 

  7   material that we have, so you can appreciate why we

 

  8   consider this a problem.

 

  9             [Slide.]

 

 10             There are two key questions.  First of

 

 11   all, is it meaningful to subsume such diverse

 

 12   events under this umbrella term "possibly suicide

 

 13   related," and is it reasonable to define "suicide

 

 14   attempt" as that subset of events that have any

 

 15   degree of self-harm, is that a reasonable

 

 16   definition of "suicide attempt."

 

 17             I want to be very clear about this.  I am

 

 18   not attempting to trivialize in any way any of the

 

 19   events that occurred.  I mean these are sick kids,

 

 20   all of these events have importance.

 

 21             The question is what classification

 

 22   approach is most useful and clinically meaningful

 

 23   in preparation for doing an analysis and in

 

 24   preparation for taking regulatory action.  That is

 

 25   really my goal here.

 

                                                               256

 

  1             [Slide.]

 

  2             Let me describe how I approached these

 

  3   cases.  For a small fraction of them, patients had

 

  4   more than one suicidality event, so for

 

  5   consistency, I focused on the first one.  That only

 

  6   applied to about 10 percent of these patients.

 

  7             Then, I went ahead and I selected a subset

 

  8   of those events where there was any indication at

 

  9   all of self-harm.  Again, this is to mimic the

 

 10   approach that the sponsors were supposed to use in

 

 11   defining suicide attempt.

 

 12             For those patients who had an indication

 

 13   of self-harm, I looked at whether or not they were

 

 14   hospitalized for the event and whether or not there

 

 15   was any indication of suicide intent.  By that, I

 

 16   mean either an active expression of intent in that

 

 17   case narrative or I accepted any concurrent

 

 18   indication of suicidal ideation.

 

 19             For the remaining patients who had

 

 20   suicidal ideation without self-harm, again, I

 

 21   looked at whether or not they had been hospitalized

 

 22   for the event and whether or not there was a

 

 23   suicidal plan, so there had to be an active

 

 24   expression in the narrative of a suicidal plan in

 

 25   association with that suicidal ideation.

 

                                                               257

 

  1             [Slide.]

 

  2             Overall, the hospitalization rate for

 

  3   these 109 patients was 43 percent.  The subgroup

 

  4   having suicidal ideation without any indication of

 

  5   self-harm was 39 percent and the remainder -- these

 

  6   were the patients who had some indication of

 

  7   self-harm -- was 61 percent.

 

  8             Again, there were no complete suicides,

 

  9   all patients were fully recovered from these

 

 10   instances of self-harm.  As sort of an interesting

 

 11   aside, in about 30 percent of these cases, the

 

 12   self-harm event appeared to occur in the context of

 

 13   some kind of interpersonal conflict.

 

 14             A typical situation would be a child had

 

 15   an argument with a parent or a sibling or a peer or

 

 16   a girlfriend or boyfriend, impulsively engaged in

 

 17   some kind of self-harm behavior, and the event was

 

 18   over, and there was no indication of suicidal

 

 19   ideation.  That applied in about 30 percent of

 

 20   these cases.

 

 21             [Slide.]

 

 22             In going through the self-harm case events

 

 23   in more detail, again, there were a total of 66 of

 

 24   these.  Nineteen of these involved cutting

 

 25   behavior.  In almost all of these cases of cutting,

 

                                                               258

 

  1   it appeared to be a superficial wound. There was

 

  2   one case where a young girl cut herself so deeply

 

  3   that there was actually blood loss.  In another

 

  4   case there was an indication that the patient

 

  5   needed three stitches to suture the wound, but in

 

  6   all the other cases, they appeared to be

 

  7   superficial.

 

  8             There were 37 overdoses.  Again, there was

 

  9   a wide range of different types of behaviors that

 

 10   were classified as overdose, ranging at the one

 

 11   end, one patient was classified as an overdose for

 

 12   taking 20 percent more medication than was

 

 13   prescribed.

 

 14             Ordinarily, this would not be considered a

 

 15   suicide attempt, and there was no indication in

 

 16   that case of suicidal ideation, but that was

 

 17   classified as an overdose.

 

 18             At the other extreme, there were patients

 

 19   who took fairly substantial quantities of either

 

 20   study medication or  usually over-the-counter

 

 21   medication, so a very wide range in terms of

 

 22   amounts of drug that was taken.

 

 23             There were two cases characterized as

 

 24   hanging behavior.  In both of those cases, what

 

 25   they really were, were interrupted attempts.  These

 

                                                               259

 

  1   were children who, in the presence of family or

 

  2   parents, engaged in what was described as hanging

 

  3   behavior, it was immediately interrupted, and so in

 

  4   neither case was there any actual self-harm.  So,

 

  5   these were interrupted cases.

 

  6             The case of burning was similar.  This

 

  7   occurred in the context of family, and the child

 

  8   was immediately interrupted although in that case

 

  9   there was some minor burns.

 

 10             One case that was classified as a suicide

 

 11   attempt was the case of a young girl who slapped

 

 12   herself in the face, and that was it.  That was all

 

 13   there was in that case, and there was no suicidal

 

 14   ideation described in that case.

 

 15             Then, there were six other cases where all

 

 16   that the case indicated was minor self-mutilation.

 

 17   It was not specified what the self-harm behavior

 

 18   was.

 

 19             [Slide.]

 

 20             Now, let me give you a breakdown of what I

 

 21   found when I looked at, first of all, the cases of

 

 22   cutting.

 

 23             There were 19 of these.  In most of these

 

 24   cases, in 16 out of the 19, there was no indication

 

 25   of either suicide intent or even any concurrent

 

                                                               260

 

  1   suicidal ideation, and 4 of those 19 cases actually

 

  2   ended up being hospitalized.

 

  3             So, most of those cases did not involve

 

  4   hospitalization and did not involve suicide intent

 

  5   or ideation.

 

  6             [Slide.]

 

  7             For the 37 cases of overdose, there were

 

  8   more hospitalizations here, but again, if you

 

  9   notice in this column, in almost every case there

 

 10   was no indication of suicide intent or suicidal

 

 11   ideation.

 

 12             A number of the hospitalizations could be

 

 13   characterized as an overnight hospitalization for

 

 14   observation.

 

 15             [Slide.]

 

 16             Finally, for the remaining 43 patients who

 

 17   had suicidal ideation without self-harm, again, I

 

 18   looked at whether or not there was a plan, an

 

 19   expressed plan, and in most of these cases there

 

 20   was not a plan.

 

 21             In the 7 where there was a plan, they were

 

 22   hospitalized, but nevertheless, a majority of these

 

 23   patients with suicidal ideation without self-harm

 

 24   were hospitalized.

 

 25             [Slide.]

 

                                                               261

 

  1             So, I hope that gives you a little bit

 

  2   better sense of the range of behaviors that we are

 

  3   dealing with here and the difficulty we had in

 

  4   including all of them under this one umbrella term

 

  5   of "possibly suicide related."

 

  6             As I said, we have gone to an outside

 

  7   group.  What I want to do in this slide is talk a

 

  8   little bit about the Columbia University

 

  9   Suicidality Research Group and why we picked them.

 

 10             I talked to a number of people about who

 

 11   should help us with this, and most everyone I

 

 12   talked to said that this group has the expertise to

 

 13   do this.  They do have expertise, they have been

 

 14   doing this for almost 20 years.

 

 15             In the last 5 years alone, they have more

 

 16   than 40 funded grants to do this kind of research.

 

 17   They are in the business of developing measures and

 

 18   manuals and methodologies for evaluation of

 

 19   suicidality.

 

 20             They are a center for training on suicide

 

 21   assessment, and research on both reliability and

 

 22   validity. They are currently involved in the NIMH

 

 23   study looking at adolescent suicide attempters.

 

 24   This is the TASA study.  They are doing the suicide

 

 25   assessment or the suicide classification for that

 

                                                               262

 

  1   trial.  As you can see, they have a very large

 

  2   number of publications over the 20 years they have

 

  3   been doing this.

 

  4             So, we think this is a good group to help

 

  5   us with this problem.

 

  6             [Slide.]

 

  7             I have two more slides left.  What I want

 

  8   to do in this slide is again remind you of what Dr.

 

  9   Katz said earlier, is that we view this meeting

 

 10   today as a preliminary meeting.  We are hoping to,

 

 11   you know, once we have had these cases

 

 12   reclassified, and have done the analysis, to come

 

 13   back to you with more definitive answers later in

 

 14   the summer.

 

 15             You are going to hear next from Dr. Kelly

 

 16   Posner from Columbia.  She is going to tell you

 

 17   about the way they think about classifying suicidal

 

 18   events and how they plan to approach these data.

 

 19             Following that, you will be hearing from

 

 20   Tarek Hammad from our Safety Group.  He is going to

 

 21   tell you about our preliminary plans for an

 

 22   appropriate patient level data analysis.

 

 23             [Slide.]

 

 24             Finally, these are the five topics for

 

 25   which the Neuropharm Division would like to have

 

                                                               263

 

  1   feedback from you.  First of all, three topics

 

  2   pertinent to the analysis of suicidality data.

 

  3             Again, I alluded to our concerns about the

 

  4   approach to case finding and how we attempted to

 

  5   resolve that, but we would be interested in knowing

 

  6   what you think about that and whether you think

 

  7   anything more needs to be done in terms of case

 

  8   finding.

 

  9             Secondly, you will be hearing from Dr.

 

 10   Posner about approaches to classifying these events

 

 11   into appropriate categories before we do the

 

 12   analysis.  Since we are actively engaged now in

 

 13   discussing this with them, this would be a good

 

 14   time to give us feedback on that.

 

 15             Thirdly, if you have thoughts about our

 

 16   plans for the patient level data analysis, we would

 

 17   be interested in hearing about that.

 

 18             In terms of future concerns, again, one of

 

 19   the striking things about these cases is how poorly

 

 20   they were described, and this may also indicate a

 

 21   less than optimal approach to ascertainment in

 

 22   these studies.

 

 23             So, if you have thoughts, we are beginning

 

 24   to talk with Kelly Posner and others about

 

 25   developing a guidance document for ascertaining

 

                                                               264

 

  1   suicidality in future studies, if you have thoughts

 

  2   about that, we would welcome them.

 

  3             Finally, I didn't get a chance to talk

 

  4   about efficacy, but obviously, the largely negative

 

  5   results from the short-term trials in pediatrics is

 

  6   clearly a concern.

 

  7             We would be interested in knowing what

 

  8   your thoughts are about that and whether or not you

 

  9   think there are other possible designs that might

 

 10   help us get at whether or not there are benefits

 

 11   with these drugs.

 

 12             One design that has been used in adult

 

 13   studies is the randomized withdrawal design.  This

 

 14   is a design where you take patients who have

 

 15   responded to medication acutely, have been stable

 

 16   for some period of time, and are then randomized to

 

 17   either continue on drug or assignment to placebo,

 

 18   and you look at time to relapse as the event, as

 

 19   another approach to trying to establish whether or

 

 20   not there are benefits.

 

 21             I am going to stop there.

 

 22             Thank you.

 

 23             DR. RUDORFER:  Thank you, Dr. Laughren.

 

 24             As Dr. Laughren said, we will now hear

 

 25   from Dr. Kelly Posner of Columbia, who will

 

                                                               265

 

  1   describe in more detail the suicidality

 

  2   classification project.

 

  3                Suicidality Classification Project

 

  4             DR. POSNER:  Thank you.

 

  5             [Slide.]

 

  6             So, why is a methodologically sound,

 

  7   research-supported classification warranted?  Let's

 

  8   back up a second and talk about the problem.

 

  9             [Slide.]

 

 10             The problem, as the cases that Dr.

 

 11   Laughren discussed exemplified, there is a clear

 

 12   lack of conceptual clarity about what suicidal

 

 13   behavior means and a corresponding lack of

 

 14   agreement on common terminology both in clinical

 

 15   descriptions of suicidal acts, as well as research

 

 16   descriptions of suicidal acts.

 

 17             Given this lack of generally accepted

 

 18   terms for referring to even the most basic suicidal

 

 19   behaviors, the importance of using definitions that

 

 20   are both reliable, meaning we all define them and

 

 21   assess them the same way, and valid, meaning there

 

 22   is some truth to them seems quite clear.

 

 23             [Slide.]

 

 24             So, what are these standardized

 

 25   research-supported definitions?  I think it is

 

                                                               266

 

  1   important to note that there really is generally

 

  2   agreement among suicide assessment experts on the

 

  3   basics of these terms.  So, we are going to start

 

  4   with the suicide intent.

 

  5             A self-injurious act committed with at

 

  6   least some intent to die.  Intent doesn't have to

 

  7   be 100 percent.  If there is any intent to die, we

 

  8   consider it an actual suicide attempt.

 

  9             Intent does not have to be explicit and

 

 10   can be inferred.  For example, if a patient denies

 

 11   intent to die, but thought that the behavior could

 

 12   be lethal, intent can be inferred.

 

 13             A real case example includes a 12-year-old

 

 14   who is angry at her mother.  She took 6 to 7

 

 15   prescription pills, said she was aware that taking

 

 16   that much medication might kill her, but she didn't

 

 17   know if she intended to die by taking the pills.

 

 18   That would clearly be categorized as a suicide

 

 19   attempt.

 

 20             Once again, it is important to note that

 

 21   once there is any possibility of injury, the act is

 

 22   defined as an attempt, meaning that if someone

 

 23   pulled the trigger of a loaded gun, but

 

 24   fortuitously missed, it is still a suicide attempt.

 

 25             [Slide.]

 

                                                               267

 

  1             Other classifications: suicidal behavior

 

  2   without injury.  Interrupted attempts are defined

 

  3   as the individual is stopped by an outside

 

  4   circumstance from starting the self-injurious act.

 

  5   Examples of these:  someone has pills in their

 

  6   hand, but they are stopped from ingesting.  Once

 

  7   even one pill is ingested, the event becomes an

 

  8   actual attempt.

 

  9             They have a gun pointed toward themselves,

 

 10   the gun is taken away by someone else or somehow

 

 11   they are prevented from pulling the trigger.  They

 

 12   are poised to jump, they are grabbed, taken down

 

 13   from the ledge.  All examples of interrupted

 

 14   attempts.

 

 15             The next classification is what is called

 

 16   an aborted attempt in which an individual takes

 

 17   steps toward making a suicide attempt, but stops

 

 18   himself before engaging in any potentially

 

 19   self-destructive behavior.

 

 20             Remember, holding a loaded gun but not

 

 21   pulling the trigger is a good example.  This could

 

 22   not possibly result in injury, therefore, it

 

 23   constitutes an aborted attempt.  It is still

 

 24   suicidal behavior, but it is not an actual attempt.

 

 25             [Slide.]

 

                                                               268

 

  1             I think it is worth focusing a moment on

 

  2   suicidal intent, because again, intent here is the

 

  3   determining factor when you are classifying

 

  4   suicidality.  It is the presence of intent to die

 

  5   that differentiates suicidal acts from self-injury.

 

  6             One must determine whether the

 

  7   self-injurious act was thought of as a means of

 

  8   causing or facilitating death. Of course, we do

 

  9   have research support for the validity of using

 

 10   intent to define suicidality.

 

 11             One example is that completed suicide is

 

 12   predicted by previous intent measures, which was

 

 13   demonstrated by Beck and his group in 1989.

 

 14             [Slide.]

 

 15              Some more case examples.  These are real

 

 16   cases again.  These are examples of non-suicidal

 

 17   self-injury.

 

 18             A teenage girl reported her mother was

 

 19   being cruel and neglectful and she wanted to escape

 

 20   from her mother's home.  She states that she

 

 21   researched lethal doses of ibuprofen to make

 

 22   certain that she took an amount that would not be

 

 23   life-threatening.  She took 6, feeling sure it was

 

 24   not enough to  kill her.  She definitely did not

 

 25   want to die, only to escape from her mother's

 

                                                               269

 

  1   house.  She was taken to the ER and then admitted

 

  2   to a psychiatric hospital.

 

  3             Another is the more common case of

 

  4   self-mutilation where the person described 12

 

  5   incidents of cutting himself, stated he did this

 

  6   only "to relieve tension" and "to play with danger

 

  7   to see how far I would go" and no part of him

 

  8   wanted to die.  Thought about it for hours before

 

  9   acting on the urge and felt relieved of tension

 

 10   afterwards, did not feel pain.

 

 11             [Slide.]

 

 12             So, what is our research support of these

 

 13   classifications?  We will start with reliability.

 

 14   We have been able to demonstrate excellent

 

 15   reliability utilizing these definitions and this

 

 16   classification system in NIMH-funded treatment,

 

 17   biological, and genetic trials across the life

 

 18   span.

 

 19             We have also been able to demonstrate

 

 20   multi-site reliability with other expert centers in

 

 21   family genetic studies and treatment trials, and

 

 22   again particularly the treatment of adolescent

 

 23   suicide attempters trials.

 

 24             In short, across domains, across the life

 

 25   span, and across institutions, we have been able to

 

                                                               270

 

  1   demonstrate excellent reliability.

 

  2             [Slide.]

 

  3             Validity.  How much truth is there to

 

  4   these definitions?  Individuals classified as

 

  5   suicide attempters have as much as 2.5 times risk

 

  6   of future attempts or completions.  So, we know

 

  7   this is a real category.

 

  8             Similarly, interrupted attempters are

 

  9   reported to be 3 times more likely to commit

 

 10   suicide than uninterrupted attempters.

 

 11             Finally aborted attempters are at risk for

 

 12   eventual attempts and were more likely to have made

 

 13   an actual attempt in the past.

 

 14             Again, all validating the classifications

 

 15   that we are using.

 

 16             [Slide.]

 

 17             So, what is the classification methodology

 

 18   that we are proposing here?

 

 19             To begin with, the data will be blinded by

 

 20   experts not on the panel.  It will be blinded not

 

 21   only to pharmaceutical information, but also to any

 

 22   relevant clinical information that would bias an

 

 23   event rating.  For example, a family history of

 

 24   suicidality.  An event classification should stand

 

 25   on its own, and we want to make sure that it is

 

                                                               271

 

  1   blinded in both domains.

 

  2             Next, we have to determine the event

 

  3   classifications based on these reliable and valid

 

  4   constructs.

 

  5             We are then going to do a training on the

 

  6   classification system to establish reliability of

 

  7   panel members who are all experts in the field.

 

  8             Once the reliability study is done, the

 

  9   expert panel will be divided into three subgroups,

 

 10   and the data will also be divided into three groups

 

 11   in order to do classifications.

 

 12             There will be additional cases, and the

 

 13   reason for the additional cases is to demonstrate

 

 14   that the classifications are all being done in the

 

 15   same way and to prevent what we call stratification

 

 16   bias.

 

 17             You want to exhibit a relationship between

 

 18   the groups and make sure it is not some other

 

 19   factor that is causing a group to rate things in a

 

 20   similar way, and then we will generate the

 

 21   classified cases.

 

 22             [Slide.]

 

 23             What are the classifications that we are

 

 24   proposing?  Suicidal, non-suicidal, and

 

 25   indeterminate.  Subclassifications of suicidal

 

                                                               272

 

  1   would include suicide attempt, suicidal behavior

 

  2   without injury, which would include aborted and

 

  3   interrupted attempts, suicidal ideation related

 

  4   events.

 

  5             Non-suicidal subclassifications would

 

  6   include self-injury or mutilation again with no

 

  7   intent associated, and other categories, accidental

 

  8   injuries or other psychiatric symptoms that we have

 

  9   been hearing a lot about today, disinhibition,

 

 10   akathisia, agitation.

 

 11             Then, finally, the indeterminate category

 

 12   either by non-consensus or inability to classify

 

 13   due to a paucity of data.

 

 14             So, if, in fact, there is a signal, the

 

 15   point is we just don't know yet what it is a signal

 

 16   of, and that is why a logical research-supported

 

 17   approach is warranted.  We want to be able to look

 

 18   at the data consistently and logically across

 

 19   trials in order to make some clinically meaningful

 

 20   sense of it.

 

 21             [Slide.]

 

 22             I think it is also worth mentioning for a

 

 23   moment future directions.  We want to develop

 

 24   guidelines as to how to better capture data,

 

 25   enabling appropriate classification and description

 

                                                               273

 

  1   of suicidality.

 

  2             We will demonstrate, based on this

 

  3   conceptual clarity, how to utilize research

 

  4   assessment tools, what questions to ask, how to ask

 

  5   them, and what measures aid in this, which will

 

  6   then lead to consistency of terminology and

 

  7   classification, as well as to improved, more valid

 

  8   identification and documentation of suicidality.

 

  9             In addition, as was mentioned earlier,

 

 10   that will also enable more active appropriate

 

 11   surveillance of suicidality, which is a great need

 

 12   clearly.

 

 13             Thank you.

 

 14             DR. RUDORFER:  Thank you, Dr. Posner.

 

 15             Our final formal speaker of the afternoon

 

 16   will be Dr. Tarek Hammad from the Division of

 

 17   Neuropharmacologic Drug Products, who will discuss

 

 18   plans for analysis of patient level data for

 

 19   pediatric studies.

 

 20               Plans for Analysis of Patient Level

 

 21                        Pediatric Studies

 

 22             DR. HAMMAD:  Good afternoon, everyone.

 

 23             I am here today to talk about our analysis

 

 24   plan for the pediatric patients data.

 

 25             [Slide.]

 

                                                               274

 

  1             These are some of the elements that I will

 

  2   cover in my talk.  After a brief description or a

 

  3   statement of the objective of this work, I will

 

  4   describe the data that we have and then I will go

 

  5   on to discussing the analysis plan.

 

  6             [Slide.]

 

  7             The objective of this work is to evaluate

 

  8   the risk of suicidality associated with the use of

 

  9   antidepressants in pediatric patients using the

 

 10   results of the blinded reclassification of cases.

 

 11             I think you have heard enough about the

 

 12   value of this reclassification.

 

 13             In the process, we will address the

 

 14   possible sources of imbalance in the data, for

 

 15   example, trial design, duration of exposure, et

 

 16   cetera, and also other potential confounders.

 

 17   These efforts will help us understand the sources

 

 18   of inconsistency between trials or between drugs,

 

 19   if any.

 

 20             [Slide.]

 

 21             The source of all data is controlled

 

 22   trials conducted in pediatric patients in nine drug

 

 23   development programs.  These are the drugs that you

 

 24   have seen before, that is the list of drugs and the

 

 25   number of trials involving each drug.

 

                                                               275

 

  1             For the analysis or at least for some

 

  2   stages of the analysis, they will be grouped into

 

  3   two categories, an SSRI group and an Atypical

 

  4   Antidepressant group.

 

  5             [Slide.]

 

  6             These trials were not done in one

 

  7   indication, and for purpose of analysis again, they

 

  8   will be categorized or divided into three different

 

  9   subgroups - MDD, anxiety disorders, and attention

 

 10   deficit hyperactivity disorder assuming, of course,

 

 11   we have enough cases within every category of

 

 12   indication.

 

 13             [Slide.]

 

 14             As far as individual patients data that we

 

 15   are requested, we developed a standard format to

 

 16   guarantee the compatibility between data coming

 

 17   from various sources.  We actually specified every

 

 18   aspect of the desired database down to the variable

 

 19   name and some description to clarify the contents,

 

 20   and some coding notes as appropriate.

 

 21             In addition, we requested descriptive

 

 22   information about every trial to evaluate the

 

 23   similarity of these trials, which as you can

 

 24   imagine is very important to determine if these

 

 25   trials can be pooled or not to gain more power

 

                                                               276

 

  1   while you are investigating this question.

 

  2             [Slide.]

 

  3             This is a list of the requested variables

 

  4   that can be categorized in many subcategories -

 

  5   demographics variables, disease-related variables,

 

  6   drug-related variables.

 

  7             [Slide.]

 

  8             Outcome-related variables, psychiatric

 

  9   history variables, and some treatment emergent

 

 10   adverse events.  As you can see, this is not just

 

 11   about having a second look at the data.  It is

 

 12   about trying to understand and appreciate and

 

 13   characterize the signal, if there is any.

 

 14             [Slide.]

 

 15             This is a list of some challenges we have

 

 16   with the data, I wanted to mention here because of

 

 17   the important implications of these challenges on

 

 18   the proposed analysis and on the actual

 

 19   interpretation.

 

 20             They can be divided roughly into two

 

 21   categories, a quality-related component and an

 

 22   analysis-related component.

 

 23             The first issue in the quality-related

 

 24   component, which is pertinent to what Dr. Laughren

 

 25   was talking about, the case ascertainment, so I

 

                                                               277

 

  1   will not belabor the issue more, but a similar

 

  2   issue is pertinent to the other pieces of

 

  3   information being collected, which is other

 

  4   variables that we requested.

 

  5             The mechanism of capturing these data

 

  6   might be different from trial to trial or from

 

  7   sponsor to sponsor, so we will investigate this,

 

  8   and that is part of the challenge, trying to see if

 

  9   these data can actually even be comparable or not.

 

 10   But for now, the rule that we will use is that we

 

 11   will not use data with missing information more

 

 12   than 10 percent.  The second issue is somewhat

 

 13   detailed and I will address in the next few slides

 

 14             The first point under the analysis-related

 

 15   component is using the trial or the patient as the

 

 16   unit of analysis.  Pooling data from different

 

 17   trials, treating them as one large trial fails to

 

 18   preserve the randomization effect and might

 

 19   introduce bias and confounding.

 

 20             That is because maintaining the

 

 21   randomization guards against the foreseen and

 

 22   unforeseen imbalances between different treatment

 

 23   groups in various trials.

 

 24             The issue of trial similarity is not only

 

 25   pertinent to having the same protocol, but it is

 

                                                               278

 

  1   also pertinent to the implementation of those

 

  2   protocols in reality.  That is why I believe the

 

  3   trial-based approach is more appropriate.

 

  4             However, we might be using some

 

  5   information using the trial as the unit of the

 

  6   analysis, because if we have zero events in one of

 

  7   the arms, for example, we have to impute some data,

 

  8   but if we have zero events in both arms, we will

 

  9   not be able to drive the information in this trial.

 

 10             So, it depends on the eventual count of

 

 11   the actual cases that we would have.  If we are

 

 12   losing too many trials, we might use the patient as

 

 13   the unit of the analysis, of course, after doing

 

 14   the appropriate adjustments.

 

 15             [Slide.]

 

 16             The second point is pertinent to the

 

 17   limitations of pooling data in general whether we

 

 18   use the trial or the patient as the unit of the

 

 19   analysis, because these trials have different

 

 20   designs, patient populations, sometimes duration of

 

 21   treatment, et cetera, and pooling them together

 

 22   with the appropriate adjustment gives you an

 

 23   average effect that is really dependent on the

 

 24   proportions of different subpopulations in these

 

 25   data.

 

                                                               279

 

  1             This effect will be different subsequently

 

  2   if these proportions are different, so careful

 

  3   evaluation of this has to be conducted and then

 

  4   adjusting for it.

 

  5             There is also the inherent class effect

 

  6   assumption that is implied by pooling data across

 

  7   drugs or within groups of indications even.  Mind

 

  8   you, we do this to try to gain more power, try to

 

  9   see some gathering of data instead of just looking

 

 10   at it trial by trial, but by doing this, if we pool

 

 11   data from drugs within certain class assumption

 

 12   here, the risk of suicidality is equal in all

 

 13   drugs.

 

 14             The problem comes in when we realize that

 

 15   we do have different size of data for different

 

 16   drugs, and the smaller opportunity to observe an

 

 17   event in one drug might lead to none being observed

 

 18   or very few.

 

 19             The question becomes whether this is

 

 20   because this drug is generally different from the

 

 21   rest of the class or because we simply don't have

 

 22   enough power.  Unfortunately, this will always be

 

 23   an open question, but I would report the results

 

 24   both ways by individual drugs and by group data.

 

 25             [Slide.]

 

                                                               280

 

  1              The analysis plan would follow a standard

 

  2   approach with initial exploratory phase, where we

 

  3   will check for the compliance with our request and

 

  4   the completeness of data, check for coding errors,

 

  5   and the like, and then we will list all the risks

 

  6   and rates by drug, by indication, and by trial just

 

  7   to see what is going on in data, in all aspects of

 

  8   the subgroups before we pool anything, so we know

 

  9   where the signal is coming from if there is any

 

 10   afterward.

 

 11             Then, we investigate the data separation,

 

 12   which is an important component.  For example, if

 

 13   all cases were among men, for example, then, this

 

 14   variable we will not be able to evaluate, and so

 

 15   on.  That is just part of the process of

 

 16   evaluation.

 

 17             Then, we go to investigate interactions

 

 18   and potential confounders to try to understand what

 

 19   is going on and try to characterize the risk, as I

 

 20   said before.

 

 21             [Slide.]

 

 22             This is just a sample of one of the tables

 

 23   that will be produced, the rates and percentages

 

 24   and the risks of suicidality by drug and by

 

 25   indication for every trial.

 

                                                               281

 

  1             [Slide.]

 

  2             To evaluate the estimate, to actually try

 

  3   to relate an overall effect, an estimate for an

 

  4   overall effect, two approaches that I discussed are

 

  5   options that we have.  First, which I believe is

 

  6   the more of an optimal approach, is using the trial

 

  7   as the unit of analysis.

 

  8             In this analysis, I will adjust the

 

  9   confounders on a trial level.  We are basically

 

 10   looking for a randomization failure in if all of

 

 11   these randomized trials, but in case there might be

 

 12   some failure in randomization, any small imbalances

 

 13   can actually be reflected on the apparent risk.

 

 14             Then, I will have done everything by trial

 

 15   and by drug.  In this particular analysis, I will

 

 16   pool trials for drug groups that I should do

 

 17   initially within indication groups.  Trials will be

 

 18   excluded if there are no cases reported in both

 

 19   arms.

 

 20              Now, depending on the heterogeneity of

 

 21   the trials' findings, the variability between

 

 22   trials will be considered in a fixed effect order

 

 23   in random effects model.

 

 24             The premise behind the fixed effects model

 

 25   is that the real effects we are trying to evaluate

 

                                                               282

 

  1   is fixed, and the observer variation between trials

 

  2   is just by chance.  The premise behind the random

 

  3   effects model is that there is an average of these

 

  4   effects that is the full distribution with a

 

  5   variation affected by the observer trials.

 

  6             Many times you will have both approaches

 

  7   yielding the same results, but I am going to do it

 

  8   both ways with some of the conditions for which

 

  9   approach is more appropriate given the actual data

 

 10   or the heterogeneity of the data.

 

 11             Now, if we opted to use the patient as the

 

 12   unit of analysis in the situation I mentioned

 

 13   before, which is a situation where we will not have

 

 14   that many cases, and we would be losing trials

 

 15   right and left, so we will try to pool and get some

 

 16   slightly more power, pooling patients as the unit

 

 17   of the analysis.

 

 18             We will use the Poisson regression to

 

 19   model the rates of suicidality, adjusting for

 

 20   potential confounders, and then again will pool

 

 21   patient data for drug groups within indication

 

 22   groups, and, of course, will adjust for trial in

 

 23   the model because these patients are coming from

 

 24   different trials.

 

 25             [Slide.]

 

                                                               283

 

  1             As you know, these trials were not

 

  2   designed to capture these particular events, so

 

  3   there is some inherent uncertainty about the

 

  4   finding.  It depends on what kind of feedback we

 

  5   get from our experts in the Columbia University.

 

  6             Some sort of sensitivity analysis might be

 

  7   warranted, stratifying by the amount of uncertainty

 

  8   in this particular finding.

 

  9             [Slide.]

 

 10             There are some limitations on the

 

 11   interpretation of data that we should know upfront.

 

 12   Just to put the limitations in context, I have here

 

 13   the first bullet to remind you about the goal of

 

 14   this particular effort, which is to evaluate the

 

 15   risk of suicidality associated with the use of

 

 16   antidepressants in pediatric patients.      

 

 17             Now, after everything is said and done,

 

 18   the observed rates will not reflect the actual

 

 19   patients in the general population.  Why?  Because

 

 20   there are some exclusions in some trials of

 

 21   patients with some baseline suicidality, so the

 

 22   observed rates will not reflect what is going on in

 

 23   real life, and this might hamper our efforts in

 

 24   trying to investigate the risk because it will lead

 

 25   to underestimation in all the arms, so we might not

 

                                                               284

 

  1   have enough power to be able to detect the actual

 

  2   thing.

 

  3             Now that we only have short-term exposure

 

  4   data, we will not be able to extrapolate this to

 

  5   what happens after long-term exposure to these

 

  6   drugs.

 

  7             Now, we don't really have any information.

 

  8   The next bullet is that we don't have any

 

  9   information on the patterns for discontinuation.

 

 10   Considerably, there might be some informative

 

 11   censoring going on with patients with suicidality

 

 12   tendencies, might be likely to be discontinued. If

 

 13   that happened more in the placebo group, then,

 

 14   there might be some apparent underestimation of the

 

 15   signal in the placebo, and this might lead to some

 

 16   spurious finding, but we don't have information on

 

 17   this which would be very hard to overcome.

 

 18             My last point is that it remains to be

 

 19   seen if we have enough statistical power to detect

 

 20   differences in the risk of suicidality among

 

 21   various drugs because of the issue that I alluded

 

 22   to before, which is there is no data for some of

 

 23   the drugs.

 

 24             [Slide.]

 

 25             In closing, there are our ideas and some

 

                                                               285

 

  1   of them were informed by our experience analyzing

 

  2   the data on the completed suicides in adults.

 

  3             So, your feedback on our approach will be

 

  4   greatly appreciated.

 

  5             DR. RUDORFER:  Thank you, Dr. Hammad.

 

  6             At this point, we are going to open up for

 

  7   discussion by the committee.  If anyone has

 

  8   questions for our speakers, now is the time to

 

  9   raise them.

 

 10             Dr. Laughren.

 

 11             DR. LAUGHREN:  Matt, I had in my original

 

 12   talk planned on giving a brief summary of the

 

 13   efficacy data, and it sounds like a number of

 

 14   people are disappointed that I didn't do that.  I

 

 15   have those data and I could, if you wanted me to

 

 16   take five minutes and do that, I would be happy to

 

 17   do that.

 

 18             DR. RUDORFER:  Yes, please do so.

 

 19             [Slide.

 

 20             DR. LAUGHREN:  What this slide does is

 

 21   summarize very briefly the outcome on the 15 trials

 

 22   that we looked at for the 7 programs in pediatric

 

 23   major depression.

 

 24             Again, there are 3 studies in the

 

 25   paroxetine program and 2 studies in each of the

 

                                                               286

 

  1   other programs, and what this slide does is to

 

  2   simply summarize in very crude form what the

 

  3   outcome was on the primary endpoint.  The protocol

 

  4   specified primary endpoint for those trials, and

 

  5   this gives the age range in these studies here.

 

  6             So, for example, for the paroxetine

 

  7   program, there were 3 studies, all negative.  For

 

  8   sertraline, 1 trended in trend, for the purposes of

 

  9   this slide, indicates a p value on that primary

 

 10   endpoint of between 0.05 and 0.1.  A negative trial

 

 11   is indicated by a p value of greater than 0.01.

 

 12             So, for paroxetine, all 3 studies were

 

 13   negative, fluoxetine, both were positive and, as

 

 14   you know, this was the one program for which we

 

 15   concluded that there was sufficient data to support

 

 16   a claim.

 

 17             Our standard, and I believe the standard

 

 18   of most other regulatory agencies for pediatric

 

 19   major depression, is 2 positive studies.

 

 20             For the sertraline program, 1 trended and

 

 21   then 1 negative.  Venlafaxine, both were negative.

 

 22   For citalopram, 1 positive and 1 negative.

 

 23   Nefazodone, 1 trend, 1 negative, and both negative

 

 24   for mirtazapine.

 

 25             Now, the one point I want to make in this

 

                                                               287

 

  1   slide is that this was our fairly conservative view

 

  2   of these data.  Others have looked at these same

 

  3   data and have reached different conclusions.

 

  4             For example, for the paroxetine study 329,

 

  5   this was the basis for a publication by Keller, et

 

  6   al.  They acknowledged that that trial was negative

 

  7   on the primary endpoint, however, they pointed out

 

  8   that it was positive on virtually all secondary

 

  9   endpoints, and on that basis, they and many others

 

 10   consider that to be a positive study.

 

 11             Similarly, for the sertraline program,

 

 12   although if you look at the individual trials,

 

 13   neither one makes it.  One of the secondary

 

 14   analyses in the plan for these identically designed

 

 15   studies was to pool them, and when that is done,

 

 16   the pooled analysis is very positive, so some view

 

 17   that -- and again this was the basis for a

 

 18   publication by Wagner, et al. -- some view the

 

 19   sertraline program as providing support for

 

 20   efficacy in major depression.

 

 21             Again, as I pointed out, the citalopram

 

 22   program had 1 of 2 studies that was clearly

 

 23   positive.

 

 24             [Slide.]

 

 25             Now, I want to talk a little bit about

 

                                                               288

 

  1   this largely negative outcome.  If you look at

 

  2   adult major depression studies, and if you look at

 

  3   drugs which we believe work and which have been

 

  4   approved for depression in adults, about half the

 

  5   time studies that on face look like they should

 

  6   make it, fail.

 

  7             These are studies that are done in what

 

  8   appears to be the right population.  The sampling

 

  9   size is appropriate, the doses appear to be

 

 10   appropriate, assessments are appropriate, but for

 

 11   whatever reason, about half the time, these studies

 

 12   fail.

 

 13             Now, if you assume that that failure rate

 

 14   can be applied to pediatric major depression

 

 15   studies, and you look at the possible outcomes for

 

 16   2 trials, for programs that involve 2 trials, you

 

 17   can very quickly reach the mathematical result that

 

 18   only about 25 percent of the time would you expect

 

 19   to get 2 positive studies.

 

 20             Most of the time you would expect either 1

 

 21   or both trials to fail if the failure rate were the

 

 22   same as is true in adults.  So, in retrospect, it

 

 23   perhaps was not as surprising as it turned out to

 

 24   be here that you get a lot of negative results.

 

 25             On the other hand, the overall success

 

                                                               289

 

  1   rate here of 3 out of 15 studies making it at 0.05

 

  2   on the primary endpoint is clearly, clearly a

 

  3   concern.

 

  4             [Slide.]

 

  5             There are a couple of other things to keep

 

  6   in mind.  If you look at the history of short-term

 

  7   trials with tricyclic antidepressants in pediatric

 

  8   depression, it is uniformly negative, and there are

 

  9   several possible interpretations of that.

 

 10             One is that the drugs don't have any

 

 11   benefit.  Another possibility is that the extent of

 

 12   heterogeneity in pediatric patients who are

 

 13   captured under these major depressive disorder

 

 14   criteria may capture patients who are even more

 

 15   heterogeneous than we believed to be the case in

 

 16   adults, and the greater the heterogeneity in that

 

 17   sample, the more likely you would end up with

 

 18   negative studies.  So, that is one possibility.

 

 19             Another thing to keep in mind is that the

 

 20   regulatory context for doing these studies was

 

 21   somewhat unusual.  In every other case, when a

 

 22   company does a study, the only gain they are going

 

 23   to get out of that study is if it turns out

 

 24   positive.

 

 25             In this case, these studies were done

 

                                                               290

 

  1   primarily for pediatric exclusivity.  As was

 

  2   pointed out earlier, there was no requirement that

 

  3   they get positive studies to get exclusivity.

 

  4   Either way, if they did the trial according to the

 

  5   terms of the written requests, they would get

 

  6   exclusivity.

 

  7             I am not suggesting in any way that

 

  8   companies set out to do inadequate studies, but

 

  9   having that somewhat unusual mind-set could operate

 

 10   against a trial in subtle ways, in terms of, for

 

 11   example, recruitment of patients.  So, it is just

 

 12   another thing to keep in mind in terms of

 

 13   interpreting these largely negative data.

 

 14             Finally, at the time that the written

 

 15   requests for these studies were issued, we were not

 

 16   routinely asking for Phase II dose finding studies,

 

 17   as we are now in all of our written requests.

 

 18             Again, to the extent that appropriate dose

 

 19   finding was not done, that would work against

 

 20   positive studies.

 

 21             So, just in summary on the efficacy side,

 

 22   I think there are several plausible explanations

 

 23   for failure to find efficacy in these trials other

 

 24   than the obvious possibility that maybe the drugs

 

 25   have no benefits in pediatric major depression.

 

                                                               291

 

  1             In any case, the failure to meet FDA's

 

  2   fairly high standard of having 2 positive trials,

 

  3   in most of these programs, we do not consider proof

 

  4   of the lack of benefit.  So, it is true they didn't

 

  5   meet the standard, but that is not quite the same

 

  6   thing as saying that it has now been proven that

 

  7   the drugs have no benefit.  That is a very

 

  8   different conclusion.

 

  9             On the other hand, the failure to show a

 

 10   benefit in major depression in most of these

 

 11   trials, obviously heightens the concern about any

 

 12   adverse events, in particular, in this case, the

 

 13   possibility of the induction of suicidality.

 

 14   Clearly, the burden is on those who believe that

 

 15   these drugs do have benefits to show it, to design

 

 16   and conduct studies that show this.

 

 17             Again, one of the questions that I have

 

 18   for the committee is what your thoughts are about

 

 19   how to go about this, in particular, the

 

 20   possibility of using a very different kind of study

 

 21   design, for example, using the randomized

 

 22   withdrawal design, which has been fairly successful

 

 23   in showing longer term benefits in adult studies.

 

 24             I will stop there.  Thank you.

 

 25                    Open Committee Discussion

 

                                                               292

 

  1             DR. RUDORFER:  I think we will now open

 

  2   this up for questions and discussion by the

 

  3   committee.

 

  4             DR. SANTANA:  Can you clarify something

 

  5   for me, so under the exclusivity rule, if the

 

  6   results are positive, those studies can then be

 

  7   used by the sponsors to make a supplemental claim,

 

  8   and that could then become part of a new indication

 

  9   in pediatrics, is that correct?

 

 10             DR. LAUGHREN:  I am sorry?

 

 11             DR. MURPHY:  Yes.

 

 12             DR. LAUGHREN:  The answer is yes.

 

 13             DR. MURPHY:  Yes.

 

 14             DR. SANTANA:  I was trying to answer this

 

 15   issue of whether there was some bias in these

 

 16   studies because they were requested under the

 

 17   exclusivity rule.  I have never interpreted it that

 

 18   way.

 

 19             DR. MURPHY:  I think what has been a

 

 20   concern from the very beginning with exclusivity,

 

 21   we think the intent of Congress was that they want

 

 22   more information.  If studies are going to be

 

 23   conducted, they want that information to be known,

 

 24   and therefore, they want to say to companies we

 

 25   want you to go out and get this information.  It

 

                                                               293

 

  1   doesn't mean you have to reach the bar of having an

 

  2   approval, because a negative study can be just as

 

  3   important as a positive study.

 

  4             But the other concern here is that you --

 

  5   and no one is saying this, so, please, I don't want

 

  6   this quoted out of context -- but there is the

 

  7   concern that it is easy to design a sloppy study,

 

  8   fail, and still get your exclusivity. That is

 

  9   always a concern, and it is our job to try to not

 

 10   allow that to happen.

 

 11             DR. RUDORFER:  Dr. Temple.

 

 12             DR. TEMPLE:  I just was going to emphasize

 

 13   the same thing.  Tom isn't suggesting that anybody

 

 14   was totally indifferent to the outcome, but the

 

 15   sense of urgency that comes when you have launched

 

 16   a very expensive program to develop a drug, you

 

 17   really must win or it's all toast, and that's not

 

 18   true here.  You can win anyway, different

 

 19   incentives.

 

 20             DR. RUDORFER:  Dr. Fink, you had a

 

 21   question.

 

 22             DR. FINK:  This is sort of an overriding

 

 23   question, not to a specific speaker.  In looking at

 

 24   the questions that are being asked of the

 

 25   committee, we have heard very little about the data

 

                                                               294

 

  1   set that is being used.

 

  2             Are the inclusion and exclusion criteria

 

  3   for these various studies appropriate in terms of

 

  4   drug history, history of substance abuse, family

 

  5   history of psychiatric diagnoses?  Because these

 

  6   were placebo-controlled trials, they probably

 

  7   enrolled less severe disease as evidenced by the

 

  8   lack of completed suicides, and finally, as has

 

  9   been mentioned, there was no need of efficacy.

 

 10             I am concerned that no amount of analyses

 

 11   of a possibly flawed or suboptimal data set will

 

 12   answer the question.  If there is shown to be a

 

 13   relationship to suicidality, we may take away drugs

 

 14   that are useful in pediatric depression with

 

 15   different trial designs.

 

 16             If the studies come out negative, we may

 

 17   be falsely reassured.  So, I am not sure that these

 

 18   re-analyses are going to answer the question that

 

 19   has been brought forward to the committee by

 

 20   particularly the audience and that maybe we need to

 

 21   start with designing what are the optimal pediatric

 

 22   trials to answer this important issue.

 

 23             DR. RUDORFER:  Does someone from the FDA

 

 24   want to respond?

 

 25             DR. TEMPLE:  Well, Tom sort of opened that

 

                                                               295

 

  1   question to a degree.  One of the things that no

 

  2   one will let you do probably is treat somebody very

 

  3   severely ill in a placebo-controlled trial, they

 

  4   would be uncomfortable, although since it is not

 

  5   clear what works, maybe they shouldn't be that

 

  6   uncomfortable.

 

  7             Nonetheless, an alternative design which

 

  8   in pediatric studies has been proven very

 

  9   attractive is to take people who appear in one way

 

 10   or another to be doing well on a particular

 

 11   therapy, and in this case it really won't be as

 

 12   critical how severe they were before, and do a

 

 13   randomized withdrawal study in which people are

 

 14   very, very closely observed for the first

 

 15   recurrence of any symptom that is worrisome.

 

 16             The Pediatric Committee has discussed this

 

 17   at considerable length, and there is more comfort

 

 18   in pediatric trials in using that design where you

 

 19   do need a placebo to interpret the trial.  So, that

 

 20   is one of the questions Tom raised, and I am sure

 

 21   we would be interested in some discussion on that.

 

 22             DR. GOODMAN:  I am also sharing the

 

 23   concern about the ability to get the answer to the

 

 24   suicidal risk associated with these drugs based

 

 25   upon the existing data set.  I think the signal is

 

                                                               296

 

  1   not going to be strong enough although we are

 

  2   clearly most interested in suicide or suicide

 

  3   attempts as the outcome.

 

  4             I wondered if one could look at these data

 

  5   sets for other possible evidence of behavioral

 

  6   toxicity that might be antecedents of suicidality.

 

  7   I think there was some allusion to that earlier,

 

  8   but there wasn't much detail on it.  I wonder

 

  9   specifically if one could look at some of the

 

 10   items, like of the HAM-D or the CDRS, looking for

 

 11   agitation or irritability.

 

 12             If those are being induced by the

 

 13   medications particularly early in the treatment

 

 14   trial, perhaps those are creating a behavioral

 

 15   state that places that individual at risk for

 

 16   suicidal behavior.

 

 17             One could, of course, validate that by

 

 18   first looking at those subjects in whom there was

 

 19   evidence of suicidality to see if it was correlated

 

 20   or associated with other symptoms, but if it is,

 

 21   then go on to look at those variables, which would

 

 22   allow you to maybe get a more sensitive measure of

 

 23   the effect of the drugs.

 

 24             DR. RUDORFER:  Dr. Nelson and then Dr.

 

 25   Katz.

 

                                                               297

 

  1             DR. NELSON:  Two questions.  The first is

 

  2   about the data set.  At the end of the day, when

 

  3   you receive the data that you are asking for, will

 

  4   you be looking at the same data set that were

 

  5   reviewed by the MHRA?  I mean are we going to be

 

  6   drawing conclusions on similar data sets?

 

  7             The second question goes to the issue of

 

  8   the interpretation of Appendix 1 and Appendix 2A.

 

  9   I am struck, if you remove fluoxetine, that you

 

 10   have got 1 out of 13 trials for effectiveness

 

 11   positive and 5 out of 13 for increased risk of

 

 12   suicidality positive, and does assay sensitivity

 

 13   apply to risks as well and why would we not

 

 14   interpret that as a pretty strong signal if, in

 

 15   fact, we accept that on the efficacy side?

 

 16             DR. LAUGHREN:  Regarding the question

 

 17   about the UK data, I can't be certain that they

 

 18   have the same data, however, if we look at the

 

 19   numbers that are presented on the UK web site, they

 

 20   are very familiar numbers.  They appear to be

 

 21   coming from the same summary data that we had

 

 22   access to in looking at this data.

 

 23             So, I am reasonably confident that we are

 

 24   dealing with the identical data sets.  The only

 

 25   difference is that we have gone beyond accepting

 

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  1   the data at face value.  It appears that the UK

 

  2   simply accepted the summary data analyses done by

 

  3   the various companies, and on the basis of a

 

  4   suggestion of a signal, and the admitted lack of

 

  5   efficacy for most of these programs, have decided

 

  6   to contraindicate these drugs.

 

  7             We have chosen on the safety side to look

 

  8   more closely at what that signal is, and that is

 

  9   really the question.  The question is -- and this

 

 10   gets in reference to your second question about

 

 11   Appendices 2 and 2A -- I agree with you that if you

 

 12   look across these trials, even though the signal is

 

 13   not consistent from study to study within programs,

 

 14   on balance, it appears like there is an excess of

 

 15   something for drug relative to placebo.

 

 16             The question is what is that.  You have

 

 17   this very broad term, "possibly suicide related,"

 

 18   but when you dig deeper and look at what those

 

 19   events are, they range all the way from something

 

 20   that everyone would agree does not represent

 

 21   anything close to a suicide attempt to very serious

 

 22   suicide attempts.

 

 23             So, that is why we think it is important

 

 24   to go back and reclassify those events, so we can

 

 25   figure out, first of all, if there is a signal, and

 

                                                               299

 

  1   secondly, a signal for what.  But I believe that

 

  2   the UK had the very same data that we have, and it

 

  3   doesn't appear to me as if they did any analysis of

 

  4   those data other than to just accept what the

 

  5   companies have done already.

 

  6             DR. RUDORFER:  Dr. Katz, did you have a

 

  7   comment?

 

  8             DR. KATZ:  Just to say that the suggestion

 

  9   about looking at other behavioral symptoms that

 

 10   might be premonitory to suicidal behavior, we are

 

 11   very interested here whether or not there are

 

 12   specific events we should be looking at that we

 

 13   haven't looked at yet along the lines of how we

 

 14   intend to look at the suicidal behavior data.

 

 15             That might involve going back and asking

 

 16   sponsors to resubmit data sets, but we are very

 

 17   interested to hear that.  Of course, the question

 

 18   of the link between those symptoms and suicidal

 

 19   behavior is also still an outstanding question,

 

 20   it's not straightforward.

 

 21             DR. RUDORFER:  Dr. Chesney.

 

 22             DR. CHESNEY:  I also felt that perhaps

 

 23   just looking at suicide attempts, basically what

 

 24   you just said and what Dr. Goodman said, may not be

 

 25   all the answer.  I am most impressed from what we

 

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  1   heard in the public hearing this morning about the

 

  2   stimulant syndrome and the number of individuals

 

  3   who had demonstrated psychoses, akathisia, mania,

 

  4   agitation, and so on.

 

  5             I was also impressed at one young lady who

 

  6   said that she wouldn't disclose that she had had

 

  7   suicidal ideation, and then particularly impressed

 

  8   with the three people we heard from whose children

 

  9   at autopsy had very elevated levels of the drug,

 

 10   which leads to my second question.

 

 11             That is, what do we know about

 

 12   pharmacokinetic data in children and in individuals

 

 13   who develop this stimulant syndrome.  I suspect

 

 14   someday that we will have pharmacogenomics to tell

 

 15   us maybe who to predict might have that, but do we

 

 16   have any information about pharmacokinetics in

 

 17   children, number one, and number two, in these

 

 18   individuals who develop these stimulant syndromes,

 

 19   is there any relationship at all?

 

 20             DR. KATZ:  Well, in the written requests,

 

 21   as a general matter, we ask sponsors to obtain

 

 22   pharmacokinetic information in the relevant

 

 23   pediatric population, so I believe we have probably

 

 24   asked for that information.

 

 25             I don't believe we know or have had

 

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  1   submitted to us in any event data linking plasma

 

  2   levels in any individual patient and particular

 

  3   adverse events.  That might be available somewhere,

 

  4   but I don't think we have it.

 

  5             DR. LAUGHREN:  Could I ask Daniel Pine to

 

  6   comment on this construct stimulation syndrome and

 

  7   whether or not that has been reasonably well

 

  8   defined in some way that is agreed to by different

 

  9   individuals?

 

 10             DR. PINE:  Sure, and then actually I have

 

 11   a couple other comments.  I don't know if you want

 

 12   me to wait until after this issue.

 

 13             But I would say across a range of

 

 14   pediatric mental syndromes, it has been fairly

 

 15   frequently described that a strong minority of

 

 16   children will get activated with SSRI medications,

 

 17   and not just children with major depression, and

 

 18   that in most studies, if it is not statistically

 

 19   greater than it is in placebo, that it is a fairly

 

 20   consistent observation across most studies, that it

 

 21   is higher on SSRIs than it is on placebo.

 

 22             DR. LAUGHREN:  Are we talking about

 

 23   something other than the anxiety and agitation

 

 24   which is well known as a drug-related risk with all

 

 25   of these drugs?  That is something that we see in

 

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  1   most of these trials, but it is not quite the same

 

  2   thing as saying that someone has a stimulant

 

  3   syndrome.

 

  4             DR. PINE:  I think if you look across the

 

  5   trials and you look at the range of terms that

 

  6   people have used to describe this so-called

 

  7   stimulant syndrome, you see that the problem that

 

  8   you were talking about with the relatively narrow

 

  9   set of behaviors, self-harm behaviors or suicidal

 

 10   behaviors, becomes even worse because across

 

 11   different trials or trials for the same medication

 

 12   done by different individuals, really a broad range

 

 13   of behaviors have been kind of linked together.

 

 14             It remains unclear the degree to which

 

 15   different investigators are talking about the same

 

 16   phenomenon or different medications are producing

 

 17   similar phenomenon.  The one thing that is clear is

 

 18   that there is an array of what some people have

 

 19   called, and Dr. Goodman referred to, as behavioral

 

 20   toxicities that are not that infrequently observed

 

 21   with SSRIs, and it might extend beyond suicidal

 

 22   ideation, and it also needs to be better

 

 23   categorized.

 

 24             I would also add that when one looks at

 

 25   those events in most of the efficacy trials, they

 

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  1   tend to be uniformly mild.  I am most familiar with

 

  2   the anxiety trials where, while they are more

 

  3   prevalent, they tend to not cause sometimes even

 

  4   discontinuation of the medication.

 

  5             DR. LAUGHREN:  If I could just follow up

 

  6   on this.  If we were, Daniel, to look for this, I

 

  7   guess the question would be how would one define it

 

  8   in a way that we could hope to find examples of it?

 

  9             DR. PINE:  I think if you look at most of

 

 10   the publications for most of the SSRI trials, you

 

 11   can see relatively broad categories that describe

 

 12   something that people would call activation, so,

 

 13   you know, in the original sertraline trial, I think

 

 14   it was called hyperactivity.  In the fluvoxamine

 

 15   trial, it was called activation.

 

 16             In the recent sertraline trial, I think it

 

 17   was called impulsivity.  So, there is a whole range

 

 18   of terms that I think you would have to canvass the

 

 19   field in terms of thinking about what are the most

 

 20   appropriate terms to include, much the way that you

 

 21   have done with suicidal ideation.

 

 22             That is not to say that this is

 

 23   necessarily related to suicidal ideation, though.

 

 24             DR. RUDORFER:  Dr. Goodman, did you have a

 

 25   follow-up comment?

 

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  1             DR. GOODMAN:  Yes.  In at least adults, I

 

  2   think as clinicians as well as clinical

 

  3   researchers, we have a good sense of kind of the

 

  4   array you were talking about of activation-like

 

  5   problems that can occur with the administration of

 

  6   SSRIs.

 

  7             Even in the labeling, we have seen that

 

  8   there are warnings that you can induce bipolarity,

 

  9   mania.  In fact, it has often been said that an

 

 10   antidepressant is probably not effective unless it

 

 11   can induce bipolarity in some patients.

 

 12             We also know about psychosis and anxiety

 

 13   induction particularly in panic disorder patients.

 

 14   So, I think in adults, we have it a little better

 

 15   characterized.  What I am concerned about with the

 

 16   children is, one, their characterization probably

 

 17   is somewhat overlapping, and also because of what

 

 18   is special about children is maybe that they are

 

 19   more likely to manifest these problems in a less

 

 20   differentiated fashion, which includes suicidal

 

 21   behavior.

 

 22             DR. PERRIN:  To follow up on two of these

 

 23   issues, one is we hear about serious adverse events

 

 24   being beyond suicide, but potentially also murder

 

 25   and other such events.

 

                                                               305

 

  1             I think maybe Dr. Pine is talking about

 

  2   strategies that might help to elicit those sorts of

 

  3   ideas in the data set, but it seems to me that is a

 

  4   critical issue to go beyond suicidality as a

 

  5   potential serious adverse event.

 

  6             I want to get back to the pediatric rule

 

  7   question for a moment, too, if I could, and just

 

  8   ask -- I show my naivete and ignorance here -- but

 

  9   what purview, what surveillance does FDA have of

 

 10   pharmaceutical companies carrying out their trials?

 

 11             The little I know about them is that these

 

 12   are often multi-site trials, fairly complicated

 

 13   data collection among a variety of providers.

 

 14             Do you have any surveillance as to how

 

 15   well this is carried out, or do you sort of rely on

 

 16   the pharmaceutical companies to say we did it

 

 17   reasonably well, and might that be a source for

 

 18   variation between pediatric rule trials compared to

 

 19   the sort of getting the drug on the market trials?

 

 20             DR. TEMPLE:  Others may want to comment.

 

 21   Usual rules apply.  We can inspect any of the

 

 22   studies.  As you can imagine, inspecting a study

 

 23   after the fact gives you only limited insight into

 

 24   how well those things went on.

 

 25             The companies are expected to provide

 

                                                               306

 

  1   oversight, the rules require that they do so, but

 

  2   our ability to know whether it is perfect or not is

 

  3   difficult at best.  What I can't tell you is how

 

  4   often we have inspected these sites.  We do

 

  5   sometimes, I don't know if we have on these.

 

  6             DR. MURPHY:  I would like to say that this

 

  7   is an issue at the level of the Office of

 

  8   Commissioner, that there is an Office of Good

 

  9   Clinical Practices, that they are addressing to

 

 10   make sure that we do have adequate surveillance and

 

 11   criteria.  I don't think we can provide you a lot

 

 12   of information right now, but it is an issue that

 

 13   they are looking at.

 

 14             DR. TEMPLE:  It would be relatively

 

 15   unusual for us unless we had a concern about

 

 16   whether they picked up adverse reactions, which we

 

 17   might in this case, first, to inspect a study that

 

 18   the company agrees is negative.  On the whole, that

 

 19   is not where you go to look.

 

 20             DR. RUDORFER:  Dr. Gorman, you have been

 

 21   waiting.

 

 22             DR. GORMAN:  One of the themes that struck

 

 23   me through the morning was the interruption or

 

 24   potential interruption of information flow through

 

 25   the system.

 

                                                               307

 

  1             I would like to continue on the thread of

 

  2   the study and then go to the information flow

 

  3   question I have.

 

  4             On the study, I think going back and

 

  5   looking at that 109 out of 3,000 patients that were

 

  6   being studied for efficacy and looking for them for

 

  7   suicidal ideation or attempts will be trying to

 

  8   make a silk purse out of a sow's ear.  I think that

 

  9   would be an adventure in futility.

 

 10             I don't think it's an unreasonable thing

 

 11   to do if it's the data that you have available, but

 

 12   I think the example used this morning was the

 

 13   needle in the haystack.

 

 14             I think we have stepped on the needle and

 

 15   we have either got to see if it's really there or

 

 16   if it is really not there, and design studies

 

 17   prospectively either using randomized, controlled

 

 18   clinical trial crossover designs or withdrawal of

 

 19   effective therapy designs.

 

 20             One of those three designs could be

 

 21   designed looking specifically at the questionnaires

 

 22   that our psychiatric and psychology colleagues tell

 

 23   us look for suicidal ideation.

 

 24             To look for suicides as a rare event I

 

 25   think is going to be again a futile search, but

 

                                                               308

 

  1   looking for suicidal ideation induced by these

 

  2   medications, I think should be relatively

 

  3   straightforward, and I would not use the set of

 

  4   mildly or majorly depressed people.

 

  5             I would look at groups of individuals on

 

  6   these medications who are not depressed, so that we

 

  7   could separate that issue out, is it the disease or

 

  8   is it the medicine.

 

  9             So, take the ODDs and take the

 

 10   post-distress syndromes and study them for suicidal

 

 11   ideation being initiated on these medications.

 

 12             Now, back to the pediatric rule, which I

 

 13   think I understand, and the Best Pharmaceuticals

 

 14   for Children Act, I thought there was a provision

 

 15   in there, I thought, that when we fixed it after

 

 16   1997, that if you went for pediatric exclusivity,

 

 17   when you finish the trial, whether the results were

 

 18   positive or negative, you got exclusivity.

 

 19             But I also think there was a requirement

 

 20   for the pharmaceutical companies to make those data

 

 21   available in a public place.  Is my understanding

 

 22   confused?

 

 23             DR. MURPHY:  No, that was a slide this

 

 24   morning.  The BPCA does say that within 180 days of

 

 25   the submission of the application, that the study

 

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  1   results, clinical trial and a summary of the

 

  2   clinical aspects and the pharmacology report will

 

  3   be posted on the web by FDA.

 

  4             DR. GORMAN:  Is there a dissemination

 

  5   issue then that it comes as a surprise to me and

 

  6   other people in this room that 12 out of 15 studies

 

  7   -- and I am sorry if I got that number wrong --

 

  8   were negative in their scope, or is that just

 

  9   something that hasn't quite made its way to the web

 

 10   site yet?

 

 11             DR. MURPHY:  No, there was an issue in

 

 12   that there was a window after BPCA was enacted in

 

 13   which the sponsors had to be informed that they now

 

 14   -- because they had been issued the written

 

 15   requests earlier -- that they now were under the

 

 16   new legislation.  They had been issued their

 

 17   written requests under prior legislation.

 

 18             In that window, a number of these studies

 

 19   came in.

 

 20             DR. RUDORFER:  Dr. Leon.

 

 21             DR. LEON:  After hearing the speakers

 

 22   today, I think there is at least three avenues to

 

 23   pursue simultaneously for being informed about this

 

 24   topic, and all three will provide important

 

 25   information about the public health risk and

 

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  1   benefits.

 

  2             First, is looking at the existing clinical

 

  3   trial data, or using the experts from Columbia

 

  4   University, that is a good start.  I think what is

 

  5   very important in looking at those data is we

 

  6   haven't yet heard what percentage of people who

 

  7   were screened to be in those clinical trials

 

  8   actually were enrolled.  Was it 5 percent, 10

 

  9   percent, 80 percent?  We have no idea.  That

 

 10   certainly affects the generalizability of those

 

 11   results.

 

 12             The people we heard from this morning

 

 13   might have been those who these data don't apply

 

 14   to, who would be excluded from trials, and we need

 

 15   to learn about those, and I will comment on that in

 

 16   just a minute.

 

 17             Also, in re-analyzing those data, I would

 

 18   really discourage the last speaker from dropping

 

 19   data in which there were no suicide attempts.  It

 

 20   provides a false sense of risk actually.  It

 

 21   inadequately characterizes exposure to the

 

 22   medication.

 

 23             The second avenue to pursue would be new

 

 24   clinical trials, which were alluded to by a few

 

 25   people today, and those should be designed with

 

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  1   very comprehensive assessments of suicidality,

 

  2   agitation, hostility, akathisia, and assessments

 

  3   that are sanctioned by the FDA, maybe with expert

 

  4   advice again from Columbia and other universities,

 

  5   other academic centers with expertise in assessing

 

  6   those constructs.

 

  7             They should carefully consider the

 

  8   comparison group.  That is probably the hardest

 

  9   part of designing those studies, whether it's a

 

 10   withdrawal study, as Dr. Laughren alluded to, or

 

 11   suggested, or maybe psychotherapy versus active med

 

 12   versus combination, I am not quite sure, but that

 

 13   certainly deserves discussion, and in those trials,

 

 14   much broader inclusion criteria should be used than

 

 15   have been used in the clinical trials to date.

 

 16             The third avenue I would encourage is the

 

 17   use of existing observational data sets.  Now,

 

 18   observational data sets, at the expense of internal

 

 19   validity, at the expense of the association between

 

 20   treatment and outcome provide wider

 

 21   generalizability, and a much broader inclusion

 

 22   criteria.

 

 23             Dr. Pfeffer, her slides referred to at

 

 24   least three different ongoing longitudinal

 

 25   observational studies of children, depressed

 

                                                               312

 

  1   children, and if those observational studies are

 

  2   used, appropriate methods for adjustment and

 

  3   stratification should be used.

 

  4             They could consider some of the methods

 

  5   used in the Division of Devices that are used to

 

  6   adjust for observational differences.

 

  7             I will stop there.

 

  8             DR. RUDORFER:  Dr. Katz and Dr. Temple.

 

  9             DR. KATZ:  I just want to comment on the

 

 10   notion of how to better design trials in the future

 

 11   to look at this question.  It is a very important

 

 12   question, it is one of the questions actually that

 

 13   Tom has drawn up, that we would like you to

 

 14   discuss, and a number of people have already

 

 15   mentioned it.

 

 16             We think it's a good idea, too.  The

 

 17   problem is I am not sure how to get those trials

 

 18   done.  As you have seen, pretty much most of the

 

 19   drugs in this class have been studied already,

 

 20   their trials have been done under the pediatric

 

 21   exclusivity provisions, and I am not sure we have

 

 22   the authority to require sponsors to go ahead and

 

 23   redesign trials of the same treatments to have a

 

 24   better look at trying to capture these events.

 

 25             I would be very interested to know if

 

                                                               313

 

  1   people have an idea about that, whether or not

 

  2   there should be an NIMH-sponsored trial perhaps of

 

  3   most of the drugs in this class, because I don't

 

  4   think we can require the sponsors to do these

 

  5   studies other than for the ones that might not yet

 

  6   have studied them under the pediatric exclusivity

 

  7   provisions, whichever ones those are, and there

 

  8   aren't many.

 

  9             DR. MURPHY:  The one possibility would be

 

 10   that these products would be put on the list of

 

 11   products that need to be studied.  We have an

 

 12   off-patent list, but we can also reissue a written

 

 13   request to a sponsor for a product which is on

 

 14   patent, and if they refuse to do it, we could send

 

 15   that request to the foundation at NIH.

 

 16             Remember, I described earlier this morning

 

 17   there is a collaboration between NIH and FDA to

 

 18   develop products for the off-patent including the

 

 19   list of products that need to be studied.  Some of

 

 20   these products have come off patent, some will be,

 

 21   and even if they haven't, there is another

 

 22   mechanism which FDA can issue a written request and

 

 23   then if the sponsor doesn't want to do it, even if

 

 24   it's still on patent, and it has a high enough

 

 25   rating, it can be sent to NIH foundation.

 

                                                               314

 

  1             I have to tell you, though, that the

 

  2   problem is that funding for that foundation to do

 

  3   studies is very small, so it would be getting in

 

  4   line for a number of studies for which the funding

 

  5   is very limited at the moment, but those are the

 

  6   possibilities I am aware of at this point.

 

  7             DR. RUDORFER:  Also, I wanted to mention

 

  8   that there is, in fact, an NIMH study that is

 

  9   nearing completion, the treatment of adolescent

 

 10   depression study, or TADS, that includes a

 

 11   controlled trial of fluoxetine and placebo, as well

 

 12   as cognitive behavior therapy alone or with drug.

 

 13   That is a 36-week acute trial followed by a 1-week

 

 14   follow-up study in a total of 400 adolescents

 

 15   coordinated at Duke.

 

 16             I understand that the results should be

 

 17   available by the beginning of June, so hopefully,

 

 18   in time to inform the FDA analysis.

 

 19             Dr. Ebert has been waiting patiently.

 

 20             DR. EBERT:  It appears in some ways that

 

 21   many of these clinical trials may not reflect the

 

 22   typical use for these agents.  We saw some data

 

 23   that showed that many of these agents are used

 

 24   other than for major depressive disorders, are

 

 25   prescribed by physicians other than psychiatrists,

 

                                                               315

 

  1   and I am wondering if there is some way that we can

 

  2   measure the adverse effects that we are seeing in

 

  3   the typical use.

 

  4             We currently have the AERS system, which I

 

  5   think admittedly is somewhat limited because of the

 

  6   voluntary reporting that is necessary, but I am

 

  7   wondering if the Agency could comment about some

 

  8   other type of a postmarketing program that could be

 

  9   set up that might focus on this more rigorously.

 

 10             DR. TEMPLE:  The people from the Office of

 

 11   Drug Safety need to comment, too.  I just wanted to

 

 12   make the observation that the most difficult

 

 13   epidemiological situation you can identify probably

 

 14   is where the events you are looking for, both the

 

 15   product of the disease and the potential product of

 

 16   the drug you are worried about, it is hard to think

 

 17   of anything more difficult, but some

 

 18   epidemiologists ought to comment further on that.

 

 19             I wanted to make one observation about

 

 20   randomized withdrawal studies, which I like very

 

 21   much.  They are not a good way to discover whether

 

 22   these drugs cause suicidal thinking, because, by

 

 23   definition, the people on those drugs are people

 

 24   who are doing well on them.

 

 25             It is a possible way to show that the

 

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  1   drugs work in a situation that is somewhat

 

  2   different from the high-intensity, high-support

 

  3   setting of the acute trial, but I don't think that

 

  4   is going to get us the answer on suicidal thinking.

 

  5   These are all bona-fide do-gooders or do-wellers if

 

  6   you like, so I don't think it is going to help on

 

  7   that.

 

  8             DR. RUDORFER:  Dr. Pfeffer.

 

  9             DR. PFEFFER:  I wanted to comment on

 

 10   something that struck me, and that is the placebo

 

 11   response rate seems to be relatively high in these

 

 12   populations in these studies, and I wondered how

 

 13   they did compare to placebo rates in adults.

 

 14             My sense is they are high and I would

 

 15   assume maybe higher, and I wonder if that leads to

 

 16   us needing to think about other covariates, for

 

 17   example, as will be done in the analyses, such as

 

 18   the environmental circumstances in which the

 

 19   children are living, and to see what that feature

 

 20   may impact on not only the suicidal state, but the

 

 21   potential for recovery.

 

 22             I wonder certainly with the placebo rate

 

 23   being a narrow range between the treated state, if

 

 24   our concerns about efficacy need to be rethought in

 

 25   terms of developmental issue.

 

                                                               317

 

  1             DR. RUDORFER:  Does someone from the FDA

 

  2   want to comment on the placebo response rate in the

 

  3   pediatric studies versus these same drugs in

 

  4   adults?

 

  5             DR. LAUGHREN:  I don't have the data in

 

  6   front of me.  My general sense is yes, that the

 

  7   placebo response rate in fact is an issue for both

 

  8   adult and pediatric studies, perhaps even more of

 

  9   an issue in pediatric studies, and that may get at

 

 10   the issue I was raising earlier about heterogeneity

 

 11   that you see when you try and capture a population

 

 12   using the MDD criteria, but yes, it is definitely a

 

 13   problem in both areas, but perhaps even more so in

 

 14   pediatrics.

 

 15             DR. RUDORFER:  Dr. Laughren, is there a

 

 16   standard way of assessing diagnosis in these MDD

 

 17   trials?  I mean as a matter of just the sponsor

 

 18   will say these subjects met DSM-IV criteria, do we

 

 19   know if they used any kind of structured interview?

 

 20             DR. LAUGHREN:   They almost always use

 

 21   some kind of structured interview.

 

 22             DR. RUDORFER:  So, presumably, if there

 

 23   were comorbidities, those would be captured?

 

 24             DR. LAUGHREN:  Yes, and there often is

 

 25   comorbidity.

 

                                                               318

 

  1             DR. PINE:  Related to that question, could

 

  2   I make one comment about it.  When one looks

 

  3   particularly across the recent studies, while every

 

  4   study will say that they used a standardized

 

  5   assessment, there is really a quite marked

 

  6   variability across studies in terms of the way in

 

  7   which they documented the rigor of that approach.

 

  8             So, if you read the recent letter in JAMA

 

  9   from Wagner, that talks about the process of

 

 10   establishing the diagnosis and the reliability

 

 11   study, that reads very differently from some of the

 

 12   other studies that maybe had a lower placebo

 

 13   response rate or smaller samples.

 

 14             So, I was wondering if it might be

 

 15   possible to in some way evaluate or rate the rigor

 

 16   with which both the diagnosis and the outcome

 

 17   variables were assessed across the studies, paying

 

 18   particular attention to issues of training and the

 

 19   demonstration of reliability by those investigators

 

 20   conducting the trial and using the instrument.

 

 21             DR. LAUGHREN:  It would be very difficult

 

 22   to do that after the fact.  If they claim to have

 

 23   done it in a particular way, to document whether or

 

 24   not it had been done in that way, involve an

 

 25   enormous amount of work, and given the time at

 

                                                               319

 

  1   which these studies were done, you know, going back

 

  2   four, five years, it would be hard to imagine how

 

  3   that would be helpful.

 

  4             DR. RUDORFER:  Dr. Wang.

 

  5             DR. WANG:  I think in addition to

 

  6   considering what the optimal design would be, if we

 

  7   all had our choosing, we should keep in mind that

 

  8   at the best, it will take a long time to do them

 

  9   even sorting out all the other logistics, so I

 

 10   think in the meantime, it is important to consider

 

 11   how to enhance the use of this existing data set,

 

 12   which will be arriving soon enough, to study this

 

 13   question.

 

 14             One thing I am particularly concerned

 

 15   about is you may lose an effect in the overall data

 

 16   set that you would otherwise be able to see in a

 

 17   high-risk population.

 

 18             I think in that list of covariates that

 

 19   you are asking the sponsors to all submit, to also

 

 20   add variables that will allow you to identify

 

 21   high-risk populations, such as people -- some that

 

 22   come to mind, kids that have insomnia at baseline

 

 23   or high anxieties, severity symptoms, or family

 

 24   histories of bipolar illness, things that allow you

 

 25   to sort of concentrate on a group that is likely to

 

                                                               320

 

  1   potentially show an effect.

 

  2             DR. RUDORFER:  Dr. Gorman.

 

  3             DR. GORMAN:  Again back to the theme of

 

  4   information flow, I was wondering if someone from

 

  5   the FDA could explain what bars we would have to

 

  6   meet for changing the labeling on these substances

 

  7   today.  The labels get made when a new product is

 

  8   approved, but then are modified through many

 

  9   mechanisms, I have no idea.

 

 10             What do we need to do to put a precaution,

 

 11   warning, or black box, or side effect or adverse

 

 12   event that lists these as potential -- what bar do

 

 13   we have to meet to potentially include these in the

 

 14   label?

 

 15             DR. KATZ:   As you heard from one of the

 

 16   speakers in the open session, it isn't required,

 

 17   for example, when we are contemplating putting

 

 18   something in the Warning section that we have

 

 19   absolute proof that the drug causes a particular

 

 20   adverse event, but reasonable suspicion.  I forget

 

 21   exactly what the words are.

 

 22             On the other hand, of course, two points,

 

 23   one, it is obviously a judgment as to whether or

 

 24   not there is reasonable evidence that a drug is

 

 25   linked to a particular adverse event.  So, if you

 

                                                               321

 

  1   ask what the bar is, it is hard to say.  It is

 

  2   highly case-dependent.

 

  3             On the other hand, even though the law

 

  4   permits us to include things in the Warning section

 

  5   that we have not yet proven to be associated with

 

  6   the drug, there is always the risk of including

 

  7   such events when we aren't really sure or almost

 

  8   sure that the drug did it, because, number one, it

 

  9   is distracting, but beyond that, you might be

 

 10   giving false information.

 

 11             So, as a general matter, we tend to put

 

 12   adverse events in the Warning section when we are

 

 13   pretty sure, when we think we have pretty good

 

 14   evidence that the drug actually does it as opposed

 

 15   to its just being associated with it.

 

 16             A boxed warning again is a judgment, but I

 

 17   would say, as a general matter, as well, we don't

 

 18   put a description of adverse events in a boxed

 

 19   warning, which is sort of the most stringent

 

 20   warning you can apply in a labeling unless we

 

 21   really believe that the drug is causally related to

 

 22   the adverse event.

 

 23             Then, of course, we don't put all causally

 

 24   related adverse events in boxed warnings, only

 

 25   those which we think are particularly serious, not

 

                                                               322

 

  1   to say that suicidal behavior would not be one of

 

  2   those events, but really boxed warning and pretty

 

  3   much warning, we like to have pretty good evidence

 

  4   that the drug actually did it.

 

  5             Of course, the type of evidence that is

 

  6   brought to bear on the question of whether or not

 

  7   the drug is causally related varies.  We like to

 

  8   have controlled data.  It isn't always controlled

 

  9   data.

 

 10             Sometimes for rare events, as you heard

 

 11   earlier, events not associated with the condition

 

 12   that you are looking at, postmarketing data,

 

 13   comparing reporting rates to what we know about

 

 14   background rates usually suffices.  I am not sure

 

 15   we can apply that sort of reasoning to this case.

 

 16             DR. TEMPLE:  We are particularly

 

 17   interested in telling people of things they can do

 

 18   to avoid problems, if there is such a thing, that

 

 19   seems reasonably likely to do it.  Current labeling

 

 20   already does tell you that early after treatment

 

 21   starts is the time to watch out.

 

 22             It doesn't attribute that to the drug, but

 

 23   it doesn't seem out of the question that wording

 

 24   like that could be enhanced and made clearer.

 

 25   Everyone seems to agree that that is a dangerous

 

                                                               323

 

  1   time whether you agree on why it is a dangerous

 

  2   time or not.

 

  3             So, there are things like that that can be

 

  4   done. Another option that we have not used for most

 

  5   of these drugs is to provide information as best we

 

  6   can for patient or caregiver use.  Those are all

 

  7   possibilities.

 

  8             DR. MURPHY:  Could I put a pragmatic

 

  9   response to that answer?  That is, that I think one

 

 10   of the other things that we need to consider --

 

 11   it's in your questions -- is that to get a change

 

 12   in label, let's just assume for some reason that

 

 13   people walked out of here today and wanted to

 

 14   change the label.

 

 15             It takes a while to get all that done and

 

 16   by the time you came back this summer, you might

 

 17   want to change the label again.

 

 18             So, I think what we are going to be asking

 

 19   you or in one of the set of questions is what are

 

 20   your recommendations about what FDA may or could

 

 21   possibly do in the interim, because I think that

 

 22   everyone is very interested in what additional

 

 23   information we can get, and we would like to make

 

 24   it the most efficient way of transmitting

 

 25   information, which would be together instead of

 

                                                               324

 

  1   trying to change things maybe two times.

 

  2             So, I think the pragmatics of it are what

 

  3   can we do to help better inform people before the

 

  4   late summer meeting in which we hope to have a more

 

  5   definitive response.

 

  6             DR. RUDORFER:  Dr. Nelson.

 

  7             DR. NELSON:  I think I will continue this

 

  8   conversation about labeling rather than what I was

 

  9   originally going to say.

 

 10             I have two suggestions.  What struck me in

 

 11   your remarks about the timing was the delay it

 

 12   appeared to take for you to actually get the data

 

 13   you were asking the sponsors to provide.  That

 

 14   could be inadvertent or it could be, in fact,

 

 15   duplicitous.

 

 16             So, I would suggest that you tell them

 

 17   that, in fact, if they don't provide the data you

 

 18   want, that you will label it based on just the

 

 19   British decision, with a warning, would be the

 

 20   first suggestion.

 

 21             But the second is, to answer Dianne's

 

 22   question about a notice, I think you could honestly

 

 23   take Appendix 2A and put that in the letter to both

 

 24   health care professionals and to patients on the

 

 25   medication saying the FDA is really worried about

 

                                                               325

 

  1   this signal and we want to look at this data, and

 

  2   if you are worried, too, you ought to talk to your

 

  3   clinician that prescribed it and discuss those

 

  4   concerns and name the drugs.

 

  5             It is unclear to me why someone couldn't

 

  6   have the opportunity to see that signal and to make

 

  7   their own evaluation as to whether or not they

 

  8   would want to be slowly tapered and put on the one

 

  9   drug that seems to be so far a winner in all of

 

 10   this, which is fluoxetine.

 

 11             DR. LAUGHREN:  Let me just clarify one

 

 12   thing.  We have the data from the companies, the

 

 13   ball is now in our court, so we are not waiting for

 

 14   anything at this point from companies unless the

 

 15   committee feels that there is some deficiencies

 

 16   here in terms of case finding, but we are satisfied

 

 17   that we have what we need.

 

 18             It is now a question of working on a

 

 19   reclassification and designing an analysis.  We

 

 20   have what we need.

 

 21             Regarding the second issue of

 

 22   disseminating Appendix 2 to prescribers, I am not

 

 23   sure what purpose would be served in doing that.  I

 

 24   mean we have already issued a health advisory in

 

 25   October saying that we are concerned, that we can't

 

                                                               326

 

  1   rule out an increased risk of suicidality.

 

  2             If we are not comfortable with what is in

 

  3   the numerators for these risks that are displayed

 

  4   in that table, I am not really sure what purpose is

 

  5   served in disseminating that.

 

  6             DR. NELSON:  One brief response to that

 

  7   and then I will be done.  What bothered me in

 

  8   listening to the testimony this morning is the

 

  9   amount of off-label use, and the amount of times

 

 10   that people mentioned that they were given samples.

 

 11   I would even go so far as to wonder if the handing

 

 12   out of samples is marketing outside of an

 

 13   indication where you could even come after a

 

 14   company.

 

 15             So, part of my desire to inform clinicians

 

 16   is to try to scare them away from off-label use

 

 17   frankly.  That bothers me, the amount of off-label

 

 18   use that appears to be going on in this particular

 

 19   market.

 

 20             DR. RUDORFER:  Dr. Griffith.

 

 21             MS. GRIFFITH:  I need to clarify, I am not

 

 22   a doctor, I am a consumer, I am a parent, and as a

 

 23   lay person, the most troubling outcome I think of

 

 24   this morning's and this afternoon's presentations

 

 25   was the urgency with which this needs to be

 

                                                               327

 

  1   resolved.

 

  2             After the presentation by Dr. Hammed, I

 

  3   was really struck by, in covering the analysis

 

  4   plan, the last statement it remains to be seen that

 

  5   if we have enough statistical power, whether or not

 

  6   there is enough statistical power.

 

  7             My question is what happens then, if there

 

  8   is not enough evidence to make a conclusion, how

 

  9   does the FDA inform the public, because as you say,

 

 10   you put out an advisory on October 27th, which I,

 

 11   as a parent and as a consumer, read, found it

 

 12   terribly confusing.

 

 13             It was reported on very contradictorily,

 

 14   and what I am suggesting is I think the FDA is

 

 15   going to have a credibility problem if it does not

 

 16   get out ahead of this with some very public

 

 17   statements about where it is going with these

 

 18   studies and with the data.

 

 19             DR. RUDORFER:  Dr. Goodman, did you want

 

 20   to respond?

 

 21             DR. GOODMAN:  I think it is going to be

 

 22   some time until at least I am comfortable that we

 

 23   have enough data and analyze it properly to be sure

 

 24   of the connection with suicidality, however, I

 

 25   think that myself -- and my guess is there are

 

                                                               328

 

  1   other people around the table -- are more

 

  2   comfortable with the assumption or, to use these

 

  3   other terms, have a reasonable suspicion that there

 

  4   is a subgroup of children who develop an

 

  5   idiosyncratic reaction to SSRIs, that include

 

  6   symptoms like insomnia, agitation, maybe

 

  7   suspiciousness, hostility, and could possibly lead

 

  8   to violent behavior including self-harm.

 

  9             I think a lot of clinicians are aware of

 

 10   this already.  I think that my colleagues in child

 

 11   psychiatry and pediatricians who are informed on

 

 12   this issue are very attentive when they are

 

 13   starting medication, if they are seeing any of

 

 14   these signs, they adjust the dosage, they may stop

 

 15   the medication, they certainly don't increase the

 

 16   dosage.

 

 17             So, there are measures that can be taken

 

 18   now by clinicians as long as they are aware of it,

 

 19   and by parents who are made aware of it, to take

 

 20   steps that may reduce the development of this

 

 21   syndrome, whatever we want to call it, in a

 

 22   susceptible group of kids that may or may not

 

 23   increase risk for more serious adverse events that

 

 24   include suicide.

 

 25             MS. GRIFFITH:  Just to follow up, I don't

 

                                                               329

 

  1   disagree and I feel that I have always been well

 

  2   informed by clinicians, but I think that there is a

 

  3   group of people who have not been able to either

 

  4   look at the data or not had access to good

 

  5   therapeutic care, and I think that it is going to

 

  6   become a public relations problem very quickly.

 

  7             If the data comes back, if you are unable

 

  8   to use it when it comes back prior to this meeting

 

  9   in the summer, you are extending some sort of

 

 10   reasonable period by which you can reasonably

 

 11   inform the families, and it will snowball and get

 

 12   completely out of control.

 

 13             DR. RUDORFER:  Dr. Katz.

 

 14             DR. KATZ:  One of the questions we have of

 

 15   the committee is what, if anything, should we do in

 

 16   the interim while we are waiting to get the final

 

 17   analyses.  Of course, as a number of people have

 

 18   suggested, it is possible that come this summer

 

 19   when we do the analyses based on these

 

 20   resubmissions of the data, that we won't be able to

 

 21   say anything definitive.

 

 22             What we really want to know from you

 

 23   folks, first of all, in the interim, what, if

 

 24   anything, we should say, and it sounds like at

 

 25   least some people think we should do something

 

                                                               330

 

  1   although I am not yet sure if and what other people

 

  2   think should be done.

 

  3             But it is possible that come this summer,

 

  4   we really won't be in a position to say anything

 

  5   more definitive.

 

  6             What we really want from you folks is, in

 

  7   part, whether or not there is anything else you

 

  8   think we can get from the data or whether or not

 

  9   there are any other additional analyses that we

 

 10   should do, so that we get as much as we possibly

 

 11   can out of the data, so that if we do come back in

 

 12   the summer and say, look, we can't give you a

 

 13   definitive answer, at least we can know that we

 

 14   have done everything that we possibly could with

 

 15   the data that we have in front of us at the moment.

 

 16             So, those are things we definitely want to

 

 17   hear from you about.

 

 18             DR. RUDORFER:  Dr. Temple.

 

 19             DR. TEMPLE:  I just want to sort of remind

 

 20   everybody that what provoked the most recent

 

 21   interest in this subject was those data, the 127

 

 22   cases.  If those prove to be uninterpretable, we

 

 23   are back where we were.

 

 24             What we then have is very impressive

 

 25   individual reports of bad outcomes.  Those have

 

                                                               331

 

  1   always been impressive when people have tried to

 

  2   look at those in controlled trial environments and

 

  3   things like that, and pooling our study data, they

 

  4   haven't turned up at least so far.

 

  5             There have been some criticisms of the way

 

  6   that was done, but leaving that aside, they haven't

 

  7   turned up.  The difficult question always is what

 

  8   to do with reports that have considerable cogency

 

  9   to them.  I mean it sort of looks like something

 

 10   happened when the person started the drug, it does,

 

 11   that you can't really confirm in controlled trials,

 

 12   and that is always a problem with the postmarketing

 

 13   data we get.

 

 14             Sometimes the events aren't the very thing

 

 15   that you are worried about happening in people with

 

 16   that diagnosis.  In this case, as I said before, it

 

 17   is particularly difficult because people who are

 

 18   depressed are the very people who have some of

 

 19   those events.

 

 20             Now, whether it looks like they were

 

 21   accelerated or not are the kinds of things we have

 

 22   to think about, so as Russ said, we are very

 

 23   interested in views as to what we can say that

 

 24   would be useful now, apart from waiting for the

 

 25   results of the trials, if there is such a thing.

 

                                                               332

 

  1             DR. RUDORFER:  We have several speakers

 

  2   lined up to continue the discussion on Question 1

 

  3   regarding capturing all events of potential

 

  4   interest, and I will ask everyone else to hold your

 

  5   questions, and then we will move on to Question 2.

 

  6   There is a lot of overlap, and I have been asked to

 

  7   try to keep these separate and distinct.

 

  8             If we could turn to Dr. Maldonado,

 

  9   followed by Dr. O'Fallon, please.

 

 10             DR. MALDONADO:  I am sorry to bring you

 

 11   back to the BPCA and rule.  I want to clarify the

 

 12   point, the failed trials that the FDA is seeing

 

 13   right now has been an issue of cost of doing

 

 14   business for the pharmaceutical industry for

 

 15   generations, is that when those so-called negative

 

 16   trials happen, the pharmaceutical industry doesn't

 

 17   even bother to come into the FDA with those trials

 

 18   because they know they are not going to get

 

 19   anything out of that.

 

 20             Now, you are seeing it in the context of

 

 21   the BPCA because it is necessary to disclose, and

 

 22   because there is incentive to disclose it.  So,

 

 23   this is not a new phenomenon and I think that the

 

 24   comment that the pharmaceutical industry is not

 

 25   making the efforts that they should make is

 

                                                               333

 

  1   unfounded.

 

  2             A lot of these trials -- that is why they

 

  3   are called trials -- a lot of these drugs failed,

 

  4   failed repeatedly, and those failures actually had

 

  5   to do more with the ignorance of the people

 

  6   developing the compound than with the drug itself.

 

  7             It is a process of learning until the

 

  8   researchers fine-tune what they want to find.  Not

 

  9   only that, if there is a doubt that these studies

 

 10   are being done according to GCPs, the FDA has the

 

 11   authority to have that oversight.

 

 12             Not only that, the FDA has a very

 

 13   historical authority now given by the government to

 

 14   issue the written request.  So, those studies are

 

 15   in response to written requests issued by the FDA.

 

 16             So, if those responses are not accurate

 

 17   and are not fulfilling the demands, then, there has

 

 18   to be a corrective that should happen there, just

 

 19   for clarification.

 

 20             DR. RUDORFER:  Dr. O'Fallon.

 

 21             DR. O'FALLON:  We are talking about three

 

 22   major topics here, and we keep flipping around

 

 23   among them.  One of them is the potential that we

 

 24   can get out of this re-analysis.  The second is

 

 25   suggestions, advice as to what to do for future

 

                                                               334

 

  1   studies.  The third is the labeling issues.

 

  2             The questions that we are getting are

 

  3   primarily focused on this re-analysis, at least the

 

  4   ones that I saw.  I want to say as a statistician

 

  5   that I don't have a whole lot of hope for your

 

  6   being able to get good information out of the

 

  7   planned re-analysis.  I think it should be done,

 

  8   but I don't think it is going to be because you are

 

  9   going to get the information.

 

 10             As a statistician again, I have learned a

 

 11   long time ago that if you don't get your data right

 

 12   the first time, that it is very, very difficult to

 

 13   go back and get the information after the fact, and

 

 14   I am afraid that you are going to find that is a

 

 15   problem.

 

 16             If the data were not collected very well,

 

 17   for whatever reason, in those original studies, you

 

 18   are going to have a hard time finding it, and there

 

 19   is no such thing as being able to go back.

 

 20             For example, if something is a genetic

 

 21   defect, if there is really a genetic defect that is

 

 22   underlying the ones that flip out, the kids that go

 

 23   crazy, no one will ever know because we don't have

 

 24   the information, we didn't ask about it, and there

 

 25   is no way to go back and get it.

 

                                                               335

 

  1             I am afraid that is what is going to

 

  2   happen with this study.  Nonetheless, I think it is

 

  3   worth going forward because I think you are going

 

  4   to learn a whole lot about methodologic issues when

 

  5   you struggle to analyze it, and I think that will

 

  6   be valuable information for writing future written

 

  7   requests for evaluating future studies, so I think

 

  8   there is a lot to be learned about it.

 

  9             I don't even want to go on the labeling,

 

 10   but I have got a whole list of stuff there.

 

 11             DR. RUDORFER:  We will come back to that.

 

 12             Dr. Chesney.

 

 13             DR. CHESNEY:  Two issues with respect to

 

 14   Question 1.  The first one, I think we have already

 

 15   gone over several times, but I would really

 

 16   strongly encourage, if it is possible to go back

 

 17   and look at every patient, to look at this

 

 18   stimulant syndrome issue, this mania, this

 

 19   irritability, and so on, which I must say I was not

 

 20   fully apprised of at all until we came today, and I

 

 21   am most impressed when I hear from, again in the

 

 22   open session, about how some of these events

 

 23   occurred very quickly.

 

 24             I know the potential explanation of being

 

 25   stimulated out of lethargy, but this sounds like

 

                                                               336

 

  1   something different to me, which brings me to my

 

  2   second question.

 

  3             I wondered of any of the psychiatrists

 

  4   could tell us if there is any association with drug

 

  5   levels, because certainly in my field, which is

 

  6   infectious diseases, drug levels are imperative or

 

  7   you wouldn't know what you were treating or how

 

  8   well you were treating it or whatnot, but certainly

 

  9   we heard levels at autopsy referred to as being

 

 10   three times I guess what was expected, and then Dr.

 

 11   Goodman made the comment about adjusting dosage.

 

 12             Do we have any idea of what the dosages

 

 13   were in these studies and how they correlated with

 

 14   body weight or levels?  For those of us not in the

 

 15   field, I just don't know anything about the value

 

 16   of pharmacokinetic studies in these drugs.

 

 17             DR. LAUGHREN:  Just to comment on a couple

 

 18   of your questions.  For the most part, blood levels

 

 19   were not obtained in these trials.  Any

 

 20   pharmacokinetic data for these pediatric programs

 

 21   were done in other smaller studies. For the most

 

 22   part, I don't think we are going to have much luck

 

 23   in getting PK data here.

 

 24             In terms of dosages, these were mostly,

 

 25   virtually all flexible dose studies, so patients

 

                                                               337

 

  1   were dosed within a range, usually the recommended

 

  2   range for that drug.  They were not fixed dose

 

  3   studies.  We have dose information, but without

 

  4   something to link it to, it probably is not going

 

  5   to be very productive.

 

  6             But I wanted to come back to your first

 

  7   point because now several people have raised this

 

  8   question about some kind of a stimulation syndrome

 

  9   and linking that in some way with mania.  If we are

 

 10   to look for that, we have to know what it is that

 

 11   we are looking for.

 

 12             I mean there has to be some kind of

 

 13   definition. Are we talking about something that is

 

 14   linked specifically to suicidal behavior or

 

 15   something that occurs independent of suicidal

 

 16   behavior.  I am not sure if this entity can be well

 

 17   enough defined for us to search for it.

 

 18             We have over 4,000 patients involved in

 

 19   these trials.  To head off looking for a syndrome,

 

 20   we have to know what it is that we are looking for.

 

 21             DR. CHESNEY:  Can I just respond to one

 

 22   comment.  I think on several occasions we heard

 

 23   that it was actually homicidal behavior that seemed

 

 24   to arise from mania, and if we just look at

 

 25   suicide, maybe that is not all we want to know

 

                                                               338

 

  1   about.

 

  2             DR. RUDORFER:  Tom, I wonder if I could

 

  3   interject a question for you.  I think the concept

 

  4   of akathisia, which again has come up repeatedly,

 

  5   captures a lot of what various speakers are talking

 

  6   about, and I wonder if the Agency's experience with

 

  7   antipsychotic drugs would be helpful in that regard

 

  8   in terms of definition.

 

  9             DR. LAUGHREN:  We could certainly search

 

 10   for akathisia.  That term is reasonably well

 

 11   understood I think clinically and would very likely

 

 12   appear in the electronic database, or one I suppose

 

 13   could come up with related terms that might get at

 

 14   akathisia if it wasn't specifically named.

 

 15             But again, my question is are we looking

 

 16   for that symptom by itself or are we looking for

 

 17   that in association with some other behavior.

 

 18   Again, there is a very widespread belief that

 

 19   akathisia is linked to suicidal behavior, but I am

 

 20   not sure how strong the data are supporting that

 

 21   belief, that is really the question.

 

 22             But again, if we are going to search this

 

 23   database for something other than what it has

 

 24   already been searched for, we have to have some

 

 25   fairly specific guidance about how to do that.

 

                                                               339

 

  1             MS. BRONSTEIN:  My comments are about

 

  2   labeling and if you want me to wait, I will, or I

 

  3   would like to get them off my chest now if I could.

 

  4             If I heard nothing from this morning's

 

  5   testimony, I heard repeatedly that people feel the

 

  6   need for patients and family to have more

 

  7   information than they have currently.

 

  8             I think that is really our responsibility

 

  9   to do something about it whether it is after this

 

 10   meeting or after the summer meeting.  I think we

 

 11   need to get something out there that describes

 

 12   akathisia in a way that patients can embrace it and

 

 13   understand it, and family members can watch for

 

 14   this radical change in behavior.

 

 15             I am seeing it as an apparent link to

 

 16   either homicidal or suicidal behavior from the

 

 17   testimony this morning and from what I have read,

 

 18   as well.

 

 19             DR. RUDORFER:  Dr. Ebert.

 

 20             DR. EBERT:  Most of my comments also had

 

 21   to do with labelings.  I just briefly wanted to

 

 22   react to what was stated earlier, though, again

 

 23   about the issues of going beyond just the suicidal

 

 24   behavior and whether it's akathisia or whether

 

 25   there may be some other characteristics which

 

                                                               340

 

  1   clearly indicate that -- and I am not in the area

 

  2   of psychiatry, so you will have to indulge me for a

 

  3   second -- but just the whole issue of kind of a

 

  4   concept of self versus others, whether it's through

 

  5   homicide or it's hostile behavior or

 

  6   aggressiveness.

 

  7             To me, these things all seem to be a

 

  8   constellation of the same types of syndrome that we

 

  9   would be looking at.

 

 10             DR. RUDORFER:  Dr. Fink.

 

 11             DR. FINK:  Another sort of global concern

 

 12   -- and I think it may be particularly apropos to

 

 13   this class of drugs -- is that when these clinical

 

 14   trials are performed, they are usually performed by

 

 15   experts in the field, yet much of the usage today,

 

 16   particularly in the managed care environment, is

 

 17   prescription of these drugs by non-mental health

 

 18   trained professionals.

 

 19             The results of a clinical trial performed

 

 20   by mental health professionals where you are

 

 21   already using a highly select audience and highly

 

 22   select practices may bear little relationship to

 

 23   what you see with the drug in use in the real

 

 24   world.

 

 25             From a labeling standpoint, it would make

 

                                                               341

 

  1   sense potentially to say that at least off-label

 

  2   use of these drugs really should be highly

 

  3   restricted to mental health professionals or make

 

  4   some kind of wording that would imply that, because

 

  5   I think that off-label use of these drugs by

 

  6   non-mental health trained professionals seems to be

 

  7   problematic, and it may well be that much of the

 

  8   placebo effect that we are seeing in the clinical

 

  9   trials is because they are receiving counseling

 

 10   about mental health.

 

 11             I am more familiar with asthma trials.

 

 12   When we do asthma trials, we see a tremendous

 

 13   placebo effect which is asthma education.  My guess

 

 14   is in mental health trials, there is a tremendous

 

 15   placebo effect because you are seeing a mental

 

 16   health professional.

 

 17             DR. RUDORFER:  Dr. Leon.

 

 18             DR. LEON:  It would be interesting to know

 

 19   what items were captured in the severity ratings,

 

 20   because if we knew the items that were there, then,

 

 21   we could see which ones correspond to the symptoms

 

 22   we heard of this morning, and look at treatment

 

 23   emergent symptoms, symptoms that weren't there at

 

 24   baseline, on the severity rating, that were

 

 25   exacerbated during the course of this trial, so

 

                                                               342

 

  1   looking at changed scores on a handful of a

 

  2   priori-defined symptoms from the rating scales

 

  3   would be very helpful.

 

  4             DR. GOODMAN:  Along those lines, as I

 

  5   mentioned earlier, the Hamilton has an item on

 

  6   agitation, the CDRS has an item on irritability, so

 

  7   that could be a first quick look, and you wouldn't

 

  8   have to look at treatment emergent, you can look at

 

  9   rating scale items.

 

 10             I agree that one needs to give careful

 

 11   thought into what symptoms or how we are describing

 

 12   this constellation of symptoms, because it could be

 

 13   very problematic.

 

 14             For one reason, a number of symptoms you

 

 15   would expect to get better with the SSRIs, and what

 

 16   we are really looking for is a minority of patients

 

 17   in whom you see a paradoxical increase in those

 

 18   symptoms.

 

 19             So, I think we need to take a very careful

 

 20   approach to this analysis.

 

 21             DR. RUDORFER:  We have four more questions

 

 22   on this topic.

 

 23             I am sorry.  Dr. Laughren.

 

 24             DR. LAUGHREN:  Just one follow up on a

 

 25   suggestion that has come up from several committee

 

                                                               343

 

  1   members now about looking at items from the rating

 

  2   scales.  That was actually done here, and it turned

 

  3   out not to be very helpful.

 

  4             Now, this was a similar analysis that had

 

  5   been done with the adult data years ago, for

 

  6   example, looking at patients who move from looking

 

  7   at the suicide item on the HAM-D and looking at

 

  8   patients who move from zero to 1 to a 3 or 4.

 

  9             That did not detect a signal in these

 

 10   trials, and part of the problem may have been that

 

 11   these events often did not occur at a time when the

 

 12   HAM-D would be done, because the HAM-D is done at

 

 13   regular intervals.

 

 14             If the event occurs between visits, which

 

 15   it almost always does, and then the patient is

 

 16   discontinued at that point, you never get a HAM-D

 

 17   or whatever other instrument is being used.

 

 18             So, companies did try that approach, and

 

 19   it was not particularly productive.

 

 20             DR. RUDORFER:  We are now going to turn to

 

 21   Drs. Malone, McGough, Pfeffer, and Ortiz, and then

 

 22   move on to Question 2 more specifically.

 

 23             DR. MALONE:  I am sorry, I just stepped

 

 24   out, so I may have missed things that were just

 

 25   discussed, but I was thinking that looking at

 

                                                               344

 

  1   agitation would be an important thing if you think

 

  2   about the way we use the recent meetings on

 

  3   antipsychotics and agitation.

 

  4             Agitation often leads to harming of self

 

  5   or others, and it might be a proxy for looking at

 

  6   suicidal behavior.  So, searching the electronic

 

  7   database for agitation, violence, and trying to

 

  8   construct an agitation -- I don't know what to call

 

  9   it -- but try to construct agitation and see if it

 

 10   does differ in those who are having suicidal

 

 11   ideation or having other such problems.

 

 12             The other thing, I end up currently

 

 13   treating children with autism, and I think this

 

 14   whole activation syndrome is something that anyone

 

 15   who treats children with autism worries about if

 

 16   they are going to consider giving an SSRI.

 

 17             There is some sense in which I think you

 

 18   could look at fairly quickly in a controlled trial

 

 19   whether populations other than depressive

 

 20   populations get agitation or get activated, and

 

 21   then get some information whether these drugs in

 

 22   children, in fact, cause this activation syndrome.

 

 23             DR. RUDORFER:  Dr. McGough.

 

 24             DR. McGOUGH:  This is really a segue I

 

 25   think to the labeling issue which keeps coming up

 

                                                               345

 

  1   again and again. First, as far as off-label use

 

  2   goes, child psychiatrists could not treat severely

 

  3   ill kids without off-label prescriptions, there is

 

  4   no doubt about that.

 

  5             Secondly, even in the absence of

 

  6   scientific clinical trial evidence, a physician

 

  7   needs to be free in specific instances to choose to

 

  8   take the risk of using a medicine even in the lack

 

  9   of a controlled study.  Again, there is no way to

 

 10   meet the needs of these really severe kids without

 

 11   this.

 

 12             To your point, unfortunately, there aren't

 

 13   enough child psychiatrists trained and available to

 

 14   do this, so it is left to other practitioners, and

 

 15   what I was really struck with, hearing the stories

 

 16   this morning, is many of the cases we heard were

 

 17   kids just naively given adult titration regimens at

 

 18   adult doses with no consideration to slow

 

 19   metabolizing, in Caucasian kids particularly, with

 

 20   no concern about the need to monitor for akathisia

 

 21   and early onset activation, so I see we can't

 

 22   restrict non-psychiatrist prescribing, we now have

 

 23   pediatricians, family docs, nurses, psychologists,

 

 24   all of whom will be prescribing these medicines.

 

 25             There has to be some way to really notify

 

                                                               346

 

  1   people or put people on notice that at least in the

 

  2   absence of efficacy data, you have to be very

 

  3   concerned about safety, and if there is any

 

  4   labeling tweaking to be done, that is what I would

 

  5   want to see put in.

 

  6             DR. RUDORFER:  Dr. Pfeffer.

 

  7             DR. PFEFFER:  I have a number of questions

 

  8   that have to do with the analysis issues and

 

  9   perhaps my concern is having heard the families and

 

 10   the sense of their urgency, if while the Columbia

 

 11   group is evaluating the suicidality question, if

 

 12   one might look at the data in a variety of other

 

 13   ways that might inform us about, for example, who

 

 14   improved and who didn't improve.

 

 15             Who improved within the placebo group and

 

 16   who improved within the treated group, and what are

 

 17   the predictors of that or vice versa, what are the

 

 18   predictors of a poor outcome, and we might find

 

 19   that that might give us some very important clues

 

 20   as to the way that this population  are responding

 

 21   to the drugs.

 

 22             The question also that I have, and I

 

 23   assume it must have been done, but I am not sure,

 

 24   and that is whether or not randomization really

 

 25   worked, and especially did randomization work, for

 

                                                               347

 

  1   example, in the suicidality issue.

 

  2             I don't know if that has been looked at,

 

  3   and certainly once Columbia group looks at the

 

  4   definition of suicidal behavior, it will be looked

 

  5   at again, but that would be an important question

 

  6   to also look at.

 

  7             Then, if I might contribute some

 

  8   information, for example, I know in the venlafaxine

 

  9   studies, they were doing blood levels of

 

 10   venlafaxine because they were looking at the

 

 11   question of slow metabolizers or not, so I wonder

 

 12   if that data might be able to be looked at to, to

 

 13   give us some clues about issues of metabolism.

 

 14             DR. RUDORFER:  Thank you.

 

 15             Dr. Ortiz.

 

 16             DR. ORTIZ:  My comments, I think are in

 

 17   response to a couple of things that Dr. Chesney

 

 18   brought up.  As far as levels in psychiatry, what

 

 19   we certainly know is that the Sinemet kinds of

 

 20   medicines, which are dopaminergic, can cause

 

 21   psychosis, and it is at different doses for

 

 22   different individuals, the same thing with

 

 23   amphetamines, they also can cause psychosis.

 

 24   Again, it is not predictable in each individual.

 

 25             I would also like to follow up on your

 

                                                               348

 

  1   suggestion to specify the adverse effects and the

 

  2   descriptions of them a little better.

 

  3             As a psychiatrist, when I am watching

 

  4   someone that I am concerned about, that may be

 

  5   developing hypomania or mania, I am watching how

 

  6   their speech patterns change, I am watching their

 

  7   activity levels, I am monitoring their sleep, and I

 

  8   think a little more precision in those kind of

 

  9   descriptions might be helpful.

 

 10             DR. RUDORFER:  Dr. Andrews will ask the

 

 11   final question related to Question 1.

 

 12             DR. ANDREWS:  I have some concerns about

 

 13   the exploration of this activation syndrome in the

 

 14   context of the existing clinical trial data.

 

 15             First of all, as has been said, we may not

 

 16   know what the elements of that syndrome are, but in

 

 17   addition to that, do we know whether the elements

 

 18   of that potential syndrome were collected

 

 19   diligently, frequently, and similarly across all of

 

 20   the studies, and I think that needs to be addressed

 

 21   before going into that expedition.

 

 22             If not, I would encourage the FDA and the

 

 23   analysts to look at more objective endpoints, which

 

 24   I think are the ones that were established for

 

 25   suicide events.

 

                                                               349

 

  1             I have a bit of concern that the study may

 

  2   not answer all of the questions because of the

 

  3   issue that was raised earlier regarding

 

  4   generalizability.  These patients may not resemble

 

  5   the patients who are treated with these drugs.

 

  6             They are probably treated in a different

 

  7   way in terms of dose titration in the context of a

 

  8   clinical trial, and in the context of a clinical

 

  9   trial, patients tend to be  monitored more

 

 10   carefully, so that perhaps those at highest risk of

 

 11   suicide or suicidal ideation might have been

 

 12   identified earlier with other symptoms and

 

 13   withdrawn from drug or had drug titrated down.

 

 14             DR. RUDORFER:  Thank you.

 

 15             I think we will come back to some of these

 

 16   issues. The sense I have from the committee is that

 

 17   while people have reservations about the

 

 18   limitations of the existing database, the sense

 

 19   seems to be that we would endorse going ahead with

 

 20   the Columbia reclassification, but with some

 

 21   additional measures.

 

 22             Dr. Laughren had also specifically asked

 

 23   us about the appropriate categories in terms of the

 

 24   definition of "possibly suicide related" and

 

 25   "suicide attempt," and I wonder if anyone has any

 

                                                               350

 

  1   feedback for the FDA on those questions.

 

  2             Dr. McGough.

 

  3             DR. McGOUGH:  I was just speaking from

 

  4   experience and also the work Dr. Shaffer showed.

 

  5   You know, my view about cutting is that it is not a

 

  6   suicidal behavior, and others might disagree, but

 

  7   that would be my approach to that.  It would be not

 

  8   to classify cutting or superficial cutting

 

  9   certainly as a suicidal behavior.

 

 10             DR. RUDORFER:  Dr. Chesney.

 

 11             DR. CHESNEY:  I was interested again this

 

 12   morning to hear in a number of instances that

 

 13   people took a drug, took a dose and then found

 

 14   themselves in jail and did not know what had

 

 15   happened in the interim.

 

 16             How is that described in psychiatric

 

 17   terms, is that confusion of thought or absence of

 

 18   presence, or is that something that you could pull

 

 19   out?  That seems a fairly profound confusion to

 

 20   just absent oneself from the situation and yet do

 

 21   some fairly striking things.

 

 22             DR. LAUGHREN:  It is phenomenologically an

 

 23   amnestic syndrome of some sort.  I did not see that

 

 24   in these trials.  At least it was not described as

 

 25   such.

 

                                                               351

 

  1             DR. GOODMAN:  Also, phenomenologically, it

 

  2   would be a dissociative or fugue state.

 

  3             DR. CHESNEY:  Was that asked for in the

 

  4   trials?  Was that a question that was on the --

 

  5             DR. LAUGHREN:  No, I am sure it was not.

 

  6             DR. LESLIE:  I wanted to add two comments.

 

  7   One is on the Question No. 1, which is I think part

 

  8   of this is a process question of where we go from

 

  9   now.  When I look at Dr. Hammad's variables that he

 

 10   has listed, I think there are some that are missing

 

 11   and it would be good to redistribute that list to

 

 12   the committee for review.

 

 13             For example, I only see after

 

 14   discontinuation.  I don't see on an increase of

 

 15   dose or decrease of dose.  The issue of family

 

 16   history has come up.

 

 17             I think all of us or there is a good

 

 18   majority here that are concerned about aggressive

 

 19   instances, and some of the family stories this

 

 20   morning were not of kids who were feeling down.

 

 21   They were of kids who acted suicidally because of

 

 22   impulsivity, and not because of a suicidal

 

 23   symptomatology that had been ongoing.

 

 24             So, I think those things are important and

 

 25   I also worry about what is hidden in some of the

 

                                                               352

 

  1   other neurological, et cetera, categories that are

 

  2   listed.

 

  3             So, again, I don't know the process here

 

  4   and how you all feel about doing this, but I think

 

  5   redistributing this list for some suggestions of

 

  6   some of the risk factors and things that might be

 

  7   important to be looking at, as several of the

 

  8   speakers have said, would be important.

 

  9             I also wanted to say that I am impressed

 

 10   that the American Academy of Child and Adolescent

 

 11   Psychiatry has been here and other groups, but

 

 12   there is no one here from the American Academy of

 

 13   Pediatrics, representing the American Academy of

 

 14   Pediatrics, although several of us are

 

 15   pediatricians and on that committee, and there is

 

 16   no one from the National Association of Nurse

 

 17   Practitioners, and there is no one from the

 

 18   American Academy of Family Practice Doctors, and

 

 19   reaching out to those organizations on an official

 

 20   level, since so many of us are the ones that are

 

 21   giving those medications, would be an important

 

 22   step to be taking.

 

 23             DR. LAUGHREN:  In terms of the lists of

 

 24   variables, all committee members have that.  It is

 

 25   attached to a memo that I wrote.  We would be happy

 

                                                               353

 

  1   to accept suggestions at any point, it wouldn't

 

  2   have to be at today's meeting, of additional

 

  3   covariates that you think might be important to add

 

  4   to this database, so please free to do that.

 

  5             DR. RUDORFER:  Dr. Gorman.

 

  6             DR. GORMAN:  If all of these 15 studies

 

  7   that we are going to re-review were not intent to

 

  8   treats, analysis based on intent to treat, we would

 

  9   not be able to answer Dr. Chesney's questions.

 

 10             DR. RUDORFER:  Dr. O'Fallon.

 

 11             DR. O'FALLON:  One process question.  Do

 

 12   you have data for all the patients in all of those

 

 13   studies?  Do you have the detailed data for all of

 

 14   the patients in all of the studies?

 

 15             DR. LAUGHREN:  What we have right now are

 

 16   in terms of data sets.  We have the data sets for

 

 17   the variables that we specifically asked for.

 

 18   Again, those are listed in an appendix to my

 

 19   review.  So, that is what we have in terms of an

 

 20   electronic data set for all patients, but it is

 

 21   limited to those variables that we asked for.

 

 22             DR. TEMPLE:  Just with respect to intent

 

 23   to treat, we expect to see all patients randomized

 

 24   who at least got some treatment.  It is typical in

 

 25   symptomatic treatments not to include people who

 

                                                               354

 

  1   don't get a treatment.  You can debate that, but it

 

  2   is usually not a big loss, but anybody who was

 

  3   treated should be in those analyses.

 

  4             DR. PERRIN:  It does seem, having read

 

  5   that list of variables on the way down this

 

  6   morning, that there are some important gaps.  They

 

  7   do include again some of the factors Dr. Pfeffer

 

  8   mentioned before which are really in the social

 

  9   environmental phenomena that might influence rates

 

 10   of responsive treatment or might influence rates of

 

 11   suicidal behaviors.

 

 12             It does seem like you don't have a lot of

 

 13   sort of data over time.  It is almost like an

 

 14   adverse event reporting system, if I am reading the

 

 15   data set right.  In other words, you don't have a

 

 16   lot of information on other response to treatment.

 

 17             We have heard, for example, a lot of

 

 18   discussion without a lot of evidence that the first

 

 19   week or two or three of treatment is really

 

 20   critical, so one would wonder a lot about what kind

 

 21   of things happened during that time that you do

 

 22   have data on, and you talked about the notion that

 

 23   maybe the next clinical trials might be a

 

 24   withdrawal trial.

 

 25             Again, there is a moderate amount of more

 

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  1   anecdotal than good evidence base that withdrawal

 

  2   is a very high-risk time, as well, for kids on

 

  3   SSRIs, and again there, having some sense of what

 

  4   happens relatively immediately in that two or

 

  5   three-week time would be extremely helpful, but I

 

  6   have a feeling you don't have those data for even

 

  7   the start-up time.

 

  8             DR. LAUGHREN:  Could you say a little bit

 

  9   more about how you would characterize that early

 

 10   response?  Are you talking about looking at formal

 

 11   assessments, HAM-D, and so forth?  I mean clearly,

 

 12   we have that.  What we might not have is more

 

 13   anecdotal information about particular ways in

 

 14   which a patient didn't do well.

 

 15             DR. PERRIN:  Well, then, maybe you do have

 

 16   it, but on what periodicity do you have things like

 

 17   the HAM-D?

 

 18             DR. LAUGHREN:  Every week, you know, early

 

 19   on certainly.

 

 20             DR. PERRIN:  Then, you may have the

 

 21   information, okay.

 

 22             DR. RUDORFER:  As I understand the

 

 23   situation, Dr. Laughren's Question 3 on patient

 

 24   level data analysis, I think we have been

 

 25   discussing essentially on important covariates that

 

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  1   should be considered in the re-analysis.

 

  2             Dr. Laughren, would you want us to address

 

  3   anything else specifically on that before we turn

 

  4   to future directions?

 

  5             DR. LAUGHREN:  No, but again let me just

 

  6   reiterate if committee members, as you continue to

 

  7   look at this list, if you have additional ideas,

 

  8   please feel free even after this meeting to submit

 

  9   them, because we want this to be as comprehensive

 

 10   as it can be.  So, if there are important

 

 11   covariates we have left out, let us know.

 

 12             DR. RUDORFER:  Dr. O'Fallon.

 

 13             DR. O'FALLON:  Looking at that list again

 

 14   with fresh eyes after this morning, you don't have

 

 15   any data that will help you to get at the

 

 16   temporality of the various things.

 

 17             For example, I look at that dose, and you

 

 18   are looking at the max of the mods, and things like

 

 19   that, but you don't have -- you know, there is no

 

 20   way in your data set then to get at whether the

 

 21   incidents occurred when the dose was raised,

 

 22   lowered, or discontinued.

 

 23             So, one of the key questions is not going

 

 24   to be able to be assessed.

 

 25             DR. LAUGHREN:  That is something that we

 

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  1   clearly have that information.  We don't have it

 

  2   now, but we could get that information and add it

 

  3   to the model.

 

  4             DR. RUDORFER:  Dr. Katz.

 

  5             DR. KATZ:  I have a question of

 

  6   clarification on Question 1, I guess it is, which a

 

  7   lot of people have been talking about, trying to

 

  8   look at these other behavioral symptoms that are

 

  9   not explicitly suicide related, like the

 

 10   stimulation syndrome, so called, or an activation

 

 11   syndrome.

 

 12             Again, you have seen what we have done to

 

 13   try and capture the explicitly suicide related

 

 14   events.  You know, we had these text strings, I

 

 15   think we had 15, we had to go back and forth with

 

 16   the sponsors and ask them to look at their verbatim

 

 17   terms, you know, that took some time.  But we spent

 

 18   a lot of time trying to figure out exactly how to

 

 19   ascertain those cases.

 

 20             Is it the committee's desire for us to

 

 21   attempt to recreate that process with regard to

 

 22   this sort of stimulation syndrome, in other words,

 

 23   look for multiple different sorts of terms that

 

 24   might be subsumed reasonably under this syndrome,

 

 25   in other words, try to cast as broad a net as

 

                                                               358

 

  1   possible?

 

  2             DR. RUDORFER:  Yes.

 

  3             DR. KATZ:  Is that a general sense of the

 

  4   committee?

 

  5             DR. RUDORFER:  Yes, the sense of the

 

  6   committee is affirmative.

 

  7             Dr. Laughren.

 

  8             DR. LAUGHREN:  Bearing in mind that going

 

  9   back to search the database involves a fair amount

 

 10   of additional time, now, we could proceed with our

 

 11   analysis based on the data that we have now, and in

 

 12   parallel, go back and ask for additional searches

 

 13   for other kinds of events like this activation

 

 14   syndrome if it can be better defined.  That is

 

 15   something we clearly could do.

 

 16             I wouldn't want to hold up the suicidality

 

 17   analysis waiting for that additional searching

 

 18   because that does introduce a lot of additional

 

 19   time to go back to companies and ask them to search

 

 20   again.

 

 21             DR. RUDORFER:  Dr. Temple.

 

 22             DR. TEMPLE:  I just want to be sure I

 

 23   understand. I think everyone's expectation is that

 

 24   there will be evidence of an activation syndrome or

 

 25   hyperactivity or those things because the drugs are

 

                                                               359

 

  1   labeled to do that.

 

  2             What use would one make out of that if it

 

  3   wasn't linked to some or one of the suicidal terms?

 

  4   I mean I guess it is more information and that is

 

  5   never bad, but is it more than that, would it help

 

  6   us understand things?

 

  7             DR. RUDORFER:  I think if I may speak for

 

  8   the committee, as I understand the discussion and

 

  9   the concerns, there are two issues.

 

 10             One is that the activation or agitation or

 

 11   akathisia may be what is actually more accessible

 

 12   both to the patient and to the family and to the

 

 13   clinician in terms of it seems, again going back to

 

 14   some of the cases we heard this morning, it sounded

 

 15   as if we heard more instances of an individual

 

 16   complaining of akathisia-like symptoms as opposed

 

 17   to volunteering suicidal ideation.

 

 18             I think that there is concern that the

 

 19   akathisia may be what is driving self-destructive

 

 20   behavior at least in some cases, and that might

 

 21   actually be more informative for the clinician to

 

 22   be watching for than actual more overt suicidality.

 

 23             I also wonder if, in fact, don't we need

 

 24   that information to see if in this database there

 

 25   is a link.

 

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  1             DR. TEMPLE:  So, you think it would be

 

  2   useful.  I mean obviously if it sort of went along

 

  3   with suicidal thinking and behavior, that would be

 

  4   certainly of interest as a possible early signal of

 

  5   that consequence.

 

  6             Suppose there isn't any link to suicidal

 

  7   thinking and all you found was a reasonable

 

  8   estimate of the rate of that in a pediatric

 

  9   population, do you think that would be useful all

 

 10   by itself?  You could then say how likely it is and

 

 11   you would know that.

 

 12             DR. GOODMAN:  I think the way I would

 

 13   approach it, as you described, as two parallel

 

 14   processes where you continue the work, looking for

 

 15   the signal and suicidality. You then develop some

 

 16   criteria that help describe this activation

 

 17   syndrome which may occur in a subset of

 

 18   individuals, and then you would test the validity

 

 19   or clinical meaningfulness of it by then plugging

 

 20   it back into seeing whether it is those individuals

 

 21   that are more likely to go on to suicide as defined

 

 22   by the first part of your study.

 

 23             So, I would agree -- one way of saying

 

 24   that -- I agree that for the purposes of our

 

 25   discussion, it would be more of an academic

 

                                                               361

 

  1   exercise and not worthwhile unless we could then

 

  2   find that that subgroup in which there is an

 

  3   activation syndrome are also more likely to go on

 

  4   to be the ones that were identified as exhibiting

 

  5   suicidal behavior.

 

  6             DR. RUDORFER:  Dr. Hudak and then Dr.

 

  7   Gorman.

 

  8             DR. HUDAK:  I have a question and a few

 

  9   comments.

 

 10             The question involves the quality of the

 

 11   data that you currently have for analysis.

 

 12   Basically, the 15 studies that are presented here

 

 13   involved 7 drugs, and I am not knowledgeable about

 

 14   these drugs and pharmacological companies, I

 

 15   presume at least 7 drug companies are doing these

 

 16   things.  They are using different protocols, they

 

 17   have different outcome measures, and they have

 

 18   different data acquisition tools, and all those

 

 19   differences, and so forth.

 

 20             The question I have specifically, the

 

 21   information that was presented in Appendix 2,

 

 22   looking at the difference between the "possibly

 

 23   suicide related" versus the "suicide attempts," as

 

 24   I understand it, that in this population of kids

 

 25   who might be sick, you are going to have more

 

                                                               362

 

  1   suicide-related type reporting, because that is

 

  2   thoughts and behaviors in excess of suicide

 

  3   attempts, which is just behavior, I mean the data

 

  4   that was presented.

 

  5             Looking at the information here, there are

 

  6   a number of these studies that basically, within

 

  7   both the drug group and the placebo group, the

 

  8   suicide related thought and behavior is exactly

 

  9   equal to the suicide attempt, which I find

 

 10   inconsistent.

 

 11             Is this the final plumbing of the data, or

 

 12   is this before the word strings were done on the

 

 13   other data?

 

 14             DR. LAUGHREN:  This is one of the problems

 

 15   that I was alluding to earlier.  When we sent out

 

 16   this request in July of last year, we asked

 

 17   companies to follow basically the same algorithm

 

 18   that Glaxo had used in looking at the Paxil data,

 

 19   which included, first of all, a general search for

 

 20   any term suggestive of possibly suicide related,

 

 21   and then an attempt to subgroup patients from that

 

 22   larger set who had any indication of self-harm.  I

 

 23   mean that is how it was defined.

 

 24             What we found is that companies, in

 

 25   carving out that subset of suicide attempt, in some

 

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  1   cases appeared to count every case as a suicide

 

  2   attempt even though, if you looked at the

 

  3   individual cases, there was not any clear

 

  4   indication of self-harm, and that was one of the

 

  5   reasons why we felt it was very important to have

 

  6   these data completely reclassified by an outside

 

  7   group.

 

  8             Basically, our position is that neither

 

  9   one of these categories, either possibly suicide

 

 10   related or suicide attempt, as it has been carved

 

 11   out and defined by the companies, is particularly

 

 12   meaningful, and that is specifically the reason why

 

 13   we want to have an outside group look at this broad

 

 14   group of events that were captured as possibly

 

 15   suicide related and help us figure out what kinds

 

 16   of bins to put those into.

 

 17             As you saw from Dr. Posner's presentation,

 

 18   we will very likely end up with different

 

 19   categories and different data than what we have

 

 20   here.  I mean this table is really a very

 

 21   preliminary table and we have very little

 

 22   confidence in what these numbers mean because we

 

 23   are not confident in what the numerators are.

 

 24             DR. HUDAK:  I understand, but even within

 

 25   the Paxil studies, there are three studies, and two

 

                                                               364

 

  1   of them show no difference, and one would think

 

  2   that the studies were constructed in somewhat the

 

  3   same way and the query was done in somewhat the

 

  4   same way, and therefore at the end, even going back

 

  5   and having Columbia group look at this, you may

 

  6   have very imperfect data to look at.

 

  7             DR. LAUGHREN:  That is undoubtedly true,

 

  8   and that is a problem that we can't fix with these

 

  9   studies.  You know, if ascertainment was poor,

 

 10   there is no way to fix it at this point.

 

 11             DR. HUDAK:  I have two additional

 

 12   comments.  One is with respect to this general

 

 13   issue here.  I think the big picture that I take

 

 14   away from this is the really unexplained doubling

 

 15   or tripling of suicide rates in particularly

 

 16   vulnerable populations that occurred over the past

 

 17   15, 20 years, which is really quite impressive.

 

 18             So, whatever socioenvironmental type

 

 19   etiology there is to this is a very significant

 

 20   public health issue.  To put this sort of into

 

 21   context, this is a doubling or tripling.  When we

 

 22   have a one-point difference in infant mortality, we

 

 23   have major committees sort of looking at why this

 

 24   occurs.

 

 25             Infant mortality over the past 20 years

 

                                                               365

 

  1   has gone down very substantially, but differences

 

  2   in infant mortality on the order of 1 in 1,000,

 

  3   which is about 10 percent of the entire infant

 

  4   mortality rate, are treated very significantly.

 

  5   And this is a huge problem, and I guess with one

 

  6   teenager and one incipient teenager is something

 

  7   that is dear to my concern.

 

  8             The other comment I have is in relation to

 

  9   looking at treatment and the amount of

 

 10   prescriptions that are written, and so forth.  I am

 

 11   struck by the fact that we have so much drug

 

 12   prescription done in a population that the efficacy

 

 13   is not established.

 

 14             I fight that every day in the nursery, to

 

 15   come around and see patients on 10 drugs, of which

 

 16   maybe 2 have been shown to be effective and trying

 

 17   to withdraw therapy, but it must be -- I have no

 

 18   problem with they are children who are clearly very

 

 19   ill and anything that can be done should be done,

 

 20   and I agree with that, but on the other hand, there

 

 21   must be a large population of children -- a lot of

 

 22   the people who spoke this morning, the picture that

 

 23   was presented of their child or someone they knew

 

 24   was not someone who was very, very ill.

 

 25             It was someone who had relatively minor

 

                                                               366

 

  1   type findings, who were put on these drugs with

 

  2   terrible consequences, and I agree with every

 

  3   speaker who said that something needs to be done to

 

  4   educate practitioners and the public that these

 

  5   things may not at all be benign.

 

  6             The fact that we don't find these things

 

  7   that are reported among the audience and the

 

  8   controlled trials is not surprising.  It may be a

 

  9   very, low incidence phenomena that you are not

 

 10   going to find unless you have got randomized

 

 11   controlled trials, you know, 10,000 or more.

 

 12             But each of these events, each of these

 

 13   anecdotes, and I have heard enough of them to think

 

 14   that, you know, you hear enough of these anecdotes,

 

 15   there must be some truth in it.  I mean I am

 

 16   willing to believe that there is an idiosyncratic

 

 17   reaction that some patients have with these drugs,

 

 18   and I think that warning needs to go out in the

 

 19   very strongest terms from the Agency as soon as

 

 20   possible.

 

 21             DR. RUDORFER:  If we can hear from Dr.

 

 22   Gorman and Dr. Chesney, please.

 

 23             DR. GORMAN:  I would like to pick up on

 

 24   the thread of where we are data mining.  One of the

 

 25   things that struck me in one of the slides that was

 

                                                               367

 

  1   put up was that in August, there was the request

 

  2   from the pharmaceutical companies to relook at

 

  3   their data and present it to the FDA.

 

  4             Within a month, one of the pharmaceutical

 

  5   companies, I am not sure they looked at their data,

 

  6   but they decided to change their labeling and

 

  7   withdraw it from the market.

 

  8             I would ask the FDA to investigate what

 

  9   signal that pharmaceutical company found in their

 

 10   data that made them want to change their label

 

 11   without going through the FDA, and ask other

 

 12   pharmaceutical companies to look in their data in

 

 13   the same way.

 

 14             DR. RUDORFER:  Dr. Laughren.

 

 15             DR. LAUGHREN:  Yes, can I just respond to

 

 16   that.  That company was Wyeth and the drug is

 

 17   Effexor and Effexor XR.  Having gotten our request

 

 18   in July, they did go back and look for suicidality,

 

 19   and they also looked for hostility, and they found

 

 20   a signal, and on their own, as I explained, they

 

 21   are allowed to do that on their own if it

 

 22   strengthens labeling under changes being effected.

 

 23             What they did is to add mention of that

 

 24   signal in the Pediatric Use section of their label.

 

 25   They did not contraindicate the drug.  They did

 

                                                               368

 

  1   send a letter out along with that label change

 

  2   recommending that clinicians not use the drug in

 

  3   pediatrics, but the labeling does not in any way

 

  4   contraindicate it.  It simply mentions the signal,

 

  5   and it is the same signal that we have seen and are

 

  6   currently evaluating.

 

  7             You know, we have their analysis, I showed

 

  8   it to you, in fact.  The question is if you go back

 

  9   and do the kinds of work that we are now proposing

 

 10   to do in terms of looking at the actual events that

 

 11   got included under those broad categories, what

 

 12   signal will you see.

 

 13             That is really the question, and that is

 

 14   why we have not acted independently to approve that

 

 15   label change, but it is basically the same data.  I

 

 16   mean there is nothing we haven't seen.  Again, it

 

 17   is not as if the drug has been pulled from the

 

 18   market.  They have simply added mention of that

 

 19   signal in one sentence in their label.

 

 20             DR. RUDORFER:  Dr. Chesney, please.

 

 21             DR. CHESNEY:  This is in response to the

 

 22   question from the FDA about why look at activation

 

 23   syndrome if it is not known whether it is directly

 

 24   related to suicidality.

 

 25             But what I heard this morning or the way I

 

                                                               369

 

  1   interpreted what I heard this morning is that the

 

  2   activation syndrome is associated or can be

 

  3   associated with very violent and very hostile

 

  4   behavior.  Whether that results in anybody's death

 

  5   or not, several of the families said that that

 

  6   became an extremely difficult issue to live with.

 

  7             Where we are dealing with a drug with no

 

  8   apparent benefit, it seems to me that any risk

 

  9   becomes incredibly important, so that is one

 

 10   additional reason that I would say it is important

 

 11   to look at this activation syndrome that some of us

 

 12   have just learned more about this morning.

 

 13             DR. LAUGHREN:  Can I just respond to that?

 

 14   Again, we are very happy to do that.  It would be

 

 15   extremely helpful if the committee could come up

 

 16   with a little bit more definition of what that is

 

 17   to help us in searching for it.

 

 18             But independent of finding it in this

 

 19   database, if there is a view that this syndrome is

 

 20   so well described and does exist, put together the

 

 21   case.  Send us literature, whatever else, and it is

 

 22   possible to make labeling changes about clear

 

 23   events that are idiosyncratic in some way.

 

 24             Again, the problem here has been that the

 

 25   events we are looking at are part and parcel of the

 

                                                               370

 

  1   disease.  If there is an activation syndrome that

 

  2   is unusual in its nature, and is not part of the

 

  3   disease that is being treated, it could be

 

  4   described in some way in labeling if there is

 

  5   enough even non-controlled data to support the

 

  6   existence of that syndrome, especially if it can be

 

  7   linked to, as you suggest, hostility and violence

 

  8   and suicidality.

 

  9             DR. RUDORFER:  Dr. Trontell.

 

 10             DR. TRONTELL:  Thank you.  I have a

 

 11   question for Dr. Posner and perhaps other members

 

 12   of the committee because of looking at your

 

 13   proposed reclassification of the cases.

 

 14             I have a concern, as we have all been

 

 15   discussing, that a very large number of cases may

 

 16   well fall into the indeterminate category using the

 

 17   very clear definitions you laid out for us.

 

 18             Is there any mechanism you can suggest in

 

 19   that category that there might be some

 

 20   classification broadly, you know, low, medium, or

 

 21   high, that might allow some sensitivity analysis?

 

 22             I am a little concerned that data that

 

 23   have been volunteered, you know, since this wasn't

 

 24   a structured inquiry into potential suicidal

 

 25   behavior, might otherwise be lost.

 

                                                               371

 

  1             DR. POSNER:  I think it was suggested

 

  2   before that we do a level of certainty variability

 

  3   and analysis, and I think that that is a very good

 

  4   point and something that we will take into account

 

  5   when we are doing those classifications.

 

  6             DR. RUDORFER:  Dr. Maldonado is next,

 

  7   please.

 

  8             DR. MALDONADO:  This is a quick question.

 

  9   I am not trying to generate more work for the

 

 10   people who are doing this work, but I also have the

 

 11   concern that Dr. O'Fallon had, that these data may

 

 12   not yield what you are looking for.

 

 13             Actually after hearing the comments in the

 

 14   morning of some of the testimonies, it appears that

 

 15   some of these reactions were very similar in adults

 

 16   also, not only in children.

 

 17             I understand that the signal is much less

 

 18   evident and that is probably why adults have been

 

 19   excluded, but since the database in adults, I

 

 20   assume it is much larger and the disease appears to

 

 21   be less heterogeneous, I don't know if there will

 

 22   be a value in looking systematically into that data

 

 23   to see if there is a signal.

 

 24             But again not knowing the data, it may not

 

 25   be warranted, but that is something that might

 

                                                               372

 

  1   actually help to understand.  I am not talking

 

  2   about only suicides and suicide attempts, I am

 

  3   talking about all the other signals, the wide net

 

  4   that has been proposed here that appears to happen

 

  5   also in adults.

 

  6             DR. RUDORFER:  We are going to hear from

 

  7   Drs. Wang, Leon, and Fost, and then look towards

 

  8   the future.

 

  9             DR. WANG:  I just wanted to follow up in

 

 10   terms of the utility of studying this

 

 11   akathisia-like symptom.  I think there is actually

 

 12   a lot of utility particularly if you focus on sort

 

 13   of the synchrony of change, not just whether there

 

 14   is a link, but also if there is, you know,

 

 15   presumably this akathisia-like syndrome or

 

 16   activation is just more frequent, so you should

 

 17   have some power to study it, but see if there is a

 

 18   time relationship, because there are so many

 

 19   questions raised about, you know, these potentially

 

 20   abrupt onsets of suicidality after developing some

 

 21   kind of activation-like symptom.

 

 22             Anyway, I would argue that there is some

 

 23   utility in studying it.

 

 24             DR. RUDORFER:  Dr. Leon.

 

 25             DR. LEON:  A point of clarification.  Dr.

 

                                                               373

 

  1   Laughren said the HAM-Ds or whatever severity

 

  2   rating is available from the trials.  Are those

 

  3   available for each week of the trial or just for

 

  4   endpoint, and are those available at the item

 

  5   level?

 

  6             DR. LAUGHREN:  They are available by week,

 

  7   and they are available by item level.  What I was

 

  8   pointing out earlier is that companies did try to

 

  9   do a similar analysis with the suicidality item

 

 10   from the HAM-D, Item 3, similar to what has been

 

 11   done with adults, and it did not generate a signal

 

 12   in general.

 

 13             DR. LEON:  But do they look at the

 

 14   agitation item?  I wouldn't expect the suicide item

 

 15   to be very sensitive, and I expect it to be even

 

 16   less sensitive in kids who are probably less

 

 17   inclined to disclose their ideation.

 

 18             DR. LAUGHREN:  I think we probably already

 

 19   know that there is an excess of anxiety and

 

 20   agitation both in adults and children with SSRIs.

 

 21             The question is what is it linked to,  and

 

 22   that is why we need help in trying to define the

 

 23   syndrome that everyone is talking about and may

 

 24   well be a real thing, but we already know about

 

 25   agitation by itself.

 

                                                               374

 

  1             DR. LESLIE:  I think part of what you may

 

  2   be raising, though, is using it as an independent

 

  3   variable, and not as an outcome variable.  I mean

 

  4   one thing would be is this is a sign of increased

 

  5   aggression on the item, on the HAM-D or increased

 

  6   irritability linked then later as an independent

 

  7   variable or a predictor variable, so not as an

 

  8   outcome variable, but as an independent variable.

 

  9             DR. LAUGHREN:  We already have agitation

 

 10   in the model.  That is one of the variables,

 

 11   agitation on drug as opposed to a baseline

 

 12   variable.  We have already included that in the

 

 13   model.  So, we should be able to look at that.

 

 14             The question is are there other things

 

 15   like that, that might be combined in some way to

 

 16   look at as some sort of a stimulation syndrome or

 

 17   activation syndrome other than just agitation by

 

 18   itself.

 

 19             DR. MALONE:  Do you have hyperactivity in

 

 20   the model?

 

 21             DR. LAUGHREN:  I am not sure that

 

 22   hyperactivity is a term that was even coded for.  I

 

 23   would have to go back and look at the dictionaries

 

 24   and see what preferred terms were used.

 

 25             Are you thinking of hyperactivity as a

 

                                                               375

 

  1   term for subsuming other investigator terms or as a

 

  2   descriptive term in itself?  I am not sure what you

 

  3   mean by "hyperactivity."

 

  4             DR. MALONE:  Increased motor activity.  In

 

  5   addition to them just being described as agitated,

 

  6   they may be described as having increased motor

 

  7   activity, sleeplessness, all as part of a syndrome.

 

  8             DR. LAUGHREN:  Or restlessness?

 

  9             DR. MALONE:  Restlessness, yes.

 

 10             DR. LAUGHREN:  Again, to the extent that

 

 11   committee members can put these thoughts together

 

 12   and help us identify something to look for, it

 

 13   would be very helpful.

 

 14             It doesn't have to be now.  Again, you can

 

 15   think about this, and if you want to send us your

 

 16   thoughts about this, we will be happy to entertain

 

 17   them.  This is the time to do it, because now is

 

 18   the time, if we are going to ask for additional

 

 19   variables, now is the time to do it.

 

 20             Dr. Fost and then Dr. Pfeffer.

 

 21             DR. FOST:  Thank you.  I have some

 

 22   comments that have to do with Questions 5, 6, and

 

 23   7, and I think they cover all three issues.

 

 24             There have been some comments both in the

 

 25   public session and among the committee and the FDA

 

                                                               376

 

  1   people that there are two problems here.

 

  2             One is the possibility of causing harm to

 

  3   children by prescribing these drugs that may induce

 

  4   suicide, and the other problem is that we may be

 

  5   scaring people away from prescribing them and there

 

  6   may be inadequate prescribing.

 

  7             That is presented as if they are sort of

 

  8   commensurate or symmetrical, but I think that is

 

  9   not quite right.  There is a reason for the first

 

 10   principle of first do no harm.  It is almost the

 

 11   whole raison d'etre of the FDA.

 

 12             The reason for that is that it is widely

 

 13   thought that it is more important not to harm

 

 14   people than to fail to help people.  There is an

 

 15   infinite number of people we maybe can help, and we

 

 16   can't do all of it.  It is unclear whether we can

 

 17   do it, but we know we shouldn't harm people.  That

 

 18   is our first responsibility.

 

 19             What is odd about this situation is that

 

 20   we may be doing both.  That is, there is not just

 

 21   concern about causing harm to children, but there

 

 22   is tremendous ambiguity about whether anyone is

 

 23   being helped.

 

 24             So, as several people have said, if there

 

 25   is any risk of harm, even if it is a very small

 

                                                               377

 

  1   risk, it is not worth it if there is nothing on the

 

  2   benefit side of the scale.

 

  3             So, it seems to me equally urgent to try

 

  4   to get some better information about the benefit

 

  5   issue, as well as the harm issue.

 

  6             Now, Bob Temple said that withdrawal

 

  7   studies can't tell us anything about harm, which I

 

  8   agree with, but they can tell us a lot about

 

  9   benefit.  In fact, they may be more powerful than

 

 10   prospective trials in showing benefit.

 

 11             So, it seems to me encouraging, however

 

 12   you can get it done, getting some withdrawal trials

 

 13   to occur might take us a long way towards assessing

 

 14   the benefit issue.  That can be done and it is not

 

 15   all that expensive to do.

 

 16             That seems to me equally urgent as

 

 17   whatever can be done mining the database to find

 

 18   out about the harm.  So, that is the first point.

 

 19   I think both of those are important.

 

 20             Second, in terms of what to do while we

 

 21   are waiting for these things to happen, while it is

 

 22   correct that this long-standing section of the

 

 23   label that says be especially careful when you

 

 24   start people on treatment can be interpreted to

 

 25   mean they might get worse.

 

                                                               378

 

  1             I don't think an ordinary person, it is

 

  2   all counterintuitive, but I don't think it occurs

 

  3   to most parents and maybe not even to doctors who

 

  4   aren't really highly informed about this, that that

 

  5   may happen, that an antidepressant can make you

 

  6   more depressed or at least more suicidal.

 

  7             I think that word needs to get out as soon

 

  8   as possible, first, that that is a real

 

  9   possibility, that the British FDA thinks it is a

 

 10   very real possibility, that the FDA, the American

 

 11   FDA is very concerned about it, seriously concerned

 

 12   Dr. Laughren has said several times, that the level

 

 13   of concern that exists among everybody in this

 

 14   room, public and committee members and FDA, is not

 

 15   adequately out there.

 

 16             For doctors, maybe psychiatrists, I can't

 

 17   speak for them, but I doubt that pediatricians are

 

 18   aware, or family practitioners, the level of

 

 19   concern about this potential problem.

 

 20             So, it seems to me while we are waiting,

 

 21   it would be very important to get that word out

 

 22   through the AAP and the AAFP, through national

 

 23   meetings, through pediatric news, through

 

 24   newsletters, through panel discussions,

 

 25   presentations at national meetings, and so on, and

 

                                                               379

 

  1   second, to parents, so that when they make what are

 

  2   ideally collaborative decisions with their doctors

 

  3   about whether to put their children on these drugs,

 

  4   they understand completely that there is at least

 

  5   serious concern and that while it is not a settled

 

  6   issue and FDA is looking into it, and you may

 

  7   withdraw the serious concern by the summer, or you

 

  8   may enhance it, but I don't think that is so

 

  9   terrible to say we are looking at it, it may take

 

 10   us another 6 or 12 months to figure it out, but

 

 11   while we are waiting, you should be very alert to

 

 12   the risk of these drugs, you should be very alert

 

 13   to this activation syndrome in your children, here

 

 14   are some signs of it.

 

 15             We don't know for sure whether it leads to

 

 16   suicide or not, but there is a lot of smart people

 

 17   who think it may very well, so you need to be

 

 18   hypervigilant about it.

 

 19             Oh, and a last point.  Just to pick up on

 

 20   something Skip Nelson said a couple of hours ago,

 

 21   there is only one drug that has really been shown

 

 22   to be effective in children, and while you haven't

 

 23   disproven efficacy, it hasn't been really well

 

 24   established either for all the other drugs, so it

 

 25   seems to me at least part of the education campaign

 

                                                               380

 

  1   to physicians is if they are going to prescribe

 

  2   anything, why not prescribe the one that we know

 

  3   the most about and have the most confidence about.

 

  4             That is not to say they may not also cause

 

  5   the suicidal problem, but at least we have efficacy

 

  6   data for fluoxetine that is stronger than for the

 

  7   other, so why mess around with these other drugs

 

  8   for which there is less encouraging data on the

 

  9   efficacy side.

 

 10             DR. RUDORFER:  Drs. Nelson, O'Fallon, and

 

 11   Pine, please.

 

 12             DR. NELSON:  I want to just make the

 

 13   observation that that point about fluoxetine

 

 14   complicates how you might then design a trial going

 

 15   forward to look at the efficacy of the other drugs,

 

 16   because you need to evaluate the alternatives that

 

 17   the child would not be on.

 

 18             So, if you are proposing to start off with

 

 19   an open-label, non-randomized treatment of a drug

 

 20   that has already been shown to not be effective in

 

 21   your short-term trials, and not put that child on

 

 22   fluoxetine, unless that child is a non-responder or

 

 23   has had an adverse effect to where you think the

 

 24   profile of the drug you are going to put them on

 

 25   would have some advantage, it is not clear to me

 

                                                               381

 

  1   that that would be a trial that would get through

 

  2   5052 on your IRB in evaluating whether it ought to

 

  3   go forward.

 

  4             DR. O'FALLON:  I recall that Dr. Murphy

 

  5   told us this morning that FDAMA was needed in order

 

  6   to basically motivate the drug industry to do the

 

  7   studies of these in the children.

 

  8             When I first went on the subcommittee, I

 

  9   was appalled to realize that a great many of the

 

 10   doctors feel they pretty much have to prescribe off

 

 11   label because there isn't anything on the label for

 

 12   an awful lot of different things.

 

 13             So, I think that harm, being able to

 

 14   identify harm in children may actually be more

 

 15   important than being able to identify benefit,

 

 16   simply because the physicians are often having to

 

 17   -- are often having to work off, you know, just try

 

 18   to figure it out on the fly.

 

 19             So, given that fact, one of the things

 

 20   that really bothers me is the fact that the

 

 21   exclusion criteria are trying to get rid of kids

 

 22   who are taking more than one drug for whatever

 

 23   reason, but the kids out in the community who are

 

 24   getting it are generally on more than one drug.

 

 25             I think that your future studies have to

 

                                                               382

 

  1   include children who are on other medications, as

 

  2   well.  They probably would have to be stratified

 

  3   and treated carefully, but you should be getting

 

  4   the data on adverse events in those populations, as

 

  5   well, because the physicians need to know what bad

 

  6   things can happen.

 

  7             I think placebos are needed because you

 

  8   aren't going to be able to sort out the stuff that

 

  9   is coming off of the disease from the stuff that is

 

 10   coming off of the treatment if you don't have a

 

 11   placebo for at least some part of the time.

 

 12             So, the forward studies, I mean there are

 

 13   a lot of things that you have got to do for future

 

 14   studies, but it seems to me you must be looking at

 

 15   these things in multi-polypharmacy, or whatever you

 

 16   call that, group of patients, as well.

 

 17             DR. RUDORFER:  Dr. Pine.

 

 18             DR. PINE:  I have a couple of comments in

 

 19   light of a couple of things that have been said

 

 20   over the last few minutes.

 

 21             The first thing is in discussing the data

 

 22   on efficacy, I think it is important to point out

 

 23   two things, the first of which is that a number of

 

 24   people have noted that the data are quite

 

 25   discrepant for fluoxetine relative to the other

 

                                                               383

 

  1   SSRIs in pediatric major depression.

 

  2             Non-psychiatrists might not be aware that

 

  3   that is highly unusual.  The data in adults, to the

 

  4   extent that SSRIs have been compared, really do not

 

  5   find that, and I think that one possibility is that

 

  6   kids are very different, and fluoxetine works, and

 

  7   the other SSRIs don't.

 

  8             Another possibility is that maybe there

 

  9   are systematic differences in terms of how the

 

 10   studies were done, and I think it is important,

 

 11   particularly from a labeling perspective, not to

 

 12   jump too quickly to say, well, fluoxetine is okay

 

 13   and nothing else is, number one.

 

 14             Number two, we spent a lot of time talking

 

 15   about the efficacy data for major depression.  As

 

 16   was said in a number of presentations throughout

 

 17   the morning, that particularly in young children,

 

 18   major depression is not the leading condition for

 

 19   which medications are prescribed, it's anxiety

 

 20   disorders.

 

 21             When one looks at the efficacy data for

 

 22   the anxiety disorders, for the SSRIs, one gets a

 

 23   very different picture, at least to the extent that

 

 24   those data have been made public and have been

 

 25   published, that the efficacy data really looks much

 

                                                               384

 

  1   stronger there.

 

  2             So, I think again it is very important to

 

  3   not rush to judgment in terms of saying that SSRIs

 

  4   have no benefits for children who present with

 

  5   various types of psychiatric disorders, because the

 

  6   fact of the matter is that a high proportion of

 

  7   individuals who present with major depression will

 

  8   also have anxiety, and I think it is very important

 

  9   to look at that issue.

 

 10             Two other quick points.  You know, I think

 

 11   that there are problems with the withdrawal design,

 

 12   and the FDA mentioned them.  Probably the biggest

 

 13   one is it doesn't do much for clinicians, for

 

 14   patients, or for parents to answer the specific

 

 15   question if my child is depressed right now, and

 

 16   they need treatment, is it better to give them an

 

 17   SSRI or not.  That is really the question that we

 

 18   need to answer.

 

 19             The last brief comment, you know, I know

 

 20   you guys are asking a lot about could we better

 

 21   define what this activation syndrome is.  Something

 

 22   that we need to consider very carefully is not only

 

 23   is it known at least among psychiatrists that this

 

 24   syndrome occurs, but usually it is mild.  So,

 

 25   usually, at least to the extent that it has been

 

                                                               385

 

  1   studied in trials, the activation syndrome that

 

  2   occurs is relatively mild.

 

  3             So, to the extent that you are going to

 

  4   look at it, it will be very important to not only

 

  5   assess the type of behaviors that are manifest, but

 

  6   to all say, well, what is the difference between a

 

  7   mild syndrome which might be relatively common and

 

  8   a severe syndrome which might be relatively rare.

 

  9             DR. RUDORFER:  Dr. Temple, would you like

 

 10   to respond to that?

 

 11             DR. TEMPLE:  Partly respond to a number of

 

 12   things that have come up.  Actually, I wanted to

 

 13   ask Dr. Fost something first.

 

 14             The proposed addition to labeling about

 

 15   the possibility of an immediate deterioration,

 

 16   would that, in your view, be based on the results

 

 17   of the controlled trials that we have heard about,

 

 18   or on the observation from various personal

 

 19   experiences that this seems to occur?

 

 20             I ask that because, as you have heard, the

 

 21   first of them were a little uncertain what it says,

 

 22   and the second is confounded by the difficulty that

 

 23   some of the consequences that have been described

 

 24   are potential consequences of the underlying

 

 25   disease, as well.

 

                                                               386

 

  1             That doesn't mean we couldn't say watch

 

  2   out without necessarily acclaiming the state of the

 

  3   evidence for it.  As you pointed out, we already do

 

  4   say this is a time to be careful when you start

 

  5   therapy, but I am just interested in what you think

 

  6   the basis for expanding that would be.

 

  7             DR. FOST:  Yes, I think there are multiple

 

  8   reasons why the FDA called this difficult meeting

 

  9   today, which is very challenging to put together

 

 10   and very stressful for a lot of people, but there

 

 11   are several streams of data that I am guessing

 

 12   triggered it.

 

 13             First, there are the data from the trials

 

 14   themselves and the reexamination of it that is

 

 15   going on, and the British conclusions from it, so,

 

 16   first, it is that.

 

 17             Second, it's, as Dr. Hudak pointed out,

 

 18   this epidemic of suicide and what is causing it,

 

 19   and maybe -- it happens to be concurrent with the

 

 20   rise of SSRIs -- maybe that has got something to do

 

 21   with it.

 

 22             DR. TEMPLE:  Wait, you must have seen

 

 23   different data than what I saw.  What I saw was

 

 24   that in recent years, approximately coinciding with

 

 25   the SSRIs, the rate of suicide is going down.  I am

 

                                                               387

 

  1   not saying that proves anything, but I don't see it

 

  2   -- you didn't show it going up.

 

  3             DR. FOST:  So be it.  The public concern,

 

  4   I mean the increasing number of anecdotes, I mean

 

  5   obviously, you think that is important or you

 

  6   wouldn't have spent so much time on it listening to

 

  7   it today.

 

  8             I mean I think there are several things

 

  9   that trigger it, but if nothing else, the data

 

 10   alone, I mean the original trials themselves have

 

 11   stimulated concern among scientific people.

 

 12             DR. TEMPLE:  As you heard, we have

 

 13   considerable reservations about what the state of

 

 14   the trials themselves mean at the moment.  I am not

 

 15   saying this is a bad idea, I am just trying to

 

 16   figure out the basis of it, because if we propose

 

 17   something, we will certainly be asked.

 

 18             DR. FOST:  I accept that you are uncertain

 

 19   about it and that is why you are going to a lot of

 

 20   trouble to look at it much more carefully and in

 

 21   much more detail, but while you are looking, I

 

 22   think sharing this concern, given the seriousness

 

 23   of it if it turns out that way, is a relatively low

 

 24   cost thing to do.

 

 25             DR. TEMPLE:  I just wanted to also say

 

                                                               388

 

  1   something about randomized withdrawal studies.

 

  2   They are not the whole nine yards obviously.

 

  3             I don't think most people would say that

 

  4   it is a good state to have only one possible drug.

 

  5   Prozac is a fine drug and everything, but it stays

 

  6   with you more or less permanently, when you stop

 

  7   it, it is very hard to get off, has a very long

 

  8   half-life with active metabolites.

 

  9             If there were other drugs that were

 

 10   effective, it would be useful to know that.  Now,

 

 11   at the moment, you can't say that there are any

 

 12   other effective drugs.

 

 13             The interest in a randomized withdrawal

 

 14   study is that you take people who, in one way or

 

 15   another, through off-label use, are on a drug

 

 16   already, and you put people into a trial because

 

 17   they seem to be doing well, not because they seem

 

 18   to be doing badly, and because the current standard

 

 19   of therapy isn't to keep kids on therapy forever,

 

 20   at some point you take them off and see how they

 

 21   do.

 

 22             Therefore, a randomized withdrawal study

 

 23   approximates or may approximate clinical practice,

 

 24   and that would be the case for saying that it's an

 

 25   ethically designed trial.  Obviously, people are

 

                                                               389

 

  1   going to look closely at all this and see if they

 

  2   agree with everything I said.

 

  3             But it can tell you that a drug -- again,

 

  4   you taper the drug slowly, you don't do an abrupt

 

  5   withdrawal or anything silly like that -- it can

 

  6   tell you I think that the drug was having a

 

  7   favorable effect.  It confirms the clinical

 

  8   observation that led people to keep the patient on

 

  9   the drug in the first place.  So, I wouldn't rule

 

 10   it out.

 

 11             DR. RUDORFER:  I wonder if I could

 

 12   interject a comment on the labeling.  We have,

 

 13   under Question 5, a quotation from the usual

 

 14   labeling about watching out for the risk of suicide

 

 15   early in treatment.

 

 16             I am thinking, in that small paragraph,

 

 17   the second sentence reads, "Prescriptions for Drug

 

 18   X should be written for the smallest quantity of

 

 19   tablets consistent with good patient management, in

 

 20   order to reduce the risk of overdose."

 

 21             I am wondering if that space could be

 

 22   better served.  I think that is a legacy from the

 

 23   tricyclic era and I don't think clinicians today

 

 24   really worry so much about their patients

 

 25   committing suicide by antidepressant overdose.

 

                                                               390

 

  1             I am wondering if instead we had a

 

  2   statement that encompassed two thoughts, one, that

 

  3   patients should be monitored frequently early in

 

  4   treatment, and, two, that any change in behavior,

 

  5   particularly early in treatment, should be reported

 

  6   to the clinician promptly, to avoid getting into

 

  7   issues of causality, which we have not settled

 

  8   since we don't have all the data yet, but I think

 

  9   -- correct me if I am wrong, committees -- but I

 

 10   think what we are saying is we want to put a speed

 

 11   bump in the road, that, in fact, the sense of the

 

 12   committee is that clinician should take these

 

 13   medications more seriously, and not dispense them

 

 14   overly liberally with inadequate monitoring.

 

 15             I think our state of knowledge is such

 

 16   that we don't have the data we want in terms of

 

 17   showing efficacy and in terms of some of the

 

 18   adverse effects, notably suicidality, obviously,

 

 19   that the analysis is very much underway and we are

 

 20   saying maybe there are other kinds of data to look

 

 21   at, but I think the concern that many of us felt

 

 22   today was that the way SSRIs and other newer

 

 23   antidepressants are being used now is such that the

 

 24   warnings, as they exist in the current labeling,

 

 25   are not adequate and/or not being taken seriously.

 

                                                               391

 

  1             My final thought is I wonder if it's time

 

  2   to reconsider the bolded warning about avoiding

 

  3   combinations with MAO inhibitors, which again I

 

  4   think that is a very important interaction to

 

  5   avoid, but I am not sure how relevant that is to

 

  6   practice today.

 

  7             Dr. Fost.

 

  8             DR. FOST:  I just want to add I think that

 

  9   last sentence adds to the confusion about that

 

 10   paragraph, because the way I read it, frankly, is

 

 11   your patient is depressed, may be suicidal, you

 

 12   have just started him or her on treatment, be

 

 13   careful how many pills you give him because it may

 

 14   take a while for the treatment to kick in and

 

 15   during that time he may take too many of them.

 

 16             It makes it look as if the message is

 

 17   don't give your patient too many pills until he is

 

 18   over the hump, he or she.  So, I agree completely

 

 19   with your sentiment.  I mean maybe that is

 

 20   important, too, but these are not major causes of

 

 21   death, overdose of these pills we have heard.

 

 22             So, it seems to me the more important

 

 23   issue is watch for this other thing where the

 

 24   patient may kill himself in some other way.

 

 25             DR. NELSON:  To continue on the labeling,

 

                                                               392

 

  1   looking through most of the labels, it says simply

 

  2   that efficacy has not been established.  Even

 

  3   though that is a true statement, I think most

 

  4   general physicians and pediatricians have been

 

  5   socialized into thinking that means that the

 

  6   studies have not been done, where the reality here

 

  7   is they were done and did not show efficacy.

 

  8             So, I would say you need to actually say

 

  9   that, in fact, the studies were done and didn't

 

 10   show efficacy, not that it has not been

 

 11   established, because that is often read as the

 

 12   studies weren't done.

 

 13             DR. RUDORFER:  We have time for Dr.

 

 14   Malone, Dr. Glode, and Dr. Irwin, and if we stay

 

 15   longer than that, we will have to pass the hat for

 

 16   rent, so we may have to wrap up.

 

 17             DR. MALONE:  I will just try to be brief.

 

 18   I wanted to reiterate what Dr. Pine had said, that

 

 19   a lot of this discussion is about efficacy in

 

 20   depression, but there is a lot of data about

 

 21   efficacy in anxiety disorders.  In fact, three of

 

 22   the drugs are labeled I think for OCD, which is an

 

 23   anxiety disorder in children.

 

 24             The second thing is if you are doing a

 

 25   discontinuation study, if the problem is that you

 

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  1   have such a high placebo response rate that it is

 

  2   hard to separate drug from placebo, and you have a

 

  3   lot of placebo responders in your study group and

 

  4   then you do the discontinuation, might it be

 

  5   difficult to find an effect.

 

  6             DR. TEMPLE:  Can I comment on our

 

  7   experience.  That is not our experience.  As Tom

 

  8   said, at least half of all conventional depression

 

  9   trials in adults fail to distinguish drug from

 

 10   placebo.  This includes only drugs we believe are

 

 11   effective because they are successful in other

 

 12   trials.

 

 13             When you do the other, when you do a

 

 14   randomized withdrawal trial, I am aware of only one

 

 15   drug that has ever failed to be successful in that

 

 16   setting.  The reasons are fairly obvious.  One, you

 

 17   are only putting in people who do well.  It is an

 

 18   enriched population for people who are likely to do

 

 19   well.  It is almost -- you know, okay, that's one.

 

 20             The second is that the support system that

 

 21   probably helps the placebo response in the acute

 

 22   episode isn't there here.  These are just people

 

 23   out in the community, they aren't seeing anybody or

 

 24   chatting with anybody.  I mean they might be, but

 

 25   they are generally not.

 

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  1             So, the history is that those trials are

 

  2   much more successful, much more at showing

 

  3   effectiveness.  Tom can I am sure elaborate, but I

 

  4   think we have seen only one fail out of a lot.

 

  5             DR. MALONE:  I am not sure, though, that

 

  6   the placebo response rates are the same in adults

 

  7   as they are in children.  That would be my only

 

  8   concern.

 

  9             DR. RUDORFER:  Dr. Glode.

 

 10             DR. GLODE:  I just wanted to add my

 

 11   support to the recommendations, if I understood

 

 12   them correctly, by Ms. Bronstein and Dr. Fost.

 

 13             I am impressed, if again I have these

 

 14   numbers right, that there were 8 million

 

 15   prescriptions in adolescents for these drugs in

 

 16   2002, so between now and June, let's say another 4

 

 17   or 5 million prescriptions may be written, and

 

 18   these may or may not be for children who were the

 

 19   same as the 3- to 4,000 children with major

 

 20   depression who were studied, again without knowing

 

 21   the exclusions for all of those studies, if

 

 22   suicidal children were excluded.

 

 23             Then, one comes to the risk of

 

 24   overinforming people because I am going to support

 

 25   additional information to be provided to parents,

 

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  1   patients, and providers, so that what is the risk

 

  2   of informing versus the benefit of informing.

 

  3             So, the risk of informing, as mentioned,

 

  4   is that parents or patients could refuse to take

 

  5   the medicine that might possibly help them,

 

  6   although again we have the limited efficacy data.

 

  7             The benefit of informing them is that then

 

  8   if you gave them the right information, they would

 

  9   re-present to their provider when they develop

 

 10   these symptoms and be re-evaluated as opposed to

 

 11   here is your two weeks of samples, you know, I hope

 

 12   you do well.

 

 13             So, it seems to me that the benefits of

 

 14   informing them probably outweighs the risks of

 

 15   informing them, and my own advice to the FDA would

 

 16   be to immediately request that information be

 

 17   provided to parents and patients at the time the

 

 18   drug is prescribed.  You know, that just gives them

 

 19   more information about this and ask them to

 

 20   re-present --.

 

 21             DR. RUDORFER:  Dr. Irwin.

 

 22             DR. IRWIN:  I would argue that the

 

 23   patients may be ahead of the curve than the

 

 24   clinicians are, and I am a person who specializes

 

 25   in caring for adolescents, I run a large adolescent

 

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  1   medicine program at the University of

 

  2   California/San Francisco.

 

  3             I would argue that most of the

 

  4   pediatricians who prescribe these agents are not as

 

  5   familiar as the psychiatrists are about the side

 

  6   effects.  I think in the way that pediatricians --

 

  7   when I was in training, you know, you treated

 

  8   everybody that walked through the door who had a

 

  9   red ear -- now, we don't do that.  We basically do

 

 10   a lot of watchful waiting.

 

 11             What I heard today from patients and

 

 12   parents, as they stood up and talked about issues,

 

 13   that many of them went to primary care physicians,

 

 14   and there was not any watchful waiting, in fact,

 

 15   there was immediate response, and the immediate

 

 16   response was based upon I think inadequate

 

 17   information that is going to clinicians who are

 

 18   acting in good faith and really committed to

 

 19   improving the lives of young people, of which,

 

 20   known in an adolescent medicine clinic, a primary

 

 21   care clinic, about 1 in 5 kids that walk through

 

 22   the door have a behavioral disorder, so you are

 

 23   really confronted with a big problem.

 

 24             So, I think it is imperative I would say

 

 25   that the FDA get something out to clinicians as

 

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  1   quickly as possible, and it can be done through a

 

  2   variety of ways that have been mentioned here,

 

  3   because I think those are the individuals that are

 

  4   really acting in ways that we need to really try to

 

  5   encourage them to be acting in a more responsible

 

  6   manner when we are coming up with what really the

 

  7   issues are.

 

  8             Thanks.

 

  9             DR. RUDORFER:  Dr. Leslie, do you have a

 

 10   word, and the we will wrap up.

 

 11             DR. LESLIE:  I wanted to echo what Dr.

 

 12   Irwin was saying as a fellow pediatrician, and also

 

 13   comment that one of the large pressures that many

 

 14   of us in primary care are under is that we cannot

 

 15   access other types of mental health services.

 

 16   There aren't mental health providers to see kids or

 

 17   they are not able to get services through managed

 

 18   care.

 

 19             So, many primary care providers are trying

 

 20   to do what they can to help families and children

 

 21   by giving these medications.  So, the other thing

 

 22   we need to do -- and I am not sure what the role of

 

 23   the FDA in this is -- demand parity for mental

 

 24   health services.

 

 25             DR. RUDORFER:  Thank you.  I think we have

 

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  1   been identifying some very crucial issues.  As Dr.

 

  2   Laughren pointed out in his handout, the FDA does

 

  3   not control the practice of medicine, so that we

 

  4   here have under the FDA's jurisdiction a limited

 

  5   part of the overall scheme.

 

  6             Nonetheless, I think the sense of the

 

  7   committee is that the FDA has a very important role

 

  8   to play, and this challenge is an opportunity to

 

  9   further protect the health of young people with

 

 10   depression while the further studies we discussed

 

 11   proceed.

 

 12             If I can sum up the sense of the

 

 13   committee, I think I have 18 seconds, I can distil

 

 14   this to two major bullets.

 

 15             First, we concur with the plan to have the

 

 16   expert group at Columbia re-analyze the data from

 

 17   the efficacy trials that were presented and some

 

 18   ideas were offered.

 

 19             We could do this in a more formal way in

 

 20   terms of other covariates, issues, such as family

 

 21   history, the activation or overstimulation,

 

 22   restlessness, akathisia spectrum, we discussed as

 

 23   useful information to have.

 

 24             It will be particularly helpful if it is

 

 25   linked with the suicidality measures, but we think

 

                                                               399

 

  1   nonetheless that is important to have established.

 

  2             Correct me if I am wrong, committees, but

 

  3   I think our sense is that we would like in the

 

  4   interim the FDA to go ahead and issue stronger

 

  5   warning indications to clinicians regarding

 

  6   possible risks of these medications, which we don't

 

  7   see as contraindicating their use, but we think

 

  8   such warnings are required to elevate the level of

 

  9   concern and attention that practitioners use in

 

 10   prescribing them.

 

 11             I think, as a group, we were recognizing

 

 12   the limitations of uncontrolled data.  We were all

 

 13   concerned about the stories we heard of the actual

 

 14   use of these very powerful, potentially very

 

 15   effective medications, but in many instances, being

 

 16   used without adequate monitoring.

 

 17             DR. TEMPLE:  I would just add to your

 

 18   summary, information to physicians and to parents.

 

 19             DR. RUDORFER:  Thank you.  I would now

 

 20   like to turn the mike over to Dr. Chesney

 

 21   representing the Pediatric Drug Subcommittee.

 

 22             DR. CHESNEY:  I just wanted to thank the

 

 23   FDA for bringing this issue to all of us and for

 

 24   being so open and listening and for asking us to

 

 25   continue to provide them with additional

 

                                                               400

 

  1   information.

 

  2             I think it really brings home to all of us

 

  3   the importance of looking at all drugs very

 

  4   carefully in children.  I also, again on behalf of

 

  5   the Pediatric Committee want to thank all the

 

  6   parents and children and individuals who came to

 

  7   share their experiences with us today.

 

  8             DR. RUDORFER:  Dr. Katz.

 

  9             DR. KATZ:  I would like to thank very much

 

 10   the committee.  I think this is a very complicated

 

 11   and important issue and through all of that, I

 

 12   think ultimately, your recommendations have been

 

 13   very clear, and I think we have a very good

 

 14   understanding of what you think we should do and

 

 15   how we should proceed at this point.

 

 16             I also would like to thank the families

 

 17   for coming forward and telling us your stories.

 

 18   That was courageous and we know it was painful, but

 

 19   I believe we heard you, I believe the committee

 

 20   heard you, and we appreciate it very, very much.

 

 21             DR. RUDORFER:  In closing, I would like to

 

 22   thank the members of the two committees, I would

 

 23   like to thank the FDA staff.  It is obvious what

 

 24   time, effort, and hard work has gone into this

 

 25   important issue, we appreciate that, and I want to

 

                                                               401

 

  1   thank everyone in the audience who came,

 

  2   particularly people who told us their painful

 

  3   stories.

 

  4             The FDA staff can attest to the fact I

 

  5   kept arguing about the time limit.  I am sorry, but

 

  6   we would probably still be in the open public

 

  7   hearing if we didn't have that red light.

 

  8             Thanks all for coming and obviously, this

 

  9   discussion is to be continued.

 

 10             Get home safely.

 

 11             [Whereupon, at 6:05 p.m., the meeting was

 

 12   adjourned.]

 

 13                              - - -