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
Matthew Rudorfer, M.D., Chair
Anuja M. Patel, M.P.H., Executive Secretary
PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE
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.
Andrew C. Leon, Ph.D.
Philip S. Wang, M.D. M.P.H., Dr. P.H.
Dilip J. Mehta, M.D., Ph.D.,
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
Steven C. Ebert, Pharm. D. (Consumer Rep)
Mary P. Glode, M.D.
Samuel D. Maldonado, M.D., M.P.H.
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
GOVERNMENT EMPLOYEE (non-voting)
Daniel S. Pine, M.D.
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
C O N T E N T S
Call to Order and Opening Remarks:
Matthew Rudorfer, M.D. 6
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
Matthew Piepenberg 125
Terri Williams 127
Glenn McIntosh 129
Delnora Duprey 132
Joe Pittman 133
Richard Mack 135
Noah Wright Smith 137
C O N T E N T S (Continued)
Open Public Hearing (Continued)
Gary Cheslek, M.D. 142
Sherri Walton 144
Peter R. Breggin, M.D. 146
Robert Fritz 148
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
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
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
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
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
complex topics. We understand
that issues raised
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
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
equivalent of a Pediatric Drugs Advisory
1 Committee chaired by Dr. Joan Chesney here to my
3 Suppose we begin by going around the table
4 for introductions. Can we start at that end,
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,
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
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.
DR. FINK: Bob Fink, pediatric
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
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
24 DR. HUDAK: Mark Hudak, neonatologist and
Professor of Pediatrics, University of Florida at
1 Jacksonville, and member of the Pediatric
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.
GRADY-WELIKY: Tana Grady-Weliky,
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
10 DR. NELSON: Robert Nelson, Pediatric
11 Critical Care Medicine at the Children's Hospital,
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.
MS. BRONSTEIN: Jean Bronstein,
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
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
suicidal ideas and behavior developing in some
1 children and adolescents during treatment of
2 depression with an SSRI or similar newer
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
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
voices be heard.
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
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
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
registered speakers to speak in the morning
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
issue of conflict of interest with respect to this
1 meeting and is made a part of the record to
2 preclude even the appearance of such at this
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
Agency's Freedom of Information Office, Room 12A-30
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
unpublished data from controlled trials in youth,
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
22 Thank you.
23 DR. RUDORFER: Thank you.
24 To put the meeting in context, I would now
like to turn to Dr. Russell Katz, Director of the
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
plans for further examination of the data, as well
1 as to ask for your comments and advice about these
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
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
using a description that seemed somewhat
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
relationship between these drugs and suicidal
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
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
standardized manner that will permit us to perform
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.
We will also present the postmarketing
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
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
allegedly represent suicidal behavior, and we are
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
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
step of our analyses convinced us that it would be
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
taking time to make this endeavor an important
1 part of your scientific and academic life. We hold
2 your advice very important and look very much
3 forward to your discussion.
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
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.
23 Acronyms. Throughout the day, you will be
24 hearing these potentially. You have FDAMA. That
the Food and Drug Administration Modernization
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
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
23 The way that is done is important to
24 understand because it is done via what is called
written request in which FDA -- and this is
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
voluntary, so it is up to the sponsor whether
1 they want to participate or not. This process is
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
11 Many of you have heard this talk, so I am
12 just quickly putting these up here to remind
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.
The Agency actually issued a statement
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
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.
So, right now here are the two things that
1 are driving pediatric drug development, so that we
2 can better understand how to use these products in
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
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
developed, that we have discovered in this process.
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
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.
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,
you will present it to the Pediatric Advisory
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.
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
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.
23 This is, quickly, and I am not going to go
24 over every one of these, but to give you an idea of
broad array of products that are being
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.
23 Some of the ongoing lessons that we have
24 learned during this process -- which we think is a
positive process, it is much better than ignorance
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
today. We are learning. We take the best
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.
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.
24 This is where you can go onto the web.
There is a tremendous amount of information posted
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
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.
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
disorder, and for that matter, other mood disorders
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.
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.
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
adolescents, females outnumber males who have
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
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
there is a question of whether some of these issues
1 are actually spectrum related or categorical
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.
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
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.
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.
The depressed mood or irritability occurs
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.
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
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
disorder, subclinical or subsyndromal depression,
1 and treatment-resistant depression.
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
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.
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
Adolescents are likely to have rapid
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.
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
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
school stress since it usually overlaps with the
1 school calendar.
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.
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.
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
approximately 20 to 50 percent of youth with major
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.
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.
The overlapping symptoms may include poor
1 self-esteem, demoralization, poor concentration,
2 irritability, dysphoria, poor sleep, appetite
3 problems, suicidal thoughts, and being overwhelmed.
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
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.
Consider other disorders if the symptoms
1 last more than six months or meet the criteria for
2 other disorders, for example, dysthymia.
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
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.
Chronic fatigue syndrome is another
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.
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.
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
children and adolescents tends to be 7 to 9 months,
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
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.
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
24 Forty to 60 percent of youth with major
depression tend to have a relapse after successful
1 acute therapy, it's a high rate. This indicates
2 the need for continuous treatment.
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
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
bipolar disorder onset would be early onset of
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
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
19 Children with depressed parents are three
20 times more likely to have a lifetime episode of a
21 major depressive disorder.
23 The prevalence of children's first-degree
24 relatives when children have major depression tends
be 30 to 50 percent. In addition,
1 may have major depression and anxiety disorders,
2 substance abuse, as well as personality disorders.
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.
23 The relation of dysthymia in major
24 depression is quite important because dysthymia is
associated with an increased risk for major
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.
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
percent rate of suicidal thinking, and close to 20
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.
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
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
combination should be the first-line treatment.
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.
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
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
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
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.
There is a need to clarify the indications
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.
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.
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
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.
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
attributable to firearms, even though there has
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.
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
23 You do get very big differences in parts
24 of Asia, but apart from that, it is remarkably
similar. That is to say that
there are very, very
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
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.
The United States ranks around about in
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.
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.
23 What one has been able to see from that
24 really was a big eye-opener. That is to say, that
suicidal ideation in high school students is
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
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
suicide death, but about 400 male attempts for
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.
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
or filtering it in.
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.
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.
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
around in the late '80s, peaked a little bit more
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.
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.
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
19-year-old male suicides, it is important to know
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.
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
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
There is a contagion factor, and the
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.
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.
15 I just want to go back to changing rates,
16 because they may be very relevant to today's
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
24 What is important is that this has not
been a United States phenomenon only.
It has been
1 reported in a large number of other industrialized
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
first guess. However, use and
abuse rates have not
1 changed, if anything, they have continued to inch
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.
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
many countries, or it could be a nonspecific
1 finding, a better recognition of adolescent suicide
2 with some nonspecific interventions or some
3 combination of the above.
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
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.
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.
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
24 A quarter of those had been prescribed
antidepressants, but in none of those cases were
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
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
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
a very heterogeneous descriptor and not all
1 types of self-harm are associated with suicidal
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
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
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
hearing speakers who have not yet signed in, please
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.
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.
For this reason -- and I am addressing the
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
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
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
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
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
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
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
12 To summarize, the published clinical trial
13 data show that the therapeutic benefits of
14 antidepressants for children is negligible at best.
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
publication bias and file drawer problems meaning
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
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
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
had rectal bleeding, she has vomited blood.
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
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
have been banned at that time in my opinion.
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
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
with this REM sleep behavior disorder are patients
1 on antidepressants, 80 percent of those on SSRI
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
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
spent his career defending the drug industry.
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
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
teens and the young adults who you will hear from
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
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
had grown up with in our old neighborhood.
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
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,
prevent this tragic story from being repeated
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
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
what I had actually done, I asked one of the
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
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
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
drugs or any medical condition. He found
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,
an SSRI antidepressant. What is scary is
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.
For the next 9 months, my life as I had
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
Due to the severe withdrawal symptoms,
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.
I will let Mark speak.
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
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.
It's in the Bible, Revelations 18, 19 through 24
1 makes it clear, sorcery means anarchy in the last
2 days and blood will be running all over the
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
more senseless and needless deaths because of these
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
trusted him when he determined that Paxil was right
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
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
against persons and property?
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
19 There is a