1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE
WITH THE PEDIATRIC SUBCOMMITTEE
OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
Holiday
Inn
2
PARTICIPANTS
Matthew
Rudorfer, M.D., Chair
Anuja M. Patel,
M.P.H., Executive Secretary
PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE
MEMBERS
Tana Grady-Weliky, M.D.
Irene
E. Ortiz, M.D.
Richard P. Malone,
M.D
Wayne K. Goodman, M.D.
James J. McGough, M.D.
Jean
E. Bronstein, R.N., M.S.
(Consumer
Rep)
Andrew C. Leon, Ph.D.
Philip S. Wang, M.D. M.P.H., Dr. P.H.
Dilip J. Mehta, M.D., Ph.D.,
(Industry Rep)
ANTI-INFECTIVE
DRUGS ADVISORY COMMITTEE
MEMBERS
Steven C. Ebert, Pharm. D. (Consumer Rep)
Mary P. Glode, M.D.
Samuel
D. Maldonado, M.D., M.P.H.
(Industry
Rep)
PEDIATRIC
SUBCOMMITTEE OF THE ANTI-INFECTIVE DRUGS
ADVISORY
COMMITTEE MEMBERS
P. Joan Chesney, M.D.
Mary
Glode, M.D.
Steven Ebert, Pharm. D. (Consumer Rep)
Robert Nelson, M.D., Ph.D.
Richard Gorman, M.D., FAAP
Robert J. Fink, M.D.
Susan Fuchs, M.D.
David Danford, M.D.
Victor Santana, M.D.
Mark Hudak, M.D.
Judith R. O'Fallon, Ph.D.
SGE CONSULTANTS
(VOTING)
Elizabeth B. Andrews, Ph.D.
Norman Fost, M.D., M.P.H.
Charles
E. Irwin, Jr., M.D.
Lauren K. Leslie, M.D., FAAP
James
M. Perrin, M.D.
Cynthia R. Pfeffer,
M.D.
SGE PATIENT
REPRESENTATIVE (VOTING)
Gail W. Griffith
3
PARTICIPANTS (Continued)
GOVERNMENT
EMPLOYEE (non-voting)
Daniel
S. Pine, M.D.
FDA
Robert Temple, M.D.
Russell
G. Katz, M.D.
Thomas Laughren, M.D.
M. Dianne Murphy, M.D.
Susan Cummins, M.D., MPH
Anne Trontell, M.D., MPH
4
C
O N T E N T S
PAGE
Call to Order
and Opening Remarks:
Matthew Rudorfer, M.D.
6
Introductions
8
Conflict of
Interest Statement:
Anuja M. Patel, MPH
15
Overview of
Issues:
Russell Katz, M.D.
19
Pediatric Drug
Development Program:
Dianne Murphy, M.D.
26
Pediatric
Depression and Its Treatment:
Cynthia R. Pfeffer, M.D.
39
Suicide and
Related Problems in Adolescents:
David Shaffer, FRCP (Lond) FRC Psych
60
Open Public
Hearing
Irving Kirsch and David Antonuccio
79
Lisa
Van Syckel
82
Ann Blake Tracy, Ph.D.
83
Tom Woodward
85
Mark Miller
87
Corey and Jay Baadsgaard
90
Joyce Storey 91
Jame Tierney
93
Donna and Mark Taylor
95
Shannon
Baker
97
Dawn Rider
98
Sara Bostock
100
Vera Hassner Sharav
103
Cynthia Brockman
104
Todd and Eileen
Shivak
107
Andy Vickery
109
Rosie Carr Meysenburg
111
Rachel Adler
112
Pepper Draper
115
Donald Marks, M.D., Ph.D.
117
Leah Harris
119
Donald Farber
121
Matthew Piepenberg
125
Terri Williams
127
Glenn McIntosh
129
Delnora Duprey
132
Joe Pittman
133
Richard Mack
135
Noah Wright Smith
137
Marion
Goff
139
5
C O N T E N T S (Continued)
PAGE
Open Public
Hearing (Continued)
Gary Cheslek, M.D.
142
Sherri Walton
144
Peter
R. Breggin, M.D.
146
Robert Fritz
148
Suzanne Vogel-Scibilia, M.D.
152
Dennis
Winter
155
Steve Cole
157
Allan Routhier
158
Daniel J. Safer, M.D.
161
Julie Magno Zito, M.D.
163
Joseph Glenmullen, M.D.
164
Linda Cheslek
165
Jeff Avery
167
Harry Skigis
169
Pamela Wild
170
Karen Barth Menzies
172
Amy Coburn
174
Sharon McBride
175
Thomas Moore, M.D.
178
Pediatric and
Adolescent Antidepressant Drug Use
in the
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
6
1
Call to Order and Opening Remarks
2
DR. RUDORFER: I am Dr.
Matthew Rudorfer,
3 a research psychiatrist at the
National Institute
4
of Mental Health, today
wearing my hat as Chair of
5 the Advisory
Committee.
6
As you settle in, please take this
7 opportunity to put into silent
mode your cell
8 phones and any other devices that
ring, beep, or
9 play show
tunes.
10
I have some official language to read.
11 All committee members and
consultants have been
12 provided with copies of background
materials from
13 the FDA and with copies of letters
from the public
14 that were received by the January
26th deadline.
15 The background materials have been
posted on the
16 FDA web site. Copies of all these materials
are
17 available for viewing at the FDA
desk outside this
18 room.
19
We have a large table and a full house as
20 you can see and a very important
and exciting topic
21 to discuss, so we would like to
start with a few
22 rules of order. FDA relies on its
advisory
23 committees to provide the best
possible scientific
24 advice available to assist us in a
discussion of
25 complex topics. We understand that issues raised
7
1 during the meeting may well lead
to conversations
2 over breaks or during
lunch.
3
However, one of the benefits of an
4 advisory committee meeting is that
discussions take
5 place in an open and public
forum. To that end,
we
6 request that members of the
committees not engage
7 in off-record conversations on
today's topic during
8 the breaks and
lunch.
9
Whenever there is an important topic to be
10 discussed, there are a variety of
opinions. One
of
11 our goals today is for this
meeting to be conducted
12 in a fair and open way where every
participant is
13 listened to carefully and treated
with dignity,
14 courtesy, and respect. Anyone
whose behavior is
15 disruptive to the meeting will be
asked to leave.
16
We are confident that everyone here is
17 sensitive to these issues and can
appreciate that
18 these comments are intended as a
gentle reminder.
19 We look forward to a productive
and interesting
20 meeting.
21
Just to reiterate a couple of points.
22 This is an unusual meeting in that
we have two
23 advisory committees represented
here,
24 Psychopharmacologic Drugs and a
subcommittee that
25 is equivalent of a Pediatric Drugs
Advisory
8
1 Committee chaired by Dr. Joan
Chesney here to my
2 left.
3
Suppose we begin by going around the table
4 for introductions. Can we start at that
end,
5 please.
6
Introductions
7
DR. TEMPLE: I am Bob
Temple. I am
the
8 Office Director for Office of Drug
Evaluation I.
9
DR. KATZ: Russ Katz,
Division Director of
10 the Division of
Neuropharmacological Drug Products,
11 FDA.
12 DR.
LAUGHREN: Tom Laughren,
Psychopharm
13 Team Leader in the Neuropharm
Division.
14
DR. MURPHY: Dianne Murphy,
Office
15 Director, Office of
Counterterrorism and Pediatric
16 Drug
Development.
17
DR. CUMMINS: Susan Cummins,
Medical Team
18 Leader with the Division of
Pediatric Drug
19 Development.
20
DR. TRONTELL: Anne Trontell,
Deputy
21 Director, Office of Drug
Safety.
22
DR. FUCHS: Susan Fuchs,
member of the
23 Pediatric Subcommittee of the
Anti-Infective Drugs
24 Advisory
Committee.
25
DR. FINK: Bob Fink,
pediatric
9
1 pulmonologist, Dayton,
Ohio.
2
DR. ORTIZ: Irene Ortiz,
geriatric
3 psychiatrist, Albuquerque VA and
the University of
4 New Mexico.
5
DR. LESLIE: Lauren Leslie, behavioral
6 and developmental pediatrician and
health services
7 researcher in San
Diego.
8
DR. LEON: Andrew Leon,
Professor of
9 Biostatistics and Psychiatry at
Cornell Medical
10 College.
11
DR. GOODMAN: Wayne Goodman,
Professor and
12 Chairman, Department of Psychiatry
at the
13 University of
Florida.
14
DR. PFEFFER: Cynthia
Pfeffer, Adolescent
15 Psychiatrist and Professor of
Psychiatry at Weill
16 Medical College of Cornell
University.
17
DR. GORMAN: Rich Gorman,
pediatrician in
18 private practice in Ellicott City
and member of the
19 Pediatric Advisory
Subcommittee.
20
DR. GLODE: Mary Glode,
Professor of
21 Pediatrics, Pediatric Infectious
Disease Specialist
22 at Children's Hospital, University
of Colorado at
23 Denver.
24
DR. HUDAK: Mark Hudak,
neonatologist and
25 Professor of Pediatrics,
University of Florida at
10
1 Jacksonville, and member of the
Pediatric
2
Subcommittee.
3
DR. MALONE: Richard Malone,
child
4 psychiatrist, Drexel University,
College of
5 Medicine, and I am a member of the
Psychopharm
6 Advisory
Committee.
7
DR. SANTANA: Victor Santana,
pediatric
8 hematologist/oncologist, St.
Jude's Children's
9 Research Hospital and University
of Tennessee at
10 Memphis,
Tennessee.
11
MS. PATEL: Anuja Patel,
Executive
12 Secretary, Advisors and
Consultants Staff.
13
DR. RUDORFER: Dr.
Matthew
Rudorfer,
14 Acting Chief, Adult Interventions
Branch, National
15 Institute of Mental Health and
Chair of the
16 Psychopharmacologic Drugs Advisory
Committee.
17
DR. CHESNEY: Joan Chesney,
Professor of
18
Pediatrics at the University
of Tennessee in
19 Memphis, and at St. Jude's
Children Research
20 Hospital, and the Pediatric
Subcommittee.
21
DR. McGOUGH: Jim McGough,
Associate
22 Professor in Child and Adolescent
Psychiatry at
23 UCLA and member of the Psychopharm
Drugs Advisory
24 Committee.
DR.
25 GRADY-WELIKY: Tana Grady-Weliky, Associate
11
1 Professor of Psychiatry at the
University of
2 Rochester, School of Medicine and
Dentistry, and
3 member of the Psychopharm Advisory
Committee.
4
DR. WANG: Philip Wang,
psychiatrist and
5 epidemiologist, Harvard Medical
School.
6
DR. O'FALLON: Judith O'Fallon,
recently
7 retired from the Cancer Center
Statistics Unit of
8 the Mayo Clinic. I am a member of the
Pediatric
9
Subcommittee.
10
DR. NELSON: Robert Nelson,
Pediatric
11 Critical Care Medicine at the
Children's Hospital,
12
Philadelphia.
13
DR. ANDREWS: Elizabeth
Andrews,
14 pharmaco-epidemiologist at
Research Triangle
15 Institute and the University of
North Carolina
16 Centers for Educational Research
and Therapeutics,
17 and I am a
consultant.
18
MS. GRIFFITH: Gail
Griffith. I am
a
19 writer. I live in Washington. I am the Patient
20 Representative, a parent of a
child suffering from
21 MDD, and a patient who suffers
from MDD.
22
DR. FOST: Norm Fost,
Professor of
23 Pediatrics and Director of the
Bioethics Program at
24 the University of
Wisconsin.
25
MS. BRONSTEIN: Jean
Bronstein, nurse with
12
1 a background in psychiatry,
retired, and I am the
2 Consumer Representative for
Psychopharm.
3
DR. EBERT: Steve Ebert,
pharmacist and
4 infectious diseases, Professor of
Pharmacy at the
5 University of Wisconsin/Madison,
member of the
6 Pediatric
Subcommittee.
7
DR. DANFORD: David Danford,
Professor of
8 Pediatrics and cardiologist in the
Joint Section of
9 Pediatric Cardiology, University
of Nebraska,
10 Creighton University, member of
the Pediatric
11
Subcommittee.
12
DR. PINE: Daniel Pine,
child
13 psychiatrist, National Institute
of Mental Health,
14 Intramural Research
Program.
15
DR. MALDONADO: Samuel
Maldonado, Chair of
16 the Pediatric Working Group at
PhRMA and member
of
17 the Pediatric
Subcommittee.
18
DR. MEHTA: Dilip Mehta from
New York. I
19 am the Industry Representative on
the
20 Psychopharmacologic Advisory
Committee.
21
DR. RUDORFER:
22 Thank you. Our session today is actually the
first
23 of two planned advisory committee
meetings convened
24 to address recent concerns about
reports of
25 suicidal ideas and behavior
developing in some
13
1 children and adolescents during
treatment of
2 depression with an SSRI or similar
newer
3
antidepressants.
4
Our goal is to gather information from a
5 variety of sources and
perspectives to help us
6 understand this complex situation
and ultimately to
7 offer the best possible
recommendations to the FDA.
8
I would like to thank the many groups,
9 individuals, and families that
submitted written
10 statements in advance of this
meeting, many of
11 which were quite informative as
well as moving.
12
Much of today's meeting will be devoted to
13 a two-part open public hearing
during which dozens
14 of people from around and even
beyond the country
15 will have the opportunity to
present their own
16 personal or professional
experiences and ideas
17 about the relative risks and
benefits of
18 antidepressant medications in
children and
19 adolescents.
20
Although the necessary consideration of
21 the clock will permit only a short
time at the
22 microphone for each speaker, I can
assure you that
23 the committee welcomes and values
input from all
24 viewpoints and feels it essential
to our work that
25 all voices be heard.
14
1
Major depression remains an
2 underdiagnosed, understudied, and
undertreated
3 serious and even life-threatening
mental disorder
4 among thousands of our nation's
youth, leading to
5 considerable dysfunction,
disability, and
6 heartbreak in many
families.
7
I am hopeful that with a fair and
8 open-minded review of the evidence
in hand and that
9 still emerging, this advisory
committee can
10 constructively address the
challenges we all share
11 to assure that interventions for
this deadly
12 disorder are available for those
young people who
13 desperately need them and that
those treatments
14 meet high standards for both
effectiveness and
15 safety.
16
Now, I will ask Anuja Patel, of the FDA
17 Center for Drug Evaluation and
Research, to review
18 some of the ground rules for the
open public
19 hearing.
20
MS. PATEL: Good
morning. As you know,
we
21 have a very full open public
hearing today and in
22 the interest of both fairness and
efficiency, we
23 are running it by some strict
rules.
24
Due to the vast majority of requests by
25 registered speakers to speak in
the morning
15
1 session, we will lengthen the
morning session of
2 open public hearing and shorten
the afternoon
3 session
accordingly.
4
To make the transitions between speakers
5 more efficient, all speakers will
be using the
6 podium in front of the
audience. Each speaker
has
7 been given their number and the
order of
8 presentation, and when the person
ahead of you is
9 speaking, we ask that you move to
the nearby next
10 speaker
chair.
11
Individual presenters and families have
12 been allotted two minutes for
their presentations.
13 The three combined groups'
presentations have been
14 allotted three minutes. We will be using a
timer
15 and speakers who run over their
time limit will
16 find that the microphone is no
longer working.
17
We apologize for the need for the strict
18 rules, but we wanted to give as
many people as
19 possible an opportunity to
participate. Thank
you
20 for your
cooperation.
21
I will now state the Conflict of Interest
22 Statement for the
record.
23
Conflict of Interest Statement
24
The following announcement addresses the
25 issue of conflict of interest with
respect to this
16
1 meeting and is made a part of the
record to
2 preclude even the appearance of
such at this
3 meeting.
4
Based on the agenda, it has been
5 determined that the topics of
today's meeting are
6 issues of broad applicability and
there are no
7 products being approved at this
meeting.
Unlike
8 issues before a committee in which
a particular
9 product is discussed, issues of
broader
10 applicability involve many
industrial sponsors and
11 academic
institutions.
12
All Special Government Employees have been
13 screened for their financial
interests as they may
14 apply to the general topics at
hand. To
determine
15 if any conflict of interest
existed, the Agency has
16 reviewed the agenda and all
relevant financial
17 interests reported by the meeting
participants.
18
The Food and Drug Administration has
19 granted general matter waivers to
the Special
20 Government Employees participating
in this meeting
21 who require a waiver under Title
18, United States
22 Code, Section
208.
23
A copy of the waiver statements may be
24 obtained by submitting a written
request to the
25 Agency's Freedom of Information
Office, Room 12A-30
17
1 of the Parklawn
Building.
2
Because general topics impact so many
3 entities, it is not prudent to
recite all potential
4 conflict of interests as they
apply to each member
5 and consultant and guest
speaker.
6
FDA acknowledges that there may be
7 potential conflicts of interest,
but because of the
8 general nature of the discussion
before the
9 committee, these potential
conflicts are mitigated.
10
With respect to FDA's invited industry
11 representatives, we would like to
disclose that Dr.
12 Dilip Mehta and Dr. Samuel
Maldonado are
13 participating in this meeting as
industry
14 representatives acting on behalf
of regulated
15 industry. Dr. Mehta is retired from Pfizer and
Dr.
16 Maldonado is employed by Johnson
& Johnson.
17
In addition, FDA would also like to note
18 that one member of the
Psychopharmacologic Drugs
19 Advisory Committee, Andrew Leon,
and an FDA
20 speaker, David Shaffer, were
members of the
21 American College of
Neuropsychopharmacology ACMP
22 Task Force that has recently
issued a preliminary
23 report on SSRIs and suicidal
behavior in youth.
24
This task force reviewed published and
25 unpublished data from controlled
trials in youth,
18
1 data from epidemiological studies,
and data from
2 autopsy
studies.
3
Based on their preliminary review, they
4 concluded that the available
evidence does not
5 suggest that SSRIs increase the
risk of suicidal
6 behavior in youth and with
depression, however,
7 they acknowledge that their
conclusions are
8 preliminary and they recommend
that the pertinent
9 data available to pharmaceutical
companies and FDA
10 be rapidly made available to ACMP
and others, so
11 that they may be independently
evaluated.
12
In the event that the discussions involve
13 any other products or firms not
already on the
14 agenda for which FDA participants
have a financial
15 interest, the participants'
involvement and their
16 exclusion will be noted for the
record.
17
With respect to all other participants, we
18 ask in the interest of fairness
that they address
19 any current or previous financial
involvement with
20 any firm whose product they may
wish to comment
21 upon.
22
Thank you.
23
DR. RUDORFER: Thank
you.
24
To put the meeting in context, I would now
25 like to turn to Dr. Russell Katz,
Director of the
19
1 FDA Division of Neuropharmacologic
Drug Products,
2 who will provide a brief overview
of the background
3 leading to today's deliberations
and the likely
4 next steps.
5
Overview of Issues
6
DR. KATZ: Thank you, Dr.
Rudorfer, and
7 good morning. I would like to also add my
welcome
8 to all of you here for this joint
meeting of the
9 Pediatric Subcommittee of the
Anti-Infective Drugs
10 Advisory Committee and the
Psychopharmacologic
11 Drugs Advisory
Committee.
12
In particular, I would like to welcome our
13 invited guests who are not members
of the
14 committee, but who have graciously
agreed to help
15 us grapple with the difficult
problem that we bring
16 to you
today.
17
As you know, we are here to discuss with
18 you an issue of enormous
importance and interest,
19 namely, the relationship, if any,
between treatment
20 of pediatric patients with
antidepressant drugs and
21 suicidal
behavior.
22
This has been an issue of extreme
23 complexity and we are here both to
inform you of
24 our efforts to date to examine the
question and our
25 plans for further examination of
the data, as well
20
1 as to ask for your comments and
advice about these
2 plans.
3
We come to you at this time for several
4 reasons. Under current law, the
Agency is required
5 to present postmarketing adverse
event data to the
6 Pediatric Subcommittee for the
first year of
7 marketing for those drugs granted
market
8 exclusivity under the pediatric
exclusivity
9 provisions of the
Act.
10
At this time, therefore, the Agency is
11 meeting its obligation under the
law to present
12 this data for Paxil and
Celexa. More
importantly,
13 however, given the intense
interest in the Agency's
14 efforts to examine the question of
antidepressant
15 use in pediatric patients and
suicidal behavior, we
16 concluded that it would be
appropriate to inform
17 you about these latter efforts at
this time, as
18 well.
19
As you know, we most recently became aware
20 of a potential signal of concern
during the review
21 of the controlled trial data for
Paxil. In the
22 course of that review, we became
aware that the
23 sponsor had categorized some
events that could have
24 represented suicidal behavior or
suicidal thinking
25 using a description that seemed
somewhat
21
1
inappropriate.
2
We asked them to clarify
their
3 presentation of the data, and
their response raised
4 a concern that such a signal
existed. Based
on
5 these concerns, the Agency issued
a public
6 statement in June of last year
recommending that
7 this drug not be used to treat
pediatric patients
8 with depression, but based on the
Paxil data and
9 the problem of idiosyncratic
characterization of
10 events of potential concern
identified in that
11 application, we asked the sponsors
of the other
12 antidepressant drugs to search
their controlled
13 trial databases in a more formal
way to identify
14 potential cases of suicidal
behavior.
15
Our review of their responses resulted in
16 a second Agency statement that
alerted
17 practitioners to a similar
potential signal for
18 other drugs in this class, and
recommended that
19 these drugs be used with caution
in these patients.
20
Our continued review of these data,
21 however, convinced us that the
data submitted from
22 the various companies involved may
not have been
23 collected or reported to us in a
form that would
24 permit us to adequately evaluate
the potential
25 relationship between these drugs
and suicidal
22
1 behavior.
2
Indeed, we became convinced that with the
3 data before us at that time, we
could not
4 adequately answer the question of
whether there was
5 such a relationship for any
specific drug or
6 whether there were any differences
between drugs.
7
You will hear in greater detail later the
8 deficiencies with these data as
previously
9 submitted and why we have
therefore continued to
10 work with the sponsors involved to
submit to us
11 data in the form that will permit
us to adequately
12 and comprehensively address the
critical question
13 before us.
14
It is because we are not yet able to do
15 this that we could not present
definitive analyses
16 at this time. It is absolutely critical, in
our
17 view, that we make every effort to
provide the best
18 answer possible to this question.
The wrong answer
19 in either direction, prematurely
arrived at, could
20 have profound negative
consequences for the public
21 health.
22
However, we now believe that we have
23 obtained from the sponsors all of
the relevant data
24 collected during the trials,
presented in a
25 standardized manner that will
permit us to perform
23
1 analyses that will give us the
best possible chance
2 to address this
question.
3 Before
we embark upon these analyses,
4 however, we are taking this
opportunity to inform
5 you and the public about the
problems we have
6 encountered in trying to answer
this question, how
7 we have attempted to address those
problems, and to
8 describe our plans for analyzing
the data.
9
We are primarily interested in your views
10 about our proposed approaches to
the data and are
11 eager to hear if you believe we
should request
12 additional data from the sponsors
and whether you
13 believe we should perform
additional analyses
14 beyond those we will describe to
you later today.
15
In our efforts to further evaluate the
16 data, we have enlisted the help of
outside experts
17 with particular expertise in the
issue of pediatric
18 depression and suicide, and in
particular, we have
19 enlisted a group from Columbia
University, who will
20 objectively reclassify potential
cases of
21 suicidality from all the drug
development programs,
22 so that we may move forward with
our more
23 definitive analyses. You will hear about this
from
24 Dr. Kelly Posner in more detail
later.
25
We will also present the postmarketing
24
1 adverse event data for the drugs
in question, but
2 as you will hear, and for the
reasons you will
3 hear, we do not believe that this
data can
4 reasonably inform our judgment
about any
5 relationship between these drugs
and suicidal
6 behavior.
7
It is the controlled trial data that we
8 believe is best able to help us
provide an adequate
9 answer to this question, but as
you have heard, and
10 you will hear throughout today's
presentations, we
11 do not believe that this data
until now has been
12 provided to us in a way that would
permit us to
13 interpret it
fully.
14
It should be noted that this view of the
15 data has not been a unanimous one
among Agency
16 staff. Some within the Agency have examined
the
17 data and concluded that the data,
as currently
18 submitted, do permit definitive
analyses and that
19 these analyses support the
conclusion that this
20 class of drugs is associated with
a risk of
21 suicidal behavior in pediatric
patients.
22
However, the staff of the
23 Neuropharmacological Drugs
Division has examined
24 the individual cases reported by
the sponsors that
25 allegedly represent suicidal
behavior, and we are
25
1 convinced that the categorization
of these events,
2 as performed idiosyncratically by
the individual
3 sponsors, is not entirely
reliable.
4
Examples of these categorizations will be
5 presented to you later today, and
we are confident
6 that this conclusion will become
clear to you.
7
Further, the pattern of these potential
8 signals is also difficult to
understand, for
9 example, arising from one single
study out of
10 several similarly size studies for
a given drug.
11 This unusual pattern gives us
further reason to
12 more closely examine the
data.
13
We are, of course, aware that there is
14 great concern among the families
of children and
15 adolescents with depression about
whether or not
16 these drugs can be used
safely. For them, I
am
17 sure answering this question has
already taken too
18 long.
19
We, too, are frustrated with the time it
20 has taken to come to a definitive
answer to this
21 question. Indeed, we had originally hoped to
be
22 able to present to you today more
definitive
23 analyses and conclusions, however,
as I have
24 described, closer examination of
the data at each
25 step of our analyses convinced us
that it would be
26
1 premature to arrive at a
conclusion without
2 additional work, the plans for
which we will
3 present to you later
today.
4
We are firmly convinced that we serve no
5 one's goals or needs by rushing to
a judgment that
6 has not considered all reasonable
sides to the
7 question. We are committed to, and fully
expect
8 to, come back to the committee in
late summer with
9 the results of the analyses we
will discuss today.
10
At that time, we expect to be able to
11 present the best possible answer
that the current
12 data can provide to the question
of whether or not
13 any of these drugs, all of these
drugs, or none of
14 these drugs increase the risk of
suicidality in
15 pediatric
patients.
16
With that as an introduction, I will turn
17 it back to Dr.
Rudorfer.
18
DR. RUDORFER: Thank you, Dr.
Katz.
19
We will now hear from Dr. Dianne Murphy,
20 Director of FDA's Office of
Counterterrorism and
21 Drug Development, who will speak
about the
22 Pediatric Drug Development
Program.
23
Pediatric Drug Development Program
24
DR. MURPHY: Welcome. Thank you very
much
25 for taking time to make this
endeavor an important
27
1 part of your scientific and
academic life. We
hold
2 your advice very important and
look very much
3 forward to your
discussion.
4
[Slide.]
5
I am going to ask you to step back for a
6 moment. My comments are not going
to focus directly
7 on the topic of depression or the
therapies for
8 that. The goal of my presentation is to
provide
9 you some background on pediatric
drug development
10 because I think you will see that
is the process
11 that has brought us some of this
data and we need
12 to make sure everybody understands
how this
13 evolved.
14
It is also an example of watch out what
15 you ask for because we now
finally, in the last few
16 years, are beginning to get the
kind of information
17 that we wanted for a long time to
be able to
18 understand how we could better
treat children with
19 the therapies that we
have.
20
Of course, we will be reviewing FDA's
21 specific responsibilities during
these activities.
22
[Slide.]
23
Acronyms. Throughout the
day, you will be
24 hearing these potentially. You have FDAMA. That
25 is the Food and Drug
Administration Modernization
28
1 Act. This is important because this is
the
2 legislative initiative that
provided the Agency
3 with the ability to provide an
incentive that has
4 been a tremendous -- I call it the
engine that has
5 really been driving this process
for being able to
6 develop information on how to use
these products in
7
children.
8
Remember, before this, most children, if
9 it was not a pediatric disease
like otitis media,
10 these products were not being
studied in children,
11 and each child was an n of 1 in
which we did not
12 learn anything, and that was not
an approach we
13 thought useful. That's FDAMA.
14
Best Pharmaceuticals for Children, renewal
15 of the legislation basically
expanding not only the
16 legislative mandate to look at
products that have
17 patents remaining where the
incentive will work,
18 but a process which mandates FDA
and NIH to work
19 together to develop the same sort
of data for
20 products that are older and would
not benefit
21 because that was an area that was
not being
22 developed.
23
The way that is done is important to
24 understand because it is done via
what is called
25 the written request in which FDA
-- and this is
29
1 distinctive from most other drug
development -- FDA
2 determines what the public health
need is and
3 issues a written request defining
the studies that
4 they think need to be done, so
that we can better
5 understand how to dose children or
if it works in
6 children, or what are the
distinctive adverse
7 events that occur in children,
because as we all
8 know, the variability between a
preemie and a
9 fullback is tremendous, and we
have that in
10 children, and evolving
developmental processes.
11
PREA was the recently legislation that in
12 essence said yes, FDA, you have
the authority to
13 require that if a sponsor submits
an application
14 for a disease -- I am going to
call it indication
15 throughout the rest of this -- for
an indication
16 that exists in children for which
this product will
17 likely be used, you are to study
it in children
18 also. You are not just to market it for
adults.
19 This
proposed pediatric study is a process
20 that applies to the written
request, which if
21 industry is interested in studying
a product, they
22 can submit it to FDA, and we can
look at that.
23
That is important because what you need to
24 understand is that this whole
exclusivity process
25 is voluntary, so it is up to the
sponsor whether
30
1 they want to participate or
not. This process
is
2 not.
3
[Slide.]
4
The interesting thing about pediatric drug
5 development is that many of the
legislation that
6 has developed has developed
because of misfortunes
7 and severe tragedies that have
happened in
8 children, and yet every time new
legislation would
9 be mandated, it would apply to
adults, and not to
10 children.
11
Many of you have heard this talk, so I am
12 just quickly putting these up here
to remind
13 everybody.
14
[Slide.]
15
We have for decades been trying to have
16 products that are being used in
children studied,
17 and this is just to give you
really the benchmarks,
18 starting in the '70s, in which the
Academy of
19 Pediatrics issued a statement
saying we ought to be
20 studying these products we are
using in children,
21 why do we think that children are
going to be less
22 variable than adults. All reason and
information
23 would say they are going to be
more variable, and
24 we need to.
25
The Agency actually issued a statement
31
1 saying we think children should be
studied, and we
2 would like you to conduct two
adequate trials also
3 for children, to evaluate the
safety and efficacy
4 in children.
5
What happened was not much, and as
6 everybody has heard, the majority
of products were
7 not studied in children until
really here.
8
In 1994, FDA published a regulation which
9 basically said we understand that
there are times
10 in which you can extrapolate
efficacy only. If
the
11 disease is similar enough, the
pathophysiology, and
12 the expected response have been
defined well
13 enough, that you might be able to
extrapolate
14 efficacy, hoping to incentivize in
a way the
15 interest in developing information
and conducting
16 trials in children. Safety and dose finding
were
17 still trials that you would need
to conduct in
18 children.
19
Again, minimal response. So,
bottom line,
20 the first incentive program was
the major push.
21 The FDA published a regulation,
which was then
22 enjoined by a court saying we
didn't have the
23 authority to require it, so
Congress came back in
24 2003 and said, yes, FDA, you
do.
25
So, right now here are the two things that
32
1 are driving pediatric drug
development, so that we
2 can better understand how to use
these products in
3 children.
4
[Slide.]
5
It has been a tremendous response.
This
6 is just simulated to
exclusivity. We have
received
7 over 300 proposals. You could have counted
the
8 number of products developed on
your fingers and
9 toes before this that weren't
primarily pediatric
10 diseases.
11
We have issued over 283 written requests
12 where FDA has determined what
needs to be developed
13 in the way of studies, and has
issued sponsors'
14 requests. This is updated from
your handout, by the
15 way, these numbers are slightly
different because
16 we updated it for the
slides.
17
The important thing about exclusivity
18 determinations, it means that over
100 products
19 have been brought in with the
studies that have
20 been requested, and you are
discussing some of
21 those today, with the type of
information that
22 helps us better
understand.
23
We have an entire one-hour talk on some of
24 the very significant findings that
have been
25 developed, that we have discovered
in this process.
33
1 Today is another example of we are
finding out what
2 more information we need if we are
going to
3 properly use these
products.
4
I only put these numbers up because once
5 exclusivity is granted, you can
see some were
6 denied, even though it may have
been denied, it
7 still could have been
approved. It just meant
that
8 they didn't meet the terms
completely that we asked
9 for.
10
There are now 63 new labels, so products
11 that are being used in children,
there are now 63
12 of them that have new labels, new
important dosing
13 and safety information in them
including
14 information that says they don't
work in kids with
15 these
studies.
16
[Slide.]
17
These are the products that were mandated,
18 not the individual products, but
the process that
19 was mandated by the Best
Pharmaceuticals, the BPCA.
20 I point this out because one of
these, our set of
21 data you are going to hear today
is the result of
22 BPCA saying FDA, one year after a
product has been
23 granted exclusivity, you will
follow all of the
24 adverse events that are reported
for that product,
25 and you will present it to the
Pediatric Advisory
34
1 Subcommittee that will soon be a
full committee,
2 and that this is an area which
BPCA wanted to make
3 sure that additional attention was
paid to the
4 process of reviewing what
happens.
5
The thing to understand about that is that
6 a product could be approved way
back 10 years ago,
7 and it could then be studied later
in its life for
8 pediatrics, so that the one-year
post-safety
9 assessment is at varying stages of
these different
10 products, they are not all the
same, and the
11 Division has tried to standardize
that for you
12
today in looking at the
safety assessments at more
13 standardized times because each
product is coming
14 in at a different
time.
15
[Slide.]
16
The only other thing I really wanted to
17 point out to everybody, to bring
us back to the
18 topic at hand today, is that this
drug development
19 process that has begun to occur
really since 1998,
20 five, six years, has brought forth
not only new
21 information that challenges some
of our
22 preconceived thoughts about safety
and how children
23 respond, it has been a tremendous
bounty of
24 information because children are
finally getting
25 studied.
35
1
We are beginning to have to figure out how
2 do you measure that endpoint in
children.
That
3 type of science was not being
developed. We
are
4 also dealing with the ethical
issues that come up,
5 that are different for kids who
cannot consent, so
6 this is a whole different process,
and I just want
7 to make sure that you all knew
that we have brought
8 various ethical issues to the
committees, and we
9 have a wonderful cadre of
ethicists who are Special
10 Government Employees, who work
with the Pediatric
11 Advisory Subcommittee, who
attended these meetings
12 and advised us on such topics as
should children be
13 enrolled in trials in which they
are not going to
14 receive direct benefit, should
children be enrolled
15 in placebo-controlled trials,
should children who
16 are especially vulnerable -- most
people think of
17 children as a vulnerable
population, but in truth,
18 there are subsets, subpopulations
that are even
19 more vulnerable, and this was a
population of
20 children with CP, how do you
develop a product in
21 that population. These are difficult
issues.
22
[Slide.]
23
This is, quickly, and I am not going to go
24 over every one of these, but to
give you an idea of
25 the broad array of products that
are being
36
1 developed in children and the
questions that have
2 come up.
3
Actually, Neuropharm, the Division of
4 Neuropharmacological Drug
Products, has brought a
5 number of these issues to the
committee, including
6 how do we develop pediatric
products -- NIMH also
7 participated in this meeting --
from such issues as
8 -- also, this was another
Neuropharm Advisory
9 Committee meeting with the
Pediatric Committee --
10 chronic hepatitis, reflux in
infants, HIV drugs,
11 how do you approach the whole
field of developing a
12 product that may be put in almost
every newborn who
13 develops hyperbilirubinemia,
tremendous issues,
14 long term study
issues.
15
Again, more, what do you do about some of
16 these products. Most of our products'
safety
17 databases are collected on weeks,
usually, maybe
18 months, but certainly not years,
what do you do
19 with products that we know can
potentially suppress
20 your adrenal axis or products that
we know can be
21 oncogenic, but have to be
used.
22 [Slide.]
23
Some of the ongoing lessons that we have
24 learned during this process --
which we think is a
25 positive process, it is much
better than ignorance
37
1 -- it is that children are even
more variable than
2 we really
thought.
3
We are finding, for certain classes, you
4 may have to have dosing based on
clearance in three
5 different age groups that is very
different, and it
6 is not just the preemies, it is
not just the
7 neonates. It is actually children of all
ages,
8 from adolescence, preschool, et
cetera.
9
Adverse reactions that are
10 pediatric-specific are being
defined.
Clearly,
11 growth is one everybody would
expect would be
12 defined, that we are finding that
products, and
13 Prozac was an example of that, are
having an effect
14 on growth. But there are many other products
that
15 we are beginning to look now, and
beginning to look
16 in a more systematic way, that we
are finding that
17 they do have an effect on
growth.
18
But there are other issues - school
19 behavior problem, other products
where aggression
20 and behavioral changes have been
seen. So, this
is
21 a very important area that we are
trying to look at
22 as we develop these
products.
23
Trial designs are being modified as we
24 learn, and I think that is
probably why we are here
25 today. We are learning. We take the best
38
1 knowledge we have, we get the best
experts, we
2 issue the type of study we think
will be the best,
3 and sometimes something happens in
the meantime,
4 more data becomes available, we
need to update
5 that, or what we thought we were
going to be able
6 to evaluate didn't turn out to be
as valuable as
7 something else in the
study.
8
We learn from these studies.
Remember,
9 there is a huge amount of science
that has not been
10 developed, that is now being
developed for
11 children, and, as I said, the
ethical issues have
12 to be reassessed from the
pediatric perspective.
13
[Slide.]
14
I just got the signal that my time is up,
15 so I will leave you with the
general principles
16 that we have developed from the
International
17 Conference on Harmonization on how
one should
18 approach the whole process
involving children in
19 trials, and this is a group that
involves European
20 nations, Japan and the United
States, and I think
21 that it is a shared
responsibility. That is why
we
22 thank you for being here
today. Thank
you.
23
[Slide.]
24
This is where you can go onto the web.
25 There is a tremendous amount of
information posted
39
1 on pediatric numbers, stats, and
studies.
2
Thank you.
3
DR. RUDORFER: Thank you, Dr.
Murphy.
4
As Dr. Katz pointed out, an important way
5 to put issues of drug safety in
context is to
6 understand more about the disorder
being treated,
7 so we are pleased to have a couple
of experts in
8 the area of depression in young
people to address
9 us on the latest understanding of
this complicated
10 disorder.
11
First, from Weill Medical College of
12 Cornell University, we are pleased
to have Dr.
13 Cynthia Pfeffer, who will address
Pediatric
14 Depression and its
Treatment.
15
Pediatric Depression and its Treatment
16
DR. PFEFFER: I want
especially to provide
17 an overview of pediatric
depression, which in fact
18 is a major mental health problem
in the United
19 States and probably
worldwide.
20
[Slide.]
21
There is a tremendous need to develop
22 treatments for these problems and
also prevention
23 efforts primarily because these
disorders,
24 particularly major depressive
disorder, dysthymic
25 disorder, and for that matter,
other mood disorders
40
1 are very prevalent and recurrent,
they have high
2 rates of morbidity and
comorbidity, they are often
3 accompanied by very poor
psychosocial outcomes for
4 children and adolescents. They are associated
with
5 high risk for suicide and also for
substance abuse.
6
[Slide.]
7
There are a number of problems which I
8 will touch on in my talk in
reducing major
9 depressive disorder in children
and adolescents,
10 and these include problems in
actually diagnosing
11 children and adolescents. There are
developmental
12 variations that need to be
considered.
13
There is a complexity of factors that are
14 associated with the clinical
course of children who
15 have such mood disorders and a
need for specificity
16 of
treatments.
17
[Slide.]
18
Epidemiologically, we know that the
19 prevalence of major depressive
disorder in children
20 who are prepubertal is
approximately 2 percent, and
21 it increases in adolescents to a
rate of between 4
22 and approximately 8
percent.
23
The male-to-female ratio for younger
24 people, prepubertal children, is
about equal, but
25 in adolescents, females outnumber
males who have
41
1 major depression 2 to
1.
2
By the time a youngster reaches the age of
3 18, there is approximately a 20
percent prevalence
4 rate of those who are depressed,
who show major
5 depression, and since prior to
World War II, each
6 successive generation seems to
have a higher risk
7 for major depressive
disorder.
8
If we look at dysthymia, the prevalence
9 rate is somewhat lower although
something to be
10 concerned about, with the highest
rate of
11 approximately 2 percent in
children, and in
12 adolescents, ranging from almost 2
to 8 percent.
13 Dysthymia is a condition that is
often
14
under-recognized.
15
[Slide.]
16
There are a number of complexities in
17 diagnosing major depression in
children and
18 adolescents. These include an overlap of a
variety
19 of the mood symptoms, and in
addition, the symptoms
20 often overlap with comorbid
disorders.
21
There are developmental variations in the
22 symptoms and how they are
manifest. There
are
23 etiological variations of mood
disorders that do
24 involve gene and environmental
interactions, and
25 there is a question of whether
some of these issues
42
1 are actually spectrum related or
categorical
2 disorders.
3
Finally, the effects of
medical conditions
4 on the prevalence and incidence of
major depression
5 and other mood disorders needs to
be considered.
6
[Slide.]
7
The DSM criteria for major depressive
8 disorder involves a pervasive
change in mood, which
9 is manifest for at least two weeks
by either being
10 depressed or irritable or having a
loss of interest
11 in pleasure.
12
There are other symptoms that are
13 necessary in making the diagnosis,
that include
14 changes in appetite, weight,
sleep, activity
15 levels, concentration, and
sometimes
16 indecisiveness, changes in energy
level,
17 self-esteem, including
worthlessness and excessive
18 guilt, changes in motivation, and
recurrent
19 suicidal ideation and
acts.
20
These symptoms should represent a change
21 from the child or adolescent's
previous functioning
22 and produce impairment. These symptoms are
not
23 attributable to substance abuse,
medications, or
24 other psychiatric illness,
bereavement, and medical
25 illness.
43
1
[Slide.]
2
There are developmental variations which
3 have been identified. For example, in
children,
4 they tend to have a greater number
of symptoms of
5 anxiety, including phobias and
separation anxiety,
6 more somatic complaints, and if
they do occur,
7 auditory
hallucinations.
8
They express irritability with temper
9 tantrums and behavioral problems,
and the children
10 tend to have fewer delusions and
fewer serious
11 suicide attempts, however,
adolescents tend to show
12 more sleep and appetite
disturbances, if they
13 occur, delusional thinking,
greater degrees of
14 suicidal ideation and acts, and
greater impairment
15 of
functioning.
16
Compared to adults, however, adolescents
17 have more behavioral problems and
fewer
18 neurovegetative
symptoms.
19
[Slide.]
20
The diagnostic criteria for dysthymia
21 involves a persistent long-term
change in mood
22 which is less intense, but more
chronic than major
23 depressive disorder. These children in
adolescence
24 have extensive psychosocial
impairment.
25
The depressed mood or irritability occurs
44
1 most of the time during the day
for at least one
2 year, and there are at least two
other symptoms
3 that are associated in making the
diagnosis.
These
4 include again changes in appetite,
sleep, lowered
5 self-esteem, problems with
concentration, problems
6 with decisionmaking, changes in
energy level, and a
7 sense of
hopelessness.
8
People who have no symptoms for more than
9 two months at a time, and do not
have a major
10 depressive disorder in the first
year of
11 disturbance, may be considered to
have dysthymic
12 disorder, and these are also
youngsters who never
13 had manic or hypomanic
episodes.
14
[Slide.]
15
Other symptoms tend to go along with
16 dysthymic disorder. These include feelings
of
17 being unloved, angry outbursts,
self-depreciation,
18 somatic complaints, anxiety, and
often
19
disobedience.
20
[Slide.]
21
There are a variety of variations that the
22 symptoms of major depressive
disorder involve.
For
23 example, psychotic depression,
bipolar depressive
24 states, atypical depression,
seasonal affective
25 disorder, subclinical or
subsyndromal depression,
45
1 and treatment-resistant
depression.
2
[Slide.]
3
I will touch on some of these variants now
4 more specifically. Psychotic depression
includes
5 major depressive disorder symptoms
that are
6 associated with mood-congruent or
incongruent
7 hallucinations and/or delusions,
and unlike
8 adolescents, children tend to
manifest more
9
hallucinations.
10
Psychotic depression occurs in up to about
11 30 percent of those youngsters
with major
12 depressive disorder. It is
associated with more
13 severe depression, greater
long-term morbidity,
14 resistance to antidepressant
monotherapy, a low
15 placebo response, increased risk
for bipolar
16 disorder, and a family history of
bipolar and
17 psychotic
depression.
18
[Slide.]
19
Bipolar depression presents similarly to
20 unipolar depressive disorder. The risks for
21 bipolar disorder is indicated by
psychosis,
22 psychomotor retardation,
psychopharmacologically
23 induced hypomania, and a family
history of bipolar
24 disorder.
25
Adolescents are likely to have rapid
46
1 cycling or mixed episodes, and an
increased suicide
2 risk and difficulty in treatment
compliance.
There
3 is a need to rule out bipolar II
disorder, which is
4 more prevalent in adolescents and
often overlooked
5 and
misdiagnosed.
6
[Slide.]
7
Atypical depression has not yet been
8 studied in children and
adolescents, and it usually
9 has an onset in adolescence, and
it is manifest by
10 increased lethargy, appetite and
weight changes,
11 and reactivity to
rejection.
12
There is hypersomnia and often
13 carbohydrate craving. In adults, it tends to
be
14 genetically distinct from major
depressive
15 disorder.
16
[Slide.]
17
Seasonal affective disorder usually has
18 its onset in adolescence in those
living in regions
19 with distinct seasons. The
symptoms are similar to
20 those of atypical depression, but
are more
21 episodic. They do not include increase
reactivity
22 to
rejection.
23
This disorder should be differentiated
24 from depression precipitated by
school problems and
25 school stress since it usually
overlaps with the
47
1 school
calendar.
2
[Slide.]
3
Treatment-resistant depression is not
4 clearly defined for children and
adolescents.
It
5 occurs in approximately 6 to 10
percent of
6 depressed children and adolescents
who suffer
7 chronic
depression.
8
In adults, treatment resistance is defined
9 as patients who have had at least
two trials with
10 two different classes of
antidepressants which are
11 administered at approximately
similar doses for at
12 least six weeks
each.
13
[Slide.]
14
Another issue that needs to be thought
15 about in understanding the mood
disorders and
16 especially major depression is
that they may be
17 affected by the complexity of
comorbid disorders
18 which may affect the recognition
and diagnosis of
19 major depression, the types and
efficacy of
20 treatments, and various
psychosocial outcomes.
21
[Slide.]
22
Comorbidity tends to be present in 40 to
23 90 percent of youth with major
depression. Two
or
24 more comorbid disorders tend to be
present in
25 approximately 20 to 50 percent of
youth with major
48
1 depression.
2
Comorbidity in youth with major depression
3 involves dysthymia or anxiety
disorders with a rate
4 of approximately 30 to 80 percent,
disruptive
5 disorders with a rate of
approximately 10 to 80
6 percent, and substance abuse
disorders with a rate
7 of approximately 20 to 30
percent.
8
Major depressive onset is usually after
9 the comorbid disorders except for
substance abuse
10 in which major depression tends to
antedate
11 substance abuse disorders. Conduct
problems may be
12 a complication of major depression
and may persist
13 after the major depressive episode
resolves.
14
Children may manifest separation anxiety
15 comorbid disorders, while
adolescents may tend to
16 manifest social phobia,
generalized anxiety
17 disorder, conduct disorder, and
substance abuse.
18
[Slide.]
19
In terms of differential diagnosis of
20 major depressive disorder, the
complexities tend to
21 be with an overlap of symptoms
with other
22 nonaffective disorders, such as
anxiety states,
23 learning problems, disruptive
disorders, and
24 personality disorders and eating
disorders.
25
The overlapping symptoms may include poor
49
1 self-esteem, demoralization, poor
concentration,
2 irritability, dysphoria, poor
sleep, appetite
3 problems, suicidal thoughts, and
being overwhelmed.
4
[Slide.]
5
One should consider in the differential
6 diagnosis the nonaffective
psychiatric disorders,
7 which include anxiety disorders
especially
8 separation anxiety, generalized
anxiety, and other
9 anxiety states, disruptive and
attention deficit
10 disorders, learning problems,
substance abuse,
11 eating disorders especially
anorexia nervosa,
12 personality disorders, and
premenstrual dysphoric
13 disorder.
14
[Slide.]
15
Another disorder that needs to be
16 considered and understood is an
adjustment disorder
17 with depressed mood. This includes
a mood change
18 and impairment of functioning
within about three
19 months of a stressor, and this
does not meet the
20 criteria for major depressive
disorder.
21
Adjustment disorder with depressed mood
22 tends to be self-limited, there
are less mood
23 disturbances associated with it,
fewer symptoms,
24 and no relapse, which is an
important issue.
25
Consider other disorders if the symptoms
50
1 last more than six months or meet
the criteria for
2 other disorders, for example,
dysthymia.
3
[Slide.]
4
General medical conditions may be another
5 complexity in understanding and
diagnosing major
6 depressive disorder. These medical conditions
may
7 be accompanied by symptoms of
depression. They
may
8 also impact the course of major
depressive
9 disorder.
10
Major depression can be diagnosed if the
11 depressive symptoms preceded or
are not solely due
12 to the medical condition or to
medications used to
13 treat the medical
condition.
14
The incidence of major depression tends to
15 be higher in certain medical
illnesses.
Chronic
16 illness may affect sleep,
appetite, and energy.
17 Guilt, worthlessness,
hopelessness, and suicidal
18 ideation are usually not
attributed to the medical
19 illness, but do suggest the
symptoms of major
20 depressive
disorder.
21
Medical conditions that are often
22 associated with major depressive
disorder include
23 cancer, hypothyroidism, lupus
erythematosus, AIDS,
24 anemia, diabetes, and
epilepsy.
25
Chronic fatigue syndrome is another
51
1 disorder that needs to be
considered, but its
2 symptoms are similar to major
depression, but there
3 tends to be more somatic symptoms,
less mood,
4 cognitive, and social
symptoms.
5
Medication-induced symptoms involve those
6 induced by stimulants,
neuroleptics, cortical
7 steroids, and
contraceptives.
8
[Slide.]
9
Bereavement is another issue that needs to
10 be considered because there are a
similarity of
11 symptoms with major depressive
disorder. The
12 diagnosis of major depression can
be made if the
13 bereaved child or adolescent has
moderate or severe
14 functional impairment, psychosis,
suicidal thoughts
15 or acts, and a prolonged
course.
16
Following bereavement, a predisposition to
17 major depression may be related to
prior major
18 depression or a family history of major
depressive
19 disorder. In general, uncomplicated
bereavement
20 often remits in 6 to 12 months
after a death.
21
[Slide.]
22
I would like to focus now on some issues
23 of clinical course for major
depressive disorder.
24 The median duration for clinically
referred
25 children and adolescents tends to
be 7 to 9 months,
52
1 and in community samples it has
been reported to be
2 shorter, approximately 1 to 2
months.
3
Predictors of a longer course or duration
4 involve the severity of
depression, the degree of
5 comorbidity, the presence of
negative life events,
6 parental psychiatric disorders,
and poor social
7 functioning.
8
Remission of major depression is defined
9 as a period of 2 weeks to 2 months
in which there
10 is one clinically significant
symptom only.
Ninety
11 percent of children and
adolescents with major
12 depression remit in 1 to 2 years
after the onset of
13 the major depressive
episode.
14
[Slide.]
15
Approximately 6 to 10 percent of those
16 with major depression have a
protracted course.
A
17 relapse is an episode of major
depression during
18 the period of remission, and
predictors of relapse
19 include the natural course of
major depression,
20 namely, the nature of the way it
manifests, lack of
21 compliance with interventions,
negative life
22 events, rapid decrease, or
discontinuation of
23 therapy.
24
Forty to 60 percent of youth with major
25 depression tend to have a relapse
after successful
53
1 acute therapy, it's a high
rate. This
indicates
2 the need for continuous
treatment.
3
[Slide.]
4
Recurrences occur also, and this is an
5 emergence of major depressive
symptoms during a
6 period of recovery, which is an
asymptomatic period
7 of more than two months. Clinical
and non-clinical
8 samples have a probability of
recurrence of
9 approximately 20 to 60 percent
within one or two
10 years after recovery, and 70
percent after five
11 years of recovery. So, this is a chronic
disorder.
12
Predictors of recurrence include the
13
earlier age of onset of
major depressive symptoms,
14 increased number of prior episodes
of major
15 depression, the severity of an
initial episode, the
16 presence of psychosis, the degree
of psychosocial
17 stressors, the presence of
dysthymia and other
18 comorbidities, and the lack of
compliance with
19 therapy.
20
[Slide.]
21
In terms of the clinical course, children
22 with major depression, 20 to 40
percent develop
23 bipolar disorder in 5 years after
the onset of
24 major depressive disorder, and
predictors for the
25 bipolar disorder onset would be
early onset of
54
1 major depression, the presence of
psychomotor
2 retardation, psychosis, a family
history of
3 psychotic depression, a heavy
family loading for
4 mood disorders, and
psychopharmacologically-induced
5 hypomania.
6
[Slide.]
7
Other factors that affect the clinical
8 course of major depression is that
the risk for
9 depression increases 2- to 4-fold
after puberty, a
10 very important developmental
issue, and that
11 various genetic, as well as
environmental, factors
12 influence the pathogenesis of
major depression.
13
For example, shared family environmental
14 or not extra-environmental
non-shared issues tend
15 to be very important in affecting
the course, as
16 well as those youngsters who have
high genetic risk
17 are more sensitive to various
environmental
18 stressors.
19
Children with depressed parents are three
20 times more likely to have a
lifetime episode of a
21 major depressive
disorder.
22
[Slide.]
23
The prevalence of children's first-degree
24 relatives when children have major
depression tends
25 to be 30 to 50 percent. In addition, parents also
55
1 may have major depression and
anxiety disorders,
2 substance abuse, as well as personality
disorders.
3
[Slide.]
4
The clinical course of children with major
5 depression is also associated with
poor school
6 success, low parental satisfaction
with the child,
7 a very important parent-child
problem, learning
8 problems, other psychiatric
disorders that
9 interfere with the child's
learning.
10
The course may also be affected by various
11 personality traits, such as the
child being
12 judgmental, having angry outbursts
frequently, poor
13 self-esteem, and dependency. Cognitive styles
and
14 temperament, such as negative
attributional styles,
15 may affect the course of major
depressive disorder.
16
Early adverse experiences, such as
17 parental separation or death, may
affect the
18 course. Recent adverse events may affect
the
19 course, family conflicts, neglect,
and abuse,
20 biological factors, such as
inability to regulate
21 emotions, and/or
distress.
22
[Slide.]
23
The relation of dysthymia in major
24 depression is quite important
because dysthymia is
25 associated with an increased risk
for major
56
1 depressive disorder. Seventy percent of youth
with
2 dysthymia tend to have major
depressive disorders.
3
Dysthymia has a mean episode of
4 approximately 3 to 4 years for both clinical
and
5 non-clinical in community
samples. A first
major
6 depressive episode usually occurs
2 to 3 years
7 after the onset of dysthymia,
which may be
8 considered a gateway to the
developing recurrent
9 major depressive
disorder.
10
The risk for dysthymia is associated with
11 chaotic families, high family
loading for mood
12 disorders particularly
dysthymia.
13
[Slide.]
14
Another important issue in terms of course
15 of children with major depression
is that they are
16 at very high risk for suicidal
tendencies.
There
17 are a few studies, some of which I
will highlight,
18 one by Marika Kovacs, which is a
9-year follow-up
19 of prepubertal children. She had various
groups
20 that she
studied.
21
At the time of follow-up, children who had
22 major depression had a 74 percent
rate of suicidal
23 thinking and a 28 percent rate of
suicide attempts.
24 Those who initially had dysthymia,
also had a 78
25 percent rate of suicidal thinking,
and close to 20
57
1 percent rate of suicide
attempts.
2
Compared to children with adjustment
3 disorder or other types of
psychiatric disorders
4 that are not mood disorders, these
rates for
5 children with mood disorders,
namely, major
6 depression and dysthymia, are
significantly greater
7 for suicidal thinking and suicidal
attempts.
8
Our own follow-up study of 6 to 8 years
9 for prepubertal inpatients
indicated that there is
10 a 5 times risk for suicide attempt
when the
11 prepubertal children reach
adolescence if they had
12 a prepubertal mood
disorder.
13
[Slide.]
14
A community sample study indicated that
15 the 1-year incidence of suicide
attempts in
16 adolescence was associated with a
12 to 15 times
17 greater risk if the youngster had
major depressive
18 disorder.
19
[Slide.]
20
There are various concerns about treating
21 major depressive disorder. The treatment
research,
22 first of all, is relatively sparse
in children and
23 adolescents. There are varied opinions
about
24 whether psychotherapy or
pharmacotherapy, or a
25 combination should be the
first-line treatment.
58
1
The initial acute treatment often depends
2 on the severity of symptoms of
major depression,
3 the number of prior episodes, the
chronicity, the
4 age, contextual issues in the
family, school, and
5 other environmental features, the
degree of
6 negative life events, the
compliance with
7 treatment, prior treatment
responses, and the
8 motivation for
treatment.
9
[Slide.]
10
Some general principles that clinicians
11 have thought about is that
psychotherapy may be
12 considered for the more mild or
moderate major
13 depressive symptoms. Empirical effect
of
14 psychotherapies that we now know
of include
15 cognitive behavioral therapy and
ITP, interpersonal
16
psychotherapy.
17 Antidepressants
may be used for youngsters
18 who have symptoms of major
depressive disorder,
19 nonrapid cycling by polar states,
psychotic
20 depression, depression with severe
symptoms that
21 prevent effective psychotherapy or
that fail to
22 respond to
psychotherapy.
23
Also, due to the psychosocial context,
24 frequently pharmacotherapy alone
may not be
25 effective.
59
1
[Slide.]
2
The treatment of children with major
3 depression, there are very few
studies of acute
4 treatment using medication. There are few
5 pharmacokinetic or dose-range
studies with children
6 and
adolescents.
7
The
SSRIs are thought to perhaps induce
8 mania, hypomania, behavioral
activation, which
9 might include impulsive behavior,
silly or agitated
10 daring, and there are no long-term
studies for the
11 treatment of major
depression.
12
I am going to actually conclude, and not
13 go over some of these studies,
which you will hear
14 about I am sure today, and to say
again that major
15 depressive disorder in children
and adolescents is
16 complex and heterogeneous
regarding its clinical
17 course, comorbidities, predictors,
of course, need
18 for specificity of treatment, and
the developmental
19 variations.
20
It is a chronic condition that recurs with
21 serious morbidity including
suicidal tendencies.
22 There are few treatment studies,
which limit our
23 knowledge of the methods to reduce
these symptoms
24 and the
morbidities.
25
There is a need to clarify the indications
60
1 for pharmacotherapy, as well as
psychotherapy
2 whether alone or used in
combination, as well as
3 that to maintain youngsters who
have already
4 exhibited major depressive
disorder.
5
Thank you.
6
DR. RUDORFER: Thank you, Dr.
Pfeffer.
7
We will now turn to Dr. David Shaffer of
8 Columbia University who will speak
on the topic of
9 Suicide and Related Problems in
Adolescents.
10 Suicide
and Related Problems in Adolescents
11
DR. SHAFFER: Good
morning.
12
[Slide.]
13
I am going to review the epidemiology of
14 youth suicide and also some of its
phenomenology as
15 it may be relevant to the
discussion that you are
16 going to be having for the rest of
the day. It
is
17 a topic that I have been involved
in for a number
18 of years, and I hope that it is
helpful.
19
[Slide.]
20
In the United States, in 2001, the last
21 year for which we have statistics
of this kind,
22 about 1,600 15- to 19-year-olds
committed suicide.
23 You will see that that is the
third leading cause
24 of death in the United States, and
in most
25
countries, it is the second
leading cause of death,
61
1 but in the United States and a few
other countries,
2 homicide comes between
that.
3
You can also see that suicide accounted
4 for more deaths, over twice as
many deaths as from
5 cancer, in fact, more deaths than
all of the other
6 major physical conditions
combined.
7
[Slide.]
8
The methods by which children commit
9 suicide are, by and large, very
similar to those --
10 with children, young people -- are
very similar to
11 those which are used by
adults. The
main
12 difference is that hanging is
somewhat more common
13 in young people, and the figures
that I have got
14 here on the left are the 5- to
19-year-olds, on the
15 right, over the rest of the
population.
16
You will see a few other things of
17 interest. Ingestion is primarily a cause of
death
18 in females, firearms are more common in males
than
19 in females, and carbon monoxide
poisoning is one of
20 the few conditions where there
have been any
21 changes in causes of death, so
that the proportion
22 of suicides attributable to carbon
monoxide
23 poisoning has declined since the
introduction of
24 catalytic converters. The proportion of
suicides
25 attributable to firearms, even
though there has
62
1 been a general decline in access
and use of
2 firearms, has not
declined.
3
You can also see from this slide that
4 cutting, which there is often a
lot of debate about
5 cutting, whether that is or is not
a form of
6 suicide, in fact, accounts for a
very negligible
7 number of deaths. I think most people would
view
8 cutting as not being part of the
suicide syndrome.
9
[Slide.]
10
This is a chart which shows the
11 distribution of suicide by
different genders and
12 ethnic groups across the life
cycle, and the top
13 line represents white males. That is followed
by
14 African-American males, then white
females and
15 black females. Where the vertical arrow is, is
the
16 rate for
adolescents.
17
You can see several things from this
18 chart. First of all, I should say that this
chart
19 is remarkably similar in one
country to another, so
20 there is something about this
pattern of mortality
21 which seems to be almost
independent of cultural
22 influence.
23
You do get very big differences in parts
24 of Asia, but apart from that, it
is remarkably
25 similar. That is to say that there are very, very
63
1 few suicides that occur before
puberty, that
2 adolescents occupies an
intermediate position
3 between childhood and adulthood,
and then one gets
4 this very striking increase in the
rate in elderly
5 males and relatively little
variation by age in
6 females.
7
[Slide.]
8
If we deconstruct this a little more and
9 thus look at adolescents, what you
can see is that
10 here, most 10- to 15-year-old
suicides actually are
11 occurring amongst 14- and
15-year-olds, and that
12 suicide before puberty is very,
very rare.
13
Sometimes you will read about big
14 increases or big changes in the
young child rate,
15 but the rates are very low and
very unstable as a
16 result of that, and I don't think
that one can draw
17 very many conclusions about
suicide before puberty.
18
That may also be relevant to the matters
19 that you are considering today,
because both
20 suicide and depression are
relatively uncommon,
21 very uncommon before puberty, and
that may mean
22 that what we should be looking at
is what are the
23 differences between adolescents
and adults.
24 [Slide.]
25
The United States ranks around about in
64
1 the bottom of the top tier of
rates in the world.
2 Most countries with the highest
rates of suicide
3 are in Northern/Eastern Europe,
but the United
4 States is 16th as far as males are
concerned, and
5 ranks 22nd as far as
females.
6
There are quite big differences in gender
7 mainly in China, where suicide is
the 7th country
8 for female deaths, but much lower
for male deaths,
9 but, in general, the United States
is not
10 distinguished by having a
particularly high or a
11 particularly low
rate.
12
[Slide.]
13
We know quite a lot about the frequency of
14 suicidal ideation and attempts
from large community
15 studies, particularly the Youth
Risk Behavior
16 Study, which is a study that is
carried out by the
17 National Center for Health
Statistics every two
18 years, for which different states
volunteer, and a
19 broad population of between 15-
and 20,000 high
20 school students are interviewed
using self-report
21 measures every two
years.
22
[Slide.]
23
What one has been able to see from that
24 really was a big eye-opener. That is to say,
that
25 suicidal ideation in high school
students is
65
1 extraordinarily common. Almost 20 percent
of
2 American high school students will
think about
3 suicide during the past
year.
4
Suicide attempts are also very common, so
5 that the overall rate is about 9
percent, and if
6 you track these YRBS results, they
don't show an
7 awful lot of variation from one
year to another.
8
I have highlighted by color the difference
9 between the self-reported attempts
and attempts
10 that received medical attention,
because only about
11 a quarter of attempts do receive
medical attention
12 or are brought to medical
attention.
13
I think what is important about this is
14 that adolescents may not disclose
even suicidal
15 attempt behavior, let alone
suicide ideation, and
16 that is frequently not known to
either their
17 parents or to others, and that
also has to be a
18 consideration, I think, in what
you are
19 considering.
20
Both ideation and attempts, and attempts
21 which receive medical attention,
are far, far more
22 common than completed suicide, and
if you were to
23 array these out by gender, we
estimate that there
24 are about 4,000 suicide attempts
for every female
25 suicide death, but about 400 male
attempts for
66
1 every male death, so that you do
get these big
2 gender discrepancies with attempts
being more
3 common in females and deaths being
more common in
4 males, but you can see that the
ratio of attempts
5 to deaths is extreme particularly
in females.
6
[Slide.]
7
Not only do many adolescents attempt and
8 think about suicide, but they do
it quite often, so
9 that from the studies that we
have, about half of
10 suicide attempters will make only one attempt
a
11 year, and nearly a half will make
two or more, in
12 many instances, four or more
deaths per year.
13
We get similar findings in clinical or
14 community studies, and we do know
from follow-up
15 studies that having made one
attempt will increase
16 the probability of another
15-fold, so that can be
17 quite an important consideration
if you are
18 planning a medication study or any
other kind of
19 therapeutic study, because maybe
what you need to
20 find out about is not so much the
state of
21 suicidality at the time of
inception into the
22 study, but the history of
suicidality as well
23 because that could be an important
factor in either
24 stratifying for suicide risk or
for filtering it
25 out or filtering it in.
67
1
The episodes of ideation, again, you can
2 see that most youngsters who think
about suicide do
3 so more than once a year, and in
many instances, it
4 is several times a
year.
5
[Slide.]
6
With respect to how suicidal adolescents
7 are excluded from psychopharm
studies, because in
8 general, the studies of depression
have excluded
9 suicidal instances, there have
been variations in
10 the techniques that have been
used, there has been
11 no uniform approach, and that may
be a
12 consideration that the committee
would want to look
13 at in weighing up different
studies and trying to
14 compare
them.
15
[Slide.]
16
Finally, with epidemiology, I just want to
17 show you how the suicide rate has
changed over the
18 last century. This is the 20th
century youth
19 suicide
profile.
20
What you can see is that starting I guess
21 in the late '50s, the top line are
males and the
22 bottom are females, the male youth
suicide rate
23 started to increase, and it
increased and increased
24 3-fold, finally, reaching some
sort of asymptote
25 around in the late '80s, peaked a
little bit more
68
1 towards the end, and then started
to decline.
2
So, starting in 1994, we have had an
3 extraordinary decline in the youth
suicide rate,
4 which is very interesting. It has been
parallel
5 twice before, once coinciding with
World War I and
6 once with World War II. We don't know what
this
7 could be due to, and that will be
something that I
8 am going to return to in a second
or two.
9
[Slide.]
10
As far as the causes of suicide, far and
11 away the most common finding in
psychological
12 autopsy studies, which interview
friends and family
13 after a death has taken place, are
the very high
14 rates of diagnosable psychiatric
illness that are
15 present, and in studies done in a
variety of
16 locations, 90 percent of completed
suicides were
17 diagnosable with a DSM diagnosis
prior to their
18 death, and the rates are extraordinarily
similar
19 from location to
location.
20
[Slide.]
21
The most common diagnoses are depression,
22 antisocial behavior, substance
abuse, and some form
23 of anxiety, and most teen suicides
occur in 16- to
24 19-year-olds, and in that group,
in 16- to
25 19-year-old male suicides, it is
important to know
69
1 that two-thirds meet the criteria
for substance or
2 alcohol
abuse.
3
So, the occurrence of completed suicide is
4 very closely linked to the
occurrence of
5 particularly alcohol
abuse.
6
[Slide.]
7
As Cynthia Pfeffer outlined, and I won't
8 repeat this, suicidality is
extraordinarily common
9 in depressed children and teens,
both at the time
10 of diagnosis -- and this is a
meta-analysis from
11 six studies -- ideation was
present in about 60
12 percent, a previous attempt in 30
percent, and
13 during the follow-up period,
attempts also occurred
14 frequently, so that when you find
ideation and
15 attempts during the course of
treatment of
16 depression, as I say, this is a
well-reported
17 phenomenon.
18
[Slide.]
19
There are other factors that predispose to
20 suicide. Imitation is one that is
particularly
21 worrying because it means that
public information
22 campaigns may have a double-edged
sword, because we
23 do know that you do get suicide
epidemics in the
24 young.
25
There is a contagion factor, and the
70
1 Centers for Disease Control are
very actively
2 engaged in trying to find ways of
reducing this,
3 and there are now a host of
studies in adults, but
4 not yet in children or
adolescents, that show that
5 biological abnormalities may
predispose to
6 impulsive responses to stress and
a family history
7 of suicide.
8
[Slide.]
9
We can devise a schema, which you have got
10 in your handout, which can show
the route from any
11 of these disorders to suicide
ideation and from
12 there to suicide, but I don't think that there
is
13 time to get into that model in
this presentation.
14 [Slide.]
15
I just want to go back to changing rates,
16 because they may be very relevant
to today's
17 discussion.
18
[Slide.]
19
As I showed you, there has been this very
20 striking and encouraging reduction
in male suicide
21 males amongst young males 15 to
24. It is
even
22 more striking actually if you look
at 15- to
23
19-year-olds.
24
What is important is that this has not
25 been a United States phenomenon
only. It has been
71
1 reported in a large number of
other industrialized
2 nations.
3
In the list that I have given here, three
4 nations, Austria, Germany, and
Switzerland, have
5 been experiencing a decline which
well predated the
6 introduction of any of the newer
groups of
7 antidepressants, but in all of the
other countries,
8 the decline started sometime after
1988.
9
There is
only one country which seems to
10 have a stable or rising rate,
which is Scotland,
11 and there are a number of possible
reasons that
12 have been debated to explain these
reductions.
13
One is that during the '90s, at least in
14 the United States, there was
economic prosperity, a
15 decline in unemployment, and other
social indices
16 tended to improve, but rates also
started to
17 decline in high youth unemployment
countries in
18 Europe, and the relationship
between SES and
19 suicide is not strong, and, in
fact, it hasn't
20 really been
established.
21
The first thought was if so many suicides
22 are associated with drug and
alcohol abuse, maybe
23 exposure to drugs and alcohol
would have been
24 reduced during this time, and this
is certainly my
25 first guess. However, use and abuse rates have not
72
1 changed, if anything, they have
continued to inch
2 up.
3
[Slide.]
4
Reduced firearm availability, the Brady
5 Act was introduced in 1994, and
there is evidence
6 from tracking studies that
ownership and use of
7 firearms started to decline around
about 1980, but
8 the proportion of suicides by
firearm has gone
9 unchanged, and although there have
been very
10 striking declines in accidents
attributable to
11 firearms, it is not clear that we
can point to the
12 reduction in suicides as being
caused by that.
13
Also, the declines have been noted in
14 countries in which there are
almost no firearm
15 suicides, so this doesn't seem to
be a very
16 plausible
explanation.
17
[Slide.]
18
More psychotherapeutic treatment is a
19 possibility, but, in fact, the
data seem to suggest
20 that visits for psychotherapy have
declined
21 consistently over the past 10 to
12 years, more
22 psychopharmacologic treatment, and
you will have
23 heard that there has been an
enormous increase in
24 exposure to antidepressants during
this period in
25 many countries, or it could be a
nonspecific
73
1 finding, a better recognition of
adolescent suicide
2 with some nonspecific
interventions or some
3 combination of the
above.
4
[Slide.]
5
A word or two about treatment.
There have
6 been some useful Cochrane analyses
looking at
7 effective treatments for suicide
attempts.
These
8 have mainly been done in adults,
and only two
9 treatments emerged as being
successful.
10
One is dialectical behavior therapy, which
11 is a very specific form of therapy which is
hard
12 to come by because very few people
are trained in
13 it, and one study looking at
flupenthixol, which is
14 an antipsychotic or neuroleptic,
in multiple
15 attempters.
16
There have also been studies showing
17 lithium or at least
discontinuation of lithium
18 results in an increase in the
suicidality, and
19 Clozaril seems to have a specific
suicide sparing
20 effect in
schizophrenia.
21
But apart from that, we don't have much to
22 guide us, and there is nothing out
there which
23 tells the clinician what to do
with this very
24 common
problem.
25
[Slide.]
74
1
Maybe that is why, but, in general, teens
2 who do commit suicide tend to be
relatively
3 undertreated compared to adults,
so that, for
4 example, the top three lines show
that between 30
5 and 60 percent of adults who
commit suicide will
6 have had mental health treatment,
but in
7 adolescents, very few have had
that, so it is
8 getting between 7 and 21 percent,
they are an
9 undertreated
group.
10
[Slide.]
11
Furthermore, one of the things that has
12 been interesting to
epidemiologists over this
13 current debate is do you find
antidepressants in
14 toxicologic studies of completed
suicides, and Exen
15 [ph] in Sweden has done a study
showing that the
16 findings in autopsy studies
suggest that suicides
17 are significantly undertreated
with SSRIs compared
18 to the rest of the
population.
19
There has only been one study in youth,
20 and that is from the Utah Youth
Suicide Study by
21 Dr. Gray, and he has looked at 50
psychological
22 autopsies, all of whom had careful
toxicology
23
investigations.
24
A quarter of those had been prescribed
25 antidepressants, but in none of
those cases were
75
1 antidepressants found at autopsy,
so we know that
2 teenagers often don't take their
medication, and
3 certainly they didn't seem to be
taking it in this
4 case.
5 [Slide.]
6
So, I would just like to conclude with
7 some cautions and
considerations. Ideation
and
8 attempts are very common in
depressed teens, and
9 they recur frequently, so finding
them in
10 youngsters being treated for
depression is, of
11 course, not surprising. That doesn't address
any
12 treatment effect that might be
found.
13
A methodological point.
Teenagers often
14 conceal ideation and attempts
unless they are asked
15 about them directly. Self-report
facilitates
16 disclosure. It is my understanding that we
are
17 heavily dependent upon event
reports in these data,
18 and event reports may be
influenced by the mode of
19 elicitation.
20
They are not
used with a glossary which
21 precisely defines how things
should be classified,
22 so misclassifications can
occur.
23
Self-harm is a term that is used by some,
24 but not others in the mental
health profession.
It
25 is a very heterogeneous descriptor
and not all
76
1 types of self-harm are associated
with suicidal
2 intent.
3
There have been no direct studies with
4 frequent and careful measurement
examining whether
5 SSRIs increase, decrease, or have
no effect on
6 suicidal ideation and behavior, so
that we are
7 dependent very much on inference,
but maybe that is
8 always the
case.
9 I
just would like to conclude with the
10 following. After increasing for 35
years, teen
11 suicide rates have been declining
consistently in
12 many countries. During this period, there has
been
13 a marked increase in exposure of
teens to SSRI
14
antidepressants.
15
These trends could be related.
This is
16 ecologic, and we don't know
whether they are
17 related, but at the moment we
don't have a better
18 explanation for the turnabout of a
condition that
19 led to the death of tens of
thousands of young
20 people.
21
I would like to stop at that point.
22
DR. RUDORFER: Thank you very
much.
23
At this time, just before our break, I
24 have one announcement to
make. Any open
public
25 hearing speakers who have not yet
signed in, please
77
1 do so immediately. We will only be able to
call
2 upon speakers who have formally
signed in, so we
3 wouldn't want you to miss your
chance.
4
We have time for a 15-second break, but I
5 am told that may not work, so why
don't we take 5
6 minutes or as close to that as we
can work, and we
7 will come back for our open public
hearing.
8 Thanks.
9
[Break.]
10
Open Public Hearing
11
DR. RUDORFER: There is
specific guidance
12 from the FDA that I would like to
read. This
13 applies to all meetings or
considered general
14 matters meetings, and as we heard
earlier from
15 Anuja, since we are not focusing
on one specific
16 product here, that encompasses
this joint meeting.
17
Both the Food and Drug Administration, or
18 FDA, and the public believe in a
transparent
19 process for information gathering
and
20 decisionmaking. To ensure such transparency at
the
21 open public hearing sessions of
the Advisory
22 Committee meeting, FDA believes
that it is
23 important to understand the
context of an
24 individual's
presentation.
25
For this reason -- and I am addressing the
78
1 speakers this morning -- FDA
encourages you, the
2 open public hearing speaker, at
the beginning of
3 your oral statement to advise the
committee of any
4 financial relationship you may
have with any
5 company or any group that is
likely to be impacted
6 by the topic of this meeting. For example, the
7 financial information may include
a company's or a
8 group's payment of your travel,
lodging, or other
9 expenses in connection with your
attendance at the
10 meeting.
11
Likewise, FDA encourages you at the
12 beginning of your statement to
advise the committee
13 if you do not have any such
financial
14 relationships. If you choose not to address
the
15 issue of financial relationships
at the beginning
16 of your statement, it will not
preclude you from
17 speaking.
18
As I mentioned earlier, the clock dictates
19 only a limited amount of time for
each speaker.
I
20 would like to run all night, but I
hear an ice
21 storm is coming, so in the
interest of time, we
22 have a light warning system, and
each speaker,
23 please be advised, when you see
the yellow light,
24 you have 30 seconds remaining, so
please start to
25 wrap up.
79
1
The flashing red light means you are out
2 of time and the microphone will go
off. I have
3 asked them to let you finish your
sentence for
4 three or four words, but it is out
of our hands.
5
We have two speaker-ready chairs, so I am
6 asked to remind you that when your
two away from
7 your number, please be sure you
are in one of
8 those.
9
Speakers are assigned by number and we
10 will begin with Number
1.
11
Irving Kirsch and David Antonuccio
12
DR. KIRSCH: My name is
Irving Kirsch.
13 Baum, Hedlund has paid for my air
tickets. I
14 decided to come before knowing
that.
15
Dr. David Antonuccio, Amanda Drews, and I
16 are reviewing the published
literature evaluating
17 the efficacy of antidepressants in
depressed
18 children. A total of 12 randomized,
controlled
19 clinical trials have been
published.
20
Two-thirds of these trials failed to find
21 any significant benefit of
medication over inert
22 placebo. Only 4 trials reported
significant
23 differences, and these did so only
on
24 clinician-rated measures, not on
patient-rated
25 measures.
80
1
When the data from these trials are
2 combined, the placebo response is
found to be 87
3 percent of the drug response. This means that
the
4 drug effect is only 13 percent of
the drug
5 response. This is not a clinically
significant
6 effect.
7
Many children get better when given
8 antidepressants, but the data
indicate that this is
9 largely a placebo effect. These conclusions
are
10 consistent with those found in 7
previous published
11 reviews.
12
To summarize, the published clinical trial
13 data show that the therapeutic
benefits of
14 antidepressants for children is
negligible at best.
15
David.
16
DR. ANTONUCCIO: These
results were drawn
17 from studies with design flaws
that typically favor
18 the study drug. For example, they
frequently
19 exclude placebo responders before
random
20 assignment, rely on ratings by
clinicians who have
21 a vested interest in the outcome,
and are likely to
22 be unblinded by medication side
effects.
23
Furthermore, these results are drawn from
24 the published literature which is
subject to
25 publication bias and file drawer
problems meaning
81
1 that many studies with negative
results do not get
2 published. Adding unpublished studies, most
of
3
which have negative results,
will surely shrink the
4 difference between antidepressants
and placebo even
5 further.
6
In order to evaluate the cost
7 effectiveness of antidepressant
use in children,
8 the committee must consider the
benefits, as well
9 as the risks. Clinically meaningful benefits
have
10 not been adequately demonstrated
in depressed
11 children, therefore, no extra risk
is warranted.
12
An increased risk of suicidal behavior is
13 certainly not justified by these
minimal benefits.
14 Neither are the established
increased risks of
15 other commonly reported side
effects, which include
16 agitation, insomnia, and
gastrointestinal problems.
17
The highest possible standard should be
18 applied to scientific data
involving drug treatment
19 of children, because children are
essentially
20 involuntary patients. Those of you on
the
21 committee who are parents know
this to be true
22 because when your children have
prescription
23 medication for something that ails
them, you make
24 them take it as prescribed whether
they want to or
25 not.
82
1
Children given
antidepressant medication
2 often do get better, but so do
children given
3 placebo. Thus, the clinical data suggest
the
4 improvement is due primarily, if
not entirely, with
5 placebo
effect.
6
Please be careful to ensure that our
7 children are not exposed to risk
without
8 commensurate
benefit.
9
DR. RUDORFER: Thank
you.
10
May we have the next speaker, Number 2.
11
Lisa Van Syckel
12
MS. SYCKEL: Good morning,
ladies and
13 gentlemen. My name is Lisa Van
Syckel, and my
14 daughter, Michelle, at the age of
15, was placed on
15 Paxil. She was diagnosed with depression
and
16 anorexia nervosa. It turned out that
that
17 diagnosis was wrong, she actually
had Lyme Disease.
18
My daughter self-mutilated, became
19 psychotic, became violent,
attempted suicide twice.
20 My daughter survived those two
suicide attempts,
21 not because of the drug, because
of the police
22 officers who were summoned to my
home.
23
Michelle has suffered severe withdrawal.
24 She is constantly ill with
flu-like symptoms.
She
25 has had rectal bleeding, she has
vomited blood.
83
1 She has had her friends at school
call her
2 "Psycho," all because she was
misdiagnosed and all
3 because everyone has withheld from
the public the
4 adverse effects of
Paxil.
5
I am a parent. It is my
right to make an
6 informed decision on behalf of my
daughter. You
7 did not allow me to make that
informed decision and
8 she was harmed. We are blessed because
Michelle
9 did not die, and Michelle is now
attending
10 university and doing
beautifully.
11
Please, have respect for our children,
12 make sure that you put proper
warnings on these
13 medications. Our children's lives are at
stake
14 here, because not only does it
cause suicide, it
15 also causes them to become
violent, very, very
16 violent.
17
Thank you.
18
DR. RUDORFER: Thank
you.
19
May we have the next speaker, Number 3.
20
Ann
Blake Tracy, Ph.D.
21
DR. TRACY: I would like to
say, first of
22 all, that this is a meeting that
should not be
23 taking place today. I testified at an FDA
hearing
24 similar to this in 1991, and these
drugs should
25 have been banned at that time in
my opinion.
84
1
I am Dr. Ann Blake Tracy, a Ph.D. in
2 health sciences with emphasis on
psychology. I
3 have spent the last 14 years
researching the SSRIs
4 and working with patients who are
having adverse
5 reactions to these
medications. I am also
the
6 author of Prozac: Panacea or
Pandora, Our Serotonin
7 Nightmare.
8
I have testified in criminal and civil
9 cases for 12 years concerning
these medications,
10 and I am greatly concerned about
the use of these
11 drugs among children, with
developing brains, who
12 have far more reactions than the
general public
13 would, as I am the elderly who are
having severe
14 adverse
reactions.
15
What I presented to the FDA in 1991, I
16 would like to present again. Each of you will
get
17 a copy of this. This is a 31-year-old patient
on
18 Prozac for six months, shows the
patient, although
19 appearing alert and functioning,
in a total
20 anesthetic sleep state while
dreaming. I
believe
21 technically, you could call that a
REM sleep
22 behavior
disorder.
23
The research now shows, this many years
24 later, that 86 percent of the
cases being diagnosed
25 with this REM sleep behavior
disorder are patients
85
1 on antidepressants, 80 percent of
those on SSRI
2
antidepressants.
3
There are some very famous cases that I
4 believe manifest that very
clearly, and in
5 representing those families today,
I would give you
6 Andrea Yates, who drowned her five
children while
7 taking Effexor and
Remeron.
8
DR. RUDORFER: Thank
you. I am afraid
we
9 are out of time
now.
10
DR. RUDORFER: Thank
you.
11
Number 4, please.
12
Tom Woodward
13
MR. WOODWARD: My name is Tom
Woodward.
14 My wife Kathy and I have been
married for 19 years
15 and until 6 months ago had 4
children. Our
oldest
16 child, Julie, hung herself after 7
days on Zoloft,
17 and she was only 17, was a
cautious child, and had
18 no history of self-harm or
suicide, nor was there
19 any history of depression or
suicide in our family.
20
The doctors we spoke with stressed that
21 Zoloft was safe and had very few
side effects. The
22 possibility of violence,
self-harm, or suicidal
23 acts was never raised. The two and a half pages
we
24 received with the Zoloft never
mentioned self-harm
25 or suicide.
86
1
Julie began experiencing akathisia almost
2 immediately. We now know from a blood test
from
3 the coroner's office that she was
not metabolizing
4 the drug.
5
We are 100 percent convinced that Zoloft
6 killed our daughter. We are here because
we
7 believe the system we have in
place is flawed.
It
8 is clear that the FDA is a
political entity and its
9 leadership has protected the
economic interests of
10 the drug industry. Under the Bush
administration,
11 the FDA has placed the interests
of the drug
12 industry over protecting the
American public.
13
Dr. McClellan understands how important
14 political contributions are
particularly since his
15 mother has headed up the Republican
fund-raising in
16 Texas. Eighty-six percent of the $14 million
in
17 political contributions given by
drug companies has
18 gone to the Bush administration
Republican
19 candidates - what did Pfizer, Eli
Lilly, and
20 GlaxoSmithKline Beecham
buy?
21
The FDA should be a jealous advocate in
22 protecting the American
people. Those
in
23 leadership positions within the
FDA must be beyond
24 reproach. FDA's chief counsel Daniel Troy
has
25 spent his career defending the
drug industry.
87
1 Suppressing unfavorable data may
be legal, but is
2 it ethical?
3
If the trials don't favor a drug, the
4 public never hears of them. Legal maneuverings
5 have thrown out the scientific
method. The
drug
6 industry must be compelled to
produce all of their
7 findings and studies. I also believe
public
8 funding of these trials is
warranted.
9
Our daughter, Julie, had been excited
10 about college and scored 1,300 in
her SATs several
11 weeks before her death. Instead of
picking out
12 colleges with our daughter, my
wife and I had to
13 pick out a cemetery plot for
her.
14
Instead of looking forward to visiting
15 Julie at school, we now visit her
grave. The
loss
16 we have experienced is
horrific. We don't
want
17 another innocent child or family
to suffer this
18 tragedy.
19
DR. RUDORFER: Thank you, Mr.
Woodward.
20
May we have the next speaker, please.
21
Mark
Miller
22
MR. MILLER: My wife Cheryl
and I
23 desperately hope that our story,
along with others
24 that you will hear today, and I so
proud of the
25 teens and the young adults who you
will hear from
88
1 today, that they have the courage
to come forward
2 and talk with you personally. I wish our son
3 could, he
cannot.
4
There is a serious problem with the way
5 SSRI medications are being
prescribed today and
6 how, in many cases, they can
directly cause
7 violence and suicidal behavior in
those we love and
8 treasure the most, our
children.
9
You see, we lost our 13-year-old son,
10 Matt, in the summer of 1997. He died after a
11 psychiatrist we did not know gave
him three sample
12 bottles of a pill we had never
heard of, for a
13 perceived illness that his doctor
could only guess
14 at.
15
We were advised with great authority that
16 Matt was suffering from a chemical
imbalance that
17 could be helped by a new,
wonderful medication
18 called Zoloft. It was safe, effective, only
two
19 minor side effects were cautioned
with us -
20 insomnia,
indigestion.
21
Now, I don't know if Matt had a chemical
22 imbalance. I do know this. We had moved into to
a
23 new neighborhood a year before, a
new school
24 setting, he was uneasy. He didn't have the
friends
25 he had grown up with in our old
neighborhood. Yes,
89
1 our son was
unhappy.
2
So, Matt's doctor, a man we know through
3 court testimony to have been a
well-paid spokesman
4 for Pfizer, gave us Zoloft. He said, "Take
these
5 for a week, call me back when you
know how Matt is
6 doing."
7
Matt didn't have a week. He
became
8 agitated on the pills. He did not sleep. He did
9 not eat. He could not sit still. That night, a
10 Sunday, before leaving on
vacation, after taking
11 his 7th Zoloft tablet, he took his
own life.
12
This is important for you to know.
Matt
13 hung himself from a bedroom closet
hook, barely
14 higher than he was tall. To commit this
15 unthinkable act, something he had
never attempted
16 before, never threatened to any
family member,
17 never talked about, he was
actually able to pull
18 his legs up off the floor and hold
himself that way
19 until he lost consciousness and
forced himself to
20 leave us.
21
Matt's autopsy showed the levels of
22 sertraline in his blood were three
times the
23 therapeutic minimum
levels.
24
You have an obligation today, this panel,
25 to prevent this tragic story from
being repeated
90
1 over and over and over again. I hope you will do
2 the right
thing.
3
DR. RUDORFER: Thank you, Mr.
Miller.
4
If we could have the next speaker, please.
5
Corey and Jay Baadsgaard
6
MR. COREY BAADSGAARD: Good
morning. My
7 name is Corey Baadsgaard. Four years ago I
was
8 diagnosed with having social
anxiety disorder, and
9 my family practitioner doctor, he
prescribed Paxil
10 20
milligrams.
11
After about 8 1/2 months, I started taking
12 40 milligrams of Paxil because it
was not working
13 at 20 milligrams. A few months after that, I
went
14 back. The same problem, it wasn't working, and
he
15 suggested I start taking a new
medication called
16 Effexor.
17
He abruptly discontinued the Paxil and put
18 me immediately on Effexor at 75
milligrams, and I
19 was supposed to work up to 300
milligrams over a
20 3-week period. The day that I took the
300
21 milligrams, I didn't feel very
well and I stayed
22 home from
school.
23
I went back to sleep and that evening I
24 woke up in a juvenile detention
center. Unaware
of
25 what I had actually done, I asked
one of the
91
1 members of the juvenile detention
center, and I
2 found out that I had taken my
high-powered rifle
3 that I use for hunting to my third
period class,
4 took 23 of my classmates hostage
and 1 teacher
5 hostage.
6
I spent 14 months in jail, not really
7 knowing why I had been there, not
really
8 remembering anything that I had
done.
9
This whole thing has changed my whole
10 family, it changed me,
myself. We were forced
to
11 move. I cannot even go back to the same town
that
12 I lived in, I have to stay at
least 25 miles away
13 from city
limits.
14
These drugs are ridiculous.
They should
15 not be prescribed unless it's
absolutely last
16 resort.
17
MR. JAY BAADSGAARD: These
drugs are hell.
18 Look at what they have done to my
son.
19
DR. RUDORFER: Thank
you.
20
May we have the next speaker, please.
21
Joyce Storey
22
MS. STOREY: My son, Brian
Storey, was 17
23 years old in 1997. Our family doctor diagnosed
him
24 with severe depression. He took blood,
checked
25 for drugs or any medical
condition. He found
92
1 neither. He gave me 14 Zoloft pills and said
come
2 back in two weeks. He never told me they had
side
3 effects and he even said if a
person is drinking or
4 doing drugs, that Zoloft works
well with them.
5
Five days later, my son killed a woman.
6 When they arrested him, he was
drug-tested.
They
7 found no illegal drugs, he was
only on Zoloft.
8 During his trial, the kids that
testified with him
9 and against him said he did no
drugs or alcohol.
10
The psychiatrist that examined him was Dr.
11 James Merkangis from
Connecticut. He is also
a
12 Doctor of Neurology and is on the
faculty at Yale
13 University. He said Brian had a manic reaction
to
14 Zoloft. He testified Brian told him it was
like
15 being in a
dream.
16
The news media called my son the
17 All-American boy, and he was. He is now serving
18 life without parole. Six months later, another
boy
19 at my son's high school, Jeff
Franklin, 17 years
20 old, on Prozac, took an ax to both
his parents and
21 three of his brothers and
sisters. Both of
his
22 parents died. He is serving two life
sentences.
23
This is not a coincidence.
There is a
24 common denominator, teenager,
severely depressed,
25 on an SSRI antidepressant. What is scary is that
93
1 you are only hearing from a few of
us that this has
2 happened to, and there are a lot
more out there.
3
I am praying you will look at these drugs
4 very closely and, at the very
least, take them out
5 of the hands of pediatricians and
GPs. These
6 doctors are not psychiatrists, and
they do not have
7 the knowledge and experience in
treating mentally
8 ill
children.
9 My
son never had a chance. There are
13
10 million people on these drugs, 6
to 8 million are
11 children. The question is why are we handing
these
12 drugs out like candy, and the
answer is $17 billion
13 a year business. It is always about money. Please
14 help before more families are
destroyed.
15
Thank you.
16
DR. RUDORFER: Thank
you.
17
Next speaker, please.
18
Jame Tierney
19
MS. JAME TIERNEY: Good
morning. My
name
20 is Jame Tierney. I was 14 years old when I
was
21 prescribed 75 milligrams of
Effexor for migraine
22 headaches. I took this for about a year. At the
23 time, the drug lost its
effectiveness and my doctor
24 doubled the
dose.
25
For the next 9 months, my life as I had
94
1 known it was gone. I thought daily about
suicide
2 and hurting myself. I felt void of
normal emotions.
3 I was so belligerent, agitated,
and filled with
4 hate - hate for my family, my
friends, and most of
5 all myself. Rage consumed me. I felt trapped.
6
I said and did things I had never done
7 before and never would do
now. I had
little
8 control and little
inhibition. It was as if I
was
9 watching a movie and some villain
was destroying
10 all the relationships around
me. I spent my
time
11 alone and viciously fighting with
my parents. They
12 would ask what was wrong and what
had happened to
13 me. I could not answer them because I did
not know
14 or understand myself. I was terrified.
15
I thank God my parents knew that wasn't
16 really me and continued to search
for answers.
17 They found the answer to my
uncharacteristic
18 behavior. It was the Effexor that my
neurologist
19 had prescribed for my migraine
headaches. I
was
20 not, repeat not, prescribed this
drug for
21 depression. I have had no history of
depression
22 prior to or after I was off the
Effexor. For
me,
23 this drug caused the very symptoms
it's supposed to
24 alleviate.
25
Due to the severe withdrawal symptoms,
95
1 Prozac was used to get me off
Effexor. It
worked,
2 but the same personality and
behavior problems
3 reemerged. Effexor and Prozac affected me the
same
4 way. I had never had these feelings before I
took
5 Effexor, I have never had these
feelings since I
6 stopped taking the Effexor and
Prozac.
7
Effexor took three years from me and I
8 will never get them back. The horror of what
these
9 drugs did to me is ineffable. These drugs are
10 destroying lives
everywhere.
11
I implore you to please protect the
12 children from these
drugs.
13
DR. RUDORFER: Thank you very
much.
14
If we can have speaker Number 9, please.
15
Donna Taylor and Mark Taylor
16
MS. TAYLOR: Hi. My name is Donna
Taylor.
17 My son was shot at Columbine. He took 7 to 13
18 bullets though his chest and
nearly died. I
also
19 have other members of the family
that have died
20 since then on these drugs, but we
can't get into
21 that right now, and many, many
people that we know,
22 that families have been divided
and separated, and
23 there is just all kinds of
divorces and all that
24 going on from these
drugs.
25
I will let Mark speak.
96
1
MR. TAYLOR: First of all, I
would thank
2 you for allowing me to come and
speak on behalf of
3 the thousands of innocent
Americans that have died
4 as a result of these
drugs.
5
I would like to start with an opening,
6 very famous statement, and it
says, "The measure of
7 a man is not his strength or how
much money he has,
8 or how good he looks or how strong
he is, or how
9 powerful he is. The measure of the man is
how
10 noble he
is."
11
I want to ask you guys, are you really
12 being noble with your choices, or
are you just
13 allowing the drug companies to
squeeze by you just
14 because they have a big
pocketbook. This
is
15 ridiculous.
16
Do you people have children, do you, do
17 any of you? Have any of you had anyone that
has
18 died on these drugs? If you have, I am amazed
that
19 you guys are even standing here
supporting these
20 drug
companies.
21
I mean this has never happened in the
22 history of America. This is a shame and it
ought
23 to be stopped today, not next
week.
24
MS. TAYLOR: And God says the
same thing.
25 It's in the Bible, Revelations 18,
19 through 24
97
1 makes it clear, sorcery means
anarchy in the last
2 days and blood will be running all
over the
3 streets.
4
MR. TAYLOR: Say yes to
America's health
5 and no to the drug
companies.
6
DR. RUDORFER: Thank you
both.
7
We are going to move on to speaker Number
8 11, Shannon
Baker.
9
Shannon Baker
10
MS. BAKER: My name is
Shannon Baker and I
11 have no financial ties to the
pharmaceutical
12 industries, nor am I here to
complain about my
13 daughter's side effects, adverse
reactions, or
14 withdrawal symptoms. I am here because she is
no
15 longer
alive.
16
I know you have all got pictures.
I am
17 here because today, I am
representing the love that
18 my daughter had for life and to be
her voice and
19 the voice of all the other
children who their
20 voices have been silenced by these
drugs.
21
Their deaths have been so senseless and
22 needless. I am here speaking in front of
you,
23 hoping that you will go the right
direction and ban
24 these drugs for children. There needs to be
no
25 more senseless and needless deaths
because of these
98
1 drugs.
2
Thank you.
3
DR. RUDORFER: Thank
you.
4
Our next speaker, Number 12, please.
5
Dawn Rider
6
MS. RIDER: My name is Dawn
Rider and I am
7 here to tell you my story, and I
represent, as
8 president of ASPIRE, more than
11,000 persons who
9 are all named on the Eli Lilly and
Prozac petition,
10 which a copy has been given to the
panel.
11
We have been educated to believe that
12 mental, emotional, and behavioral
disorders are
13 caused by chemical imbalances in
the brain.
The
14 fact is that this is only theory,
and this theory
15 is pushed on us as if it were the
absolute truth.
16
The reality is that the best of scientists
17 do not completely understand the
complex inner
18 actions of the myriad chemicals in
our brains.
19 Those of us who elect to believe
this theory and
20 subject ourselves to treatment
become guinea pigs
21 in an ongoing
experiment.
22
I know this from personal experience. I
23 trusted our family doctor when he
explained that
24 depression is caused by a chemical
imbalance. We
25 trusted him when he determined
that Paxil was right
99
1 for my husband, and Prozac for my
son.
2
We weren't educated enough at that time to
3 ask him to provide us with the
test results that
4 proved which chemicals were being
balanced.
5
I am not going to go into details of what
6 happened to our family. I have given you
all
7 documentation, it's very
painful. Suffice it
to
8 say that my beautiful 14-year-old
son is now dead,
9 and when we discovered the
problems with these
10 drugs, we decided it would be
better for my husband
11 to suffer through depression than
end up dead like
12 our son, and we found out that he
could not get off
13 of Paxil.
14 He
went through over a year of hell before
15 he was able to finally withdraw
from the drug, and
16 in the process it destroyed our
marriage of over 20
17 years.
18
I say with no apology whatsoever that
19 these SSRI drugs destroyed what
was once a loving
20 and vibrant family. Why do we
believe that street
21 drugs like heroin and LSD can lead
to outcomes such
22 as this, yet, we won't accept that
legally
23 prescribed drugs, working on the
same
24 neurochemicals, can result in
horrific crimes
25 against persons and property?
100
1
Why do we accept that a drug like
2 penicillin, beneficial as it is
for some, can prove
3 fatal for others? We fail to accept that
these
4 drugs can have paradoxical
effects. These
drugs
5 are not safe for
everyone.
6
They should be labeled with the strongest
7 of precautions and dispensed only
by trained
8 physicians who have time to
adequately monitor the
9 patient. Most doctors do not have time for
this
10 level of
care.
11
Also, patients should be required to sign
12 letters of informed consent. Please carefully
13 consider the documentation that I
have left with
14 you and look at the faces of those
that are here
15 today and the faces that out in
the hall, those
16 children who cannot speak for
themselves because
17 they are dead. They are not merely
anecdotal
18 evidences.
19
There is a preponderance of evidence that
20 will be presented before you
today. Please
21 consider it carefully and do the
right thing.
22
Thank you.
23
DR. RUDORFER: Thank
you.
24
We are up to Number 13.
25
Sara Bostock
101
1
MS. BOSTOCK: I have slides,
so please
2 look at the
screen.
3
My daughter Cecily had only been taking
4 Paxil for two weeks before she
died, during which
5 time her condition greatly
worsened.
6
By the day of her death, was pale, unable
7 to sleep, almost unable to
converse, and in a
8 frightened, agitated state,
jumping at the
9 slightest noise. That night she got up and
without
10 turning on any lights, went into
our kitchen only
11 40 feet from where I was half
asleep. She
stabbed
12 herself twice in the chest with a
large chef's
13 knife. The only noise was a slight yelp and
a
14 thump when she fell on the
floor.
15
This was a young woman who had everything
16 to live for. She had just completed
applications
17 to grad school and received a
large pay increase
18 the month
before.
19
She had a boyfriend who loved her and
20 scores of wonderful friends. She had never been
21 suicidal. To die in this violent, unusual
fashion
22 without making a sound after the marked
worsening
23 of her condition led me to believe
that Paxil must
24 have put her over the
edge.
25
Her autopsy revealed she had a very high
102
1 blood level of Paxil, which
reflects poor
2 metabolization and is a feature
common to many of
3 these suicides. I believe this induced
an
4 intensely dissociative state,
perhaps even
5 sleepwalking. SSRIs suppress rapid eye
movement
6 and block the muscle paralysis
which occurs in this
7 stage of
sleep.
8
The whole regulation of waking, sleeping,
9 dreaming occurs in the brain stem
where the
10 serotonin neurons are clustered
and where SSRIs are
11 having their impact. Patients taking SSRIs
had
12 rapid eye movement during non-REM
sleep and while
13 awake when they were not
paralyzed. This
atypical
14 REM is often associated with
strange behaviors
15 including
hallucinations.
16
The effects of SSRIs on sleeping, waking,
17 unconsciousness itself are ill
understood.
From
18 accounts of people under the
influence of these
19 drugs, I believe SSRIs can alter
consciousness in
20 some mysterious and frightening
way that is not
21 normally seen even in mental
illness. I am
certain
22 this is what happened to my
daughter.
23
Untold thousands have died because of the
24 drug companies and the FDA's
failure to heed the
25 evidence over the past 17 years.
103
1
DR. RUDORFER: Thank
you.
2
Again, I apologize for the short time.
3
Number 14, please.
4
Vera
Hassner Sharav
5
MS. SHARAV: I am Vera Sharav
and I am
6 president of the Alliance for
Human Research
7 Protection.
8
The family testimonies that you are
9 hearing today are not
anecdotes. They
are
10 corroborated by a Harvard review
of children's
11 medical charts, which found that
within three
12 months of treatment on an SSRI, 22
percent suffered
13 drug-induced adverse psychiatric
effects, and
14 overall, 74 percent of children
suffered adverse
15 events during the course of
treatment.
16
The FDA has known for years, but failed to
17 reveal that antidepressants
consistently fail to
18 demonstrate a benefit in
children. At least 12
of
19 15 trials failed. The FDA has known and failed
to
20 warn physicians and the public
that SSRIs increase
21 the risk of suicide and hostility
in children.
22
FDA's 1996 Zoloft review found "7-fold
23 greater incidence of suicidality
in children
24 treated with Zoloft than
adults." The British
Drug
25 Regulatory Authority reviewed the
evidence, which
104
1 is not being shown in this
meeting, and they
2 determined that the risks far
outweigh any
3 benefits. They took action to protect
children.
4 When is the FDA going to take
action?
5
The FDA is foot dragging, equivocating,
6 and tinkering with definitions
while children are
7 dying. The San Francisco Chronicle reports
that
8 the FDA has barred its own medical
reviewer who
9 reviewed more than 20 trials
involving 4,000
10 children, and his findings
confirmed the British
11 finding, which is that SSRIs
increase the risk of
12 suicide.
13
DR. RUDORFER: Thank
you.
14
If we could have speaker 16, please.
15
Cynthia Brockman
16
MS. BROCKMAN: Thank you for
allowing me
17 to address you about the 1999
Zoloft-induced drug
18 reactions that my son Chris had at
16, resulting in
19 a woman's death and a life
sentence for him.
20
My son and I want to express sincere
21 sorrow for that death. Our sympathies also
extend
22 to all victims of SSRI's deadly
mind-altering
23 effects.
24
The medical community has tolerated mental
25 health care in which patients are
worse off after
105
1 treatment than before with the
worst cases ending
2 in death.
3
I urge you to ban SSRI use in children,
4 and not to let another life be
destroyed by lack of
5 adequate SSRI
regulation.
6
Chris took Zoloft or Adderall,
7 deteriorated from drug-induced
akathisia, could not
8 bear adverse symptoms of inner
turmoil, loss of
9 conscious behavior. He described overpowering
drug
10 effects, his uncontrollable fits
of anger, pitches
11 and voices setting him off, not
wanting to be
12 touched, feeling horrible all over
his body, not
13 being in
reality.
14
After his offense, his drug reactions
15 stopped, went off all SSRIs for
about a year, but
16 restarted when depressed and put
on Zoloft again.
17 Prison doctors ignored warnings,
forced him to take
18 harmful drugs drugging him into
hallucinating,
19 irrational, suicidal
state.
20
May 2002, I met with the Texas House
21 Committee on Corrections who
ordered prison doctors
22 to correct this health crisis
caused by these
23 drugs. Various drugs had triggered
severe
24 suicidal, homicidal symptoms for
about two years in
25 a clinical setting of doctors
starting and stopping
106
1 his meds.
2
When doctors stopped all drugs, all
3 symptoms disappeared. Doctors released Chris
as
4 recovered from the prison psych
hospital to a
5 regular unit May 2003. Chris has not had any
psych
6 drugs since.
7
These clinical events show dangerous
8 reactions caused by SSRI-induced
psychosis through
9 challenge, de-challenge,
re-challenge.
Medical
10 experts said Chris would not have
been suicidal,
11 homicidal had he not been reacting
to SSRI drugs.
12
Dr. O'Donnell concluded Chris' offense was
13 from combined toxic drug effects
which altered
14 behavior, enhanced violent
thoughts and actions,
15 impaired judgment, was unable to
form intent.
16
Citizens Commission on Human Rights
17 confirmed SSRIs caused his
symptoms. Now
Chris
18 take omega-3 fatty acids and fish
oil to restore
19 his mental health that was damaged
from SSRIs.
He
20 is doing well without medications,
and I thank
21 Jesus Christ for
that.
22
Please ban these drugs and their use in
23 children.
24
Thank you.
25
DR. RUDORFER: Thank you.
107
1
We will move on now to Number 18, please.
2
Todd Shivak
3
MR. SHIVAK: Good
morning. We are
Todd
4 and Eileen Shivak. We do not have any
financial
5 relationship to anyone
here.
6
Our story is much like the cases everyone
7 else here today is bringing
forward to you.
8
Our son Michael was 11 when he was
9 prescribed Paxil for what was
diagnosed as
10 depression. The consequences of this still
live
11 with us today. Thank God he is alive and with
us
12 today, but Michael is afraid of
his doctors, how
13 can he trust what they will give
him next.
14
He is afraid of the police.
He has been
15 wrestled down, handcuffed and
taken to jail.
The
16 police are supposed to protect us
and look what
17 they have done to
him.
18
It is difficult for him to trust his
19 teachers. They still look at
Michael as a
20 troublemaker even though he
currently is an A/B
21 student with much improving
grades. His
peers
22 still think of him as a freak, the
kid who tried to
23 slash his wrists while in
class.
24
As parents, our most important job is to
25 protect our kids. We thought we were doing the
108
1 right thing. The doctors convinced us that
taking
2 these drugs was the only thing
that we could do for
3 Michael. Now, Michael wonders whether we are
going
4 to have him arrested, sentenced,
physically
5 restrained and punished
again. If he can't
trust
6 his parents, who can he
trust?
7 Our
daughter, Catherine, was 5 years old
8 at the time. She witnessed firsthand some of
the
9 most terrifying sights that I have
ever had to deal
10 with. Our family is finally getting back to
the
11 loving family we once were, but
the fear of what
12 happened still haunts
us.
13
Worse yet, how could all the doctors not
14 recognize what was happening? Michael saw three
15 different social workers, two
different
16 psychiatrists, and went through at
least four
17 different emergency room
psychological evaluations
18 in two different
hospitals.
19
We are here to plead that you do something
20 to stop the prescriptions of these
drugs, so that
21 no one else has to go what we are
all going
22 through. It is impossible to describe the pain
and
23 utter helplessness we all felt
watching Michael
24 suffer, watch him cry, take up
weapons against us,
25 and beg us to let him die. How do you erase the
109
1 picture of your child trying to
run in front of a
2 moving car?
3
Please save our children from this drug.
4
DR. RUDORFER: Thank
you.
5
If we can have speaker 19,
please.
6
Andy Vickery
7
MR. VICKERY: Good
morning. My name
is
8 Andy Vickery and I am a trial
lawyer from Houston,
9 Texas. For the last eight years, I
have
10 represented parents who lost their
children to
11 suicide induced by these
drugs. You have
heard
12 from two of my clients this
morning already and
13 will hear from
another.
14
I only have two minutes and I can tell you
15 a lot more than two minutes. The title of the
16 paper that I filed with you is
"Needle in the
17 Haystack." I applaud your desire to look at
the
18 randomized clinical trials
comprehensively to see
19 if they confirm the signal that
Dr. Katz
20 acknowledged
exists.
21
I applaud that, however, I am concerned as
22 Lilly was told in 1990 that you
are looking for a
23 needle in a haystack, you are off
on a wild goose
24 chase. These trials were not designed to
detect
25 suicidality, they did not use the
Beck Suicide
110
1 Ideation Scale which would make
the kind of refined
2 measurements that the
epidemiologist gentleman who
3 spoke earlier said are
needed. They did not
use
4 the Barnes Scale, as Dr. Mann
himself had
5 recommended in a '91 article to
measure treatment
6 emergent
akathisia.
7
They weren't designed to answer the
8 problem, and in 1990 or '91, when
Lilly met -- and
9 you have the handwritten notes of
this in the
10 materials I gave you -- when they
met with outside
11 consultants including Dr. Jerold
Rosenbaum, he
12 said, "There is a data problem,
you are looking for
13 a needle in a
haystack."
14
Find these vulnerable people and
15 rechallenge them. Please look at
the way Lilly
16 sought to study this issue in
1990. They
followed
17 a protocol by Charles Beasley that
said don't use
18 RCTs, don't use epi studies, find
these people and
19 rechallenge them. That was done by
Anthony
20 Rothschild who said these patients
need to be
21 reassured it's not
them.
22
In the meantime, because the signal is
23 there, please issue warnings;
while you look at the
24 data, issue
warnings.
25
DR. RUDORFER: Thank you.
111
1
We are up to speaker 20.
2
Rosie Carr Meysenburg
3
MS. MEYSENBURG: My name is
Rosie Carr
4 Meysenburg. I am from Dallas,
Texas. I have
no
5 financial ties with anybody but my
husband of 40
6 years.
7
In my handout, I have highlighted what I
8 am speaking about
here.
9
The first paper is a personal letter from
10 Dr. Peter S. Jensen. At that time, he was the
head
11 of Child & Adolescent
Disorders Research Branch of
12 the NIMH, the National Institute
of Mental Health.
13 He said that research indicates
that
14 antidepressants for depressed
adolescents are not
15 very
effective.
16
The second paper is a personal letter from
17 Dr. Larry S. Goldman, Director of
the AMA, the
18 American Medical Association. He writes
physicians
19 have known for many years the
dangers of giving any
20 antidepressant to patients with
certain disorders.
21 There is a substantial risk of
precipitating mania
22 or
psychosis.
23
The
last item is a journal article from
24 the Journal of Clinical Psychiatry
researched at
25 Yale University. It states that 11 percent of all
112
1 psychiatric hospital admissions
were from
2 antidepressant-induced mania and
psychosis.
3
It also states another area of research
4 that would be relevant to this
issue is the work of
5 Winter and colleagues showing that
Prozac and other
6 SSRIs can simulate the effects of
LSD. In other
7 words, this is saying for some
people, taking an
8 SSRI is the same as taking
LSD.
9
About two million people enter a
10 psychiatric hospital every year,
11 percent then is
11 over 200,000 people a year who
have an
12 antidepressant-induced psychosis
and who are
13 hospitalized. Not all are hospitalized. Some of
14 them have either committed
suicide, a homicide, or
15 a
murder/suicide.
16
DR. RUDORFER: Thank you.
17
Number 21, please.
18
Rachel Adler
19
MS. ADLER: Mr. Chairman, I
respectfully
20 request that my entire remarks be
entered in the
21 record. My name is Rachel Adler. I am on the
22 board of directors of the Child
and Adolescent
23 Bipolar Foundation, CABF, a
parent-led,
24 not-for-profit organization, that
is the leading
25 source of public information for
pediatric bipolar
113
1 disorder.
2
Board members Sheila McDonald and John
3 Adler are here with me, as
well.
4
Bipolar disorder may emerge with an
5 episode of major depression, an
illness which often
6 causes suicidality even in
preschoolers.
Children
7 with depression are at a high risk
to switch to
8 bipolar
disorder.
9
We surveyed 17,000 members last month and
10 received a 15 percent response
rate over a 5-day
11 period. Eighty-nine percent of the
respondents
12 report that their child had been
treated with an
13
antidepressant.
14
We have received favorable comments, but
15 some responses indicate that in
some subgroups of
16 children, suicidal ideation and
behavior may emerge
17 for the first time or worsen when
a child is given
18 an antidepressant. Some of these children
perhaps
19 have a vulnerability to a bipolar
disorder.
20
For these reason, CABF urges the FDA to
21 require manufacturers to add a
black box warning on
22 the labeling for antidepressants
to alert
23 clinicians and parents to the
possibility that
24 antidepressants can trigger and
worsen suicidality,
25 as well as mania or rapid cycling
bipolar disorder
114
1 in some
children.
2
CABF opposes any ban on the off-label use
3 of these or other psychiatric
medications in
4 children because many of our
members report them to
5 be necessary and even lifesaving
for their children
6 with mood disorders especially
when used in
7 combination with a mood
stabilizer.
8
CABF also urges the pharmaceutical
9 industry and the Federal
Government to fund
10 research to analyze what factors
are shared by
11 those children who, according to
parent reports,
12 became suicidal shortly after
taking an
13
antidepressant.
14 Finally,
CABF calls upon the
15 pharmaceutical industry and the
National Institutes
16 of Health to make public all
safety and efficacy
17 data from unpublished studies in
children.
18
I would also like to say that what I am
19 hearing is a lot of people blaming
a medication for
20 what happened to their children,
and have a direct
21 blame. What I would sort of like to see is
more
22 trained psychiatrists who actually
know the side
23 effects as well themselves and who
are talking to
24 the parents, telling them about
the possibility of
25 side effects, about that
depression inherently, you
115
1 know, can result in suicidality
and that the
2 medication might increase
that.
3
But to blame the medication itself that
4 has helped so many people and has
also prevented so
5 many suicides, I don't think is
the right way, but
6 we do need to have much more
clinicians guiding our
7 patients and parents, so that they
know what kind
8 of side effects are
possible.
9
Thank you.
10
DR. RUDORFER: Thank
you.
11
We are going to move on to Number 23.
12 Pepper
Draper
13
MS. DRAPER: Good
morning. My name
is
14 Pepper Draper. I am a Director of
the
15 International Coalition for Drug
Awareness. I
have
16 absolutely no financial gain. I do this
completely
17 100 percent voluntary, and the
reason for that is
18 because of my own son's
problems.
19
My child was prescribed Ritalin, which
20 became very depressed, and we
bought into the whole
21 serotonin theory, so we were
naturally raising that
22 serotonin, which unfortunately
started causing him
23 to become severely depressed and
suicidal.
24
Unfortunately or fortunately I should say
25 is that we were able to finally
understand the
116
1 truth about serotonin, that
raising serotonin and
2 stopping the metabolism of it has
caused suicide
3 and aggression, and that is well
documented.
4
Unfortunately, Dr. Tracy was not able to
5 talk about that, but what I want
to share with you
6 is that there is going to be
others here from
7 Arizona who are going to share
with you how
8 wonderful these drugs have been
for the State of
9 Arizona, but I am here to tell you
that I deal with
10 these people every day who are
tired of their
11 mental health workers putting them
on another
12 medication and another medication
and another
13 medication, until these children
are now being put
14 in mental hospitals at an enormous
rate.
15
They are being given electric shock
16 therapy and it is very tragic what
I am seeing, and
17 I just want to share with you that
I know that if
18 we will teach them the right ways
to take care of
19 their bodies and cut out the
things that are
20 addictive, like these medications
are, that we can
21 help our youth learn to deal with
what is going on
22 in their lives, and I just want to
share with you
23 one last
thing.
24
I am really saddened that the fact that
25 every single parent cannot share
what has happened
117
1 to their child because if they
could, my mother
2 would be here, standing up here,
sharing what has
3 happened to her adult
son.
4
DR. RUDORFER: Thank
you.
5
If we could have speaker 24, please, Dr.
6 Marks.
7
Donald Marks, M.D., Ph.D.
8
DR. MARKS: Good
morning. My name is
Dr.
9 Donald Marks and I address your
subcommittee as a
10 prescribing physician, as a
father, and as a former
11 associate director and director
for clinical
12 research for two multinational
pharmaceutical
13 companies. I am here at my own expense because
I
14 believe in the importance of these
issues.
15
SSRI manufacturing and sales is serious
16 business with tens of millions of
patients in the
17 U.S. and a market in the tens of
billions of
18 dollars.
19
My experience working for pharmaceutical
20 companies is that any attempt to
decrease sales by
21 increasing warnings will be met
with severe
22 organized resistance. SSRI drugs are
mostly
23 prescribed by primary care
physicians who have
24 limited time with patients,
limited training in
25 childhood and adolescent
neuropsychiatry and
118
1 neuropsychopharmacology, and
minimal time to
2 evaluate properly patient
suitability and response
3 to pharmacologic versus
non-pharmacologic
4
interventions.
5
The seriousness and severe adverse event
6 effects of SSRI drugs make their
use hardly
7 justified in the majority of cases
because SSRIs
8 are well known to have limited
efficacy over
9 placebo and against
non-pharmacologic treatments.
10
There are many studies in the peer
11 reviewed medical literature
supporting the causal
12 role of serotonin in disinhibition
and violence.
13 My own prescribing experience with
SSRI drugs and
14 evaluation of numerous cases
referred to me has
15 revealed significant agitation and
aggression,
16 akathisia, activation of mania and
hypomania,
17 increased depression, serious
dependency and
18 withdrawal difficulties, suicidal
ideation, and
19 toxic interactions with other
drugs.
20
It is important to be aware that these
21 symptoms of SSRI toxicity can be
mistaken for the
22 progression of the underlying
mental state being
23 treated, leading to use of more of
the same and
24 other offending SSRI drugs rather
than to
25 withdrawal of the causative SSRI
agent.
119
1
This creates coding problems for
2 physicians, coding problems by
clinical researchers
3 and sponsoring companies reporting
adverse events
4 in SSRIs.
5
SSRI manufacturers, such as Glaxo and
6 Pfizer, have conducted clinical
trials in depressed
7 children, many of which show no
efficacy against
8 placebo, and this has led to an
increased warning
9 in England that Paxil should not
be prescribed as
10 new therapy for depressed children
under the age of
11 18.
12
DR. RUDORFER: Thanks. I am sorry we are
13 out of time, but thank you, Dr.
Marks.
14
We are going to move on to speaker 25.
15
Leah Harris
16
MS. HARRIS: Good
morning. My name
is
17 Leah Harris and I am here at my
own expense.
18
The two minutes I have to speak will not
19 permit me to go into the details
of what I suffered
20 while taking Prozac, Paxil, and
Zoloft from age 12
21 to 18. I provided additional information in
my
22 submitted written
statement.
23
I went from being a shy and mildly
24 depressed, but never suicidal kid
to being overcome
25 with thoughts of hurting and
killing myself while
120
1 on the SSRI drugs, thoughts which
I acted on.
2
Since quitting SSRIs over a decade ago, I
3 have never again self-mutilated or
had suicidal
4 thoughts. All other things being equal,
the
5 suicidality simply vanished. For
me, this is clear
6 proof that the drugs must have
played a role, and I
7 am one of the lucky ones, I have
survived to tell
8 the tale.
9
I am not an anecdote and my story is not
10 anecdotal evidence. As a tax-paying
American
11 citizen who was hurt by these
drugs throughout my
12 childhood, I demand that the FDA
take seriously the
13 British decision of December 2003
banning all SSRIs
14 except Prozac for use in
children.
15
Please consider all the evidence
16 especially that which the
pharmaceutical industry
17 does not want you to see. The FDA
must take action
18 now regarding this grave issue of
public health.
19
Yes, many people claim to be helped by
20 these drugs, and that is
wonderful, but what about
21 those of us who are harmed? Medical
professionals
22 and the public must be informed of
the very serious
23 risks that are associated with
SSRIs.
24
In light of these risks, at the very
25 least, isn't it time for the FDA
to require that
121
1 the drugs be labeled with clear
warnings that might
2 save lives? Such warnings may negatively
affect
3 sales, as Dr. Marks referred,
which may not please
4 the pharmaceutical industry, but
the FDA was
5 created as an independent
regulatory agency to
6 serve the interests of the
American public, not Big
7 Pharma.
8
American children are no less precious
9 than British children, and they
are in need of our
10 protection,
too.
11
Thank you.
12
DR. RUDORFER: Thank
you.
13
We are up to speaker 26.
14
Donald Farber
15
MR. FARBER: I am Donald
Farber of Marin
16 County, California. I am a plaintiff's
attorney.
17 I have represented antidepressant
victims for five
18 years.
19
As a lawyer, I look at the evidence, too.
20 I hear the emotional stories, but
I look at the
21 evidence.
22
On
January 27th, six days ago, I got a
23 writing that I have been waiting
for the FDA for 15
24 years, from GlaxoSmithKline. Attempted suicides
on
25 Paxil during all premarketing
testing were
122
1 frequent, placebo, it was actually
rare, but due to
2 the fact they manipulated the
figures in the
3 re-analysis of the data, it was
infrequent.
So,
4 even by this standard, we should
have had a warning
5 12 years ago. What do we have to do to get
a
6 warning?
7
Dr. Katz mentioned the re-analysis of the
8 data. I call it tinkering with the
data.
9
Here is what happened to Paxil to get it
10 approved. Dr. Laughren knows about
these figures.
11 Here is what happened with the
tinkering of the
12 data before and
after.
13
Look at the difference.
These are not
14 lawyer figures, these are their
figures. They
15 manipulated the data, Paxil
suicides went down,
16 placebo suicides, which is the key
figure here for
17 you mathematicians, went way up,
so that the result
18 was statistical insignificance by
the time the PDAC
19 met in October of
'92.
20
Whether the drugs go on the market or not,
21 they have to be given a
warning. I am for
full
22 disclosure. I am not for banning these drugs,
but
23 I want full disclosure, and the
FDA doesn't need a
24 citizens' petition to do their
job.
25
Finally,
I do object to this entire
123
1 meeting. I would venture that 95 percent of
you
2 are pro-industry and it is time
for people like Joe
3 Glenmullen and Peter Breggin to
sit on this
4 committee as well as you
distinguished people.
5
Thank you.
6
DR. RUDORFER: Thank you,
sir.
7
Could we have speaker 27, please.
8
Lorraine Slater
9
MS. SLATER: Informed
parental consent is
10 only possible as long as full
disclosure is made by
11 the pharmaceutical companies, the
FDA, and the
12 medical
community.
13
How can you imagine I feel as Dominique's
14 mother knowing now that I was
slowly poisoning my
15 daughter every day as I was
dispensing her
16 antidepressant medication
including Celexa and
17 which she made her first suicide
attempt after
18 being on it for almost one month,
and effects of
19 the last medication she was on
when she did commit
20 suicide?
21
Yes, Dominique's mind and behavior were
22 slowly being altered to the point
that she became
23 very agitated, irrational,
ultimately suicidal,
24 because none of the so-called
medical professionals
25 acknowledged the drug's role in
her irrational and
124
1 suicidal behavior or properly
withdrew her from
2 their suicidal
effects.
3
Our lovely 14-year-old daughter is dead.
4 Dominique has been denied the
unalienable right by
5 her creator of the pursuit of
life, liberty, and
6 happiness. She will no longer be able to
pursue
7 her dreams of becoming either a
computer software
8 engineer, computer graphics
engineer, or marine
9 biologist, and someday an
entrepreneur, she had
10 hoped.
11
Gone, too, is the ability to be able to
12 watch Dominique blossom into
womanhood, as well as
13 motherhood, as she expressed the
desire to someday
14 have five kids. Now, we will never have
the
15 opportunity to continue sharing
our lives with
16 Dominique, whom we loved and
cherished so much.
17 She
was not only very intelligent,
18 humorous, delightful, insightful,
and innovative,
19 she was also very caring and
thoughtful.
Dominique
20 had a way of making others feel
special and loved.
21 She touched so many lives. For example,
Dominique
22 made 1,000 paper origami cranes
and sent them to
23 Governor George Pataki of New York
for the first
24 anniversary of
9/11.
25
It was because of Dominique's very loving
125
1 and genuine nature that around 300
people showed up
2 to her memorial service. They couldn't
believe
3 that for someone who was so loving
and caring, she
4 would herself take her own
life.
5 I submit to
you today, ladies and
6 gentlemen, that Dominique's life
was taken from her
7 as a result of drug-induced
psychosis and suicidal
8 ideations, not to mention the
probability of
9 experiencing akathisia, extreme
agitation. As
a
10 14-year-old adolescent, her brain
was experiencing
11 the second largest growth period,
and her hormones
12 were
unbalanced.
13
How can teenagers be allowed to be given
14 antidepressants that were never
approved for
15 adolescent consumption, only for
adults? How
come
16 the medical profession doesn't
fully disclose the
17 possible harmful and fatal effects
of medication as
18 well as watch carefully for
diverse effects on its
19 adolescent
population?
20
DR. RUDORFER: I am sorry
that we are out
21 of time, but thank you very
much.
22
If we could have speaker 28, please.
23
Matthew Piepenburg
24
MR. PIEPENBURG: Well, there
are very
25 impressive credentials around this
room and
126
1 certainly at this panel, and
impressive schools and
2 qualifications and professorial
positions at very
3 elite
institutions.
4
There are also a number of impressive
5 terms of art tossed around -
morbidity,
6 idiosyncratic. I like Mr. Katz's term
controlled
7 data or controlled trial
data.
8
What I would like to suggest is behind me
9 is a number of things that do not
show up in
10 controlled trial data that need to
be heard, that
11 are as important as what can be
achieved
12
statistically.
13
I don't think for parents who spend a
14 great deal of time in cemeteries,
controlled trial
15 data is as pervasive or
persuasive.
16
I do not suggest or believe that everyone
17 here has a negative or a grotesque
motive or is all
18 greedy. I do think there are legitimate
motives
19 here, and I think these things do
need to be
20 discussed without being
incendiary.
21
Nevertheless, it is important to recognize
22 the human dimension here. We had prepared a
23 two-page speech full of FDA talk
papers, adverse
24 reporting events on Paxil in
particular, my family
25 friend, Paul Domb, has suffered as
a victim of
127
1 Paxil. It is just very hard to go over that
when
2 you hear these
stories.
3
Last night, we were at a restaurant. We
4 gave the waiter our speech to
print out for us off
5 of a disk. He came back. He had suffered
Paxil
6 side effects that led to suicidal
thoughts, violent
7 thoughts after a 40-year marriage,
and he saw our
8 speech and sat down for 20 minutes
and basically
9 cried before
us.
10
It is a pattern and epidemic that is
11 pervasive and has more importance
to me than the
12 statistics we were going to
read. Let me
just
13 suggest also that this individual
had been to
14 Vietnam, lost most of his platoon
and most of his
15 body in Vietnam, crawled for two
and a half days
16 through the jungle to
survive.
17
None of that caused him the depression or
18 the desire to jump off a bridge
like Paxil did.
If
19 he could handle Vietnam with
poise, how are 13- and
20 12-year-old kids supposed to
handle Paxil?
21
Thank you very much.
22
DR. RUDORFER: Thank
you.
23
Could we have speaker 29, please.
24
Terri Williams
25
MS. WILLIAMS: My son, Jacob
Williams, was
128
1 born on October the 15th,
1986. Jacob was
an
2 exceptional athlete who
participated in football on
3 both the varsity and junior
varsity football teams
4 in his
school.
5
In September of 2000, Jacob experienced a
6 loss of interest in his school
activities.
He
7 maintained his interest in
football, however, there
8 was a conflict with his grades and
his attendance.
9
As a result of this issue, his father and
10
I attended a conference at
his school on October
11 the 11th, 2000 with various
representatives from
12 the school. The school administrator
suggested
13 that Jacob may be depressed and
that we should seek
14 medical
help.
15
I contacted Jacob's
pediatrician and made
16 an appointment for 3:45 that
afternoon. On
October
17 the 11th, 2000, his pediatrician
prescribed 10
18 milligrams of Prozac, which was
increased to 20
19 milligrams three weeks
later.
20 Shortly
after starting the initial dose,
21 Jacob began to complain of having
strange dreams,
22 which he had said were bad. Shortly after the
23 dosage was increased, I began
to notice an
24 aggressive behavior, which had not
been there
25 before. Jacob also became destructive and
129
1 destroyed some of his favorite
things.
2
His friends would later tell me they had
3 noticed the same behavioral
change. He also
showed
4 a verbal aggression and short
temper, which had not
5 been present
before.
6
When questioned about this behavior, he
7 stated I don't know what is making
me do this.
At
8 this time, I thought this could be
a part of normal
9 adolescent behavior and did not
pursue the matter
10 any further.
11
On December the 5th, 2000, I discovered
12 Jacob's body hanging from the
rafter in our attic.
13 He had hung himself with his own
belt. A
letter
14 was placed on the ladder leading
up to our attic
15 thanking us for giving him 14
years of a happy
16 life.
17
Something had to have gone wrong in the
18 thinking process to have brought
this about. Had
I
19 know that this was a potential
side effect,
20 suicide, I would have never
allowed my son to take
21 the drug
Prozac.
22
Thank you.
23
DR. RUDORFER: We are now
going to go to
24 speaker 32,
please.
25
Glenn McIntosh
130
1
MR. McINTOSH: I would like
to introduce
2 you to my daughter, Caitlin
Elizabeth McIntosh.
3 Well, it is actually only a
2-dimensional image of
4 her, but it is all I have
left. She died
of
5 suicide at age 12 years, 3 months,
just 8 weeks
6 after being put on Paxil, and then
Zoloft.
7
Caitlin was a straight "A" student in the
8 fifth grade, a talented musician,
artist, and poet,
9 who loved animals and wanted to be
a veterinarian.
10 The sixth grade began, and that,
combined with the
11 onset of puberty, this bright,
sensitive girl who
12 had once loved going to school,
started having some
13 trouble coping, as many kids do in
the sixth grade,
14 it's a tough
adjustment.
15
She was also having some problems sleeping
16 due to a mild seizure
disorder. We wanted to
help,
17 of course, so we took her to our
family physician,
18 who prescribed her Paxil. He said it would
help
19 with her coping and her
sleep.
20
She didn't do well on it at all, so he
21 took her off it cold turkey, which
you are not
22 supposed to do. When we saw a psychiatrist a
week
23 later, he put her on Zoloft. She then started
24 having strong suicidal ideations,
along with severe
25 agitation known as akathisia and
hallucinations,
131
1 and she was put in the adolescent
ward of a mental
2 hospital to "balance her
meds."
3
Well, there, things only got worse, as she
4 was put on other strong
psychotropic drugs to treat
5 the symptoms that we now know were
actually caused
6 by the SSRIs, and let me be very
clear about
7 something. The dramatic and severe symptoms
that
8 led to my daughter's suicide
manifested only after
9 she started taking antidepressant
drugs.
10
The downward spiral continued until
11 January 5th, 2000, when she hung
herself with her
12 shoelaces in the girl's bathroom
in the middle
13 school she was
attending.
14
We were told that antidepressants like
15 Paxil and Zoloft were wonder
drugs, that they were
16 safe and effective for
children. We were lied
to.
17 The pharmaceutical companies have
known for years
18 that these drugs could cause
suicide in some
19 patients. Why didn't we?
20
I implore you, ban the use of
21 antidepressants here in the United
States so that
22 other parents will not have to
endure the pain I
23 felt and other children might be
saved.
24
DR. RUDORFER: Thank
you.
25
Speaker 33, please.
132
1
Delnora Duprey
2
MS. DUPREY: My name is
Delnora Duprey,
3 and it has been well over two
years since I have
4 seen my grandson play ball, ride a
bike, talk on
5 the phone, or run in to say, "Hey,
grandma, what's
6 for dinner?"
7
All the normal everyday things in his life
8 are lost. He is not here to get his
restricted
9 license in April, see his little
sister start
10 school, to ride with his big
sister when she
11 started driving, or just to go out
and have pizza
12 and see a
movie.
13
A tall, thin boy, quiet and well liked and
14 respectful to everyone, a big heart
and a smile
15 that made you ask what are you up
to, a boy who
16 loved his family dearly, had hopes
and dreams for a
17 future. A future of uncertainty now - he is
locked
18 away in a detention center
awaiting trial for the
19 murder of two people who he loved
most in the
20 world.
21
A nightmare that started with a diagnosis
22 of depression and placed on
medication that was
23 never tested on children and never
meant for their
24 use. He had no say in this. We, as adults,
trust
25 our doctors and the FDA to know
what they are
133
1 doing. Even when we get complaints, we say
the
2 doctor said it will help
you.
3
A sweet boy who never hurt himself or
4 anyone else went to live with his
grandparents.
5 His medication was changed from
Paxil, which he had
6 been on a very short time, to
Zoloft.
7
From a family physician, this medication
8 was increased to 200 milligrams
for an 80-pound
9 child. Within 48 hours, his grandparents
were
10 dead, and he is sitting, facing a
life of
11 uncertainty, a life of maybe total
incarceration
12 for the rest of his life, a child
that does not
13 even know what has happened to
him.
14
I don't want to see any more families go
15 through this nightmare that we
have all endured.
16 The child's life changed
forever. Next time
it
17 might be one of your own
family. We must
stop
18 these drugs for children and
strengthen our
19 restrictions on the doctors who
prescribe them.
20
DR. RUDORFER: Thank
you.
21
Number 34, please.
22 Joe
Pittman
23
MR. PITTMAN: Hello. My name is Joe
24 Pittman.
25
My son, at the tender age of 12, killed my
134
1 parents. I am going to read you a letter he
wrote
2 to me to you
all.
3
"Dear FDA: My name is Chris
Pittman. I
4 am now 14 years old. I would like to tell you
what
5 happened to me, what the
medication did to me and
6 how it made me
feel.
7
"When I was taking Zoloft, I took the
8 lives of two people that I loved
more than
9 anything, my grandparents. I went to the
doctor
10 and he gave me a sample pack of
Zoloft. He told me
11 to take 50 milligrams once in the
morning and
12 another 50 at
night.
13
"I didn't notice a change in my behavior
14 until I was completely off the
medication. It
made
15 me hate everyone. The smallest things made me
blow
16 up, and I started getting into
fights, which was
17 not me. I would usually avoid fights. Before the
18 medication, I had only been in two
fights my whole
19 life. I just hated the whole world for no
apparent
20 reason.
21
"A week after the doctor gave me the
22 sample packs, he increased my
dosage to 200
23 milligrams a day. Everything just kept
getting
24 worse. Then, I snapped. I took everything out
on
25 my grandparents who I loved so
very much.
135
1
"When I was lying in my bed that night, I
2 couldn't sleep because my voice in
my head kept
3 echoing through my mind telling me
to kill them
4 until I got up, got the gun, and I
went upstairs
5 and I pulled the trigger. Through the whole
thing
6 it was like watching your favorite
TV show. You
7 know what is going to happen, but
you can't do
8 anything to stop it. All you can do is just
watch
9 it in
fright.
10
"Because of my own personal experience on
11 the medication, I would not want
anyone to go
12 through what I have then and now,
losing the lives
13 of my loved ones for the effects
of homicide or
14 suicide, or both, due to the
medication.
15
"Thank you. Christopher
Pittman."
16
DR. RUDORFER: Thank
you.
17
Number 35, please.
18
Richard Mack
19
MR. MACK: My name is Richard
Mack. I am
20 a retired law enforcement officer
and sheriff from
21 Arizona.
22
My expertise in that field was juvenile
23 delinquency, school violence, and
narcotics
24
investigations.
25
My first experience with SSRIs was when I
136
1 was a parent of a second grader,
my wife and I were
2 called into the school, our son
had a problem
3 staying in his chair. What was the
government
4 school's answer? Drug your son into submission,
so
5 he will stay in his
chair.
6
We refused and we thank God now that we
7 did. Our son turned out just fine,
played
8 basketball, baseball, and excelled
at school and
9 sports.
10
I was a sheriff of a small community in
11 Arizona. We had an abnormal amount
of high rate of
12 suicide and teen violence. I am just an
13 investigator, I just present the
facts. One
thing
14 that we could not ignore was the
circumstantial
15 evidence that the common
denominator in all of
16 these cases was the victims or
perpetrators were on
17 SSRIs.
18
In investigating these events, it became
19 quite commonplace for all of us to
ask the same
20 question as we got to the next
event of horrified
21 and traumatized people and
families. You
have
22 heard from many of them
today.
23
Some people don't have the adverse
24 reaction to these drugs, some
do. I learned
the
25 same with LSD when I investigated
that as an
137
1 undercover narcotics officer. I can only say
that
2 the evidence is mounting over and
over as did our
3
investigations.
4
We cannot, as law enforcement officials,
5 ignore such circumstantial
evidence. I doubt
very
6 seriously if you could
either. I am an
advocate
7 for state's rights and I do
believe that if the FDA
8 fails to take action, the state
and local
9 authorities will have
to.
10
Thank you.
11
DR. RUDORFER: Thank
you.
12
Speaker 36.
13
Noah Wright Smith
14
MS. SMITH: My name is Noah
Wright Smith
15 and I am a 15-year-old victim of
legalized drug
16 abuse. My mother had me put on Ritalin when I
was
17 5. I felt sick all the time on Ritalin and
it was
18 just the beginning of bad things
happening to me
19 because of
drugs.
20
My grandparents won custody of me last
21 year. When they won, they got upset because I
was
22 in bad shape and on a lot of
drugs. They picked
me
23 up at Broughton Mental Hospital in
Morganton, North
24 Carolina, and learned I was on
1,000 milligrams of
25 drugs a day. In my lifetime, I have been on 16
138
1 psychotropic drugs including
Zoloft, Paxil, and
2 Effexor, and all of them made me
feel sick and do
3 very bad
things.
4
I wasn't a bad kid. I was a
badly abused
5 kid, abused by my mother and my
stepfather.
The
6 Department of Social Services knew
I was being
7 abused, but they didn't do
anything except put me
8 on more
drugs.
9
The drugs made me sick and do bad things
10 like trying to stab my teacher
with scissors.
11 Sometimes it made me want to kill
my parents, and I
12 told them that, and was put in a
mental hospital.
13
Some drugs made me have bad nightmares, so
14 I tried very hard not to sleep
every night, so they
15 gave me drugs to make me
sleep. Some of the
drugs
16 made me want to kill myself. I couldn't stop
17 thinking about killing
myself. When I told
the
18 doctors, they sent me to still
another mental
19 hospital.
20
One day I tried to jump off a very high
21 railing to kill myself. I was put in a
mental
22 hospital again for doing that, but
I really wanted
23 to die. I really did want to, and I was so
scared
24 and mad, too. In those mental hospitals, they
kept
25 giving me more drugs, and I got
depressed. I got
139
1 diabetes and high blood
pressure.
2
My grandparents won my custody and took me
3 to a new psychiatrist. We have worked
hard
4 together and he found I really
don't need any
5 drugs. Last year he took me off all of them,
one
6 at a time. No more nightmares or wanting to
hurt
7 or kill other people, and I don't
want to kill
8 myself
anymore.
9
Drugs almost ruined my life and almost
10 killed me. What about the kids
that have to take
11 these drugs? I don't want kids to kill
themselves.
12 Who is taking care of them? Who
really cares about
13 us kids? I don't even know if you care, do
you?
14 Somebody had better listen to kids
who say the
15 medicines make them want to kill
themselves, and
16 make them sick, and do bad things,
because they are
17 telling you the
truth.
18
Thank you for listening to me.
Now,
19 please, help the other kids, so
that they don't get
20 hurt by drugs, and so they don't
kill themselves.
21 I almost killed myself and I am
glad I am alive.
22
DR. RUDORFER: Number 37,
please.
23
Marion Goff
24
MS. GOFF: I do not have any
financial
25 ties. I am her with my daughter, Alex. We are
140
1 here to tell you about her twin
sister, Devon, when
2 she was 9 years old. We are also joined by
Senator
3 Lincoln Chafee's wife Stephanie
who is a friend of
4 ours.
5
In 2002, Devon developed an
6 obsessive-compulsive disorder very
suddenly and
7 very severely. In a three-month period, she
lost
8 10 pounds. We consulted a specialist
who
9 prescribed Zoloft on her second
visit with him.
10 Soon thereafter, he increased the
Zoloft to 50
11 milligrams or more, but it didn't
help, so he
12 changed her prescription to
Paxil.
13
She was hospitalized and Devon's medical
14 condition was compromised in that
she had developed
15 a cardiac arrhythmia and had to be
placed on a
16 heart monitor. She was in the hospital for
one
17 month, and she was on the heart
monitor and bed
18 rest for the entire
time.
19
During this time, her Paxil was increased
20 to 20 milligrams. A few days later she was
started
21 on Zyprexa also. Devon was not getting any
better,
22 in fact, her behaviors grew
worse. She
began
23 hitting her head against the metal
hospital bed.
24 She threatened to jump out of the
window on two
25 occasions.
141
1
On two other occasions, we found a pair of
2 sharp scissors in her bed. Our child was
never
3 suicidal before these
medications. At one
point,
4 my 9-year-old child, who weighed
little more than
5 60 pounds, was on 30 milligrams of
Paxil and 10
6 milligrams of
Zyprexa.
7
Our gentle daughter would now fly into a
8 rage several times each day. It became part of
our
9 life to have my husband and myself
restrain Devon
10 at times for fear that she would
truly hurt
11 herself.
12
During these times, she would try to
13 inflict injury upon herself by
banging her head on
14 walls, beds, floors. She would punch herself
in
15 the legs and arms. She grew extremely
violent
16 toward us. She would run to the silverware
drawer
17 and get a knife and attempt to
stab herself.
18
The worst moment happened when I looked in
19 on her, in her room one night, to
find her by her
20 open second floor bedroom window
with one leg out
21 the window in a position as if she
appeared she
22 would jump.
23
Devon is presently being treated for Lyme
24 Disease. In summary, our experience has been
one
25 of absolute terror to watch your
9-year-old
142
1 daughter suffer so much, so
suddenly, and to be so
2 lost in helping
her.
3
So often we would ask why this was
4 happening, and we were told to
forget about the
5 etiology.
6
DR. RUDORFER: I am sorry, we
are out of
7 time. Thank you very
much.
8
Number 38, please.
9
Gary Cheslek, M.D.
10
DR. CHESLEK: Actually, my
wife is
11 speaking
later.
12
My name is Gary Cheslek, and I am a
13 practicing dentist from Vicksburg,
Mississippi, and
14 I am speaking today, not just as a
health care
15 professional, but also as a
parent.
16
I am here today to tell you an anecdote.
17 Webster defines an anecdote as a
short narrative of
18 an interesting or amusing
biographical event, an
19 anecdote or anecdotal. That is the euphemism
the
20 manufacturers of Prozac, Paxil,
Effexor, and Zoloft
21 use to describe the thousands of
reported out of
22 character, violent, homicidal,
suicidal events that
23 occur in a vulnerable subset of
patients who ingest
24 their SSRI antidepressants. They would have us
25 believe that these are mere
coincidences and don't
143
1 prove
anything.
2
My son, Justin, was a 20-year-sophomore at
3 the University of Southern
Mississippi when he went
4 to the Student Health Clinic
complaining of
5 insomnia. He was given a thorough
examination
6 including bloodwork. Significant in the
doctor's
7 note at that initial visit is the
notation, "No
8 suicidal
ideation."
9
Complaining that the sleep medication he
10 was prescribed made him feel
sedated and depressed,
11 he was put on Paxil for two
weeks. During
those
12 two weeks, he repeatedly told his
doctor he didn't
13 like the way the Paxil made him
feel, so he was
14 switched to
Effexor.
15
Within 24 hours of the switch to Effexor,
16 he had a seizure. Five days later he hung
himself
17 in his apartment. He didn't leave a note. Beneath
18 him was his laptop computer and a
glass of Coke.
19 It was as if some sudden impulse
had made him do
20 this.
21
We grilled his girlfriend about his mood
22 and behavior in the months prior
to his death.
She
23 said his demeanor changed
dramatically around her
24 birthday, February 22. Justin started taking
Paxil
25 February 21.
144
1
Last June, regulators in the UK and Canada
2 banned Effexor and Paxil for use
in children and
3 adolescents, and recently expanded
that ban to all
4 SSRIs except Prozac. Last August, Wyeth issued
a
5 Dear Doctor letter alerting the
health care
6 professionals that the clinical
trials had not
7 established the safety and
effectiveness of Effexor
8 in children, and revealed an
increased risk of
9 suicidal ideation and
self-harm.
10
The letter does not, however, indicate
11 that some of these trials were
done seven years
12 ago.
13
DR. RUDORFER: Thank you very
much.
14 Sherri
Walton
15
MS. WALTON: My name is
Sherri Walton and
16 I am here as a volunteer
advocate. This is
my
17 14-year-old daughter, Jordan. We have traveled
18 here from Arizona at our own
expense because we
19 know that public forums, such as
this, usually only
20 hear from those who have had
negative experiences.
21 We felt it was important for us to
share our story.
22
Jordan was diagnosed with Tourette's
23 syndrome when she was 7 years
old. As is
typical
24 of Tourette's syndrome, she also
has OCD and ADHD.
25 She was originally prescribed an
SSRI medication to
145
1 relieve the anxiety that consumed
her because she
2 could not control her thoughts or
behaviors.
3
This medication allowed her to participate
4 in, and understand, the cognitive
behavior therapy
5 that gave her some semblance of
normalcy. In
6 fourth grade, Jordan was still
being hampered by
7 the obsessive thoughts caused by
her OCD. In
the
8 classroom, this was overwhelming
and extremely
9 frightening for
her.
10
Her medication was changed to a different
11 SSRI and within a few months, her
obsessive
12 thoughts became less and less
intense. They
were
13 still there, but now she was able
to recognize what
14 they were and usually work through
them.
15
Dance is Jordan's passion.
It is what she
16 wants to do with her life. In November of
2002,
17 she announced she wanted to quit
dance. As she
18 burst into tears, she said that
she wanted to die,
19 she wanted to kill
herself.
20
She was diagnosed with clinical depression
21 and her medication was changed
from the SSRI she
22 had taken for four years to a
different SSRI to
23 treat both her OCD and
depression.
24
As Jordan has struggled to find success in
25 school and in her relationships
with peers, her
146
1 meds were sometimes the only thing
she could count
2 on to help her. The daughter I have here
now
3 standing next to me is a happy,
healthy, successful
4 teenager. There is no doubt in my mind that
the
5 SSRI medication saved her life,
and like the other
6 SSRI antidepressants she is taking
gave her a
7 chance for a full and complete
life.
8
With the greatest sympathy for any
9 families who have lost children to
suicide, I ask
10 that you identify and fix any
breakdown in the
11 system that could lead to such
tragedy. At
the
12 same time, I ask that you
appreciate and take into
13 account the enormous benefits that
these
14 medications have had for children
and their
15 families.
16
Please urge the FDA not to take away the
17 tools that have allowed my
daughter and millions of
18 other sons and daughters out there
to be successful
19 in life, and, in fact, to have
lives.
20
As a parent, I call on the FDA to take no
21 action that would harm my
child.
22
DR. RUDORFER: Thank
you.
23
We are up to speaker 40.
24 Peter
R. Breggin, M.D.
25
DR. BREGGIN: Hello. I am Dr. Peter
147
1 Breggin. I am a psychiatrist and one of the
few
2 experts in the world on
medications who isn't
3 involved in any way with the drug
industry. I
4 think there are handful of
us.
5
I have given you a peer-reviewed article
6 that came out just a few weeks ago
that I wrote,
7 which is the most extensive review
to date on
8 violence, suicide, and mania
caused by the SSRIs,
9 and it has just, I don't know,
maybe hundreds of
10 citations.
11
Back in the 1980s when Prozac was being
12 approved, Richard Kapit, the chief
medical officer
13 at the FDA, identified a stimulant
syndrome in
14 association with Prozac, and he
repeatedly warned
15 in in-house documents that this
stimulant effect
16 would turn depression into
agitated depression and
17 cause a deterioration in the
individual.
18
Since then, we have been able to identify
19 a continuum of stimulation that
has at least four
20 syndromes involved, that I have
now seen produce
21 violence and suicide in dozens of
patients in my
22 clinical consultations and in my
medical/legal
23 work.
24
The syndrome, first and foremost, includes
25 manic-like behavior. We know that Luvox, for
148
1 example, just in its label has a 4
percent rate of
2 mania. From Emslie's study, hidden in the fine
3 print, we know that Prozac,
controlled clinical
4 trials, 6 percent rate of
mania.
5
The second syndrome is the agitated
6 depression, it is hard to tell
often clinically
7 from mania.
8
The third syndrome is this obsessive
9 suicidality and violence, and the
fourth syndrome
10 is akathisia, which we now know,
and is even in the
11 old DSM, can produce psychosis and
agitation, and a
12 variety of other problems leading
to suicide and to
13 violence.
14
The literature is extensive.
You have got
15 to go beyond the needle in the
haystack.
Please
16 look at my
review.
17
DR. RUDORFER: Thank you, Dr.
Breggin.
18
Speaker 41.
19
Robert Fritz
20
MR. FRITZ: People have been
pleading with
21 the FDA for 11-plus years to put
warnings on
22 prescriptions for antidepression
medication to no
23 avail. The FDA has had people present
information
24 about suicidal tendency increase
and numerous
25 completed suicides, and still no
warnings of
149
1 increased risk of suicide were
issued.
2
The people of the United States have a
3 right to know what risks are
associated with taking
4 these drugs. I have a right to know what risks
are
5 associated with taking these
drugs, so I can make
6 an informed decision as to whether
or not I want my
7 children to take these
drugs.
8
The need for a warning is compounded by
9 the fact that doctors are
prescribing these
10 medications off label. My daughter, Stephanie
Raye
11 Fritz was taking Zoloft. We weren't told of
any
12 risk of increased suicidal
tendencies or increased
13 suicide
attempts.
14
She hung herself on the evening of
15 November 11th in her bedroom after
finishing her
16 homework. She showed no signs of
increased
17 depression or imminent suicidal
thoughts, and, in
18 fact, was still recruiting people
to see her sing
19 the following
month.
20
We had no warning of what Zoloft could do
21 to our daughter, but you people,
the FDA, certainly
22 did. On October 27th, two weeks before she
took
23 her life, you put out a Public
Health Advisory and
24 notified physicians about
preliminary data from
25 studies suggesting an excess of
reported suicidal
150
1 ideation and suicide attempts for
pediatric
2 patients receiving certain of
these antidepressant
3
drugs.
4
Why weren't we, the parents of the kids
5 taking Zoloft, notified with this
advisory? It
is
6 too late for my daughter, but for
the FDA to
7 continue to sit on this
information and not let the
8 public know the risks associated
with these drugs
9 is a gross misuse of
power.
10
I am not asking that these drugs be taken
11 off the market. I don't know enough about
their
12 safety to recommend that. What I am seeking
is
13 that when the drugs are prescribed
off label, or
14 when drugs are prescribed after an
advisory is
15 issued suggesting new adverse side
effects, that
16 the FDA make it mandatory that the
physicians
17 prescribing such drugs explain in
plain English
18 what the risks are and that an
informed written
19 consent be received from the
parents or the
20 patient's
guardian.
21
I hope that you will agree that all
22 Americans deserve to know what
risks they are
23 assuming when they take
medication. I believe
that
24 most Americans, including most
elected officials,
25 agree with that.
151
1
How many more people have to die before a
2 warning gets
issued?
3
DR. RUDORFER: Thank
you.
4
We are going to move ahead to speaker 43.
5
Lawrence Greenhill, M.D.
6
DR. GREENHILL: My name is
Lawrence
7 Greenhill. I am a child psychiatrist, Professor
of
8 Child Psychiatry and Pharmacology
at Columbia.
I
9 am speaking today on behalf of the
American Academy
10 of Child and Adolescent Psychiatry
where I serve as
11 Chairman of the Program Committee
and as Chair of
12 the Pediatric Psychopharmacology
Initiative
13 Committee.
14
First, I want to extend my sympathy to all
15 the families who spoke so moving
here today about
16 their losses. I think similarly,
the membership,
17 who are comprised of 7,000 child
psychiatrists at
18 the American Academy of Child and
Adolescent
19 Psychiatry, are concerned about
these families, and
20 they want to get the results of
this review to help
21 their patients with safe and
effective treatments.
22
In that regard, the American Academy of
23 Child and Adolescent Psychiatry
supports the review
24 that is going on and it
specifically supports the
25 reclassification of suicidal
events using patient
152
1 charts, that is, patient level
analysis, as the
2 category that turned up in Dr.
Laughren's report of
3 possible suicide-related events
was one most
4 subject to possible methodological
bias that might
5 be addressed by patient level
analyses and
6
reclassification.
7
Furthermore, I support the mandatory
8 registration of all clinical
trials as advocated in
9 JAMA by Dickerson and Rennie in
July of 2003.
That
10 is because one of the greatest
roadblocks to
11 understanding the safety and
efficacy of trials is
12 the lack of public access and its
disclosure of
13 these data sets due to laws that
treat some of the
14 data as proprietary trade
secrets.
15
I join my colleagues at Columbia in
16 encouraging the field to carry out
further
17 prospective placebo-controlled
trials using methods
18 such as we have heard today, the
randomized
19
withdrawal discontinuation
or challenge,
20 de-challenge
--.
21
DR. RUDORFER: Thank you, Dr.
Greenhill.
22
Number 46, please.
23
Suzanne Vogel-Scibilia, M.D.
24
DR. VOGEL-SCIBILIA: I would
like to have
25 my remarks into the written
record, and I want to
153
1 let you know I am here at my own
expense.
2
Good morning. My name is Dr.
Suzanne
3 Vogel-Scibilia. I a member of the NAMI board
of
4 directors. As a person diagnosed with
bipolar
5 disorder, I am proud to serve on
the NAMI Board and
6 proud that NAMI is the nation's
voice on mental
7 illness representing both
consumers and family
8 members. I am also proud to be the mother of
five
9 children, two who are diagnosed
with mental
10 illnesses and one who is currently
being treated
11 with an
SSRI.
12
I am also a practicing clinical
13 psychiatrist with no financial
ties to the
14 pharmaceutical industry. I represent thousands
of
15 families across the
country.
16
My son, Anthony, had a very severe mental
17 illness primarily depression and
attention deficit
18 disorder as a manifestation of his
bipolar
19 disorder, and another son has had
treatment with
20 numerous antidepressant
medications including
21 several
SSRIs.
22
My children have had tremendous
23 improvement with their illnesses
and lead very full
24 and functional lives because of
SSRI medication,
25 along with other psychotropic
medications. I
154
1 shudder to think of their plight
if these
2 medications were not
available.
3
One of my sons has had suicide attempts
4 and violent incidents with
knives. He has also
run
5 out of our house - in a fit of
terror --in subzero
6 weather only to be found freezing
and hypothermic
7 by our local police department in
the next town.
8 These incidents all occurred while
his illness was
9 not adequately treated with an
antidepressant
10 medication.
11
My other son suffers from disabling
12 obsessive- compulsive disorder
symptoms and
13 depression, and has had his life
dramatically
14 improve from treatment with
SSRIs.
15
I want to talk and speak about suicide and
16 the consequences of untreated
mental illnesses.
17
We are pleased that the FDA is looking
18 closely at the data related to
SSRI use and
19 suicidality. NAMI is deeply concerned with
the
20 public health crisis and the
number of youths who
21 commit suicide. The U.S. Surgeon General
reports
22 that up to 80 percent of our youth
who need mental
23 health treatment receive none at
all.
24
In summary, I would like to thank the
25 committee for allowing 200,000
members of NAMI to
155
1 share our views on this critically
important issue.
2 I hope and pray that this
committee will render a
3 decision based, not on
emotion-filled pleas of
4 individuals whose experience are
not supported by
5 adequate
research.
6
Thank you very much.
7
DR. RUDORFER: Thank
you.
8
If we could have speaker 48, please.
9
Dennis Winter
10
MR. WINTER: I am Dennis
Winter. I am
11 here today with Karine Winter and
Mary Lou Winter,
12 Beth's mom.
13
Four months ago or less than four months
14 ago, Beth, a 22-year-old recent
graduate from the
15 University of Rhode Island, she
graduated summa cum
16 laude, she was a child who was
loving, from a very
17 tight, close family, never any
instance of alcohol
18 or drug abuse, never any problems,
a wonderful
19 student, a wonderful girl, a
loving sister to her
20
brothers and sisters,
committed suicide after being
21 on Paxil for seven
days.
22
Now, what I think is critical here is the
23 fact that she can go to her
general practitioner on
24 the first visit and be prescribed
Paxil. I
think
25 it is clear that you need to come
out with warning
156
1 labels for practitioners and
doctors, so the
2 lawyers in this room, when those
labels are out
3 there, if the doctors continue to
do it, will be
4 able to bring actions. If you bring out
the
5 warning labels, there is enough
legal community in
6 this world that will police
itself.
7
Let me go on. As we are
sitting here
8 today, we heard a lot about
idiosyncratic data, all
9 permitted data, requested data
available, data we
10 are permitted to evaluate fully,
and it comes down
11 to this data stream that we don't
know that
12 happened 15, 20 years ago, the
data stream you are
13 trying to
analyze.
14
I don't know, like Mr. Farber said, if you
15 are going to be analyze all that
data and come out
16 with that data. You should put out warning
labels
17 because you are not going to get a
clear answer.
18
I am running out of time, but Dr. Healy
19 provided testimony in federal
court on May 22nd,
20 2001. Everybody needs to be read that
testimony.
21 He gave it under oath, under
threat of perjury, and
22 that is very enlightening to
anybody involved here,
23 and you really need to read
it.
24
Also, you need to look at confidentiality
25 agreements. A lot of families of people who commit
157
1 suicide are embarrassed. When the lawyers
come,
2 they sign confidentiality
agreements, and you don't
3 hear about what is really
happening out there.
4
DR. RUDORFER: Thank you very
much.
5 We are
going to move along to speaker 51.
6
Steve Cole
7
MR. COLE: I am Steve
Cole. I am here
at
8 my own
expense.
9
My father committed suicide after 13 days
10 on Prozac. He has absolutely no history of
mental
11 illness, in fact, quite the
contrary. He and
my
12 mom had just built a new house, a
lot of the work
13 he did himself. He and I and a friend built
a
14 cabin out of raw
lumber.
15
These are not the type of things that you
16 do if you are planning on
dying. Let me
repeat
17 that. You do not do
that.
18
He was looking forward to his new house.
19 He was planning many
activities. He was upbeat,
he
20 didn't drink or gamble, and he did
not have any
21 recognized prerequisites for
suicide unless you
22 want to consider all 70-year-old
men suicidal, and
23 I just don't buy that. Generally, he was in
very
24 good health.
25
Next slide.
158
1
He experienced some chest pains about a
2 month and a half after moving into
the new house.
3 As a precaution, he went to his cardiologist. His
4 heart tested perfectly well. He was upbeat and
had
5 a new grandbaby on the
way.
6
He was prescribed Prozac off label for the
7 chest pain. The doctor, who is an
outstanding,
8 wonderful man, stood behind us on
this, and stated
9 that he has no doubt that it was
Prozac induced.
10 Eleven days after he started, he
demonstrated
11 symptoms of akathisia, he was
jittery. His
fingers
12 and his skin felt odd, he was
easily agitated.
13
He told me, "I cannot stand the way this
14 drug makes me feel." Two days later he
committed
15 suicide.
16
Growing up, he watched a lot of westerns.
17 He loved westerns, but he would
turn the channel if
18 a man was hung or lynched. This is the way my
19 father died. He hung himself. It was completely
20 out of character. He died by means of his
own
21 nightmare.
22
Thank you very much.
23
DR. RUDORFER: Thank
you.
24
Number 52, please.
25
Allan Routhier
159
1
MR. ROUTHIER: I am here to
request that
2 Wellbutrin be recognized as
another dangerous drug.
3 Information was sent to this
committee by some
4 researchers and myself as to the
reasons for
5 inclusion. There are too many cases of suicide
and
6 deaths caused by this drug. It is known to
cause
7 akathisia, depression, psychosis,
serotonin
8 syndrome, seizures,
hallucinations, and many other
9 serious adverse
effects.
10
One suicide while on Wellbutrin for ADHD
11 was 9-year-old Carey Brooks, who
had to kneel down
12 to hang himself with his
shoelace. There are
many
13 reasons these drugs are
prescribed, and they can
14 cause suicide in non-depressed
people.
15
Do not blame acts of drug-induced
16 psychosis on depression especially
when this is
17 happening to people given these
drugs for other
18 purposes. It is not only SSRIs. SSRI is a
19 misnomer. None of them are selective to
serotonin.
20 When you affect one
neurotransmitter, you affect
21 others.
22
Remeron, Serzone, Effexor are not SSRIs.
23 Effexor works on serotonin,
norepinephrine, and
24 dopamine, as does Wellbutrin. FDA Med Watch
25 reports hundreds of suicides on
Wellbutrin.
160
1 Wellbutrin is structurally similar
to amphetamine
2 and overstimulates many
people.
3
Six months ago my wife went to the doctor
4 sick and was sent home with
Wellbutrin. After
six
5 days of serious adverse reactions
and insomnia, she
6 shot herself. This was not her. Forty years
old,
7 beautiful, with two boys, she was
a perfect wife
8 and mother, married for 18 years,
almost 25 years
9 working in the Welfare
Office.
10
She was never depressed. She
was the most
11 loving, unselfish person anyone
could know.
12 Immediately after starting
Wellbutrin, she was not
13 herself. This was an act of psychosis. This has
14 been happening for too long. People are worth
more
15 than
profits.
16
How many
more have to die before something
17 is done? Don't be fooled by manipulated
studies.
18 This was whitewashed in 1991, now
they are trying
19 to do it again. This happens to
adults, as well as
20 children, prescribed for any
reason, not just MDD.
21
My wife was murdered. The
FDA is supposed
22 to protect us from these pill
pushers.
23
Thank you.
24
DR. RUDORFER: Thank
you.
25
Number 53, please.
161
1
Daniel J. Safer, M.D.
2
DR. SAFER: I am Daniel
Safer. I am a
3 child psychiatrist, and I have no
conflict of
4 interest in coming
here.
5
I think the major finding of the British
6 Committee on the Safety of
Medicines was that most
7 of the data that they got were
unavailable to them
8 prior to the company coming in for
an indication,
9 so when they found the data, they
were surprised to
10 see that most of the studies were
negative or
11 failed for the treatment of
depression in children
12 using SSRIs. So, that was I think the
major
13 finding as far as I am concerned
of the British
14 Committee.
15 The
second finding indeed was that most of
16 the studies, the vast majority of
the studies they
17 looked at were either failed or
negative for the
18 treatment of depression in
children.
19
The third finding had to do with the side
20 effects of particularly the
suicidality issue,
21 which I consider a minor finding
of the British
22 report. It was about 1 and a quarter percent
rate
23 for placebo and about 3.5 percent
for the active
24 medication.
25
I think that is fairly understandable
162
1 because the medication, the SSRIs
are known, and
2 have been known, to increase the
risk of agitation
3 and activation and children. In
fact, the rate is
4 about 15 to 20 percent when you
look over about 40
5 or 50 studies on
SSRIs.
6
It is a high rate, so you would expect
7 that children who were depressed
might have an
8 increased rate of suicidality if
they are agitated
9 or anxious or activated under
medication.
10
Now, there is a lot of concern about the
11 fact that a lot of these studies
are not published,
12 they simply are put in a file
drawer. I think
that
13 is a big concern, it's a big
concern for Eric Kahn
14 [ph] and Michael Thase and Norman
Sussman, some of
15 the major people in the field of
psychiatry.
16
So, I think the focus of the meeting is
17 sort of unfortunate by focusing on
suicidality
18 because I think the big issue here
is that we don't
19 have access to the data that we
need from the
20 controlled trials, that are simply
put in a file
21 drawer by the
companies.
22
So, I would like to close by quoting
23 Daniel Conner in the American
Journal of American
24 Academy of Child and Adolescent
Psychiatry this
25 month. Oh, I will leave the quote out.
163
1
DR. RUDORFER: We will look
it up. Thank
2 you.
3
Speaker 54, please.
4
Julie Zito, Ph.D.
5
DR. ZITO: I am Julie Zito
from the
6 University of Maryland/Baltimore,
and I bring to my
7 comments this morning 20 years'
experience in
8 psychiatric
pharmacoepidemiology.
9
I would like the committee to consider the
10 following drug safety issues in
making their
11
recommendations.
12 First,
symptoms like activation and
13 agitation are reported very
inconsistently,
14 anywhere from no incidence in a
clinical trial to
15 as many as 55 percent of the
children in an SSRI
16 trial. This information suggests a lack
of
17 standardization of measurements
and methods with
18 which to assess these
events.
19
Second, we need research on behavioral
20 toxicity in order to separate
symptoms associated
21 with drug from those associated
with the underlying
22 psychiatric disorder. I don't think we can
just
23 assume it.
24
Third, because suicide is a very rare
25 event, we need research that
requires active
164
1 surveillance, not passive
surveillance, active
2 surveillance in large,
well-defined populations.
3 We have the capacity to do that
with research
4 methods in pharmacoepi, but as
yet, there is no
5 federal mandate to go beyond Med
Watch.
6
Thank you.
7
DR. RUDORFER: Thank
you.
8
Speaker 55, please.
9
Joseph Glenmullen, M.D.
10
DR. GLENMULLEN: I am Joe
Glenmullen. I
11 am a psychiatrist and clinical
instructor in
12 Psychiatry at Harvard Medical
School and the author
13 of Prozac Backlash, which
describes my experience
14 seeing patients become suicidal on
SSRIs.
15
I am here at my own expense because there
16
is a specific side effect of
SSRIs called akathisia
17 that can make some patients so
agitated that they
18 feel death would be a welcome
relief.
19
This side effect is so well established
20 that it is clearly described with
SSRIs in the
21 Diagnostic and Statistical Manual,
the DSM, the
22 American Psychiatric Association's
official
23 diagnostic
manual.
24
If you look at the transcript of the FDA
25 hearing on this very side effect
10 years ago, you
165
1 will see the FDA saying repeatedly
we don't know
2 what to do, we need more
research. It is a
tragedy
3 to be here 10 years later and hear
the FDA saying
4 the same
thing.
5
The industry's response to this side
6 effect has been to blame the
underlying psychiatric
7 conditions of patients, to dismiss
legitimate
8 medical case reports as anecdotes,
and to scare the
9 media away from the subject,
claiming that it would
10 frighten patients away from
treatment.
11
Indeed, there is a prevailing
12 authoritarian attitude don't warn
patients, you
13 might scare
them.
14
Well, I prescribe SSRIs and I warn
15 patients, and they are not
frightened away from
16 treatment. Let's stop blaming patient's
underlying
17 psychiatric conditions. Let's stop blaming
the
18 victims and deal with this very
real side effect.
19
Thank you.
20
DR. RUDORFER: Thank
you.
21
Speaker 56, please.
22
Linda Cheslek
23
MS. CHESLEK: Hello. My name is Linda
24 Cheslek. I am a pediatric nurse practitioner and
I
25 have prescribed medications for
pediatric patients
166
1 for 25
years.
2
In the past, I thought that when an FDA
3 drug was approved, that it had
gone through a
4 rigorous battery of independent
tests and trials
5 under the auspices of the FDA, but
I can longer
6 believe
this.
7
Why? Well, this summer I
received this
8 letter from Wyeth. It is a Dear Doctor letter. It
9 goes to all health care
professionals, and it told
10 me an update on Effexor, that the
safety and
11 effectiveness in pediatric
patients had not been
12 established, but there were
reports of increased
13 hostility, suicide, adverse
events, suicidal
14 ideation, and
self-harm.
15
This letter that came to my home confirmed
16 what I already knew, that my son,
who had a
17 three-week trial of Paxil and
Effexor became very
18 much worse. He developed the akathisia you
have
19 been hearing about. He developed
serotonin
20 syndrome symptoms and a
seizure.
21
Wyeth had this information for almost
22 seven years. Why did not the FDA
require this trial
23 data to be submitted along with
the other data?
24 The FDA allows the drug sponsors
to manipulate and
25 massage the data, to present it in
a way that they
167
1 feel is promoting their drug, and
not the truth.
2 I
ask you to require them to submit all
3 the data and to give a warning
about these
4 medications. When you go to bed tonight, I
hope
5 you will see my face, the face of
my son, and maybe
6 of other faces of these people,
and give a warning.
7
Thank you.
8
DR. RUDORFER: Thank
you.
9
We are to speaker 57.
10
Jeff Avery
11
MR. AVERY: Hello. My name is Jeff
Avery.
12
My 16-year-old stepson, Brandon Ferris,
13 committed suicide on July 22nd,
2001, about three
14 weeks after he began taking
Zoloft. Brandon was
a
15 bright and socially outgoing teen
who got along
16 well with others. He was a black-belt
instructor
17 in Tai Kwon Do, active in the
church's youth group,
18 and held a part-time
job.
19
His mother home-schooled Brandon and
20 worked at the Tai Kwon Do School,
so she was very
21 active in Brandon's
activities.
22
In
June of 2001, Brandon expressed that he
23 was feeling down, and not his
usual energetic self.
24 It was decided that he should take
some time off
25 and see a counselor.
168
1
The counselor suggested that he see a
2 doctor. The doctor, who found no
physical
3 problems, prescribed
Zoloft.
4
Sunday, July 22nd, Brandon and I went to
5 church. On the way home Brandon volunteered
to
6 make a cake for his mother's
birthday. He
asked
7 permission to go on a boating
trip. He spent
the
8 rest of the day with his friends
and an older
9 brother
Randy.
10
When he came home from his youth group
11 meeting at 9:15, he seemed
fine. At 9:45 he
asked
12 his mother about the boating
trip. At 10:30
he
13 went to check his e-mail, but his
brother was using
14 the computer. At 11 o'clock, he was found in
his
15 room hung by the neck from a belt
in his closet.
16 We called 911, we performed CPR to
no avail. He
17 was pronounced dead at the
hospital.
18
Reflecting on the day's events, I could
19 not detect any indication of
forethought to
20 suicide. However, later conversations with
others
21 close to Brandon inferred that he
may have been
22 having problems with the
medication.
23
The obvious question is what happened in
24 Brandon's mind between 10:30 and
10:45.
25
This was not the end of unspeakable
169
1 tragedy. Five months later, Barbara, unable
to
2 cope with the loss of her youngest
son, took her
3 life.
4
Since then I have collaborated with
5 Brandon's biological father, Dan
Ferris, to obtain
6 information that would point to
the cause of
7 Brandon's death. We believe, after having
done
8 much research, that the drug
Zoloft had a causal
9 effect in Brandon's final
actions.
10
Thank you.
11
DR. RUDORFER: Speaker 58,
please.
12
Harry Skigis
13
MR. SKIGIS: What can I say
that hasn't
14 really already been said, but I
had a speech
15 prepared and decided to revamp it
while sitting
16 here in the
audience.
17
I tried to kill myself and luckily didn't
18 succeed. I am still on Paxil
because I am hooked on
19 a nonhabit-forming drug. I don't know if I
will
20 live long enough to see how this
thing ends up, but
21 I am going to
try.
22
I have always believed that do unto others
23 as you would have done to
yourself. Would
you
24 people put your children on this
drug? Would
you
25 take it yourselves? I doubt it.
170
1
Probably not all the statistics in the
2 world can't bring back the people
that are dead
3 because of the irresponsibility of
the FDA. How
4 can I put in any faith in a
government that still
5 somewhat denies that cigarettes
are addictive?
6
I wonder if you people can sleep at night
7 while your decisions are killing
innocent people
8 every day. I leave my life in your hands and
hope
9 that you will apologize to all the
people here for
10 your decision and ignorance in
this matter and how
11 it has shattered so many people's
lives.
12
I really hope you guys can do something
13 about this or at least tell us who
will help us,
14 because a lot of people are dead
here today, and
15 it's all in your hands. So good luck.
16
DR. RUDORFER: Thank
you.
17
Speaker 59, please.
18
Pamela Wild
19
MS. WILD: On September 9,
2001, in a
20 state of confusion and
hopelessness, I put a.38
21 Special, Smith & Wesson
revolver under my chin and
22 pulled the
trigger.
23
In going through
withdrawal from Paxil, I
24 lost all ability to cope and
reason and without
25 realizing it, became
suicidal. I suffered from
171
1 sleeplessness, night sweats, light
and sound
2 sensitivity, irritability, and
dizziness.
3
I was in a constant state of terrible
4 anxiety and felt as though the
only thing holding
5 me together was my skin. I couldn't understand
why
6 others weren't seeing things my
way, as though I
7 was speaking in another language.
I was told by my
8 therapist that I had drifted into
a fantasyland.
9
She said it was though my system had been
10 poisoned somehow, I was told not
to worry, the only
11 way to die from this drug was to
fill a tub with
12 Paxil and water and drown in
it.
13
The side effects I experienced on Paxil,
14 even though I reported them to my
doctor, were
15 dismissed because no one was
warned that Paxil
16 could cause what I was
experiencing.
17
If I, at 41 years old, could not
18 articulate what was happening, how
do you expect a
19 child to?
20
There is no real medical explanation for
21
my survival. The front of my face was blown
away,
22 leaving a hole large enough to encompass a
man's
23 fist. The bullet miraculously only took
two-thirds
24 of my tongue, most of my mandible
and my cheek
25 bones. The maxilla was shattered.
172
1
The orbit of my left eye was broken and
2 forced the eyeball out onto what
remained of my
3 left cheek. It completely destroyed my hard
and
4 soft palate along with my nose and
sinus cavity.
5
I was blessed, though. I may
not able to
6 taste or smell, but at least I
lived. I can
see,
7 talk, and I can hear. But more surprising than
any
8 of those, I have brain
function. I truly
believe
9 my life was spared for a reason.
That reason is so
10 I can prevent others from
experiencing what I
11 experienced.
12
DR. RUDORFER: Thank you very
much.
13
We are up to speaker 60.
Thank you.
14
Karen Barth Menzies
15
MS. MENZIES: Good
morning. My name
is
16 Karen Barth Menzies and I am an
attorney for Baum,
17 Hedlund. We represent several thousand
SSRI
18 victims. We have been doing this for 12
years.
19
The U.S. Code of Federal Regulations
20 201.57 mandates that you require
the drug companies
21 to warn when there is reasonable
evidence, not
22 causation, reasonable evidence of
an association of
23 a serious
risk.
24
The clinical researchers who did these
25 trials on kids and the drug
companies themselves
173
1 confirmed that there are multiple
events of
2 suicidality caused by the
drug. The
methodology
3 that you are going to be using is
designed to
4 explain away those
events.
5
Even Dr. Laughren admits in the memo he
6 gave you for this hearing today
that there is
7 evidence in these trials of an
increased risk of
8 suicidality, reasonable evidence
is there. If
9 there is reasonable evidence, you
must make them
10 warn.
11
Serious risk, we certainly have that.
12 Akathisia, psychosis, mania. When you are
looking
13 at this data, you are not just
looking at the
14 suicide, also look for signs of
akathisia and
15 psychosis and mania. These aren't as
easily
16 explained away by the drug
companies, by blaming
17 the disease, by blaming the
victims.
18
When you take the potentially fatal risk
19 and couple that with lack of
efficacy of these
20 cases, why take that risk
especially when it comes
21 to our kids.
22
Paul Leber [ph] predicted this day when he
23 said that the FDA would come under
attack because
24 they weren't as demanding as they
ought to have
25 been when they were looking at the
efficacy of the
174
1 antidepressant
products.
2
Put me out of business for the right
3 reasons, warn about these drugs
and disclose.
4
DR. RUDORFER: Thank
you.
5
Speaker 61, please.
6
Amy Coburn
7
MS. COBURN: Hi. My name is Amy
Coburn.
8 I have flown here from Salt Lake
City, Utah, at my
9 own expense.
10
I am here on behalf of my father, myself,
11 and my family. My father's name was Wayne
Coburn.
12 Most people remember him as a man
full of life and
13 willing to help anyone in
need.
14
I remember my dad as a man who loved his
15 family very much and was very
loved in return, a
16 man full of ideas and hope for the
future, but like
17 many people, he found he got a
little down in the
18 wintertime. He was diagnosed with
seasonal
19 depression without suicidal
tendencies.
20
When I was 13 years old, he was put on
21 Paxil. Three weeks later he pulled his car into
an
22 old factory garage, started his
engine, and there
23 waited until he died of carbon
monoxide poisoning.
24
This naturally shocked me and my family
25 and we all had a hard time coping
with his death.
175
1 I started going to a counselor to
work through my
2 grief, and I was put on Paxil, the
same drug my
3 father was
on.
4
I started acting differently, then very
5 soon after I started having
suicidal thoughts, mood
6 swings, I was fighting with my
friends, and the one
7 thing my mom noticed is that I
wouldn't talk about
8 how I was feeling. The only thing she could
get
9 out of me was "I am fine, leave me
alone."
10
Six weeks after I was put on the drug, I
11 stayed home from school, wrote my
good-bye letters,
12 and swallowed a cupful of
poisonous bathroom
13 cleaner. I immediately got scared and ran to
my
14 neighbor's house. She called 911 and luckily
I
15 survived and I am standing here
today.
16
We soon found out that we weren't the only
17 ones who had problems with these
drugs.
Hundreds
18 of families have lost people they
love because they
19 had no idea of the effect they
could have on a
20 person's mind. All me and my family want
are
21 warnings on these
drugs.
22
DR. RUDORFER: Thank
you. I am sorry,
we
23 are out of time. Thanks.
24
Speaker 62, please.
25
Sharon McBride
176
1
MS. McBRIDE: I am here as a
mother and I
2 am here at my own
expense.
3 When
our daughter was 13 years old, she
4 came to me and said that something
was wrong with
5 her. After discussion, I took her to the
emergency
6 room where she was diagnosed with
depression.
7
After three years of intense psychotherapy
8 to discover and help the cause,
she experienced her
9 first manic episode. She was hospitalized
and
10 given lithium and a mild dose of
antipsychotic
11 medication for a brief period of
time.
12
The resulting acne and weight gain caused
13 her further depression
thereafter. Due to
my
14 inability to accept the diagnosis,
we took her to a
15 psychologist rather than a
psychiatrist to get a
16 middle-of-the-road
opinion.
17
Because she was so depressed, we did
18 eventually see a psychiatrist
again, and she was
19 prescribed one of the SSRI
medication, Zoloft.
20 Shortly after beginning this
treatment, she had a
21 serious suicide attempt. The doctor at the
22 hospital first thought that it was
just another
23 attempt trying to get attention,
but after he
24 interviewed her, his opinion
changed.
25
While she had been depressed, she had
177
1 never attempted suicide before
this time.
2 Eventually, she was prescribed
three medications,
3 one of which was Paxil. Three different times
in
4 her life she abruptly stopped
taking the
5 medications including Paxil, which
resulted in
6 manic
episodes.
7
Before her last episode, she had been
8 stable for five years. Then, during a
very
9 stressful time with her
grandmother dying, she
10 abruptly stopped the Paxil and
experienced her
11 worst manic episode with
hallucinations and other
12 health
problems.
13
She finally had to be court-ordered into
14 the hospital and it devastated her
life. She
lost
15 her job as a security assistant at
a hospital, and
16 her roommates could no longer live
with her because
17 this was not the person that they
had known and
18 loved.
19
That was two years ago and she is just
20 beginning to put her life back
together. I
would
21 encourage the committee to look
very closely at the
22 suicide attempt ratio for children
and teenagers
23 taking these SSRI
medications.
24
Thank you.
25
DR. RUDORFER: We are up to I
believe our
178
1 final speaker of the morning
session, and that is
2 Dr. Thomas
Moore.
3
Thomas Moore, M.D.
4
DR. MOORE: Good
afternoon. I
represent
5 Drug Safety Research. I have completed two
studies
6 that raise additional questions
about the safety of
7 antidepressant drugs, and both of
those studies
8 should be in your
binders.
9
The first of those concerns the medical
10 use of these drugs, who are taking
them, and the
11 headline finding is that in the
four-period 1998 to
12 2001, use of antidepressant drugs
in children
13 doubled.
14
The second finding is that less than 10
15 percent of these cases were these
drugs being
16 prescribed for FDA-approved use,
and the remaining
17 90 percent of the cases, they were
for unapproved
18 use or ones that raised safety
concerns. Let
me
19 give you some examples of what I
found.
20
Among boys 6 to
12 years old, 52 percent
21 of the use was for treating
attention deficit or
22 conduct disorders typically in
combination with an
23 antipsychotic or a stimulant, such
as Ritalin.
24
Now, I know of no scientific evidence that
25 says that combination therapy is
effective in these
179
1 disorders, and I know of no
evidence that it is
2 safe either.
3
As you go on, combination therapy was very
4 common in the real world. Twenty-two percent
were
5 taking two antidepressant drugs,
17 percent were
6 taking drugs that were ineffective
in clinical
7 trials, 42 percent were taking two
of more
8 antidepressant
drugs.
9
So, what we are seeing is when drugs are
10 ineffective, rather than
abandoning them or trying
11 alternatives, doctors increase the
dose or combine
12 the drugs in ways, the safety of
which we are not
13 aware.
14
The second major study that I submitted to
15 you today is of the adverse event
experience,
16 largely the same data set, but
different criteria
17 from what the FDA has
conducted.
18
The two key findings there are, number
19 one, it appears based on the
medical use of these
20 drugs that these drugs cause
suicidal and related
21 behaviors at double the expected
rate compared to
22 adults. So, they seem to be being reported
more
23 frequently in
children.
24
The second finding is there appeared to be
25 no difference in adverse event
reports between the
180
1 two drugs for which there were
warnings, and those
2 four drugs for which we do not
have warnings.
3
DR. RUDORFER: Thank you, Dr.
Moore.
4
We will now end our morning session. I
5 want to thank all our open public
hearing speakers
6 for raising very important issues
for the
7 committee. I believe we will have two
additional
8 public speakers during the
afternoon session, but
9 we are now going to take our lunch
break.
10
We will reconvene at 1 o'clock.
11
[Whereupon, at 11:59 a.m., the proceedings
12 were recessed, to be resumed at
1:00 p.m.
181
1
A F T E R N O O N P R O C E
E D I N G S
2
[1:10
p.m.]
3
DR. RUDORFER: Good
afternoon.
4
We are going to begin this afternoon's
5 session with several speakers from
the FDA. What
6 we are going to do is hear a total
of six speakers
7 from the FDA, as well as our two
remaining public
8 speakers. There will be a break along the
way.
9
I am going to ask the committee to save
10 your questions until the end. We will have a lot
11 of time for discussion later this
afternoon.
12
First, I would like to introduce Dr.
13 Gianna Rigoni from the Office of
Drug Safety of the
14 FDA.
15
Pediatric and Adolescent Antidepressant
16
Drug Use in the U.S.
17
DR.
RIGONI: Thank you, Dr. Rudorfer,
and
18 good
afternoon.
19
[Slide.]
20
Today, I would like to describe for you
21 antidepressant drug use trends in
children and
22 adolescents in outpatient settings
to provide a
23 context for further discussions
this afternoon.
24
[Slide.]
25
First, I will describe the use of selected
182
1 antidepressant products by
prescriptions dispense
2 in the United States, followed by
the proportion of
3 those prescriptions dispensed to
1- to
4
17-year-olds.
5
Next, I will examine the specialties of
6 the physicians responsible for
prescribing these
7 products to children and
adolescents.
8
Finally, I will identify the primary
9 diagnoses for which these products
are used in
10 these
populations.
11
[Slide.]
12
The antidepressants examined in this
13 analysis include the selective
serotonin reuptake
14 inhibitors, or SSRIs, as we refer
to today, and the
15 atypical antidepressants seen on
this list here.
16 Atypical include nefazodone,
venlafaxine, and
17 mirtazapine.
18 These
products will be presented at the
19 molecule level, therefore,
fluoxetine will refer to
20 Prozac, Prozac Weekly, Sarafem,
and all generic
21 fluoxetine equivalents, and so on,
for each
22 product.
23
All references to the term
24 "antidepressants" in this talk
will refer only to
25 these 10 products. Tricyclic antidepressants,
183
1 MAOIs, and other products used to
treat depression
2 were not examined for this
analysis.
3
[Slide.]
4
At this time, only three SSRI products
5 have FDA-approved labeling for use
in pediatric
6 population. Fluoxetine is the only
product
7 approved for the treatment of
pediatric major
8 depressive disorder at this time,
while fluoxetine,
9 sertraline, and fluvoxamine are
approved for the
10 treatment of obsessive-compulsive
disorder in this
11 population.
12
Although only three products have
13 FDA-approved labeling for the
treatment of MDD and
14 OCD, use of SSRIs and atypical
antidepressants
15 outside of current FDA labeling in
pediatrics is
16 endorsed by many in the medical
community through
17 various clinical practice
guidelines.
18
[Slide.]
19
I will now describe the methods that were
20 used in this
analysis.
21
[Slide.]
22
Since data for 2003 was not complete in
23 time for this presentation, we
will look at drug
24 use trends from 1988, the year
fluoxetine was
25 launched, through 2002.
184
1
When examining trends and prescriber
2 specialties and diagnoses related
to prescribing
3 these products, trends over a
five-year period of
4 time, from 1998 to 2002, were
used. Data on
drug
5 utilization will be presented from
sources FDA has
6 available under various
contracts. For
this
7 analysis, outpatient data was
obtained from two
8
IMS Health audits.
9
IMS is a source of marketing data commonly
10 used by the pharmaceutical
industry and government
11 agencies, and is used to obtain
numbers of
12 prescriptions dispensed, as well
as diagnoses
13 related to the recommendation of
pharmaceutical
14 products in physicians' offices in
the U.S.
15
[Slide.]
16
The first IMS Health Audit examined the
17 National Prescription Audit Plus,
or NPA Plus, as I
18 will refer from now on, measures
dispensed
19 prescriptions from the outpatient
pharmacy settings
20 seen here. We have chain, independent,
mass
21 merchandisers, food stores with
pharmacies, mail
22 order and long-term care
pharmacies.
23
The number of estimated prescriptions
24 dispensed are obtained from a
sample of
25 approximately 22,000 pharmacies in
the U.S., and
185
1 are projected
nationally.
2
[Slide.]
3
Next, we examined data from the National
4 Disease and Therapeutic Index
Audit, or NDTI, from
5 IMS Health. NDTI collects data on drug
products
6 and diagnoses mentioned during
office-based
7 physician
visits.
8
A mention is a physician's treatment
9 intention where they believe one
of the selected
10 antidepressants is appropriate,
and important to
11 remember is it could result in
either a
12 prescription, a refill
authorization, or samples
13 given to the
patient.
14
Information on trends of diagnoses,
15 patients, and treatment patterns
occurring during
16 these visits are linked to each
drug. NDTI
data
17 are obtained from a sample of
2,000 to 3,000
18 physicians representing
approximately 100
19 specialties in the U.S., and are
projected
20 nationally to reflect national
prescribing
21 patterns.
22 The
exact distribution of the specialties
23 participating in the sample each
year is
24 unavailable at this time, but is
roughly
25 proportional to the distribution
of office-based
186
1 practice specialties in the United
States.
2
[Slide.]
3
We will now examine antidepressant
4 prescription trends, prescriber
specialties, and
5 diagnoses from 1988 through
2002. I will
first
6 describe antidepressant use in the
U.S. for all
7 ages and then zoom in more
specifically on the
8 younger pediatric and adolescent
age groups.
9
[Slide.]
10
It was estimated that over 157 million
11 prescriptions for SSRIs and
atypical
12 antidepressants were dispensed in
the United States
13 for all ages in 2002. The market leaders
among
14 these 10 products were sertraline,
accounting for
15 over 31 million prescriptions,
followed closely by
16 paroxetine, with 30.5
million.
17
[Slide.]
18
I will now graphically show you the use
19 trends of these products since the
launch of
20 fluoxetine. This graph has a lot of information
on
21 it, but it displays the national
estimates of
22 antidepressant use in the U.S. in
millions of
23 prescriptions dispensed for all
ages, so this y
24 axis here is in millions, and each
product is
25 represented by a different color
line.
187
1
Here, we see how the four products on the
2 previous slide make up the highest
volumes
3 dispensed. Here, you see paroxetine,
sertraline,
4 fluoxetine, and citalopram. But more
importantly,
5 we see that for the past 15 years,
there is an
6 increasing and substantial number
of prescriptions
7 dispensed in outpatient pharmacy
settings for these
8 products.
9
We will now examine the estimated use of
10 these products in the younger
pediatric and
11 adolescent
populations.
12
[Slide.]
13
First, I must describe how we estimated
14 these numbers. Since NPA Plus data does
not
15 include the demographic
information about the
16 patients receiving each
prescription, we used NDTI
17 to estimate the number of
prescriptions dispensed
18 to 1- to
17-year-olds.
19
NPA Plus and NDTI were designed by IMS to
20 be comparable in terms of volume
of prescriptions
21 dispensed and the proportion of
office visits
22 mentioning products dispensed in
larger volumes.
23
So, to estimate the number of SSRI and
24 atypical antidepressant
prescriptions dispensed to
25 1- to 17-year-olds, the proportion
of office visits
188
1 in that population that involved
the mention of one
2 of these products were applied to
the total number
3 of prescriptions dispensed for
that year.
4
[Slide.]
5
Applying the proportion of office visits
6 to the national prescription
estimates for 2002, I
7 present to you the top five
selected
8 antidepressants in thousands of
prescriptions
9 dispensed to 1- to
17-year-olds.
10
Approximately, 10.8 million total
11 prescriptions were dispensed for
all SSRIs and
12 atypicals in this population,
representing a
13 substantial 7 percent of the
market in 2002.
14
Sertraline accounted for the highest
15 volume of prescriptions dispensed,
at 2.9 million,
16 and paroxetine followed closely
with approximately
17 2.2 million, and this is for
2002.
18
Next, I will more closely examine these
19 patterns by breaking the 1- to
17-year age group
20 into the younger pediatric
population, which will
21 represent 1- to 11-year-olds, and
the adolescent
22 population, which will represent
12- to
23
17-year-olds.
24
[Slide.]
25
When we examined use in these
189
1 subpopulations, we can still see
substantial use of
2 these products in both
groups. The
younger
3 pediatric population accounted for
approximately
4 2.7 million prescriptions
dispensed in 2002.
5 Sertraline again was the most
commonly prescribed
6 product, accounting for about 31
percent of
7 dispensed antidepressants,
followed by paroxetine
8 and then
fluoxetine.
9
The adolescent population accounted for
10 approximately 8.1 million
prescriptions dispensed
11 in 2002, and this is close to
about 5 percent of
12 all antidepressants dispensed in
that year.
13
Again, sertraline was the most commonly
14 prescribed, accounting for 26
percent, but this
15 time followed closely by
paroxetine, with 22
16 percent.
17
[Slide.]
18
Now that we better understand the trends
19 in prescriptions dispensed for
these products to
20 children and adolescents, we need
to better
21 understand the specialties of the
physicians most
22 often prescribing these
products.
23
The top prescribers of SSRIs and atypical
24 antidepressants in 1998 were
compared to those of
25 2002, and the top ranked
specialties are listed
190
1 here by age group and by
year.
2 Here,
it makes sense to see psychiatry as
3 the top prescribing specialty over
time since it is
4 hard to diagnose mental illness in
younger
5 populations. There does appear to be some
shifting
6 in prescribers over time, though,
as the pediatric
7 specialty becomes responsible for
a more
8 substantial proportion of mentions
of these
9 products in
2002.
10
As you can see, the proportion of
11 pediatricians prescribing doubles
over that
12
five-year period in both
populations, or nearly
13 doubles in
adolescents.
14
[Slide.]
15
Now, we will examine the diagnoses most
16 commonly associated with these
products in
17 office-based practices. All
diagnoses naturally
18 fell into the following four
categories:
19
Mood disorders, represented here by the
20 blue portion of the bar, include
bipolar affective
21 disorders and all depressive
disorders; anxiety
22 disorders are represented by the
red portion of the
23 bar, and they include anxiety,
obsessive-compulsive
24 disorder, and
phobias.
25
Attention-deficit disorder is represented
191
1 by the yellow portion of the bar,
and Other
2 disorders are represented by the
green portion.
3
Now, these Other disorders include other
4 diagnoses for psychiatric
illnesses, such as
5 adjustment disorder, personality
disorder, and
6 psychotic disorders, as well as
including diagnoses
7 for autism, migraine, convulsions,
menstrual
8 symptoms, eating disorders, and
drug and alcohol
9 dependency.
10
We see nearly 900,000 physician office
11 visits involved the mention of an
antidepressant in
12 the younger pediatric population
in 2002. This
13 represents approximately 1.6
percent of all visits
14 in the U.S. for these products
across all ages.
15
We also see that anxiety and mood
16 disorders were the most common
diagnoses in 2002,
17 accounting for 30 percent and 26
percent,
18 respectively, in this
population.
19
Office visits involving the mention of one
20 of these products in adolescents
is much higher, at
21 2.6 million visits for 2002, and
that represents
22 about 5 percent of the visits in
the U.S. Mood
23 disorders were the most common
diagnoses treated
24 with this product, accounting for
nearly 60
25 percent.
192
1
Next, we will look at these bars more in
2 depth as we examine diagnoses
trends for specific
3 drugs in younger pediatric and
adolescent
4 populations.
5
[Slide.]
6
This slide contains a lot of information,
7 but I believe it is important to
show that not all
8 of these products are used in the
same way in the
9 younger pediatric
population.
10
The following graph displays
the
11 distribution of diagnoses for the
top five
12 antidepressants mentioned in 2002
to this
13 population. Notice here the percent scale on the
y
14 axis. Each bar represents all mentions for
these
15 products to this age group, and
the percent is what
16 percent of the mentions for that
drug were for each
17 disorder.
18
In the younger pediatric population, we
19 see some variation in how these
products are being
20 used, and from the previous slide,
we saw that both
21 anxiety and depression or mood
disorders were
22 primarily treated with these
products. It is seen
23 right here in the
graph.
24
When we look at the top five, we also see
25 that bupropion has the distinctive
use in treating
193
1 attention deficit disorders in
this population, so
2 that middle bar signifies
bupropion, and the yellow
3 portion is
ADD.
4
[Slide.]
5
In the adolescent population, we see there
6 is not much variation in
prescribing of these
7 products. Mood disorders were the
primary
8 diagnosis being treated with all
five products, but
9 we do, however, once again see this
distinctive use
10 of bupropion for attention deficit
disorders.
11
[Slide.]
12
Next, we wanted to determine if
13 prescribing trends for these
products has changed
14 over the last five years. In the younger
pediatric
15 population, we saw a shift in
prescribing from 1998
16 to 2002, from these
antidepressants being used
17 primarily to treat mood disorders,
which were
18 identified before as bipolar and
other depressive
19 disorders, to being used more to
treat anxiety
20 disorders, such as OCD and other
anxiety or phobia
21 disorders.
22
We saw that in the adult population, there
23 was no change in prescribing from
1998 to 2002, and
24 that continuously over this time
period, these
25 products were used to treat mood
disorders in this
194
1 population.
2
[Slide.]
3
Some limitations of our drug use data
4 analysis are, first, data on
prescriptions
5 dispensed include prescriptions
filled in
6 outpatient pharmacies only. Inpatient and
7 institutional use of these
products was not
8 included in this
analysis.
9
Secondly, prescriptions dispensed to 1- to
10 17-year-olds were extrapolated
from the proportion
11 of these populations visiting a
physician and
12 receiving a prescription sample or
refill
13 authorization for one of these
products, and this
14 methodology has not yet been fully
validated.
15
Finally, data on diagnoses related to the
16 use of these antidepressants
reflects office-based
17 physicians prescribing based on a
small sample of
18 physicians. The small sample size may make
these
19 numbers unstable and could
underestimate the
20 prescribing patterns of certain
subspecialists.
21
Also, since these patients are not
22 followed into the pharmacy after
their appointment,
23 a patient may not actually fill
the antidepressant
24
prescription.
25
[Slide.]
195
1
In conclusion, use of SSRIs and atypical
2
antidepressants is
substantial in children and
3 adolescents, and appears to be
increasing rapidly
4 every year. Pediatric specialists,
pediatricians,
5 and primary care providers
continue to be the
6 leading prescribers of these
products, and over the
7 past five years, the proportion of
pediatricians
8 prescribing these products has
nearly doubled.
9
Finally, diagnoses related to the use of
10 these antidepressants are slightly
different among
11 the younger pediatric population
who are being
12 treated for mood and anxiety
disorders, and the
13 adolescent population who are
being treated mostly
14 for mood
disorders.
15
Thank you.
16
DR. RUDORFER: Thank you very
much.
17
This morning we heard from Dr. Murphy
18 about the mandated adverse event
review associated
19 with one-year post-exclusivity for
some
20 medications. Now, I am pleased to welcome
Dr.
21 Solomon Iyasu from the Division of
Pediatric Drug
22 Development who will give us a
review of that
23 information for paroxetine and
citalopram.
24
One-Year Post-Exclusivity Mandated Adverse
25
Event Review for Paroxetine and Citalopram
196
1
DR. IYASU: Good
afternoon.
2
Today, I am going to be presenting adverse
3 event reports that have been
received by FDA and
4 reviewed as mandated by the Best
Pharmaceuticals
5 for Children
Act.
6
[Slide.]
7
The Best Pharmaceuticals for Children Act
8 was enacted January 4, 2003, and
Section 17
9 mandates to FDA to review all
adverse events for
10 one year post-exclusivity
determination, and then
11 report to the Pediatric Advisory
Subcommittee for
12 their
review.
13
[Slide.]
14
The data source for my presentation, as
15 well as Dr. Mosholder's
presentation following
16 mine, is the FDA's Adverse Event
Reporting System,
17 which is a spontaneous and
voluntary reporting
18 system.
19
FDA maintains an electronic database of
20 postmarketing reports of adverse
drug reactions,
21 and reporters to this system
include health care
22 providers, pharmacies, consumers,
and
23 pharmaceutical manufacturers. A large majority
of
24 these reports come from
manufacturers.
25
[Slide.]
197
1
To make today's presentation relevant to
2 today's topic, I will be focusing
the later part of
3 my presentation on the psychiatric
adverse events
4 that have been reported during
this one-year
5 post-exclusivity
period.
6
[Slide.]
7
To give you some background about the drug
8 that I will be talking about
today, paroxetine is
9 an antidepressant that belongs to
the class of
10 drugs which are called SSRIs, is
marketed by
11
GlaxoSmithKline.
12
Adult indications that are approved by FDA
13 include major depressive
disorder,
14 obsessive-compulsive disorder,
panic disorder,
15 social anxiety disorder,
generalized anxiety
16 disorder, and posttraumatic stress
disorder.
17
The typical adult dose, which are
18 approved, are 20 to 60 milligrams
per day.
There
19 are no approved pediatric
indications, and the
20 exclusivity was granted January
27, 2002.
21
I have to point out here that exclusivity
22 to a sponsor can be granted
without getting an
23 approved indication as long as
they do the study
24 set that have been asked in the
written request
25 that FDA issues, and that they
have met the
198
1 criteria fairly as part of the
written request.
2
[Slide.]
3
To give you some important information
4 that is on the label already,
paroxetine is
5 Pregnancy Category C drug, which
means that
6 paroxetine has not been studied in
pregnancy and
7 therefore should be used only if
potential benefit
8 justifies the risk to the
fetus. It also should
be
9 used with caution in nursing
mothers.
10
There is also information on the
11 Precautions section of the label,
suicide risk is
12 inherent in major depressive
disorders especially
13 before remission occurs,
therefore, high-risk
14 patients should be supervised very
closely
15 especially during the initial
phases of therapy.
16
There are also similar precautions about
17 mania and also about seizures, and
recommendations
18 to use this medication with
caution in patients who
19 have a history of mania or
seizures.
20
There is also, on the same section,
21 adverse events with abrupt
discontinuation, which
22 includes symptoms like agitation,
anxiety,
23 dizziness, sensory disturbance,
that is related to
24 withdrawal, and therefore, the
recommendation is to
25 taper it slowly.
199
1
[Slide.]
2
Now, I would just summarize the drug use
3 trends for paroxetine, extensively
discussed by
4 Gianna before me, but paroxetine
is the second most
5 commonly used SSRI in
children. Both pediatric
and
6 adult prescriptions have steadily
increased between
7 1999 and
2003.
8
The main diagnosis linked with its use
9 include depression, anxiety,
and
10 obsessive-compulsive disorders in
children.
11
Pediatric patients account for
12 approximately 3.5 percent of the
total U.S.
13 prescriptions of Paxil between
July 2002 and June
14 2003.
15
[Slide.]
16
To give you an overview of the adverse
17 event reports that have been
received by FDA since
18 the original marketing for this
medication, there
19 were a total of 17,000 adult and
pediatric reports
20 including domestic and foreign
that were received
21 by FDA. This included duplicates, as well, and
68
22 percent of them were
domestic. Less than 5
percent
23 of these reports were in pediatric
patients
24
Looking at the top 20 pediatric adverse
25 events for this entire period, the pediatric
200
1 adverse event in the top 20 was
similar to those
2 reported in adults. The majority were
limited
3 events related to mostly the
events that resulted
4 from maternal exposure, prenatal
exposure.
5
[Slide.]
6
Looking at the annual reports of adverse
7 events for this drug since 1992,
there was
8 distinctly an increase in 2002
compared to prior
9 years. These data, the bar graphs represent
raw
10 counts of adverse events that were
received by FDA,
11 and do not exclude the duplicate
reports, and they
12 are unadjusted for
use.
13
You will notice that the last bar graph,
14 which is really representing the
first half of the
15 year, the numbers were 87, which
seems to suggest
16 that there is this continuing
increase that was
17 observed in
2002.
18
[Slide.]
19
Just to provide some context, I want to
20 mention the timeline for some
important events that
21 may have some importance in this
deliberation.
22
First, the yellow line as you see here is
23 the period of that inclusive
post-exclusivity
24 one-year period, and during that
period, there was
25 a BBC show, which is "The Secret
of Seroxat," that
201
1 was aired on October 2002 in the
British TV, which
2 subsequently got very widespread
media coverage
3 around the U.S. and other parts of
the world.
4
In 2003, the British Government warned
5 against the use of Paxil, and FDA
issued a talk
6 paper on Paxil for its treatment
of depression in
7 June 2003. Following the post-exclusivity
period,
8 in October 27, 2003, there was an
FDA public
9 advisory for antidepressants and
suicide.
10
The contents of this will be discussed
11 more fully, I think when Dr.
Laughren presents his
12 talk.
13
[Slide.]
14
Now, focusing on the mandated period,
15 which is a one-year post-exclusivity
determination
16 period, after manual review of the
reports, there
17 were a total of 127 unduplicated
pediatric adverse
18 event reports. The gender distribution was
61
19 females and 59
males.
20
The age distribution for these 127 reports
21 were zero to 2, about 32, which
mostly represented
22 maternal exposures or prenatal
exposures; 2 to 5,
23 about 6, the majority were
actually in the older
24 kids.
25
The outcomes for the 127, 10 percent of
202
1 the reports included outcomes of
death, which were
2 13. Approximately, a third of them also
ended up
3 in hospitals or at ER
visits.
4
[Slide.]
5
The age distribution, to give you a flavor
6 by type of exposure, is that in
the
7 maternal/breastfeeding exposure,
the majority were
8 in males, and in the direct
pediatric exposure, the
9 majority were
females.
10
The age distribution, as expected, in the
11 maternal/breastfeeding group, 32
of them were less
12 than 2 years of age, which
actually most of them
13 were in less than 1 month. In the direct
exposure,
14 most of the reports came from
older kids, mostly 12
15 to 16, and 6 to
11.
16
[Slide.]
17
Looking at the pediatric exposures by
18 reasons for exposure to
paroxetine, looking at 127,
19 33 of them were maternal exposure
or breastfeeding
20 exposure, and the rest of them are
described in
21 depression/dysthymia, 28;
anxiety/panic or
22 posttraumatic syndrome disorder,
about 15; ADHD, 2;
23 OCD, 1. There were about 18 of them that
had
24 multiple diagnosis of psychiatric
conditions, and
25 then Others, which are a
smattering of other
203
1 conditions which occurred in
single digit.
Unknown
2 were in 21, we did not have any
information in the
3 reports about what the reason for
exposure was.
4
[Slide.]
5
Looking again at the 127, concomitant
6 medications were described in 55
out of the 127
7 reports. Specifically, paroxetine was mentioned
as
8 the only drug used in 5 cases. In
most, it was
9 actually not described whether
there was
10 concomitant medication or
not.
11
Reporters for this 127, looking at the
12 type of reporter, one-third of the
reports were
13 actually from health
professionals, two-thirds of
14 them were from consumers, media,
or litigation
15 sources, which is really atypical
in the sense that
16 most of the reports that we get at
FDA, two-thirds
17 often come from health
professionals.
18
The dose range in the reports range from 5
19 to 60 mg/day. This excluded the
20 maternal/breastfeeding exposure.
This was really
21 looking at the children that were
exposed directly.
22
[Slide.]
23
The pediatric adverse events, looking at
24 them from predominant events,
there were about 68
25 psychiatric adverse events, and
discontinuation
204
1 syndrome or decreasing dose was
observed in 7,
2 maternal exposure in 33 as
previously described.
3
Today, I am going to be focusing more on
4 the psychiatric adverse events,
which are 68
5 reports that were received, and
then the rest of
6 the presentation in terms of
describing the other
7 events will be in tomorrow's
presentation which I
8 will be doing to the same
committee.
9
[Slide.]
10
Looking at those 68 adverse events, and
11 looking at labeled and unlabeled
events, there were
12 about 9 completed suicides
reported, 17 suicide
13 attempts, and suicidal ideation in
11 patients, and
14 occurrence of other psychiatric
symptoms that
15 included mania, impulsivity,
disinhibition, or
16 obsessive behavior, and so
forth.
17
Then, unlabeled events were self-injurious
18 behavior in about 10 patients,
completed homicides
19 in about 4, and then aggression,
hostility,
20 homicidal ideation in about 8
patients.
21
[Slide.]
22
Looking more closely at the psychiatric
23 events, the gender distribution
was 57 percent of
24 them were in females. The age distribution,
most
25 of them were in the older children
12 to 16 years
205
1 of age, 60 percent of them, and 35
percent in 6 to
2 11 years
old.
3
Concomitant medications were described
4 only in 24 patients out of the 68,
we did not have
5 any information on the rest of
them. In 20 of
the
6 24 patients, there were other
psychotherapeutic
7 agents being used, as
well.
8
Discontinuation or decrease in dose was
9 noted in about 11 of the 68
patients that were
10 reported.
11
[Slide.]
12
Going more in detail as to the
13 discontinuation or decrease in
dose with respect to
14 psychiatric events, among the
completed suicide, 1
15 out of the 9, there was
discontinuation or decrease
16 in dose involved; suicidal
attempts, 5 out of the
17 17, and 2 out of the 4 for
homicides, and then 3
18 out of the 8 for the
aggression/hostility/homicidal
19 ideation.
20
[Slide.]
21 Looking
closely at the suicide attempts,
22 which were about 17, the majority
of them were
23 being treated for MDD or bipolar
disorder.
24 Concomitant medications were
mentioned in
25 approximately one-third of these
patients, and
206
1 discontinuation or decrease in
dose in
2 approximately
one-fourth.
3
[Slide.]
4
Pediatric deaths, there were a total of 13
5 as I mentioned before. Because of the topic
today,
6 I will talk about the 9 completed
suicides, and the
7 rest of the patients will be
discussed in
8 tomorrow's
presentation.
9
[Slide.]
10
Among the 9, the age distribution was 12
11 to 16 years, and then the gender
distribution of 5
12 females and 4 males. Initial diagnosis in
these
13 patients, 5 of them was major
depressive disorder,
14 1 explosive disorder, in 3 of them
it was not
15 known.
16 Duration
of treatment ranged from 14 days
17 to 1 year. Discontinuation was mentioned in
2
18 patients. Concomitant medications, that
included
19 also some psychotherapeutic
agents, was mentioned
20 in 4 patients, and there was
possible substance
21 abuse in 4 patients, and a history
of prior
22 attempts in 3 of
them.
23
[Slide.]
24
In summary, the causality assessment was
25 very difficult in many of the
reviews that we have
207
1 done with these reports, and many
of the
2 psychiatric events that were
described in the
3 reports occurred in patients with
underlying
4 psychiatric disorders, therefore,
severity of
5 illness/underlying disease may
play a role, and it
6 was very difficult to disentangle
its effect from
7 what might have been going
on.
8
There is also a prior history of suicide
9 attempts in some of the patients,
and in others,
10 there was no negative history of
this. The
other
11 factors in terms of patient
factors are concomitant
12 medications that were mentioned in
several of these
13 patients, and also the lack in
others. So,
there
14 is the variability in terms of the
type and the
15 quality of the reports that we
got.
16
In terms of the reporting factors, there
17 was inadequate detail in
describing the event.
18 They also varied in terms of
descriptions that were
19 in the
reports.
20
The timing of event in relationship to the
21 medication was not always clear in
many of these
22 reports, and also ascertainment of
reported events
23 by medical professions was absent
in many of these
24 reports. The lack of follow-up information
also
25 made it difficult to assess.
208
1
[Slide.]
2
I also want to mention the nature of the
3 data system that we have, which is
really a passive
4 spontaneous and voluntary system,
and it suffers
5 from a number of
limitations.
6
Often there is underreporting of important
7 events, and there may be also the
reporting biases
8 that are influenced by either
media publicity, and
9 also the well-known variability in
terms of reports
10 that we get or the frequency of
report related to
11 the length of time that a drug has
been in the
12 market. In the early period of the
marketing,
13 there are more reports than
later.
14
The report quality, as I said, also may
15 vary, missing details, example,
concomitant
16 medications is a common
problem. Also,
because
17 this is really enumerated data, we
could not really
18 estimate true incidence rate of
events or exposure
19 risk for many of these medications
that we have
20 reports for.
21
So, the AERS database has some serious
22 limitations in terms of
interpreting the data that
23 we have.
24
[Slide.]
25
In closing, the psychiatric events
209
1 described in the adverse event
reports may actually
2 reflect to the underlying disease,
because many of
3 these events are also unexpected
in other natural
4 progression of the disease or part
of the disease
5 picture.
6
It may also be a drug effect or other
7 concomitant medication, or it may
actually be lack
8 of effectiveness of the drug, and
it is very
9 difficult from these reports to
sort out what is
10 going on.
11
Therefore, evaluation of the controlled
12 trials is necessary to sort out
causality in terms
13 of the observed adverse
events.
14
[Slide.]
15
I am going to continue with the next drug,
16 which is citalopram, but I would
like to
17 acknowledge the following
individuals for their
18 contribution for their
review.
19
[Slide.]
20
Next, I will cover, as mandated by BPCA,
21 citalopram, and will be talking
about the adverse
22 events in
detail.
23
[Slide.]
24
To give you some background again about
25 citalopram, it's an antidepressant
belonging to
210
1 SSRIs, and marketed by Forest
Pharmaceuticals.
2
Its current approved adult indication is
3 for major depressive
disorder. The adult
dose
4 ranges from 20 to 40 mg/day. There are no
approved
5 pediatric
indications.
6
The original market approval was July 17,
7 1998, and exclusivity was granted
July 9, 2002.
8
[Slide.]
9
Again, to mention some of the relevant
10 safety labeling which already
exists, Pregnancy
11 Category C, as I mentioned before,
and also a
12 caution against the use in nursing
mothers.
13
There is also a Precaution section that
14 mentions, similar to what is
observed for Paxil,
15 suicide risk inherent in
depression and also the
16 danger of activation of mania and
hypomania.
17
Also, additional events mentioned in the
18 precautions, any psychoactive
agent may impair
19 intellectual or psychomotor
functions, and
20 therefore, care should be
exercised in prescribing
21 these medications when individuals
have to operate
22 machinery or other things that may
require
23 intellectual and motor
functions.
24
Seizures is another precaution that is
25 mentioned especially in those with
history of
211
1 seizure.
2
[Slide.]
3
Additional safety information in the
4 Adverse Reaction section is about
agitation with
5 the use of citalopram, and also
additional
6 premarketing reports which are
frequent, impaired
7 concentration, depression, suicide
attempt, and
8 confusion; and infrequently
reported in premarket
9 reports are aggressive reaction,
psychotic
10 reaction, delusion, paranoid
reaction, emotional
11 lability, and panic
reaction.
12
[Slide.]
13
To give you just a summary of the drug use
14 pattern, it is the fourth most
commonly used SSRI
15 in children. Again, use had been increasing
in
16 recent years. Pediatric patients account
for
17 approximately 3.3 percent of the
total U.S.
18 prescriptions of
Celexa.
19
Pediatric diagnoses most often linked with
20 its use are depressive
disorders,
21 obsessive-compulsive disorder, and
attention
22 deficit
order.
23
[Slide.]
24
Since marketing, there were over 6,000
25 reports which included also
duplicates that were
212
1 reported to FDA, 79 percent of
them were domestic.
2 Less than 5 percent of the reports
were in
3 pediatric
patients.
4
The top 20 pediatric adverse events were,
5 looking at that, all adverse
events related to in
6 utero exposure were unlabeled,
which actually
7 happened to be in the top 20 for
pediatric adverse
8 events.
9
Adverse event reports for children
10 involving direct exposure were
generally similar to
11 those reported for
adults.
12
[Slide.]
13
After a
manual review of the one-year
14 post-exclusivity period, there
were 42 unduplicated
15 reports that were pediatric. Sixteen of them
were
16 in utero exposures, and resulted
in unlabeled
17 events and one
death.
18
There were 26 children
involving direct
19 exposure, 8 unlabeled events, and
no deaths in this
20 group.
21
Looking at the outcomes, there were 16
22 serious outcomes, 10
hospitalizations, 4
23 life-threatening, and 2 was
disability. For
the
24 direct exposure group, the dose
range was typically
25 5 to 60 mg/day. The median dose was about 20
213
1 mg/day in these
reports.
2
[Slide.]
3
Again looking at the age distribution, in
4 the in utero exposure, most of
them female, as well
5 as in the direct exposure group,
and age
6 distribution is 0 to 1 in 15
patients, and then
7 most of the direct exposure group,
in older
8 children.
9
[Slide.]
10
Looking at the reasons for exposure to
11 citalopram, there were 26 direct
pediatric
12 exposures and then 16 in utero
exposures. I
am
13 going to just focus on the adverse
events
14 pertaining to psychiatric, but
these are the
15 reasons for why they were
exposed.
16
[Slide.]
17
There were only 5 psychiatric events, in 5
18 patients where there were
psychiatric events, and
19 these are broken down by labeled
and unlabeled
20 events.
21
In the labeled events are the cognitive
22 impairment, aggression, agitation,
mania, and
23 delusions, suicidality, and
psychotic reaction.
24
Unlabeled events are the violent/homicidal
25 behavior, which were observed in 2
of the patients.
214
1
[Slide.]
2
Looking at these 5 patients with
3 psychiatric events, there were 4
males and 1
4 female. The age distribution as 6 to 11 years
with
5 2; 11 to 16, about 3 of them. Diagnosis in 4 of
6 them was MDD, and 1 case was
oppositional defiant
7 disorder,
ODD.
8
Concomitant medications were reported in 2
9 patients, Prozac in 1, and
another, Keppra and
10 clonazepam. Symptom resolved once
citalopram
11 discontinued in 4 according to the
reports.
12
[Slide.]
13
In closing, I would like to say there were
14 few psychiatric events that were
reported during
15 this one-year post-exclusivity
period, unable
16 really to determine causality due
to limitations of
17 the AERS database, therefore, we
will continue to
18 monitor these adverse events in
children.
19
I would like to reiterate the same
20 limitations that I mentioned
before with respect to
21 paroxetine when I talked about
limitations of the
22 AERS
database.
23
Thank you very much for your attention.
24
DR. RUDORFER: Thank
you.
25
Dr. Andrew Mosholder will now speak on the
215
1 Office of Drug Safety Data
Resources for the Study
2 of Suicidal
Events.
3
Andy.
4
Office of Drug Safety Data Resources for
5
the Study of Suicidal Events
6
DR. MOSHOLDER: Thank you
very much.
7
I am very pleased to be here this
8 afternoon. I am going to talk about how we
looked
9 at some of our Office of Drug
Safety data resources
10 to see if they would be relevant
to exploration of
11 this issue.
12
[Slide.]
13
It is very much a team effort and I want
14 to start by acknowledging my
colleagues who
15 assisted me.
16
[Slide.]
17
The objective of my brief presentation
18 will be to describe the data
resources we have
19 available in the Office of Drug
Safety at FDA that
20 are relevant to this issue, and,
in particular,
21 looked at two types of databases,
the first being
22 the postmarketing surveillance
database that Dr.
23 Iyasu just described, and also
some
24 population-based epidemiological
databases.
25
Also, I will be describing the context of
216
1
spontaneous postmarketing reports of these
2 types of events with newer
antidepressants.
3
[Slide.]
4
Turning first to the postmarketing
5 surveillance data from the AERS
system as you have
6 just heard
about.
7
[Slide.]
8
We did a special search for these events,
9 and I will describe the
methods. The list of
drugs
10 is shown here, and it is the same
drugs we have
11 been discussing throughout the
day. We limited
the
12 age on the report to patients
17 years or
younger,
13 and we looked at U.S. reports
only.
14
[Slide.]
15
In the AERS database, the events are
16 classified under particular
adverse event terms
17 according to the so-called MedDRA
dictionary.
We
18 chose a list of event terms that
we thought would
19 capture suicidal behaviors and
ideation. I
will
20 let you read for yourselves the
list, but that was
21 the list of terms that we searched
in the AERS data
22 base for those
events.
23
[Slide.]
24
The results showed for all those drugs
25 over their full marketing history,
there was a
217
1 total of 524 case reports, of
which 110 were death
2 reports. I should add that these are raw
counts,
3 which means there was no hands-on
review for
4 duplicate
reports.
5
Occasionally, the same case will be
6 reported by more than one health
professional or
7 the health professional and the
consumer, and those
8 are referred to as duplicate
reports. So,
these
9 are just the raw
counts.
10
[Slide.]
11
Here they are broken down by drug, and you
12 see they are ranked in order. You see fluoxetine
13 has the most, and, roughly
speaking, the numbers of
14 reports parallels the prevalence
of their use in
15 the pediatric population, so that
is not too
16 surprising.
17
[Slide.]
18
What this displays is the same totals
19 broken down by year of
reports. So, we see
the
20 year the report was received down
here on the x
21 axis, and the number of
reports.
22
A couple of things to observe here.
First
23 of all, for most of the drugs, we
see that there is
24 between, say, zero and 10 reports
annually, and
25 then, of course, there are these
two sort of
218
1 exceptions to that. There is a peak over here
in
2 the early '90s, and that is for
fluoxetine, and
3 then in the last two to three
years, there is
4 another peak, and that is for
paroxetine.
5
The one thing to point out here relevant
6 to the fluoxetine, as I am sure
everyone is aware,
7 this peak coincides with the
controversy in the
8 early '90s about whether
fluoxetine can induce
9 suicidality. In fact, in 1991, there was
an
10 advisory committee about that
topic.
11
To understand this increase with the
12 paroxetine reports, we looked at
that in a little
13 more detail, as I will show
you.
14
[Slide.]
15
This shows the proportion of reports
16 according to whether they were
consumer or health
17 professional, and the interesting
thing here is
18 that while the health professional
reports have
19 remained fairly constant over the
years, what we
20 see in the last two to three years
is an increase
21 in the proportion of reports that
are coming from
22 consumers, which, of course,
doesn't mean that they
23 are not legitimate reports, but it
does illustrate
24 that there is some influence on
the spontaneous
25 reporting that is encouraging
consumers to report
219
1 more of the these events in the
last few years, and
2 that seems to account for this
increase.
3
[Slide.]
4
To go into things a little more in depth,
5 we decided to look at reports from
the first three
6 years of marketing and do an
in-depth review.
7
We took reports for all 10 drugs from the
8 first three years that they were
marketed in the
9 U.S. This is a standard way
in
10 pharmacoepidemiology of comparing
reports across
11 drugs to account for the so-called
Weber effect
12 that applies during the first
three years of a
13 drug's marketing
history.
14
Even so, during this time period, there
15 was limited pediatric use of these
drugs, and
16 because of secular trends, changes
in reporting
17 systems, and other variables, it
is still very
18 difficult to make quantitative
comparisons between
19 drugs.
20
[Slide.]
21
So, we looked at these reports, we
22 eliminated duplicate reports, and
we chose four
23 suicide-related categories -
suicidal ideation,
24 suicide attempt, completed
suicide, and
25 self-mutilation, and classified
the reports into
220
1 one of those
categories.
2
[Slide.]
3
This shows the results.
There were 94
4 reports retrieved from the AERS
system. After
5 review for duplicates, there were
78 unduplicated
6 reports, which gives you an idea
of the proportion
7 of duplication. It is something like 15
percent.
8
This was for 9 drugs, no cases for
9 nefazodone. Out of these 78 reports, most
were
10 female, most were over 12 years of
age, and that is
11 consistent with what we know about
the epidemiology
12 of suicidal behavior in
adolescents. Most of
the
13 events were classified as suicide
attempts.
14
There were 7 completed suicides, 6 with
15 fluoxetine, 1 paroxetine, 4 males,
and 3 females.
16 We found no reports of rechallenge
with the same
17 drug, which is sometimes used as
an indication of
18 evaluating the
causality.
19
[Slide.]
20
This slide shows the numbers of reports by
21 category here and by drug. If you look at the
22 total, you see that, as I already
mentioned, 67 out
23 of 78 were in the suicide attempt
category.
24
Again, these are ranked in terms of the
25 totals. You see that fluoxetine again has the
221
1 most. Again, this sort of roughly
parallels the
2 prevalence of their pediatric
use.
3
[Slide.]
4
So, interpreting these results, we would
5 say that suicidality was reported
with all drugs.
6 The drugs with the largest numbers
of reports
7 coincided, roughly speaking, with
the greatest
8 amount of pediatric
use.
9
The reporting is variable and appears to
10 be influenced by various events
and also because of
11 the quality and variability and
low pediatric use,
12 the data really do not support
quantitative
13 comparison between
drugs.
14
[Slide.]
15
In general, AERS data are most useful for
16 distinctive or rare adverse drug
reactions, such as
17 aplastic anemia. The problem here, as Dr.
Iyasu
18 has already described, is that the
outcome of
19 interest that we are tracking,
which is
20 suicidality, is also an outcome of
the indication
21 for which the drug is prescribed,
so that it is
22 very difficult to sort out whether
the drug played
23 a role or whether it was the
underlying disorder
24 from evaluating data of this
type.
25
[Slide.]
222
1
I want to move on to look at some other
2 data resources that we have in ODS
and tell you
3 about that.
4
[Slide.]
5
We looked at four principal sources that
6 could be used, one, the Tennessee
Medicaid.
That
7 is a health care claims
database. We have
two
8 surveillance databases. I will let you read
the
9 descriptions, but they are
maintained by CDC and
10 the Consumer Products Safety
Commission.
11
This one applies to hospital emergency
12 rooms, and this one applies to
emergency rooms and
13 also ambulatory
care.
14
Finally, there is the Oregon Adolescent
15 Suicide Attempt Data System. In the State of
16 Oregon, adolescent suicides and
suicide attempts
17 are reportable conditions, so that
the State Center
18 for Health Statistics maintains a
database on those
19 reports.
20
[Slide.]
21
To summarize briefly, there are
22 significant limitations in
attempting to use these
23
data sources to evaluate
this issue. One
was
24 rarity of completed suicide,
difficulty in
25 identifying individuals with
outcome of completed
223
1 suicide. It may not generate a health care
claim,
2 for example.
3
There is great difficulty in classifying
4 non-fatal suicidal behavior, as we
have already
5 heard about, difficulty obtaining
data on drug
6 exposure prior to the event, lack
of suitable
7 control groups, confounding by
indication, and
8 privacy
restrictions.
9
[Slide.]
10
In conclusion, for the study of this issue
11 of pediatric suicidal behavior
associated with
12 antidepressant treatment, the
available
13 pharmacoepidemiological data and
postmarketing
14 surveillance data is of limited
utility, and
15 randomized, controlled trial data
should be
16 superior to these
sources.
17
Thank you very much.
18
DR. RUDORFER: Thank
you.
19
Open Public Hearing
20
DR. RUDORFER: We will now
turn to the
21 afternoon portion of our open
public hearing.
22
I am mandated to read the ground rules for
23 meetings of general matters, so if
you will bear
24 with me for a moment, I need to
address our open
25 public hearing speakers.
224
1
Both the FDA and the public believe in a
2 transparent process for
information gathering and
3 decisionmaking. To ensure such transparency
at
4 this open public hearing session
of the Advisory
5 Committee meeting, FDA believes
that it is
6 important to understand the
context of an
7 individual's
presentation.
8
For this reason FDA encourages you, the
9 open public hearing speaker, at
the beginning of
10 your oral statement to advise the
committee of any
11 financial relationship that you
may have with any
12 company or any group that is
likely to be impacted
13 by the topic of this meeting. For example, the
14 financial information may include
a company's or a
15 group's payment of your travel,
lodging, or other
16 expenses in connection with your
attendance at the
17 meeting.
18
Likewise, FDA encourages you at the
19 beginning of your statement to
advise the committee
20 if you do not have any such
financial
21 relationships. If you choose not to address
the
22 issue of financial relationships
at the beginning
23 of your statement, it will not
preclude you from
24 speaking.
25
With that, we will turn to our first
225
1 afternoon speaker, David
Fassler.
2
David Fassler, M.D.
3
DR. FASSLER: Thank you. My name is David
4 Fassler. I am a child and adolescent
psychiatrist
5 practicing in Burlington,
Vermont. I am
speaking
6 today on behalf of the American
Psychiatric
7 Association where I serve on the
board of trustees.
8
The APA represents over 35,000 psychiatric
9 physicians across the
country. The APA
receives
10 funding from a variety of sources
including
11 pharmaceutical companies, but no
pharmaceutical
12 funding was used in conjunction
with my appearance
13 today or the preparation of my
comments.
14
You have already heard lots of testimony
15 today, so let me try and briefly
highlight and
16 underscore a few key
issues.
17
First, childhood and adolescent depression
18 is a very real illness which will
affect between 3
19 and 5 percent of all young
people. The good
news
20 is that we can help most kids who
suffer from this
21 disorder. Intervention is most effective when
it
22 begins early and when it involves
a comprehensive
23 treatment plan individualized to
the needs of the
24 child and
family.
25
Because we care deeply about children, we
226
1 encourage parents to be advocates
for their kids,
2 to ask lots of questions about any
proposed course
3 of treatment. We also encourage the FDA to
develop
4 mechanisms to enhance access to
data from clinical
5 trials including negative trials,
as well as
6 unpublished
research.
7
We believe that such access would
8 facilitate scientific discussion
and dialogue and
9 help physicians and parents make
fully informed
10 decisions about treatment
options.
11
Second, with specific reference to
12 suicidal ideation, it is important
to emphasize
13 that such thinking is always a
very real concern,
14 and as you have heard this
morning, it is also not
15 uncommon.
16
From the Youth Risk Behavior Survey, we
17 know that 1 adolescent in 5 thinks
about suicide
18 each year, and that by the end of
high school, at
19 least 1 in 10 has made an actual
suicide attempt.
20
Third, medications can be extremely
21 helpful and even lifesaving for
some children, but
22 medication alone is rarely a
sufficient treatment
23 for complex child psychiatric
disorders such as
24 depression.
25
Finally, we are concerned that the
227
1 publicity surrounding this issue
may frighten some
2 parents and discourage them from
seeking help for
3 their children. This would be a real tragedy
since
4 the reality is that we really can
help most of
5 these kids.
6
DR. RUDORFER: Thank you, Dr.
Fassler.
7
Our next speaker is Dr. Lawrence Diller.
8
Lawrence Diller, M.D.
9
DR. DILLER: Last but not
least. I am
10 behavioral developmental
pediatrician who has
11 prescribed psychiatric drugs to
children for 26
12 years. I have no financial connections to
the
13 industry.
14
I am the author of Running on Ritalin and
15 Should I Medicate My
Child.
16
As a front-line practitioner, I have lost
17 faith in my research academic
colleagues to provide
18 me the data information, opinion,
and conclusions
19 in an objective and unbiased
fashion. I
20 desperately need that information
in order to
21 validate and augment the clinical
decisions I must
22 make every day on who does and
doesn't get
23 medication.
24
Unfortunately, in my quarter century of
25 practice, I have seen child
psychiatry's biologic
228
1 revolution hijacked by a
for-profit drug industry.
2 Drug companies so pervasively
influence academic
3 research, professional education,
now direct
4 consumer information, ultimately
determining the
5 very way society views its own
problems.
6
I see top research leaders in the field of
7 child psychiatry simultaneously
publishing papers
8 in scientific peer-reviewed
journals while
9 appearing in press conferences for
corporations
10 that have funded the research,
which is then
11 reported in the Wall Street
Journal.
12
We learn of nonpublication agreements of
13 negative finding studies and
limited access to raw
14 data that potentially allows for
completely
15 different interpretations or
conclusions based upon
16 the published
information.
17
At this time, the conflict of interest
18 between my academic colleagues and
the drug
19 industry rivals that of the stock
analysts and the
20 brokerage firms. Doctors are at risk of
being
21 regulated by the government, but
this is unlikely
22 to happen soon since the public
and the Congress
23 have been similarly influenced or
bought by these
24 powerful
corporations.
25
Unfortunately, it will take children dying
229
1 followed by trial lawyer class
action suits to get
2 changes either in the practice or
the regulation of
3 the SSRIs. That is a heck of a costly way,
both
4 the individual families and the
public, for what
5 should be routine formal
postmarketing drug
6 surveillance funded by neutral
third parties.
7
Until then, I hope there is more
8 government-funded research, but as
long as I only
9 have research funded or suppressed
by drug
10 companies, I will remain quite
cautious and
11 hypervigilant over what I
prescribe the youth of
12 America.
13
Thank you.
14
DR. RUDORFER: Thank you, Dr.
Diller.
15
At this time we are going to take just a
16 very quick break and return for
further speakers
17 from the FDA. Let's say five
minutes if possible.
18 Thanks.
19 [Break.]
20
DR. RUDORFER: We have three
additional
21 speakers from the FDA who will
address some of the
22 important data at hand and that is
still emerging.
23
First, I am pleased to introduce Dr.
24 Thomas Laughren, who is team
leader of the Division
25 of Neuropharmacologic Drug
Products, who will
230
1 discuss with us the regulatory
history on
2 antidepressants and suicidality,
and give us an
3 update on current plans for the
analysis of
4 pediatric suicidality
data.
5
Regulatory History on Antidepressants and
6
Suicidality and Update on Current Plans
7
for Analysis of Pediatric Suicidality Data
8
DR. LAUGHREN: Thank you,
Matt.
9
[Slide.]
10
I am going to talk very briefly about the
11 regulatory history of
antidepressants and
12 suicidality, and then spend most
of my time talking
13 about our current plans for
looking at the
14 pediatric suicidality data coming
out of the
15 controlled
trials
16
But first I would like to thank the
17 families who came forward this
morning to talk
18 about their very personal stories,
both the
19 families that talked about tragic
outcomes and
20 those who talked about children
who appear to have
21 been helped by
medications.
22
It is very hard to do that, and I think it
23 helps us to put all of this
discussion in context,
24 but a very important point, and
this has been made
25 several times, it is very
difficult to assess
231
1 causality based on individual
cases. That is
true
2 both of those cases where the
outcome is tragic,
3 but also true of the cases where
the outcome is
4 good.
5
For either of those, we have to turn to
6 controlled trials, so my focus is
going to be on
7 the controlled
trials.
8
[Slide.]
9
What I have given you in this slide is
10 the standard language which is in
all
11 antidepressant labeling, and has
been in
12 antidepressant labeling for
decades. This is
in
13 the Precaution section. Essentially, it
warns
14 clinicians of the possibility of a
suicide attempt
15 in major depressive disorder, and
advises
16 clinicians especially early in
treatment to watch
17 patients very
carefully.
18
Now, this statement does not explicitly
19 warn of the possible linkage
between antidepressant
20 use and the emergence of
suicidality, but I think
21 it allows for that interpretation
and, in fact,
22 this idea that antidepressants may
be associated
23 with the emergence of suicidality
early in
24 treatment has been around for a
very long time in
25 psychiatry.
232
1
[Slide.]
2
This is a statement from a textbook of
3 psychiatry published in 1960. This was the time
at
4 which the tricyclic
antidepressants had just come
5 on the scene. Let me read it.
6
It says, "With beginning convalescence,
7 the risk of suicide once more
becomes serious as
8 retardation
fades."
9
[Slide.]
10
What this statement is referring to is
11 what is commonly known as the roll
back phenomenon.
12 This is the observation again of
emergent
13 suicidality early in treatment and
the belief, the
14 belief that that is in some way
linked to the use
15 of the drug, and the view, the
mechanism proposed
16 is that antidepressants give
patients increased
17 energy, particularly those with
psychomotor
18 retardation, that allows them to
act on their
19 suicidal ideas before the drug has
had a chance to
20 affect mood.
21
So, this is one proposed mechanism for
22 this observation. In fact, it is only one
of
23 several proposed mechanisms. When we met with
the
24 advisory committee in 1991, to
talk at that time
25 about Prozac and the possibility
of suicidal
233
1 induction, Dr. Martin Teicher from
Harvard
2 University reviewed a number of
proposed mechanisms
3 to explain this observation
including the roll back
4 phenomenon.
5
But he also talked about the possibility
6 of actually a paradoxical
worsening of depression,
7 in other words, the mood actually
becoming worse
8 rather than
better.
9
He talked about the possible role of
10 akathisia, which is associated
with many of these
11 drugs, about the induction of
anxiety and panic
12 attacks by some of these drugs,
about the idea that
13 patients with bipolar depression
may experience a
14 stage shift, in other words,
moving from depression
15 to a mixed state, and finally,
even the induction
16 of insomnia.
17
All of these ideas, the idea is that once
18 these behaviors are induced, there
is then a link
19 from that behavior to suicidality,
and all of these
20 proposed mechanisms have some
plausibility, but it
21 is quite a different matter
between proposing a
22 mechanism and empirically
establishing that there
23 is, in fact, a link between the
use of an
24 antidepressant and the emergence
of suicidality.
25
[Slide.]
234
1
That is really the question that we are
2 dealing with here today and that
is the question we
3 hope to be able to address with
these clinical
4 trials data for these pediatric
studies: Is
there
5 a causal link between
antidepressant drug use and
6 suicidality in pediatric patients
with major
7 depressive disorder or with other
psychiatric
8 disorders?
9
We agree that
this is a critically
10 important question to answer, but
we also feel that
11 it is important to answer it in a
careful and
12 thoughtful manner because to err
in either
13 direction has significant
consequences.
14 Clearly,
we do not want to miss a signal
15 of increased risk of suicidality,
because that
16 would give us greater comfort in
the use of these
17 drugs than would be
warranted.
18
On the other hand, we don't want to reach
19 a premature decision on the
strength of the signal
20 because that could result either
in the overly
21 conservative use of these
medications or in their
22 lack of availability all together
for treating
23 pediatric depression. So, it is important to
get
24 it right.
25
[Slide.]
235
1
In this slide, what I have done is to list
2 the 9 drugs that are involved in
our ongoing
3
review. You have seen this list before
today.
4 This involves a total of 25
studies in pediatrics,
5 16 of them in major depression,
the others in
6 various other pediatric disorders,
involving a
7 total of over 4,000
patients.
8
[Slide.]
9
Right now let me talk a little bit about
10 how the signal came onto our radar
screen. We
had
11 reviewed over the past three to
four to five years
12 pediatric supplements for 8 drugs,
and we looked at
13 the safety and efficacy data for
these drugs.
14
In the course of putting together a report
15 for FDA, companies code their
adverse event data,
16 and they do this in their own
ways. We don't
tell
17 them how to code the data, they
choose their own
18 dictionaries and they set about
coding the data
19 before they send it
in.
20
This applied to any events suggestive of
21 suicidality, as well as any other
adverse events.
22 We reviewed those supplements over
this period of
23 three to four years, and
suicidality did not emerge
24 as a matter of concern based on
those reviews.
25
However, the Paxil review did raise a
236
1 question about data management in
that events
2 suggestive of suicidality were
coded under the
3 general preferred term "emotional
lability."
4
This struck the reviewer as rather odd,
5 and so in responding to GSK, we
asked them to
6 separate out the verbatim terms
suggestive of
7 suicidality under a term specific
to suicidality.
8
[Slide.]
9
That request to GlaxoSmithKline resulted
10 in additional work and ultimately
resulted in a
11 report on paroxetine and pediatric
suicidality.
12 That report went first to the MHRA
-- that is FDA's
13 counterpart in the UK -- and
shortly thereafter to
14 FDA in May of last
year.
15
That report indeed suggested an increased
16 risk of suicidality associated
with paroxetine use
17 in particular in one of the three
studies done in
18 pediatric
depression.
19
[Slide.]
20
What I am going to do in the next two
21 slides is to quickly walk you
through a timeline of
22 key events that occurred over the
past eight months
23 to try and give you a sense of how
we got from the
24 time of that initial report up to
the present time.
25
So, that report was issued in May.
In
237
1 June, both FDA and MHRA issued
regulatory
2 responses. As you heard earlier, the
MHRA
3 essentially contraindicated
paroxetine in pediatric
4 depression. FDA came out with fairly
strong
5 language that recommended against
its use in
6 pediatric depression, but stopped
short of a
7 contraindication, and, in essence,
we said that we
8 were continuing to look at the
data.
9
In July, we issued a request to sponsors
10 of the eight other antidepressant
products asking
11 them to look at the suicidality
data in their
12 databases using an approach
similar to that, that
13 had been used by GSK, and I will
talk about that
14 approach a little bit
later.
15
So, in essence, we wanted to look at
16 summary data from the other
programs, similar to
17 what had been given to us for
Paxil. In August
of
18 last year, we went back and
relooked at the
19 suicidality data in the pediatric
supplements.
20
In August, Wyeth, the manufacturer of
21 Effexor, having responded to our
July request and
22 having looked at their data,
decided that they did
23 have a signal and they made a
labeling change which
24 they are allowed to do under
changes being effected
25 without our prior approval, so
they changed their
238
1 labeling, adding information about
that perceived
2 signal, and they also sent a Dear
Doctor letter
3 which essentially recommended
against the use of
4 Effexor in
pediatrics.
5
Also, at that time, MHRA contraindicated
6 Effexor in pediatric
depression.
7
In September of last year, we held an
8 internal regulatory briefing at
FDA. We hold
these
9 briefings basically to update
upper management on
10 key issues that are before us, and
this certainly
11 was a key issue, and we have the
briefing.
12
There were a number of recommendations
13 that came out of that
briefing. Two were
of
14 critical importance to our ongoing
review. One
of
15 those was the suggestion that we
think about
16 reclassifying the cases, because
there was some
17 uncertainty about what this
diverse array of events
18 coded under this broad term
"possibly
19 suicide-related" actually
meant. So, there was
a
20 suggestion that we do
that.
21
There was also a suggestion that we think
22 about doing a more refined data
analysis, allowing
23 the use of adjustment for
covariates.
24
[Slide.]
25
In September and October, we began to get
239
1 responses to our July requests for
summary data for
2 other antidepressants, and it gave
us some cause
3 for concern, because we were
seeing that sponsors
4 had not used exactly the same
approaches that we
5 had suggested in our July
request.
6
In October, we issued an updated Public
7 Health Advisory, at this time
essentially
8 broadening the concern to all
antidepressants.
In
9 essence, we advised clinicians to
use caution when
10 using these drugs in pediatric
depression,
11 essentially, to pay attention to
the language that
12 is already in
labeling.
13
In October, having thought more about a
14 patient level data analysis
allowing us to look at
15 covariates, we issued a response
to all
16 antidepressant manufacturers
asking them to give us
17 patient level data sets to allow
us to do this
18 analysis.
19
Also, in October, having thought more
20 about the reclassification effort,
we decided,
21 instead of trying to do this
inside FDA, we decided
22 to go outside FDA and get an
outside expert group
23 to help us with this
reclassification.
24
In November and December, having thought
25 more about this problem of case
finding that I had
240
1 alluded to earlier in response to
our July request,
2 we issued a second and actually
then a third
3 response to companies to give us
cases to look at.
4
Finally, in December, as was pointed out
5 several times earlier today, MHRA,
having completed
6 its review of all the pediatric
data, decided to go
7
ahead and contraindicate all
the other new
8 generation antidepressants except
for fluoxetine.
9
So, as I understand it, fluoxetine is the
10 only current generation
antidepressant available
11 for treating pediatric depression
in the UK.
12
[Slide.]
13
I have used the terms summary data and
14 patient level data several times,
and I want to
15 make sure that you understand what
it is I am
16 talking
about.
17
By "summary data," I am referring to data
18 tables that are provided to us by
sponsors based on
19 their own analyses, that include
only numbers of
20 patients with events as the
numerators and either
21 total patients exposed or total
accumulated
22
person-time as the
denominators.
23
These are the data that we got from Glaxo
24 back in May and that we have since
gotten from all
25 the other sponsors. These are summary data.
241
1
"Patient level data" are data sets that
2 are provided by sponsors in
response to a detailed
3 request from FDA for electronic
data sets that are
4 structured to include one row per
patient
5 participating in each study, so
that we have data
6 for all patients participating in
those trials, and
7 we have multiple variable data for
each patient.
8
These data sets allow us to do adjustments
9 for covariates that may be
important for any
10 particular event of interest,
while summary data of
11 course do
not.
12
In the next slide, I am going to summarize
13 for you the suicidality risk data
from the seven
14 programs for the antidepressants
that were studied
15 in pediatric depression. Before I
do that, I want
16 to clarify what the two event
categories are that
17 we are dealing
with.
18
[Slide.]
19
The first event category is an umbrella
20 term, "possibly suicide
related." This is the
term
21 that Glaxo developed in looking at
its own
22 database, and it is the term that
we asked other
23 sponsors to look at in going
through their data
24 sets.
25
Basically, it was intended to capture any
242
1 event in their databases that
included any thoughts
2 or behaviors that the sponsor
considered to
3 represent possible suicidality, so
it is a very
4
broad
term.
5
The term "suicide attempt," as defined for
6 these analyses, was the subset of
that umbrella
7 term, so a subset of these
originally captured
8 events that met the conditions of
having any
9 indication of self-harm. So, this is how
"suicide
10 attempt" was defined in this
analysis.
11
So, the overall umbrella term "possibly
12 suicide related" and then the
subset of those
13 events that had some indication of
self-harm.
14 [Slide.]
15
This is, I am sorry, a very busy slide.
16 These are the risk data coming out
of these seven
17 programs, and I am going to walk
you through this.
18
Again, there were seven programs -
19 paroxetine, fluoxetine,
sertraline, venlafaxine,
20 citalopram, nefazodone, and
mirtazapine. I
have
21 divided these up into different
colored rows so you
22 can see the number of studies in
each program, two
23 of them involving three studies,
the rest all
24 two-study
programs.
25
This is risk data. So, this
is simply the
243
1 number of patients having one or
more of these
2 events divided by the total number
of patients
3 exposed. There is no adjustment for time
here.
4 This is crude risk. In parentheses, I have got
the
5 percent.
6
The way this is set up, first of all, the
7 overall umbrella category
"possibly suicide
8 related," and then the subset of
these events that
9 met the criterion for "suicide
attempt."
Again,
10 that criterion was any indication
of self-harm.
11
Let's just walk through the individual
12 programs. Again, paroxetine had
three trials.
For
13 the first trial, 329, you see a risk ratio
of
14 roughly 6, 6.5 percent for drug,
1.1 percent for
15 placebo, so definitely a signal of
something.
16
However, if you look at the other two
17 studies in this program, 377 and
701, these were
18 also fairly large studies, in
fact, this one was
19 slightly larger, the risk ratio
was around 1.
So,
20 the signal for paroxetine is
essentially coming out
21 of one study, a big signal, but
the other studies
22 show essentially
nothing.
23
If you look at fluoxetine, there really
24 isn't any signal coming out of the
fluoxetine
25 program, the risk ratios are all
in the vicinity of
244
1 1.
2
For sertraline, again, you have one study
3 which is suggestive of a signal,
4.1 percent versus
4 zero, drug versus placebo, but for
the other study,
5 similarly sized, in fact, these
were identically
6 designed studies, there is no
signal. It's 2.2
7 percent for
both.
8
If you look at venlafaxine, there appears
9 to be a signal coming out of both
studies in that
10 program. For citalopram, again, you have
two
11 studies, both large studies. One
study, no signal,
12 in fact, if anything, it is
slightly in favor of
13 drug. The other study, a weak signal, but
many
14 more events, many more events in
this study, and a
15 risk ratio of rough
1.6.
16
The number of events in the nefazodone and
17 mirtazapine programs is so small
that it is hard to
18 know what to make of
that.
19
There are two points that I want you to
20 take away from this slide. First of all, I
think
21 in looking at these data, there is
enough of a
22 suggestion of a signal of
something that clearly it
23 is worth pursuing
this.
24
Everyone at FDA concluded that there is
25 obviously something going on here,
we need to
245
1 pursue this, but one troubling
thing about this set
2 of data is the inconsistency in
the signal across
3 studies within the
programs.
4
In
most of these programs where there is a
5 signal except for venlafaxine, it
appears to be
6 coming from one study. So, that is something
that
7 we felt that we need to try and
explore in some
8 way.
9
[Slide.]
10
In the remaining time what I am going to
11 do is talk about the concerns we
have had in
12 interpreting these suicidality
data.
13
I should have mentioned at the outset, I
14 am sorry, I made a number of
changes in my slides
15 over the weekend, so I
apologize. I have had
to
16 delete some of the material. I didn't talk
about
17 efficacy, and I am not planning on
talking about
18 efficacy here, you know, in the
discussion section
19 I am happy to do
that.
20
I thought it would be useful if I focused
21 instead on the clinical cases
because one of the
22 concerns we have had is what these
reported events
23 that are captured under this broad
term "possibly
24 suicide related" actually
represent.
25
So, I put together a number of slides over
246
1 the weekend to try and give you a
better sense of
2 that, and that is why the slide
package you have is
3 different than what I am
presenting.
4
In any case, there are three concerns that
5 we have looked at. One has to do with
case
6 finding, and that is the first
bullet, and I
7 alluded to that earlier. In looking at the
summary
8 data that sponsors gave us, it
appeared that
9 somewhat different approaches were
used to
10 capturing and presenting these
cases to us. So,
I
11 will talk about how we explore
that.
12
Secondly, there is the issue
I talked
13 about of the question of how you
classify these
14 cases into meaningful categories
for the purposes
15 of analysis and regulatory
decisionmaking.
16
Finally, I have already alluded to the
17 issue of the inconsistency in the
signal across
18 individual studies within the
programs, and that
19 was one of the findings that led
us to want to do a
20 more refined analysis looking at
covariates. It
is
21 one of several reasons, but that
is one
22 justification for that
analysis.
23
[Slide.]
24
Let me first focus on the issue of case
25 finding. This is a very busy
slide, I apologize for
247
1 that, but I will walk you through
it. This is
the
2 algorithm that was used initially
by Glaxo and that
3 we then asked the other companies
to apply to their
4 databases in finding
cases.
5
In essence, there were two components to
6 this. There was an electronic
string search, which
7 I will talk about, and what they
were to do is to
8 apply this string search, and they
were to blindly
9 look at the events that were
turned up with that
10 search and decide whether or not
those events were
11 of interest from the standpoint of
suicidality and
12 then give us those
data.
13
So, the string search was one part of the
14 search. The other part was to do a
blinded review
15 of narratives for any deaths or
other serious
16 adverse events in their
databases. Now, there
were
17 no deaths in any of these trials,
so this part of
18 the search focused on narratives
for serious
19 adverse
events.
20
So, let go back to the string search.
21 There were two components to the
string search.
22 First of all, we asked companies
to look at their
23 preferred terms. These are the dictionary
terms
24 that companies use in coding
data. We asked
them
25 to look at the text string "suic"
and "overdos" to
248
1 pick up any instances of events
that were coded
2 under either suicidality or
overdose, or any
3 variation of
that.
4
Now, the bullet underneath here suggests
5 that we ask for a separate listing
for events coded
6 as accidental overdose. Accidental overdose
is
7 usually, just to give you an
example, where a
8 patient misses a dose on one day
and then on the
9 next day thinks he should take two
doses. So,
that
10 would not be a suicide attempt,
that is what is
11 usually considered an accidental
overdose.
12
So, we didn't want those to be included
13 among the events, but we wanted to
be able to see
14 them to see which ones were
excluded.
15
The second part of this was to do a string
16 search for the actual verbatim
investigator terms.
17
Here we used -- again, this is the
18 approach that was used by Glaxo,
and we passed this
19 on to the other sponsors -- a
variety of terms
20 suggestive of either self-harm or
of overdose or
21 suicidality.
22
So, this was to go through the
23 investigator terms and try and
capture any events
24 that were suggestive either of
suicidality overdose
25 or some type of self-harm.
249
1
Again, we allowed exclusions from that
2 list for what I am calling false
positives. A
3 false positive, for example, would
be when the text
4 string inadvertently picks up a
term that has
5 nothing at all to do with
suicidality, so, for
6 example, the test string g-a-s,
for gas, would pick
7 up gastrointestinal, so we allowed
companies to
8 exclude those events from their
lists.
9
Once they came up with a list of events
10 that they considered
representative of suicidality,
11 we asked them to go through and
blindly select out
12 from that overall group of
possibly suicide-related
13 events, the events that were
suggestive of suicide
14 attempt.
15
Again, the definition of that was any
16 indication of self-harm. So, again, the
overall
17 umbrella term and then the subset
of suicide
18 attempts.
19
We asked them then to provide us a
20 narrative of all of those cases
that had been
21 turned up. So, that was the algorithm for
finding
22 events.
23
[Slide.]
24
Now, we had hoped in doing that, that we
25 would get a fairly complete
accounting of the
250
1 original list of events that had
been turned up and
2 the exclusions. Unfortunately, we weren't
explicit
3 about that, and it is not what we
got.
4
Often, we got only the narratives for the
5 events that the companies had
already decided
6 represented the suicidality set,
and did not
7 include the exclusions. Often, there was
little
8 explanation for why certain events
had been
9 excluded or what the criteria had
been in excluding
10 events. So, that was one
problem.
11
[Slide.]
12
Another problem was that we had failed to
13 ask for narratives on accidental
injuries. I
had
14 mentioned earlier that we had
asked for a listing
15 of accidental overdose, but not accidental
16 injuries. In talking to sponsors about this,
and
17 asking them to give us some of the
accidental
18 injuries, we turned up a couple of
events that
19 caused us some
concern.
20
This was one particular example.
This was
21 a child who had been excluded,
this event had been
22 excluded from the list. It was a patient
who
23 stabbed himself in the neck with a
pencil while
24 taking a
test.
25
Now, this probably was an accident, but it
251
1 occurred to us that we wanted to
see all of these.
2 We wanted to see all of the events
that had been
3 excluded as accidental injury, so
that our experts
4 -- because at this point, we had
already decided to
5 go outside and have an outside
group look at these
6 cases, we wanted to have a
complete set of events
7 for them to look at, so we asked
for all the
8 accidental
injuries.
9
[Slide.]
10
Another thing that we discovered when we
11 started talking to companies about
the application
12 of the search algorithm is that
one company in
13 particular acknowledged that it
had not done the
14 searching blindly of the narratives
for serious
15 adverse events, and this was a
problem, because
16 again this had to be done blindly
to be done
17 properly.
18
Another issue that turned up when we
19 started looking at these cases is
that some
20 companies had excluded events that
were not
21 "treatment
emergent."
22
Now, when looking at adverse event data,
23 it is entirely appropriate to be
interested in
24 events that either occur for the
first time on
25 assigned treatment, or if present
at baseline, are
252
1 worse on treatment than at
baseline. That is
what
2 we mean by "treatment
emergent."
3
So, it is not that it was improper to do
4 that. The problem was that we wanted to see
which
5 events were excluded for that
reason, so that we
6 could assess ourselves whether or
not it was an
7 appropriate exclusion. So, again, in going
back,
8 we have now asked for all the
events excluded as
9 treatment
emergent.
10
Finally, in looking and comparing the
11 strength of the signal coming out
of the pediatric
12 supplement re-review and the
signal coming out of
13 the summary data, in one
particular case we noted a
14 fairly substantial discrepancy
between the strength
15 of the signal. That again raised a question
about
16 case
finding.
17
[Slide.]
18
So, the bottom line is that having looked
19 at these initial summary reports
from companies, we
20 did not have complete confidence
in the case
21 finding, so we issued, as I
mentioned, a second
22 request for clarification both of
how the search
23 had been done and then a complete
accounting of how
24 the companies winnowed down to the
list of events
25 that they considered to represent
the suicidality
253
1 set, so that we could see what
events had been
2 excluded, for what reason, and so
that we could be
3 confident that we had a complete
set of data to
4 start with.
5
In addition, we asked for narratives for
6 all serious adverse events rather
than just the
7 ones that the companies decided
represented
8 suicidality, so again our outside
experts could go
9 through all of these data and
independently and
10 blindly themselves decide which
were representative
11 of
suicidality.
12
So, that is the case finding issue.
13
[Slide.]
14
Next, I want to talk about the issue of
15 reclassification. There were two issues that
again
16 caused us concern about the
approach to classifying
17 these cases.
18
One was in looking at the events that got
19 captured, we noticed that there
was an extremely
20 wide variability in the types of
events that got
21 included under either the broad
umbrella category
22 or also under the narrower term
"suicide attempt."
23
We also notice that companies appeared to
24 have used very different
approaches to capturing
25 the subset of events labeled
"suicide attempt."
254
1
Some companies used a fairly conservative
2 approach, others essentially
labeled all of the
3 events as suicide attempts even
though there was
4 nothing in the case report to
suggest self-harm.
5
[Slide.]
6
So, what I have done, and these are the
7 slides that I put together this
weekend, I have
8 gone back to look at the 109
patients having one or
9 more possibly suicide-related
events. These
were
10 the patients who were included in
the numerators
11 for the table that I showed you
earlier.
12
So, these are the cases, and the
13 collection of 109 patients goes
across all studies,
14 not just the depression
studies.
15
A couple of points to make.
First of all,
16 the point about there were no
completed suicides
17 among these 109 cases. As I mentioned, there
was
18 very wide variability in the types
of verbal
19 expressions and behaviors that
were considered by
20 companies to be representative of
suicidality.
21
Another problem with these cases is that
22 the majority of them were not well
described. We
23 did not have the level of detail
in these cases
24 that one would have liked to do a
rational
25 classification.
255
1
My goal in doing this is to provide you
2 with a sense of the range of
events to consider.
3 You know, this is not a formal
classification.
4 Again, we have contracted with an
outside group to
5 do the classification, but I
wanted you to have a
6 sense of the kind of variability
in the case
7 material that we have, so you can
appreciate why we
8 consider this a
problem.
9
[Slide.]
10
There are two key questions.
First of
11 all, is it meaningful to subsume
such diverse
12 events under this umbrella term
"possibly suicide
13 related," and is it reasonable to
define "suicide
14 attempt" as that subset of events
that have any
15 degree of self-harm, is that a
reasonable
16 definition of "suicide
attempt."
17
I want to be very clear about this.
I am
18 not attempting to trivialize in
any way any of the
19 events that occurred. I mean these are sick
kids,
20 all of these events have
importance.
21
The question is what classification
22 approach is most useful and
clinically meaningful
23 in preparation for doing an
analysis and in
24 preparation for taking regulatory
action. That
is
25 really my goal here.
256
1
[Slide.]
2
Let me describe how I approached these
3 cases. For a small fraction of them, patients
had
4 more than one suicidality event,
so for
5 consistency, I focused on the
first one. That
only
6 applied to about 10 percent of
these patients.
7
Then, I went ahead and I selected a subset
8 of those events where there was
any indication at
9 all of self-harm. Again, this is to mimic
the
10 approach that the sponsors were
supposed to use in
11 defining suicide
attempt.
12
For those patients who had an indication
13 of self-harm, I looked at whether
or not they were
14 hospitalized for the event and
whether or not there
15 was any indication of suicide
intent. By that,
I
16 mean either an active expression
of intent in that
17 case narrative or I accepted any
concurrent
18 indication of suicidal
ideation.
19
For the remaining patients who had
20 suicidal ideation without
self-harm, again, I
21 looked at whether or not they had
been hospitalized
22 for the event and whether or not
there was a
23 suicidal plan, so there had to be
an active
24 expression in the narrative of a
suicidal plan in
25 association with that suicidal
ideation.
257
1
[Slide.]
2
Overall, the hospitalization rate for
3 these 109 patients was 43
percent. The
subgroup
4 having suicidal ideation without
any indication of
5 self-harm was 39 percent and the
remainder -- these
6 were the patients who had some
indication of
7 self-harm -- was 61
percent.
8
Again, there were no complete suicides,
9 all patients were fully recovered
from these
10 instances of self-harm. As sort of an
interesting
11 aside, in about 30 percent of
these cases, the
12 self-harm event appeared to occur
in the context of
13 some kind of interpersonal
conflict.
14
A typical situation would be a child had
15 an argument with a parent or a
sibling or a peer or
16 a girlfriend or boyfriend,
impulsively engaged in
17 some kind of self-harm behavior,
and the event was
18 over, and there was no indication
of suicidal
19 ideation. That applied in about 30 percent
of
20 these cases.
21
[Slide.]
22
In going through the self-harm case events
23 in more detail, again, there were
a total of 66 of
24 these. Nineteen of these involved
cutting
25 behavior. In almost all of these cases of cutting,
258
1 it appeared to be a superficial
wound. There was
2 one case where a young girl cut
herself so deeply
3 that there was actually blood
loss. In
another
4 case there was an indication that
the patient
5 needed three stitches to suture
the wound, but in
6 all the other cases, they appeared
to be
7 superficial.
8
There were 37 overdoses.
Again, there was
9 a wide range of different types of
behaviors that
10 were classified as overdose,
ranging at the one
11 end, one patient was classified as
an overdose for
12 taking 20 percent more medication
than was
13 prescribed.
14
Ordinarily, this would not be considered a
15 suicide attempt, and there was no
indication in
16 that case of suicidal ideation,
but that was
17 classified as an
overdose.
18
At the other extreme, there were patients
19 who took fairly substantial
quantities of either
20 study medication or usually
over-the-counter
21 medication, so a very wide range
in terms of
22 amounts of drug that was
taken.
23
There were two cases characterized as
24 hanging behavior. In both of those cases,
what
25 they really were, were interrupted
attempts. These
259
1 were children who, in the presence
of family or
2 parents, engaged in what was
described as hanging
3 behavior, it was immediately
interrupted, and so in
4 neither case was there any actual
self-harm.
So,
5 these were interrupted
cases.
6
The case of burning was similar.
This
7 occurred in the context of family,
and the child
8 was immediately interrupted
although in that case
9 there was some minor
burns.
10
One case that was classified as a suicide
11 attempt was the case of a young
girl who slapped
12 herself in the face, and that was
it. That was
all
13 there was in that case, and there
was no suicidal
14 ideation described in that
case.
15
Then, there were six other cases where all
16 that the case indicated was minor
self-mutilation.
17 It was not specified what the
self-harm behavior
18 was.
19
[Slide.]
20
Now, let me give you a breakdown of what I
21 found when I looked at, first of
all, the cases of
22 cutting.
23
There were 19 of these. In
most of these
24 cases, in 16 out of the 19, there
was no indication
25 of either suicide intent or even
any concurrent
260
1 suicidal ideation, and 4 of those
19 cases actually
2 ended up being
hospitalized.
3
So, most of those cases did not involve
4 hospitalization and did not
involve suicide intent
5 or ideation.
6
[Slide.]
7
For the 37 cases of overdose, there were
8 more hospitalizations here, but
again, if you
9 notice in this column, in almost
every case there
10 was no indication of suicide
intent or suicidal
11 ideation.
12
A number of the
hospitalizations could be
13 characterized as an overnight
hospitalization for
14 observation.
15
[Slide.]
16
Finally, for the remaining 43 patients who
17 had suicidal ideation without
self-harm, again, I
18 looked at whether or not there was
a plan, an
19 expressed plan, and in most of
these cases there
20 was not a
plan.
21
In the 7 where there was a plan, they were
22 hospitalized, but nevertheless, a
majority of these
23 patients with suicidal ideation
without self-harm
24 were
hospitalized.
25
[Slide.]
261
1
So, I hope that gives you a little bit
2 better sense of the range of
behaviors that we are
3 dealing with here and the
difficulty we had in
4 including all of them under this
one umbrella term
5 of "possibly suicide
related."
6
As I said, we have gone to an outside
7 group. What I want to do in this slide is talk
a
8 little bit about the Columbia
University
9 Suicidality Research Group and why
we picked them.
10
I talked to a number of people about who
11 should help us with this, and most
everyone I
12 talked to said that this group has
the expertise to
13 do this. They do have expertise, they have
been
14 doing this for almost 20
years.
15
In the last 5 years alone, they have more
16 than 40 funded grants to do this
kind of research.
17 They are in the business of
developing measures and
18 manuals and methodologies for
evaluation of
19 suicidality.
20
They are a center for training on suicide
21 assessment, and research on both
reliability and
22 validity. They are currently
involved in the NIMH
23 study looking at adolescent
suicide attempters.
24 This is the TASA study. They are doing the
suicide
25 assessment or the suicide
classification for that
262
1 trial. As you can see, they have a very
large
2 number of publications over the 20
years they have
3 been doing
this.
4
So, we think this is a good group to help
5 us with this
problem.
6
[Slide.]
7
I have two more slides left.
What I want
8 to do in this slide is again
remind you of what Dr.
9 Katz said earlier, is that we view
this meeting
10 today as a preliminary
meeting. We are hoping
to,
11 you know, once we have had these
cases
12 reclassified, and have done the
analysis, to come
13 back to you with more definitive
answers later in
14 the summer.
15
You are going to hear next from Dr. Kelly
16 Posner from Columbia. She is going to tell
you
17 about the way they think about
classifying suicidal
18 events and how they plan to
approach these data.
19
Following that, you will be hearing from
20 Tarek Hammad from our Safety
Group. He is going
to
21 tell you about our preliminary
plans for an
22 appropriate patient level data
analysis.
23
[Slide.]
24
Finally, these are the five topics for
25 which the Neuropharm Division
would like to have
263
1 feedback from you. First of all, three
topics
2 pertinent to the analysis of
suicidality data.
3
Again, I alluded to our concerns about the
4 approach to case finding and how
we attempted to
5 resolve that, but we would be
interested in knowing
6 what you think about that and
whether you think
7 anything more needs to be done in
terms of case
8 finding.
9
Secondly, you will be
hearing from Dr.
10 Posner about approaches to
classifying these events
11 into appropriate categories before
we do the
12 analysis. Since we are actively engaged now
in
13 discussing this with them, this
would be a good
14 time to give us feedback on
that.
15
Thirdly, if you have thoughts about our
16 plans for the patient level data
analysis, we would
17 be interested in hearing about
that.
18
In terms of future concerns, again, one of
19 the striking things about these
cases is how poorly
20 they were described, and this may
also indicate a
21 less than optimal approach to
ascertainment in
22 these
studies.
23
So, if you have thoughts, we are beginning
24 to talk with Kelly Posner and
others about
25 developing a guidance document for
ascertaining
264
1 suicidality in future studies, if
you have thoughts
2 about that, we would welcome
them.
3
Finally, I didn't get a chance to talk
4 about efficacy, but obviously, the
largely negative
5 results from the short-term trials
in pediatrics is
6 clearly a
concern.
7
We would be interested in knowing what
8 your thoughts are about that and
whether or not you
9 think there are other possible
designs that might
10 help us get at whether or not
there are benefits
11 with these
drugs.
12
One design that has been used in adult
13 studies is the randomized
withdrawal design.
This
14 is a design where you take
patients who have
15 responded to medication acutely,
have been stable
16 for some period of time, and are
then randomized to
17 either continue on drug or
assignment to placebo,
18 and you look at time to relapse as
the event, as
19 another approach to trying to
establish whether or
20 not there are
benefits.
21
I am going to stop there.
22
Thank you.
23
DR. RUDORFER: Thank you, Dr.
Laughren.
24
As Dr. Laughren said, we will now hear
25 from Dr. Kelly Posner of Columbia,
who will
265
1 describe in more detail the
suicidality
2 classification
project.
3
Suicidality Classification Project
4
DR. POSNER: Thank
you.
5
[Slide.]
6
So, why is a methodologically sound,
7 research-supported classification
warranted?
Let's
8 back up a second and talk about
the problem.
9
[Slide.]
10
The problem, as the cases that Dr.
11 Laughren discussed exemplified,
there is a clear
12 lack of conceptual clarity about
what suicidal
13 behavior means and a corresponding
lack of
14 agreement on common terminology
both in clinical
15 descriptions of suicidal acts, as
well as research
16 descriptions of suicidal
acts.
17
Given this lack of generally accepted
18 terms for referring to even the
most basic suicidal
19 behaviors, the importance of using
definitions that
20 are both reliable, meaning we all
define them and
21 assess them the same way, and
valid, meaning there
22 is some truth to them seems quite
clear.
23
[Slide.]
24
So, what are these standardized
25 research-supported
definitions? I think it is
266
1 important to note that there
really is generally
2 agreement among suicide assessment
experts on the
3 basics of these terms. So, we are going to
start
4 with the suicide
intent.
5
A self-injurious act committed with at
6 least some intent to die. Intent doesn't have
to
7 be 100 percent. If there is any intent to die,
we
8 consider it an actual suicide
attempt.
9
Intent does not have to be explicit and
10 can be inferred. For example, if a patient
denies
11 intent to die, but thought that
the behavior could
12 be lethal, intent can be
inferred.
13
A real case example includes a 12-year-old
14 who is angry at her mother. She took 6 to 7
15 prescription pills, said she was
aware that taking
16 that much medication might kill
her, but she didn't
17 know if she intended to die by
taking the pills.
18 That would clearly be categorized
as a suicide
19 attempt.
20
Once again, it is important to note that
21 once there is any possibility of
injury, the act is
22 defined as an attempt, meaning
that if someone
23 pulled the trigger of a loaded
gun, but
24 fortuitously missed, it is still a
suicide attempt.
25
[Slide.]
267
1
Other classifications: suicidal behavior
2 without injury. Interrupted attempts are
defined
3 as the individual is stopped by an
outside
4 circumstance from starting the
self-injurious act.
5 Examples of these: someone has pills in
their
6 hand, but they are stopped from
ingesting.
Once
7 even one pill is ingested, the
event becomes an
8 actual
attempt.
9
They have a gun pointed toward themselves,
10 the gun is taken away by someone
else or somehow
11 they are prevented from pulling
the trigger.
They
12 are poised to jump, they are
grabbed, taken down
13 from the ledge. All examples of
interrupted
14 attempts.
15
The next classification is what is called
16 an aborted attempt in which an
individual takes
17 steps toward making a suicide
attempt, but stops
18 himself before engaging in any
potentially
19 self-destructive
behavior.
20
Remember, holding a loaded gun but not
21 pulling the trigger is a good
example. This
could
22 not possibly result in injury,
therefore, it
23 constitutes an aborted
attempt. It is
still
24 suicidal behavior, but it is not
an actual attempt.
25
[Slide.]
268
1
I think it is worth focusing a moment on
2 suicidal intent, because again,
intent here is the
3 determining factor when you are
classifying
4 suicidality. It is the presence of intent to
die
5 that differentiates suicidal acts
from self-injury.
6
One must determine whether the
7 self-injurious act was thought of
as a means of
8 causing or facilitating death. Of
course, we do
9 have research support for the
validity of using
10 intent to define
suicidality.
11
One example is that completed suicide is
12 predicted by previous intent
measures, which was
13 demonstrated by Beck and his group
in 1989.
14
[Slide.]
15
Some more case examples.
These are real
16 cases again. These are examples of
non-suicidal
17 self-injury.
18
A teenage girl reported her mother was
19 being cruel and neglectful and she
wanted to escape
20 from her mother's home. She states that
she
21 researched lethal doses of
ibuprofen to make
22 certain that she took an amount
that would not be
23 life-threatening. She took 6, feeling sure it
was
24 not enough to kill her. She definitely did
not
25 want to die, only to escape from
her mother's
269
1 house. She was taken to the ER and then
admitted
2 to a psychiatric
hospital.
3
Another is the more common case of
4 self-mutilation where the person
described 12
5 incidents of cutting himself,
stated he did this
6 only "to relieve tension" and "to
play with danger
7 to see how far I would go" and no
part of him
8 wanted to die. Thought about it for hours
before
9 acting on the urge and felt
relieved of tension
10 afterwards, did not feel
pain.
11
[Slide.]
12
So, what is our research support of these
13 classifications? We will start with
reliability.
14 We have been able to demonstrate
excellent
15 reliability utilizing these
definitions and this
16 classification system in
NIMH-funded treatment,
17 biological, and genetic trials
across the life
18 span.
19
We have also been able to demonstrate
20 multi-site reliability with other
expert centers in
21 family genetic studies and
treatment trials, and
22 again particularly the treatment
of adolescent
23 suicide attempters
trials.
24
In short, across domains, across the life
25 span, and across institutions, we
have been able to
270
1 demonstrate excellent
reliability.
2
[Slide.]
3
Validity. How much truth is
there to
4 these definitions? Individuals classified
as
5 suicide attempters have as much as
2.5 times risk
6 of future attempts or
completions. So, we
know
7 this is a real
category.
8
Similarly, interrupted attempters are
9 reported to be 3 times more likely
to commit
10 suicide than uninterrupted
attempters.
11
Finally aborted attempters are at risk for
12 eventual attempts and were more
likely to have made
13 an actual attempt in the
past.
14
Again, all validating the classifications
15 that we are
using.
16
[Slide.]
17 So,
what is the classification methodology
18 that we are proposing
here?
19
To begin with, the data will be blinded by
20 experts not on the panel. It will be blinded
not
21 only to pharmaceutical
information, but also to any
22 relevant clinical information that
would bias an
23 event rating. For example, a family history
of
24 suicidality. An event classification should
stand
25 on its own, and we want to make
sure that it is
271
1 blinded in both
domains.
2
Next, we have to determine the event
3 classifications based on these
reliable and valid
4 constructs.
5
We are then going to do a training on the
6 classification system to establish
reliability of
7 panel members who are all experts
in the field.
8
Once the reliability study is done, the
9 expert panel will be divided into
three subgroups,
10 and the data will also be divided
into three groups
11 in order to do
classifications.
12
There will be additional cases, and the
13 reason for the additional cases is
to demonstrate
14 that the classifications are all
being done in the
15 same way and to prevent what we
call stratification
16 bias.
17
You want to exhibit a relationship between
18 the groups and make sure it is not
some other
19 factor that is causing a group to
rate things in a
20 similar way, and then we will
generate the
21 classified
cases.
22
[Slide.]
23
What are the classifications that we are
24 proposing? Suicidal, non-suicidal,
and
25 indeterminate. Subclassifications of suicidal
272
1 would include suicide attempt,
suicidal behavior
2 without injury, which would
include aborted and
3 interrupted attempts, suicidal
ideation related
4 events.
5
Non-suicidal
subclassifications would
6 include self-injury or mutilation
again with no
7 intent associated, and other
categories, accidental
8 injuries or other psychiatric
symptoms that we have
9 been hearing a lot about today,
disinhibition,
10 akathisia,
agitation.
11
Then, finally, the indeterminate category
12 either by non-consensus or
inability to classify
13 due to a paucity of
data.
14
So, if, in fact, there is a signal, the
15 point is we just don't know yet
what it is a signal
16 of, and that is why a logical
research-supported
17 approach is warranted. We want to be able to
look
18 at the data consistently and
logically across
19 trials in order to make some
clinically meaningful
20 sense of it.
21
[Slide.]
22
I think it is also worth mentioning for a
23 moment future directions. We want to develop
24 guidelines as to how to better
capture data,
25 enabling appropriate
classification and description
273
1 of
suicidality.
2
We will demonstrate, based on this
3 conceptual clarity, how to utilize
research
4 assessment tools, what questions
to ask, how to ask
5 them, and what measures aid in
this, which will
6 then lead to consistency of
terminology and
7 classification, as well as to
improved, more valid
8 identification and documentation
of suicidality.
9 In
addition, as was mentioned earlier,
10 that will also enable more active
appropriate
11 surveillance of suicidality, which
is a great need
12 clearly.
13
Thank you.
14
DR. RUDORFER: Thank you, Dr.
Posner.
15
Our final formal speaker of the afternoon
16 will be Dr. Tarek Hammad from the
Division of
17 Neuropharmacologic Drug Products,
who will discuss
18 plans for analysis of patient
level data for
19 pediatric
studies.
20
Plans
for Analysis of Patient Level
21
Pediatric Studies
22
DR. HAMMAD: Good afternoon,
everyone.
23
I am here today to talk about our analysis
24 plan for the pediatric patients
data.
25
[Slide.]
274
1
These are some of the elements that I will
2 cover in my talk. After a brief description or
a
3 statement of the objective of this
work, I will
4 describe the data that we have and
then I will go
5 on to discussing the analysis
plan.
6
[Slide.]
7
The objective of this work is to evaluate
8 the risk of suicidality associated
with the use of
9 antidepressants in pediatric
patients using the
10 results of the blinded
reclassification of cases.
11
I think you have heard enough about the
12 value of this
reclassification.
13
In the process, we will address the
14 possible sources of imbalance in
the data, for
15 example, trial design, duration of
exposure, et
16 cetera, and also other potential
confounders.
17 These efforts will help us
understand the sources
18 of inconsistency between trials or
between drugs,
19 if any.
20
[Slide.]
21
The source of all data is controlled
22 trials conducted in pediatric
patients in nine drug
23 development programs. These are the drugs that
you
24 have seen before, that is the list
of drugs and the
25 number of trials involving each
drug.
275
1
For the analysis or at least for some
2 stages of the analysis, they will
be grouped into
3 two categories, an SSRI group and
an Atypical
4 Antidepressant
group.
5
[Slide.]
6
These trials were not done in one
7 indication, and for purpose of
analysis again, they
8 will be categorized or divided
into three different
9 subgroups - MDD, anxiety
disorders, and attention
10 deficit hyperactivity disorder
assuming, of course,
11 we have enough cases within every
category of
12 indication.
13
[Slide.]
14 As
far as individual patients data that we
15 are requested, we developed a
standard format to
16 guarantee the compatibility
between data coming
17 from various sources. We actually specified
every
18 aspect of the desired database
down to the variable
19 name and some description to
clarify the contents,
20 and some coding notes as
appropriate.
21
In addition, we requested descriptive
22 information about every trial to
evaluate the
23 similarity of these trials, which
as you can
24 imagine is very important to
determine if these
25 trials can be pooled or not to
gain more power
276
1 while you are investigating this
question.
2
[Slide.]
3
This is a list of the requested variables
4 that can be categorized in many
subcategories -
5 demographics variables,
disease-related variables,
6 drug-related
variables.
7
[Slide.]
8
Outcome-related variables, psychiatric
9 history variables, and some
treatment emergent
10 adverse events. As you can see, this is not
just
11 about having a second look at the
data. It is
12 about trying to understand and
appreciate and
13 characterize the signal, if there
is any.
14
[Slide.]
15
This is a list of some challenges we have
16 with the data, I wanted to mention
here because of
17 the important implications of
these challenges on
18 the proposed analysis and on the
actual
19
interpretation.
20
They can be divided roughly into two
21 categories, a quality-related
component and an
22 analysis-related
component.
23
The first issue in the quality-related
24 component, which is pertinent to
what Dr. Laughren
25 was talking about, the case
ascertainment, so I
277
1 will not belabor the issue more,
but a similar
2 issue is pertinent to the other
pieces of
3 information being collected, which
is other
4 variables that we
requested.
5
The mechanism of capturing these data
6 might be different from trial to
trial or from
7 sponsor to sponsor, so we will
investigate this,
8 and that is part of the challenge,
trying to see if
9 these data can actually even be
comparable or not.
10 But for now, the rule that we will
use is that we
11 will not use data with missing
information more
12 than 10 percent. The second issue is
somewhat
13 detailed and I will address in the
next few slides
14
The first point under the analysis-related
15 component is using the trial or
the patient as the
16 unit of analysis. Pooling data from
different
17 trials, treating them as one large
trial fails to
18 preserve the randomization effect
and might
19 introduce bias and
confounding.
20
That is because maintaining the
21 randomization guards against the
foreseen and
22 unforeseen imbalances between
different treatment
23 groups in various
trials.
24
The issue of trial similarity is not only
25 pertinent to having the same
protocol, but it is
278
1 also pertinent to the
implementation of those
2 protocols in reality. That is why I believe
the
3 trial-based approach is more
appropriate.
4
However, we might be using some
5 information using the trial as the
unit of the
6 analysis, because if we have zero
events in one of
7 the arms, for example, we have to
impute some data,
8 but if we have zero events in both
arms, we will
9 not be able to drive the
information in this trial.
10
So, it depends on the eventual count of
11 the actual cases that we would
have. If we
are
12 losing too many trials, we might
use the patient as
13 the unit of the analysis, of
course, after doing
14 the appropriate
adjustments.
15
[Slide.]
16
The second point is pertinent to the
17 limitations of pooling data in
general whether we
18 use the trial or the patient as
the unit of the
19 analysis, because these trials
have different
20 designs, patient populations,
sometimes duration of
21 treatment, et cetera, and pooling
them together
22 with the appropriate adjustment
gives you an
23 average effect that is really
dependent on the
24 proportions of different
subpopulations in these
25 data.
279
1
This effect will be different subsequently
2 if these proportions are
different, so careful
3 evaluation of this has to be
conducted and then
4 adjusting for
it.
5
There is also the inherent class effect
6 assumption that is implied by
pooling data across
7 drugs or within groups of
indications even.
Mind
8 you, we do this to try to gain
more power, try to
9 see some gathering of data instead
of just looking
10 at it trial by trial, but by doing
this, if we pool
11 data from drugs within certain
class assumption
12 here, the risk of suicidality is
equal in all
13 drugs.
14
The problem comes in when we realize that
15 we do have different size of data
for different
16 drugs, and the smaller opportunity
to observe an
17 event in one drug might lead to
none being observed
18 or very few.
19
The question becomes whether this is
20 because this drug is generally
different from the
21 rest of the class or because we
simply don't have
22 enough power. Unfortunately, this will always
be
23 an open question, but I would
report the results
24 both ways by individual drugs and
by group data.
25
[Slide.]
280
1
The analysis plan would follow a standard
2 approach with initial exploratory
phase, where we
3 will check for the compliance with
our request and
4 the completeness of data, check
for coding errors,
5 and the like, and then we will
list all the risks
6 and rates by drug, by indication,
and by trial just
7 to see what is going on in data,
in all aspects of
8 the subgroups before we pool
anything, so we know
9 where the signal is coming from if
there is any
10 afterward.
11
Then, we investigate the data separation,
12 which is an important
component. For example,
if
13 all cases were among men, for
example, then, this
14 variable we will not be able to
evaluate, and so
15 on. That is just part of the process
of
16 evaluation.
17
Then, we go to investigate interactions
18 and potential confounders to try
to understand what
19 is going on and try to
characterize the risk, as I
20 said before.
21
[Slide.]
22
This is just a sample of one of the tables
23 that will be produced, the rates
and percentages
24 and the risks of suicidality by
drug and by
25 indication for every trial.
281
1
[Slide.]
2
To evaluate the estimate, to actually try
3 to relate an overall effect, an
estimate for an
4 overall effect, two approaches
that I discussed are
5 options that we have. First, which I believe
is
6 the more of an optimal approach, is
using the trial
7 as the unit of
analysis.
8
In this analysis, I will adjust the
9 confounders on a trial level. We are basically
10 looking for a randomization
failure in if all of
11
these randomized trials, but
in case there might be
12 some failure in randomization, any
small imbalances
13 can actually be reflected on the
apparent risk.
14
Then, I will have done everything by trial
15 and by drug. In this particular analysis, I
will
16 pool trials for drug groups that I
should do
17 initially within indication
groups. Trials will
be
18 excluded if there are no cases
reported in both
19 arms.
20
Now, depending on the heterogeneity of
21 the trials' findings, the
variability between
22 trials will be considered in a
fixed effect order
23 in random effects
model.
24
The premise behind the fixed effects model
25 is that the real effects we are
trying to evaluate
282
1 is fixed, and the observer
variation between trials
2 is just by chance. The premise behind the
random
3 effects model is that there is an
average of these
4 effects that is the full
distribution with a
5 variation affected by the observer
trials.
6
Many times you will have both approaches
7 yielding the same results, but I
am going to do it
8 both ways with some of the
conditions for which
9 approach is more appropriate given
the actual data
10 or the heterogeneity of the
data.
11
Now, if we opted to use the patient as the
12 unit of analysis in the situation
I mentioned
13 before, which is a situation where
we will not have
14 that many cases, and we would be
losing trials
15 right and left, so we will try to
pool and get some
16 slightly more power, pooling
patients as the unit
17 of the
analysis.
18
We will use the Poisson regression to
19 model the rates of suicidality,
adjusting for
20 potential confounders, and then
again will pool
21 patient data for drug groups
within indication
22 groups, and, of course, will
adjust for trial in
23 the model because these patients
are coming from
24 different
trials.
25
[Slide.]
283
1
As you know, these trials were not
2 designed to capture these
particular events, so
3 there is some inherent uncertainty
about the
4 finding. It depends on what kind of feedback
we
5 get from our experts in the
Columbia University.
6
Some sort of sensitivity analysis might be
7 warranted, stratifying by the
amount of uncertainty
8 in this particular
finding.
9
[Slide.]
10
There are some limitations on the
11 interpretation of data that we
should know upfront.
12 Just to put the limitations in
context, I have here
13 the first bullet to remind you
about the goal of
14 this particular effort, which is
to evaluate the
15 risk of suicidality associated
with the use of
16 antidepressants in pediatric
patients.
17
Now, after everything is said and done,
18 the observed rates will not
reflect the actual
19 patients in the general
population. Why? Because
20 there are some exclusions in some
trials of
21 patients with some baseline
suicidality, so the
22 observed rates will not reflect
what is going on in
23 real life, and this might hamper
our efforts in
24 trying to investigate the risk
because it will lead
25 to underestimation in all the
arms, so we might not
284
1 have enough power to be able to
detect the actual
2 thing.
3
Now that we only have short-term exposure
4 data, we will not be able to
extrapolate this to
5 what happens after long-term
exposure to these
6 drugs.
7
Now, we don't really have any information.
8 The next bullet is that we don't
have any
9 information on the patterns for
discontinuation.
10 Considerably, there might be some
informative
11 censoring going on with patients
with suicidality
12 tendencies, might be likely to be
discontinued. If
13 that happened more in the placebo
group, then,
14 there might be some apparent
underestimation of the
15 signal in the placebo, and this
might lead to some
16 spurious finding, but we don't
have information on
17 this which would be very hard to
overcome.
18
My last point is that it remains to be
19 seen if we have enough statistical
power to detect
20 differences in the risk of
suicidality among
21 various drugs because of the issue
that I alluded
22 to before, which is there is no
data for some of
23 the drugs.
24
[Slide.]
25
In closing, there are our ideas and some
285
1 of them were informed by our
experience analyzing
2 the data on the completed suicides
in adults.
3
So, your feedback on our approach will be
4
greatly
appreciated.
5
DR. RUDORFER: Thank you, Dr.
Hammad.
6
At this point, we are going to open up for
7 discussion by the committee. If anyone has
8 questions for our speakers, now is
the time to
9 raise them.
10
Dr. Laughren.
11
DR. LAUGHREN: Matt, I had in
my original
12 talk planned on giving a brief
summary of the
13 efficacy data, and it sounds like
a number of
14 people are disappointed that I
didn't do that.
I
15 have those data and I could, if
you wanted me to
16 take five minutes and do that, I
would be happy to
17 do that.
18
DR. RUDORFER: Yes, please do
so.
19
[Slide.
20
DR. LAUGHREN: What this
slide does is
21 summarize very briefly the outcome
on the 15 trials
22 that we looked at for the 7
programs in pediatric
23 major
depression.
24
Again, there are 3 studies in the
25 paroxetine program and 2 studies
in each of the
286
1 other programs, and what this
slide does is to
2 simply summarize in very crude
form what the
3 outcome was on the primary
endpoint. The
protocol
4 specified primary endpoint for
those trials, and
5 this gives the age range in these
studies here.
6
So, for example, for the paroxetine
7 program, there were 3 studies, all
negative. For
8 sertraline, 1 trended in trend,
for the purposes of
9 this slide, indicates a p value on
that primary
10 endpoint of between 0.05 and
0.1. A negative
trial
11 is indicated by a p value of
greater than 0.01.
12
So, for paroxetine, all 3 studies were
13 negative, fluoxetine, both were
positive and, as
14 you know, this was the one program
for which we
15 concluded that there was
sufficient data to support
16 a claim.
17
Our standard, and I believe the standard
18 of most other regulatory agencies
for pediatric
19 major depression, is 2 positive
studies.
20
For the sertraline program, 1 trended and
21 then 1 negative. Venlafaxine, both were
negative.
22 For citalopram, 1 positive and 1
negative.
23 Nefazodone, 1 trend, 1 negative,
and both negative
24 for
mirtazapine.
25
Now, the one point I want to make in this
287
1 slide is that this was our fairly
conservative view
2 of these data. Others have looked at these
same
3 data and have reached different
conclusions.
4
For example, for the paroxetine study 329,
5 this was the basis for a
publication by Keller, et
6 al. They acknowledged that that trial was
negative
7 on the primary endpoint, however,
they pointed out
8 that it was positive on virtually
all secondary
9 endpoints, and on that basis, they
and many others
10 consider that to be a positive
study.
11
Similarly, for the sertraline program,
12 although if you look at the
individual trials,
13 neither one makes it. One of the
secondary
14 analyses in the plan for these
identically designed
15 studies was to pool them, and when
that is done,
16 the pooled analysis is very
positive, so some view
17 that -- and again this was the
basis for a
18 publication by Wagner, et al. --
some view the
19 sertraline program as providing
support for
20 efficacy in major
depression.
21 Again, as I
pointed out, the citalopram
22 program had 1 of 2 studies that
was clearly
23 positive.
24
[Slide.]
25
Now, I want to talk a little bit about
288
1 this largely negative
outcome. If you look
at
2 adult major depression studies,
and if you look at
3 drugs which we believe work and
which have been
4 approved for depression in adults,
about half the
5 time studies that on face look
like they should
6 make it,
fail.
7
These are studies that are done in what
8 appears to be the right
population. The
sampling
9 size is appropriate, the doses
appear to be
10 appropriate, assessments are
appropriate, but for
11 whatever reason, about half the
time, these studies
12 fail.
13
Now, if you assume that that failure rate
14 can be applied to pediatric major
depression
15 studies, and you look at the
possible outcomes for
16 2 trials, for programs that
involve 2 trials, you
17 can very quickly reach the
mathematical result that
18 only about 25 percent of the time
would you expect
19 to get 2 positive
studies.
20
Most of the time you would expect either 1
21 or both trials to fail if the
failure rate were the
22 same as is true in adults. So, in retrospect,
it
23 perhaps was not as surprising as
it turned out to
24 be here that you get a lot of
negative results.
25 On
the other hand, the overall success
289
1 rate here of 3 out of 15 studies
making it at 0.05
2 on the primary endpoint is
clearly, clearly a
3 concern.
4
[Slide.]
5
There are a couple of other things to keep
6 in mind. If you look at the history of
short-term
7 trials with tricyclic
antidepressants in pediatric
8 depression, it is uniformly
negative, and there are
9 several possible interpretations
of that.
10
One is that the drugs don't have any
11 benefit. Another possibility is that the extent
of
12 heterogeneity in pediatric
patients who are
13 captured under these major
depressive disorder
14 criteria may capture patients who
are even more
15 heterogeneous than we believed to
be the case in
16 adults, and the greater the
heterogeneity in that
17 sample, the more likely you would
end up with
18 negative studies. So, that is one
possibility.
19
Another thing to keep in mind is that the
20 regulatory context for doing these
studies was
21 somewhat unusual. In every other case, when
a
22 company does a study, the only
gain they are going
23 to get out of that study is if it
turns out
24 positive.
25
In this case, these studies were done
290
1 primarily for pediatric
exclusivity. As
was
2 pointed out earlier, there was no
requirement that
3 they get positive studies to get
exclusivity.
4 Either way, if they did the trial
according to the
5 terms of the written requests,
they would get
6 exclusivity.
7
I am not suggesting in any way that
8 companies set out to do inadequate
studies, but
9 having that somewhat unusual
mind-set could operate
10 against a trial in subtle ways, in
terms of, for
11 example, recruitment of
patients. So, it is
just
12 another thing to keep in mind in
terms of
13 interpreting these largely
negative data.
14
Finally, at the time that the written
15 requests for these studies were
issued, we were not
16 routinely asking for Phase II dose
finding studies,
17 as we are now in all of our
written requests.
18
Again, to the extent that appropriate dose
19 finding was not done, that would
work against
20 positive
studies.
21
So, just in summary on the efficacy side,
22 I think there are several
plausible explanations
23 for failure to find efficacy in
these trials other
24 than the obvious possibility that
maybe the drugs
25 have no benefits in pediatric
major depression.
291
1
In any case, the failure to meet FDA's
2 fairly high standard of having 2
positive trials,
3 in most of these programs, we do
not consider proof
4 of the lack of benefit. So, it is true they
didn't
5 meet the standard, but that is not
quite the same
6 thing as saying that it has now
been proven that
7 the drugs have no benefit. That is a very
8 different
conclusion.
9
On the other hand, the failure to show a
10 benefit in major depression in
most of these
11 trials, obviously heightens the
concern about any
12 adverse events, in particular, in
this case, the
13 possibility of the induction of
suicidality.
14 Clearly, the burden is on those
who believe that
15 these drugs do have benefits to
show it, to design
16 and conduct studies that show
this.
17
Again, one of the questions that I have
18 for the committee is what your
thoughts are about
19 how to go about this, in
particular, the
20 possibility of using a very
different kind of study
21 design, for example, using the
randomized
22 withdrawal design, which has been
fairly successful
23 in showing longer term benefits in
adult studies.
24
I will stop there. Thank
you.
25
Open Committee Discussion
292
1
DR. RUDORFER: I think we
will now open
2 this up for questions and
discussion by the
3 committee.
4
DR. SANTANA: Can you clarify
something
5 for me, so under the exclusivity
rule, if the
6 results are positive, those
studies can then be
7 used by the sponsors to make a
supplemental claim,
8 and that could then become part of
a new indication
9 in pediatrics, is that
correct?
10
DR. LAUGHREN: I am
sorry?
11
DR. MURPHY:
Yes.
12
DR. LAUGHREN: The answer is
yes.
13
DR. MURPHY:
Yes.
14
DR. SANTANA: I was trying to
answer this
15 issue of whether there was some
bias in these
16 studies because they were
requested under the
17 exclusivity rule. I have never interpreted it
that
18 way.
19 DR.
MURPHY: I think what has been
a
20 concern from the very beginning
with exclusivity,
21 we think the intent of Congress
was that they want
22 more information. If studies are going to
be
23 conducted, they want that
information to be known,
24 and therefore, they want to say to
companies we
25 want you to go out and get this
information. It
293
1 doesn't mean you have to reach the
bar of having an
2 approval, because a negative study
can be just as
3 important as a positive
study.
4
But the other concern here is that you --
5 and no one is saying this, so,
please, I don't want
6 this quoted out of context -- but
there is the
7 concern that it is easy to design
a sloppy study,
8 fail, and still get your
exclusivity. That is
9 always a concern, and it is our
job to try to not
10 allow that to
happen.
11
DR. RUDORFER: Dr.
Temple.
12
DR. TEMPLE: I just was going
to emphasize
13 the same thing. Tom isn't suggesting that
anybody
14 was totally indifferent to the
outcome, but the
15 sense of urgency that comes when
you have launched
16 a very expensive program to
develop a drug, you
17 really must win or it's all toast,
and that's not
18 true here. You can win anyway,
different
19 incentives.
20
DR. RUDORFER: Dr. Fink, you
had a
21 question.
22
DR. FINK: This is sort of an
overriding
23 question, not to a specific
speaker. In looking
at
24 the questions that are being asked
of the
25 committee, we have heard very
little about the data
294
1 set that is being
used.
2
Are the inclusion and exclusion criteria
3 for these various studies
appropriate in terms of
4 drug history, history of substance
abuse, family
5 history of psychiatric
diagnoses? Because
these
6 were placebo-controlled trials,
they probably
7 enrolled less severe disease as
evidenced by the
8 lack of completed suicides, and
finally, as has
9 been mentioned, there was no need
of efficacy.
10
I am concerned that no amount of analyses
11 of a possibly flawed or suboptimal
data set will
12 answer the question. If there is shown to be
a
13 relationship to suicidality, we
may take away drugs
14 that are useful in pediatric
depression with
15 different trial
designs.
16
If the studies come out negative, we may
17 be falsely reassured. So, I am not sure that
these
18 re-analyses are going to answer
the question that
19 has been brought forward to the
committee by
20
particularly the audience
and that maybe we need to
21 start with designing what are the
optimal pediatric
22 trials to answer this important
issue.
23
DR. RUDORFER: Does someone
from the FDA
24 want to
respond?
25
DR. TEMPLE: Well, Tom sort of opened that
295
1 question to a degree. One of the things that
no
2 one will let you do probably is
treat somebody very
3 severely ill in a
placebo-controlled trial, they
4 would be uncomfortable, although
since it is not
5 clear what works, maybe they
shouldn't be that
6
uncomfortable.
7
Nonetheless, an alternative design which
8 in pediatric studies has been
proven very
9 attractive is to take people who
appear in one way
10 or another to be doing well on a
particular
11 therapy, and in this case it
really won't be as
12 critical how severe they were
before, and do a
13 randomized withdrawal study in
which people are
14 very, very closely observed for
the first
15 recurrence of any symptom that is
worrisome.
16
The Pediatric Committee has discussed this
17 at considerable length, and there
is more comfort
18 in pediatric trials in using that
design where you
19 do need a placebo to interpret the
trial. So,
that
20 is one of the questions Tom
raised, and I am sure
21 we would be interested in some
discussion on that.
22
DR. GOODMAN: I am also
sharing the
23 concern about the ability to get
the answer to the
24 suicidal risk associated with
these drugs based
25 upon the existing data set. I think the signal is
296
1 not going to be strong enough
although we are
2 clearly most interested in suicide
or suicide
3 attempts as the
outcome.
4
I wondered if one could look at these data
5 sets for other possible evidence
of behavioral
6 toxicity that might be antecedents
of suicidality.
7 I think there was some allusion to
that earlier,
8 but there wasn't much detail on
it. I wonder
9 specifically if one could look at
some of the
10 items, like of the HAM-D or the
CDRS, looking for
11 agitation or
irritability.
12
If those are being induced by the
13 medications particularly early in
the treatment
14 trial, perhaps those are creating
a behavioral
15 state that places that individual
at risk for
16 suicidal
behavior.
17
One could, of course, validate that by
18 first looking at those subjects in
whom there was
19 evidence of suicidality to see if
it was correlated
20 or associated with other symptoms,
but if it is,
21 then go on to look at those
variables, which would
22 allow you to maybe get a more
sensitive measure of
23 the effect of the
drugs.
24
DR. RUDORFER: Dr. Nelson and
then Dr.
25 Katz.
297
1
DR. NELSON: Two
questions. The first
is
2 about the data set. At the end of the day,
when
3 you receive the data that you are
asking for, will
4 you be looking at the same data
set that were
5 reviewed by the MHRA? I mean are we going to
be
6 drawing conclusions on similar
data sets?
7
The second question goes to the issue of
8 the interpretation of Appendix 1
and Appendix 2A.
9 I am struck, if you remove
fluoxetine, that you
10 have got 1 out of 13 trials for
effectiveness
11 positive and 5 out of 13 for
increased risk of
12 suicidality positive, and does
assay sensitivity
13 apply to risks as well and why
would we not
14 interpret that as a pretty strong
signal if, in
15 fact, we accept that on the
efficacy side?
16
DR. LAUGHREN: Regarding the
question
17 about the UK data, I can't be
certain that they
18 have the same data, however, if we
look at the
19 numbers that are presented on the
UK web site, they
20 are very familiar numbers. They appear to be
21 coming from the same summary data
that we had
22 access to in looking at this
data.
23
So, I am reasonably confident that we are
24 dealing with the identical data
sets. The
only
25 difference is that we have gone
beyond accepting
298
1 the data at face value. It appears that the
UK
2 simply accepted the summary data
analyses done by
3 the various companies, and on the
basis of a
4 suggestion of a signal, and the
admitted lack of
5 efficacy for most of these
programs, have decided
6 to contraindicate these
drugs.
7
We have chosen on the safety side to look
8 more closely at what that signal
is, and that is
9 really the question. The question is -- and
this
10 gets in reference to your second
question about
11 Appendices 2 and 2A -- I agree
with you that if you
12 look across these trials, even
though the signal is
13 not consistent from study to study
within programs,
14 on balance, it appears like there
is an excess of
15 something for drug relative to
placebo.
16 The
question is what is that. You
have
17 this very broad term, "possibly
suicide related,"
18 but when you dig deeper and look
at what those
19 events are, they range all the way
from something
20 that everyone would agree does not
represent
21 anything close to a suicide
attempt to very serious
22 suicide
attempts.
23
So, that is why we think it is important
24 to go back and reclassify those
events, so we can
25 figure out, first of all, if there
is a signal, and
299
1 secondly, a signal for what. But I believe that
2 the UK had the very same data that
we have, and it
3 doesn't appear to me as if they
did any analysis of
4 those data other than to just
accept what the
5 companies have done
already.
6
DR. RUDORFER: Dr. Katz, did
you have a
7 comment?
8
DR. KATZ: Just to say that
the suggestion
9 about looking at other behavioral
symptoms that
10 might be premonitory to suicidal
behavior, we are
11 very interested here whether or
not there are
12 specific events we should be
looking at that we
13 haven't looked at yet along the
lines of how we
14 intend to look at the suicidal
behavior data.
15
That might involve going back and asking
16 sponsors to resubmit data sets,
but we are very
17 interested to hear that. Of course, the
question
18 of the link between those symptoms
and suicidal
19 behavior is also still an
outstanding question,
20 it's not
straightforward.
21
DR. RUDORFER: Dr.
Chesney.
22
DR. CHESNEY: I also felt
that perhaps
23 just looking at suicide attempts,
basically what
24 you just said and what Dr. Goodman
said, may not be
25 all the answer. I am most impressed from what we
300
1 heard in the public hearing this
morning about the
2 stimulant syndrome and the number
of individuals
3 who had demonstrated psychoses,
akathisia, mania,
4 agitation, and so
on.
5
I was also impressed at one young lady who
6 said that she wouldn't disclose
that she had had
7 suicidal ideation, and then
particularly impressed
8 with the three people we heard
from whose children
9 at autopsy had very elevated
levels of the drug,
10 which leads to my second
question.
11
That is, what do we know about
12
pharmacokinetic data in
children and in individuals
13 who develop this stimulant
syndrome. I
suspect
14 someday that we will have
pharmacogenomics to tell
15 us maybe who to predict might have
that, but do we
16 have any information about
pharmacokinetics in
17 children, number one, and number
two, in these
18 individuals who develop these
stimulant syndromes,
19 is there any relationship at
all?
20
DR. KATZ: Well, in the
written requests,
21 as a general matter, we ask
sponsors to obtain
22 pharmacokinetic information in the
relevant
23 pediatric population, so I believe
we have probably
24 asked for that
information.
25
I don't believe we know or have had
301
1 submitted to us in any event data
linking plasma
2 levels in any individual patient
and particular
3 adverse events. That might be available
somewhere,
4 but I don't think we have
it.
5 DR.
LAUGHREN: Could I ask Daniel Pine
to
6 comment on this construct
stimulation syndrome and
7 whether or not that has been
reasonably well
8 defined in some way that is agreed
to by different
9 individuals?
10
DR. PINE: Sure, and then actually I
have
11 a couple other comments. I don't know if you
want
12 me to wait until after this
issue.
13
But I would say across a range of
14 pediatric mental syndromes, it has
been fairly
15
frequently described that a
strong minority of
16 children will get activated with
SSRI medications,
17 and not just children with major
depression, and
18 that in most studies, if it is not
statistically
19 greater than it is in placebo,
that it is a fairly
20 consistent observation across most
studies, that it
21 is higher on SSRIs than it is on
placebo.
22
DR. LAUGHREN: Are we talking
about
23 something other than the anxiety
and agitation
24 which is well known as a
drug-related risk with all
25 of these drugs? That is something that we see in
302
1 most of these trials, but it is
not quite the same
2 thing as saying that someone has a
stimulant
3 syndrome.
4
DR. PINE: I think if you
look across the
5 trials and you look at the range
of terms that
6 people have used to describe this
so-called
7 stimulant syndrome, you see that
the problem that
8 you were talking about with the
relatively narrow
9 set of behaviors, self-harm
behaviors or suicidal
10 behaviors, becomes even worse
because across
11 different trials or trials for the
same medication
12 done by different individuals,
really a broad range
13 of behaviors have been kind of
linked together.
14
It remains unclear the degree to which
15 different investigators are
talking about the same
16 phenomenon or different
medications are producing
17 similar phenomenon. The one thing that is clear
is
18 that there is an array of what
some people have
19 called, and Dr. Goodman referred
to, as behavioral
20 toxicities that are not that
infrequently observed
21 with SSRIs, and it might extend
beyond suicidal
22 ideation, and it also needs to be
better
23 categorized.
24
I would also add that when one looks at
25 those events in most of the
efficacy trials, they
303
1 tend to be uniformly mild. I am most familiar
with
2 the anxiety trials where, while
they are more
3 prevalent, they tend to not cause
sometimes even
4 discontinuation of the
medication.
5
DR. LAUGHREN: If I could
just follow up
6 on this. If we were, Daniel, to look for this,
I
7 guess the question would be how
would one define it
8 in a way that we could hope to
find examples of it?
9
DR. PINE: I think if you
look at most of
10 the publications for most of the
SSRI trials, you
11 can see relatively broad
categories that describe
12 something that people would call
activation, so,
13 you know, in the original
sertraline trial, I think
14 it was called hyperactivity. In the fluvoxamine
15 trial, it was called
activation.
16
In the recent sertraline trial, I think it
17 was called impulsivity. So, there is a whole
range
18 of terms that I think you would
have to canvass the
19 field in terms of thinking about
what are the most
20 appropriate terms to include, much
the way that you
21 have done with suicidal
ideation.
22
That is not to say that this is
23 necessarily related to suicidal
ideation, though.
24
DR. RUDORFER: Dr. Goodman,
did you have a
25 follow-up comment?
304
1
DR. GOODMAN: Yes. In at least adults,
I
2 think as clinicians as well as
clinical
3 researchers, we have a good sense
of kind of the
4 array you were talking about of
activation-like
5 problems that can occur with the
administration of
6 SSRIs.
7
Even in the labeling, we have seen that
8 there are warnings that you can
induce bipolarity,
9 mania. In fact, it has often been said that
an
10 antidepressant is probably not
effective unless it
11 can induce bipolarity in some
patients.
12
We also know about psychosis and anxiety
13 induction particularly in panic
disorder patients.
14 So, I think in adults, we have it
a little better
15 characterized. What I am concerned about with
the
16 children is, one, their
characterization probably
17 is somewhat overlapping, and also
because of what
18 is special about children is maybe
that they are
19 more likely to manifest these
problems in a less
20 differentiated fashion, which
includes suicidal
21 behavior.
22
DR. PERRIN: To follow up on
two of these
23 issues, one is we hear about
serious adverse events
24 being beyond suicide, but
potentially also murder
25 and other such events.
305
1
I think maybe Dr. Pine is talking about
2 strategies that might help to
elicit those sorts of
3 ideas in the data set, but it
seems to me that is a
4 critical issue to go beyond
suicidality as a
5 potential serious adverse
event.
6
I want to get back to the pediatric rule
7 question for a moment, too, if I
could, and just
8 ask -- I show my naivete and
ignorance here -- but
9 what purview, what surveillance
does FDA have of
10 pharmaceutical companies carrying
out their trials?
11
The little I know about them is that these
12 are often multi-site trials,
fairly complicated
13 data collection among a variety of
providers.
14
Do you have any surveillance as to how
15 well this is carried out, or do
you sort of rely on
16 the pharmaceutical companies to
say we did it
17 reasonably well, and might that be
a source for
18 variation between pediatric rule
trials compared to
19 the sort of getting the drug on
the market trials?
20
DR. TEMPLE: Others may want
to comment.
21 Usual rules apply. We can inspect any of
the
22 studies. As you can imagine, inspecting a
study
23 after the fact gives you only
limited insight into
24 how well those things went
on.
25
The companies are expected to provide
306
1 oversight, the rules require that
they do so, but
2 our ability to know whether it is
perfect or not is
3 difficult at best. What I can't tell you is
how
4 often we have inspected these
sites. We do
5 sometimes, I don't know if we have
on these.
6
DR. MURPHY: I would like to
say that this
7 is an issue at the level of the
Office of
8 Commissioner, that there is an
Office of Good
9 Clinical Practices, that they are
addressing to
10 make sure that we do have adequate
surveillance and
11 criteria. I don't think we can provide you a
lot
12 of information right now, but it
is an issue that
13 they are looking
at.
14
DR. TEMPLE: It would be
relatively
15 unusual for us unless we had a
concern about
16 whether they picked up adverse
reactions, which we
17 might in this case, first, to
inspect a study that
18 the company agrees is
negative. On the whole,
that
19 is not where you go to
look.
20
DR. RUDORFER: Dr. Gorman,
you have been
21 waiting.
22
DR. GORMAN: One of the
themes that struck
23 me through the morning was the
interruption or
24 potential interruption of
information flow through
25 the system.
307
1
I would like to continue on the thread of
2 the study and then go to the
information flow
3 question I
have.
4
On the study, I think going back and
5 looking at that 109 out of 3,000
patients that were
6 being studied for efficacy and
looking for them for
7 suicidal ideation or attempts will
be trying to
8 make a silk purse out of a sow's
ear. I think
that
9 would be an adventure in
futility.
10
I don't think it's an unreasonable thing
11 to do if it's the data that you
have available, but
12 I think the example used this
morning was the
13 needle in the
haystack.
14
I think we have stepped on the needle and
15 we have either got to see if it's
really there or
16 if it is really not there, and
design studies
17 prospectively either using
randomized, controlled
18 clinical trial crossover designs
or withdrawal of
19 effective therapy
designs.
20
One of those three designs could be
21 designed looking specifically at
the questionnaires
22 that our psychiatric and
psychology colleagues tell
23 us look for suicidal
ideation.
24
To look for suicides as a rare event I
25 think is going to be again a
futile search, but
308
1 looking for suicidal ideation
induced by these
2 medications, I think should be
relatively
3 straightforward, and I would not
use the set of
4 mildly or majorly depressed
people.
5
I would look at groups of individuals on
6 these medications who are not
depressed, so that we
7 could separate that issue out, is
it the disease or
8 is it the
medicine.
9
So, take the ODDs and take the
10 post-distress syndromes and study
them for suicidal
11 ideation being initiated on these
medications.
12
Now, back to the pediatric rule, which I
13 think I understand, and the Best
Pharmaceuticals
14 for Children Act, I thought there
was a provision
15 in there, I thought, that when we
fixed it after
16 1997, that if you went for
pediatric exclusivity,
17 when you finish the trial, whether
the results were
18 positive or negative, you got
exclusivity.
19
But I also think there was a requirement
20 for the pharmaceutical companies
to make those data
21 available in a public place. Is my
understanding
22 confused?
23
DR. MURPHY: No, that was a
slide this
24 morning. The BPCA does say that within 180 days
of
25 the submission of the application,
that the study
309
1 results, clinical trial and a
summary of the
2 clinical aspects and the
pharmacology report will
3 be posted on the web by
FDA.
4
DR. GORMAN: Is there a
dissemination
5 issue then that it comes as a
surprise to me and
6 other people in this room that 12
out of 15 studies
7 -- and I am sorry if I got that
number wrong --
8 were negative in their scope, or
is that just
9 something that hasn't quite made
its way to the web
10 site yet?
11
DR. MURPHY: No, there was an
issue in
12 that there was a window after BPCA
was enacted in
13 which the sponsors had to be
informed that they now
14 -- because they had been issued
the written
15 requests earlier -- that they now
were under the
16 new legislation. They had been issued
their
17 written requests under prior
legislation.
18
In that window, a number of these studies
19 came in.
20
DR. RUDORFER: Dr.
Leon.
21
DR. LEON: After hearing the
speakers
22 today, I think there is at least
three avenues to
23 pursue simultaneously for being
informed about this
24 topic, and all three will provide
important
25 information about the public
health risk and
310
1 benefits.
2
First, is looking at the existing clinical
3 trial data, or using the experts
from Columbia
4 University, that is a good
start. I think what
is
5 very important in looking at those
data is we
6 haven't yet heard what percentage
of people who
7 were screened to be in those
clinical trials
8 actually were enrolled. Was it 5 percent,
10
9 percent, 80 percent? We have no idea. That
10 certainly affects the
generalizability of those
11 results.
12
The people we heard from this morning
13 might have been those who these
data don't apply
14 to, who would be excluded from
trials, and we need
15 to learn about those, and I will
comment on that in
16 just a
minute.
17 Also,
in re-analyzing those data, I would
18 really discourage the last speaker
from dropping
19 data in which there were no
suicide attempts.
It
20 provides a false sense of risk
actually. It
21 inadequately characterizes
exposure to the
22 medication.
23
The second avenue to pursue would be new
24 clinical trials, which were
alluded to by a few
25 people today, and those should be
designed with
311
1 very comprehensive assessments of
suicidality,
2 agitation, hostility, akathisia,
and assessments
3 that are sanctioned by the FDA,
maybe with expert
4 advice again from Columbia and
other universities,
5 other academic centers with
expertise in assessing
6 those
constructs.
7
They should carefully consider the
8 comparison group. That is probably the
hardest
9 part of designing those studies,
whether it's a
10 withdrawal study, as Dr. Laughren
alluded to, or
11 suggested, or maybe psychotherapy
versus active med
12 versus combination, I am not quite
sure, but that
13 certainly deserves discussion, and
in those trials,
14 much broader inclusion criteria
should be used than
15 have been used in the clinical
trials to date.
16
The third avenue I would encourage is the
17 use of existing observational data
sets. Now,
18 observational data sets, at the
expense of internal
19 validity, at the expense of the
association between
20 treatment and outcome provide
wider
21 generalizability, and a much
broader inclusion
22 criteria.
23
Dr. Pfeffer, her slides referred to at
24 least three different ongoing
longitudinal
25 observational studies of children,
depressed
312
1 children, and if those
observational studies are
2 used, appropriate methods for
adjustment and
3 stratification should be
used.
4
They could consider some of the methods
5 used in the Division of Devices
that are used to
6 adjust for observational
differences.
7
I will stop there.
8
DR. RUDORFER: Dr. Katz and
Dr. Temple.
9
DR. KATZ: I just want to
comment on the
10 notion of how to better design
trials in the future
11 to look at this question. It is a very
important
12 question, it is one of the
questions actually that
13 Tom has drawn up, that we would
like you to
14 discuss, and a number of people
have already
15 mentioned
it.
16
We think it's a good idea, too.
The
17 problem is I am not sure how to
get those trials
18 done. As you have seen, pretty much most of
the
19 drugs in this class have been
studied already,
20 their trials have been done under
the pediatric
21 exclusivity provisions, and I am
not sure we have
22 the authority to require sponsors
to go ahead and
23 redesign trials of the same
treatments to have a
24 better look at trying to capture
these events.
25
I would be very interested to know if
313
1 people have an idea about that,
whether or not
2 there should be an NIMH-sponsored
trial perhaps of
3 most of the drugs in this class,
because I don't
4 think we can require the sponsors
to do these
5 studies other than for the ones
that might not yet
6 have studied them under the
pediatric exclusivity
7 provisions, whichever ones those
are, and there
8 aren't many.
9
DR. MURPHY: The one
possibility would be
10 that these products would be put
on the list of
11 products that need to be
studied. We have
an
12 off-patent list, but we can also
reissue a written
13 request to a sponsor for a product
which is on
14 patent, and if they refuse to do
it, we could send
15 that request to the foundation at
NIH.
16
Remember, I described
earlier this morning
17 there is a collaboration between
NIH and FDA to
18 develop products for the
off-patent including the
19 list of products that need to be
studied. Some
of
20 these products have come off
patent, some will be,
21 and even if they haven't, there is
another
22 mechanism which FDA can issue a
written request and
23 then if the sponsor doesn't want
to do it, even if
24 it's still on patent, and it has a
high enough
25 rating, it can be sent to NIH
foundation.
314
1
I have to tell you, though, that the
2 problem is that funding for that
foundation to do
3 studies is very small, so it would
be getting in
4 line for a number of studies for
which the funding
5 is very limited at the moment, but
those are the
6 possibilities I am aware of at
this point.
7
DR. RUDORFER: Also, I wanted
to mention
8 that there is, in fact, an NIMH
study that is
9 nearing completion, the treatment
of adolescent
10 depression study, or TADS, that
includes a
11 controlled trial of fluoxetine and
placebo, as well
12 as cognitive behavior therapy
alone or with drug.
13 That is a 36-week acute trial
followed by a 1-week
14 follow-up study in a total of 400
adolescents
15 coordinated at
Duke.
16
I understand that the results should be
17 available by the beginning of
June, so hopefully,
18 in time to inform the FDA
analysis.
19
Dr. Ebert has been waiting patiently.
20
DR. EBERT: It appears in
some ways that
21 many of these clinical trials may
not reflect the
22 typical use for these agents. We saw some data
23 that showed that many of these
agents are used
24 other than for major depressive
disorders, are
25 prescribed by physicians other
than psychiatrists,
315
1 and I am wondering if there is
some way that we can
2 measure the adverse effects that
we are seeing in
3 the typical
use.
4
We currently have the AERS system, which I
5 think admittedly is somewhat
limited because of the
6 voluntary reporting that is
necessary, but I am
7 wondering if the Agency could
comment about some
8 other type of a postmarketing
program that could be
9 set up that might focus on this
more rigorously.
10
DR. TEMPLE: The people from
the Office of
11 Drug Safety need to comment,
too. I just wanted
to
12 make the observation that the most
difficult
13 epidemiological situation you can
identify probably
14 is where the events you are
looking for, both the
15 product of the disease and the
potential product of
16 the drug you are worried about, it
is hard to think
17 of anything more difficult, but
some
18 epidemiologists ought to comment
further on that.
19
I wanted to make one observation about
20 randomized withdrawal studies,
which I like very
21 much. They are not a good way to discover
whether
22 these drugs cause suicidal
thinking, because, by
23 definition, the people on those
drugs are people
24 who are doing well on
them.
25
It is a possible way to show that the
316
1 drugs work in a situation that is
somewhat
2 different from the high-intensity,
high-support
3 setting of the acute trial, but I
don't think that
4 is going to get us the answer on
suicidal thinking.
5 These are all bona-fide do-gooders
or do-wellers if
6 you like, so I don't think it is
going to help on
7 that.
8
DR. RUDORFER: Dr.
Pfeffer.
9
DR. PFEFFER: I wanted to
comment on
10 something that struck me, and that
is the placebo
11 response rate seems to be
relatively high in these
12 populations in these studies, and
I wondered how
13 they did compare to placebo rates
in adults.
14
My sense is they are high and I would
15 assume maybe higher, and I wonder
if that leads to
16 us needing to think about other
covariates, for
17 example, as will be done in the
analyses, such as
18 the environmental circumstances in
which the
19 children are living, and to see
what that feature
20 may impact on not only the
suicidal state, but the
21 potential for
recovery.
22
I wonder certainly with the placebo rate
23 being a narrow range between the
treated state, if
24 our concerns about efficacy need
to be rethought in
25 terms of developmental issue.
317
1
DR. RUDORFER: Does someone
from the FDA
2 want to comment on the placebo
response rate in the
3 pediatric studies versus these
same drugs in
4 adults?
5
DR. LAUGHREN: I don't have
the data in
6 front of me. My general sense is yes, that
the
7 placebo response rate in fact is
an issue for both
8 adult and pediatric studies,
perhaps even more of
9 an issue in pediatric studies, and
that may get at
10 the issue I was raising earlier
about heterogeneity
11 that you see when you try and
capture a population
12 using the MDD criteria, but yes,
it is definitely a
13 problem in both areas, but perhaps
even more so in
14 pediatrics.
15
DR. RUDORFER: Dr. Laughren,
is there a
16 standard way of assessing
diagnosis in these MDD
17 trials? I mean as a matter of just the
sponsor
18 will say these subjects met DSM-IV
criteria, do we
19 know if they used any kind of
structured interview?
20
DR. LAUGHREN: They
almost always use
21 some kind of structured
interview.
22
DR. RUDORFER: So,
presumably, if there
23 were comorbidities, those would be
captured?
24
DR. LAUGHREN: Yes, and there
often is
25 comorbidity.
318
1
DR. PINE: Related to that
question, could
2 I make one comment about it. When one looks
3 particularly across the recent
studies, while every
4 study will say that they used a
standardized
5 assessment, there is really a
quite marked
6 variability across studies in
terms of the way in
7 which they documented the rigor of
that approach.
8
So, if you read the recent letter in JAMA
9
from Wagner, that talks
about the process of
10 establishing the diagnosis and the
reliability
11 study, that reads very differently
from some of the
12 other studies that maybe had a
lower placebo
13 response rate or smaller
samples.
14
So, I was wondering if it might be
15 possible to in some way evaluate
or rate the rigor
16 with which both the diagnosis and
the outcome
17 variables were assessed across the
studies, paying
18 particular attention to issues of
training and the
19 demonstration of reliability by
those investigators
20 conducting the trial and using the
instrument.
21
DR. LAUGHREN: It would be
very difficult
22 to do that after the fact. If they claim to
have
23 done it in a particular way, to
document whether or
24 not it had been done in that way,
involve an
25 enormous amount of work, and given
the time at
319
1 which these studies were done, you
know, going back
2 four, five years, it would be hard
to imagine how
3 that would be
helpful.
4
DR. RUDORFER: Dr.
Wang.
5
DR. WANG: I think in
addition to
6 considering what the optimal
design would be, if we
7 all had our choosing, we should
keep in mind that
8 at the best, it will take a long
time to do them
9 even sorting out all the other
logistics, so I
10 think in the meantime, it is
important to consider
11 how to enhance the use of this
existing data set,
12 which will be arriving soon
enough, to study this
13 question.
14
One thing I am particularly concerned
15 about is you may lose an effect in
the overall data
16 set that you would otherwise be
able to see in a
17 high-risk
population.
18
I think in that list of covariates that
19 you are asking the sponsors to all
submit, to also
20 add variables that will allow you
to identify
21 high-risk populations, such as
people -- some that
22 come to mind, kids that have
insomnia at baseline
23 or high anxieties, severity
symptoms, or family
24 histories of bipolar illness,
things that allow you
25 to sort of concentrate on a group
that is likely to
320
1 potentially show an
effect.
2
DR. RUDORFER: Dr.
Gorman.
3
DR. GORMAN: Again back to
the theme of
4 information flow, I was wondering
if someone from
5 the FDA could explain what bars we
would have to
6 meet for changing the labeling on
these substances
7 today. The labels get made when a new product
is
8 approved, but then are modified
through many
9 mechanisms, I have no
idea.
10
What do we need to do to put a precaution,
11 warning, or black box, or side
effect or adverse
12 event that lists these as
potential -- what bar do
13 we have to meet to potentially
include these in the
14 label?
15
DR. KATZ: As you heard
from one of the
16 speakers in the open session, it
isn't required,
17 for example, when we are
contemplating putting
18 something in the Warning section
that we have
19 absolute proof that the drug
causes a particular
20 adverse event, but reasonable
suspicion. I
forget
21 exactly what the words
are.
22
On the other hand, of course, two points,
23 one, it is obviously a judgment as
to whether or
24 not there is reasonable evidence
that a drug is
25 linked to a particular adverse
event. So, if you
321
1 ask what the bar is, it is hard to
say. It is
2 highly
case-dependent.
3
On the other hand, even though the law
4 permits us to include things in
the Warning section
5 that we have not yet proven to be
associated with
6 the drug, there is always the risk
of including
7 such events when we aren't really
sure or almost
8 sure that the drug did it,
because, number one, it
9 is distracting, but beyond that,
you might be
10 giving false
information.
11
So, as a general matter, we tend to put
12 adverse events in the Warning
section when we are
13 pretty sure, when we think we have
pretty good
14 evidence that the drug actually
does it as opposed
15 to its just being associated with
it.
16
A boxed warning again is a judgment, but I
17 would say, as a general matter, as
well, we don't
18 put a description of adverse
events in a boxed
19 warning, which is sort of the most
stringent
20 warning you can apply in a
labeling unless we
21 really believe that the drug is
causally related to
22 the adverse
event.
23
Then, of course, we don't put all causally
24 related adverse events in boxed
warnings, only
25 those which we think are
particularly serious, not
322
1 to say that suicidal behavior
would not be one of
2 those events, but really boxed
warning and pretty
3 much warning, we like to have
pretty good evidence
4 that the drug actually did
it.
5
Of course, the type of evidence that is
6 brought to bear on the question of
whether or not
7 the drug is causally related
varies. We like
to
8 have controlled data. It isn't always
controlled
9 data.
10
Sometimes for rare events, as you heard
11 earlier, events not associated
with the condition
12 that you are looking at,
postmarketing data,
13 comparing reporting rates to what
we know about
14 background rates usually
suffices. I am not
sure
15 we can apply that sort of
reasoning to this case.
16
DR. TEMPLE: We are
particularly
17 interested in telling people of
things they can do
18 to avoid problems, if there is
such a thing, that
19 seems reasonably likely to do
it. Current
labeling
20 already does tell you that early
after treatment
21 starts is the time to watch
out.
22
It doesn't attribute that to the drug, but
23 it doesn't seem out of the
question that wording
24 like that could be enhanced and
made clearer.
25 Everyone seems to agree that that
is a dangerous
323
1 time whether you agree on why it
is a dangerous
2 time or not.
3
So, there are things like that that can be
4 done. Another option that we have
not used for most
5 of these drugs is to provide
information as best we
6 can for patient or caregiver
use. Those are
all
7
possibilities.
8
DR. MURPHY: Could I put a
pragmatic
9 response to that answer? That is, that I think
one
10 of the other things that we need
to consider --
11 it's in your questions -- is that
to get a change
12 in label, let's just assume for
some reason that
13 people walked out of here today
and wanted to
14 change the
label.
15
It takes a while to get all that done and
16 by the time you came back this
summer, you might
17 want to change the label
again.
18
So, I think what we are going to be asking
19 you or in one of the set of
questions is what are
20 your recommendations about what
FDA may or could
21 possibly do in the interim,
because I think that
22 everyone is very interested in
what additional
23 information we can get, and we
would like to make
24 it the most efficient way of
transmitting
25 information, which would be
together instead of
324
1 trying to change things maybe two
times.
2
So,
I think the pragmatics of it are what
3 can we do to help better inform
people before the
4 late summer meeting in which we
hope to have a more
5 definitive
response.
6
DR. RUDORFER: Dr.
Nelson.
7
DR. NELSON: I think I will continue
this
8 conversation about labeling rather
than what I was
9 originally going to
say.
10
I have two suggestions. What
struck me in
11 your remarks about the timing was
the delay it
12 appeared to take for you to
actually get the data
13 you were asking the sponsors to
provide. That
14 could be inadvertent or it could
be, in fact,
15 duplicitous.
16
So, I would suggest that you tell them
17 that, in fact, if they don't
provide the data you
18 want, that you will label it based
on just the
19 British decision, with a warning,
would be the
20 first
suggestion.
21
But the second is, to answer Dianne's
22 question about a notice, I think
you could honestly
23 take Appendix 2A and put that in
the letter to both
24 health care professionals and to
patients on the
25 medication saying the FDA is
really worried about
325
1 this signal and we want to look at
this data, and
2 if you are worried, too, you ought
to talk to your
3 clinician that prescribed it and
discuss those
4 concerns and name the
drugs.
5
It is unclear to me why someone couldn't
6 have the opportunity to see that
signal and to make
7 their own evaluation as to whether
or not they
8 would want to be slowly tapered
and put on the one
9 drug that seems to be so far a
winner in all of
10 this, which is
fluoxetine.
11
DR. LAUGHREN: Let me just
clarify one
12 thing. We have the data from the companies,
the
13 ball is now in our court, so we
are not waiting for
14 anything at this point from
companies unless the
15 committee feels that there is some
deficiencies
16 here in terms of case finding, but
we are satisfied
17 that we have what we
need.
18
It is now a question of working on a
19 reclassification and designing an
analysis. We
20 have what we
need.
21
Regarding the second issue of
22 disseminating Appendix 2 to
prescribers, I am not
23 sure what purpose would be served
in doing that.
I
24 mean we have already issued a
health advisory in
25 October saying that we are
concerned, that we can't
326
1 rule out an increased risk of
suicidality.
2
If we are not comfortable with what is in
3 the numerators for these risks
that are displayed
4 in that table, I am not really
sure what purpose is
5 served in disseminating
that.
6
DR. NELSON: One brief
response to that
7 and then I will be done. What bothered me
in
8 listening to the testimony this
morning is the
9 amount of off-label use, and the
amount of times
10 that people mentioned that they
were given samples.
11 I would even go so far as to
wonder if the handing
12 out of samples is marketing
outside of an
13 indication where you could even
come after a
14 company.
15
So, part of my desire to inform clinicians
16 is to try to scare them away from
off-label use
17 frankly. That bothers me, the amount of
off-label
18 use that appears to be going on in
this particular
19 market.
20
DR. RUDORFER: Dr.
Griffith.
21
MS. GRIFFITH: I need to
clarify, I am not
22 a doctor, I am a consumer, I am a
parent, and as a
23 lay person, the most troubling
outcome I think of
24 this morning's and this
afternoon's presentations
25 was the urgency with which this
needs to be
327
1 resolved.
2
After the presentation by Dr. Hammed, I
3 was really struck by, in covering
the analysis
4 plan, the last statement it
remains to be seen that
5 if we have enough statistical
power, whether or not
6 there is enough statistical
power.
7
My question is what happens then, if there
8 is not enough evidence to make a
conclusion, how
9 does the FDA inform the public,
because as you say,
10 you put out an advisory on October
27th, which I,
11 as a parent and as a consumer,
read, found it
12 terribly
confusing.
13
It was reported on very contradictorily,
14 and what I am suggesting is I
think the FDA is
15 going to have a credibility
problem if it does not
16 get out ahead of this with some
very public
17 statements about where it is going
with these
18 studies and with the
data.
19
DR. RUDORFER: Dr. Goodman,
did you want
20 to respond?
21
DR. GOODMAN: I think it is
going to be
22 some time until at least I am
comfortable that we
23 have enough data and analyze it
properly to be sure
24 of the connection with
suicidality, however, I
25 think that myself -- and my guess
is there are
328
1 other people around the table --
are more
2 comfortable with the assumption
or, to use these
3 other terms, have a reasonable
suspicion that there
4 is a subgroup of children who
develop an
5 idiosyncratic reaction to SSRIs,
that include
6 symptoms like insomnia, agitation,
maybe
7 suspiciousness, hostility, and
could possibly lead
8 to violent behavior including
self-harm.
9
I think a lot of clinicians are aware of
10 this already. I think that my colleagues in
child
11 psychiatry and pediatricians who
are informed on
12 this issue are very attentive when
they are
13 starting medication, if they are
seeing any of
14 these signs, they adjust the
dosage, they may stop
15 the medication, they certainly
don't increase the
16 dosage.
17
So, there are measures that can be taken
18 now by clinicians as long as they
are aware of it,
19 and by parents who are made aware
of it, to take
20 steps that may reduce the
development of this
21 syndrome, whatever we want to call
it, in a
22 susceptible group of kids that may
or may not
23 increase risk for more serious
adverse events that
24 include
suicide.
25
MS. GRIFFITH: Just to follow
up, I don't
329
1 disagree and I feel that I have
always been well
2 informed by clinicians, but I
think that there is a
3 group of people who have not been
able to either
4 look at the data or not had access
to good
5 therapeutic care, and I think that
it is going to
6 become a public relations problem
very quickly.
7
If the data comes back, if you are unable
8 to use it when it comes back prior
to this meeting
9 in the summer, you are extending
some sort of
10 reasonable period by which you can
reasonably
11 inform the families, and it will
snowball and get
12 completely out of
control.
13
DR. RUDORFER: Dr.
Katz.
14
DR. KATZ: One of the
questions we have of
15 the committee is what, if
anything, should we do in
16 the interim while we are waiting
to get the final
17 analyses. Of course, as a number of people
have
18 suggested, it is possible that
come this summer
19 when we do the analyses based on
these
20 resubmissions of the data, that we
won't be able to
21 say anything
definitive.
22
What we really want to know from you
23 folks, first of all, in the
interim, what, if
24 anything, we should say, and it
sounds like at
25 least some people think we should
do something
330
1 although I am not yet sure if and
what other people
2 think should be
done.
3
But it is possible that come this summer,
4 we really won't be in a position
to say anything
5 more
definitive.
6
What we really want from you folks is, in
7 part, whether or not there is
anything else you
8 think we can get from the data or
whether or not
9 there are any other additional
analyses that we
10 should do, so that we get as much
as we possibly
11 can out of the data, so that if we
do come back in
12
the summer and say, look, we
can't give you a
13 definitive answer, at least we can
know that we
14 have done everything that we
possibly could with
15 the data that we have in front of
us at the moment.
16
So, those are things we definitely want to
17 hear from you
about.
18
DR. RUDORFER: Dr.
Temple.
19
DR. TEMPLE: I just want to
sort of remind
20 everybody that what provoked the
most recent
21 interest in this subject was those
data, the 127
22 cases. If those prove to be uninterpretable,
we
23 are back where we
were.
24
What we then have is very impressive
25 individual reports of bad
outcomes. Those have
331
1 always been impressive when people
have tried to
2 look at those in controlled trial
environments and
3 things like that, and pooling our
study data, they
4 haven't turned up at least so
far.
5
There have been some criticisms of the way
6 that was done, but leaving that
aside, they haven't
7 turned up. The difficult question always is
what
8 to do with reports that have
considerable cogency
9 to them. I mean it sort of looks like
something
10 happened when the person started
the drug, it does,
11 that you can't really confirm in
controlled trials,
12 and that is always a problem with
the postmarketing
13 data we get.
14
Sometimes the events aren't the very thing
15 that you are worried about
happening in people with
16 that diagnosis. In this case, as I said before,
it
17 is particularly difficult because
people who are
18 depressed are the very people who
have some of
19 those
events.
20
Now, whether it looks like they were
21 accelerated or not are the kinds
of things we have
22 to think about, so as Russ said,
we are very
23 interested in views as to what we
can say that
24 would be useful now, apart from
waiting for the
25 results of the trials, if there is
such a thing.
332
1
DR. RUDORFER: We have
several speakers
2 lined up to continue the
discussion on Question 1
3 regarding capturing all events of
potential
4 interest, and I will ask everyone
else to hold your
5 questions, and then we will move
on to Question 2.
6 There is a lot of overlap, and I
have been asked to
7 try to keep these separate and
distinct.
8
If we could turn to Dr. Maldonado,
9 followed by Dr. O'Fallon,
please.
10
DR. MALDONADO: I am sorry to
bring you
11 back to the BPCA and rule. I want to clarify
the
12 point, the failed trials that the
FDA is seeing
13 right now has been an issue of
cost of doing
14 business for the pharmaceutical
industry for
15 generations, is that when those
so-called negative
16 trials happen, the pharmaceutical
industry doesn't
17 even bother to come into the FDA
with those trials
18 because they know they are not
going to get
19 anything out of
that.
20
Now, you are seeing it in the context of
21 the BPCA because it is necessary
to disclose, and
22 because there is incentive to
disclose it.
So,
23 this is not a new phenomenon and I
think that the
24 comment that the pharmaceutical
industry is not
25 making the efforts that they
should make is
333
1 unfounded.
2
A lot of these trials -- that is why they
3 are called trials -- a lot of
these drugs failed,
4 failed repeatedly, and those
failures actually had
5 to do more with the ignorance of
the people
6 developing the compound than with
the drug itself.
7
It is a process of learning until the
8 researchers fine-tune what they
want to find.
Not
9 only that, if there is a doubt
that these studies
10 are being done according to GCPs,
the FDA has the
11 authority to have that
oversight.
12
Not only that, the FDA has a very
13 historical authority now given by
the government to
14 issue the written request. So, those studies
are
15 in response to written requests
issued by the FDA.
16
So, if those responses are not accurate
17 and are not fulfilling the
demands, then, there has
18 to be a corrective that should
happen there, just
19 for
clarification.
20
DR.
RUDORFER: Dr.
O'Fallon.
21
DR. O'FALLON: We are talking
about three
22 major topics here, and we keep
flipping around
23 among them. One of them is the potential that
we
24 can get out of this
re-analysis. The second
is
25 suggestions, advice as to what to
do for future
334
1 studies. The third is the labeling
issues.
2
The questions that we are getting are
3 primarily focused on this
re-analysis, at least the
4 ones that I saw. I want to say as a
statistician
5 that I don't have a whole lot of
hope for your
6 being able to get good information
out of the
7 planned re-analysis. I think it should be
done,
8 but I don't think it is going to
be because you are
9 going to get the
information.
10
As a statistician again, I have learned a
11 long time ago that if you don't
get your data right
12 the first time, that it is very,
very difficult to
13 go back and get the information
after the fact, and
14 I am afraid that you are going to
find that is a
15 problem.
16
If the data were not collected very well,
17 for whatever reason, in those
original studies, you
18 are going to have a hard time
finding it, and there
19 is no such thing as being able to
go back.
20
For example, if something is a genetic
21 defect, if there is really a
genetic defect that is
22 underlying the ones that flip out,
the kids that go
23 crazy, no one will ever know
because we don't have
24 the information, we didn't ask
about it, and there
25 is no way to go back and get it.
335
1
I am afraid that is what is going to
2 happen with this study. Nonetheless, I think it
is
3 worth going forward because I
think you are going
4 to learn a whole lot about
methodologic issues when
5 you struggle to analyze it, and I
think that will
6 be valuable information for
writing future written
7 requests for evaluating future
studies, so I think
8 there is a lot to be learned about
it.
9
I don't even want to go on the labeling,
10 but I have got a whole list of
stuff there.
11
DR. RUDORFER: We will come
back to that.
12
Dr. Chesney.
13
DR. CHESNEY: Two issues with
respect to
14 Question 1. The first one, I think we have
already
15 gone over several times, but I
would really
16 strongly encourage, if it is
possible to go back
17 and look at every patient, to look
at this
18 stimulant syndrome issue, this
mania, this
19 irritability, and so on, which I
must say I was not
20 fully apprised of at all until we
came today, and I
21 am most impressed when I hear
from, again in the
22 open session, about how some of
these events
23 occurred very
quickly.
24
I know the potential explanation of being
25 stimulated out of lethargy, but
this sounds like
336
1 something different to me, which
brings me to my
2 second
question.
3
I wondered of any of the psychiatrists
4 could tell us if there is any
association with drug
5 levels, because certainly in my
field, which is
6 infectious diseases, drug levels
are imperative or
7 you wouldn't know what you were
treating or how
8 well you were treating it or
whatnot, but certainly
9 we heard levels at autopsy
referred to as being
10 three times I guess what was
expected, and then Dr.
11 Goodman made the comment about
adjusting dosage.
12
Do we have any idea of what the dosages
13 were in these studies and how they
correlated with
14 body weight or levels? For those of us not in
the
15 field, I just don't know anything
about the value
16 of pharmacokinetic studies in
these drugs.
17
DR.
LAUGHREN: Just to comment on a
couple
18 of your questions. For the most part, blood
levels
19 were not obtained in these
trials. Any
20 pharmacokinetic data for these
pediatric programs
21 were done in other smaller
studies. For the most
22 part, I don't think we are going
to have much luck
23 in getting PK data
here.
24
In terms of dosages, these were mostly,
25 virtually all flexible dose
studies, so patients
337
1 were dosed within a range, usually
the recommended
2 range for that drug. They were not fixed
dose
3 studies. We have dose information, but
without
4 something to link it to, it
probably is not going
5
to be very
productive.
6
But I wanted to come back to your first
7 point because now several people
have raised this
8 question about some kind of a
stimulation syndrome
9 and linking that in some way with
mania. If we
are
10 to look for that, we have to know
what it is that
11 we are looking
for.
12
I mean there has to be some kind of
13 definition. Are we talking about
something that is
14 linked specifically to suicidal
behavior or
15 something that occurs independent
of suicidal
16 behavior. I am not sure if this entity can be
well
17 enough defined for us to search
for it.
18
We have over 4,000 patients involved in
19 these trials. To head off looking for a
syndrome,
20 we have to know what it is that we
are looking for.
21
DR. CHESNEY: Can I just
respond to one
22 comment. I think on several occasions we
heard
23 that it was actually homicidal
behavior that seemed
24 to arise from mania, and if we
just look at
25 suicide, maybe that is not all we
want to know
338
1 about.
2
DR. RUDORFER: Tom, I wonder
if I could
3 interject a question for you. I think the
concept
4 of akathisia, which again has come
up repeatedly,
5 captures a lot of what various
speakers are talking
6 about, and I wonder if the
Agency's experience with
7 antipsychotic drugs would be
helpful in that regard
8 in terms of
definition.
9
DR. LAUGHREN: We could
certainly search
10 for akathisia. That term is reasonably
well
11 understood I think clinically and
would very likely
12 appear in the electronic database,
or one I suppose
13 could come up with related terms
that might get at
14 akathisia if it wasn't
specifically named.
15
But again, my question is are we looking
16 for that symptom by itself or are
we looking for
17 that in association with some
other behavior.
18 Again, there is a very widespread
belief that
19 akathisia is linked to suicidal
behavior, but I am
20 not sure how strong the data are
supporting that
21 belief, that is really the
question.
22
But again, if we are going
to search this
23 database for something other than
what it has
24 already been searched for, we have
to have some
25 fairly specific guidance about how
to do that.
339
1
MS. BRONSTEIN: My comments
are about
2 labeling and if you want me to
wait, I will, or I
3 would like to get them off my
chest now if I could.
4
If I heard nothing from this morning's
5 testimony, I heard repeatedly that
people feel the
6 need for patients and family to
have more
7 information than they have
currently.
8
I think that is really our responsibility
9 to do something about it whether
it is after this
10 meeting or after the summer
meeting. I think
we
11 need to get something out there
that describes
12 akathisia in a way that patients
can embrace it and
13 understand it, and family members
can watch for
14 this radical change in
behavior.
15
I am seeing it as an apparent link to
16 either homicidal or suicidal
behavior from the
17 testimony this morning and from
what I have read,
18 as well.
19
DR. RUDORFER: Dr.
Ebert.
20
DR. EBERT: Most of my
comments also had
21 to do with labelings. I just briefly wanted
to
22 react to what was stated earlier,
though, again
23 about the issues of going beyond
just the suicidal
24 behavior and whether it's
akathisia or whether
25 there may be some other
characteristics which
340
1 clearly indicate that -- and I am
not in the area
2 of psychiatry, so you will have to
indulge me for a
3 second -- but just the whole issue
of kind of a
4 concept of self versus others,
whether it's through
5 homicide or it's hostile behavior
or
6
aggressiveness.
7
To me, these things all seem to be a
8 constellation of the same types of
syndrome that we
9 would be looking
at.
10
DR. RUDORFER: Dr.
Fink.
11
DR. FINK: Another sort of
global concern
12 -- and I think it may be
particularly apropos to
13 this class of drugs -- is that
when these clinical
14 trials are performed, they are
usually performed by
15 experts in the field, yet much of
the usage today,
16 particularly in the managed care
environment, is
17 prescription of these drugs by
non-mental health
18 trained
professionals.
19
The results of a clinical trial performed
20 by mental health professionals
where you are
21 already using a highly select
audience and highly
22 select practices may bear little
relationship to
23 what you see with the drug in use
in the real
24 world.
25
From a labeling standpoint, it would make
341
1 sense potentially to say that at
least off-label
2 use of these drugs really should
be highly
3 restricted to mental health
professionals or make
4 some kind of wording that would
imply that, because
5 I think that off-label use of
these drugs by
6 non-mental health trained
professionals seems to be
7 problematic, and it may well be
that much of the
8 placebo effect that we are seeing
in the clinical
9 trials is because they are
receiving counseling
10 about mental
health.
11
I am more familiar with asthma trials.
12 When we do asthma trials, we see a
tremendous
13 placebo effect which is asthma
education. My
guess
14 is in mental health trials, there
is a tremendous
15 placebo effect because you are
seeing a mental
16 health
professional.
17 DR.
RUDORFER: Dr.
Leon.
18
DR. LEON: It would be
interesting to know
19 what items were captured in the
severity ratings,
20 because if we knew the items that
were there, then,
21 we could see which ones correspond
to the symptoms
22 we heard of this morning, and look
at treatment
23 emergent symptoms, symptoms that
weren't there at
24 baseline, on the severity rating,
that were
25 exacerbated during the course of
this trial, so
342
1 looking at changed scores on a
handful of a
2 priori-defined symptoms from the
rating scales
3 would be very
helpful.
4
DR. GOODMAN: Along those
lines, as I
5 mentioned earlier, the Hamilton
has an item on
6 agitation, the CDRS has an item on
irritability, so
7 that could be a first quick look,
and you wouldn't
8 have to look at treatment
emergent, you can look at
9 rating scale
items.
10
I agree that one needs to give careful
11 thought into what symptoms or how
we are describing
12 this constellation of symptoms,
because it could be
13 very
problematic.
14
For one reason, a number of symptoms you
15 would expect to get better with
the SSRIs, and what
16 we are really looking for is a
minority of patients
17 in whom you see a paradoxical
increase in those
18 symptoms.
19
So, I think we need to take a very careful
20 approach to this
analysis.
21
DR. RUDORFER: We have four
more questions
22 on this
topic.
23
I am sorry. Dr.
Laughren.
24
DR. LAUGHREN: Just one
follow up on a
25 suggestion that has come up from
several committee
343
1 members now about looking at items
from the rating
2 scales. That was actually done here, and it
turned
3 out not to be very
helpful.
4
Now, this was a similar analysis that had
5 been done with the adult data
years ago, for
6 example, looking at patients who
move from looking
7 at the suicide item on the HAM-D
and looking at
8 patients who move from zero to 1
to a 3 or 4.
9
That did not detect a signal in these
10 trials, and part of the problem
may have been that
11 these events often did not occur
at a time when the
12 HAM-D would be done, because the
HAM-D is done at
13 regular
intervals.
14
If the event occurs between visits, which
15 it almost always does, and then
the patient is
16 discontinued at that point, you
never get a HAM-D
17 or whatever other instrument is
being used.
18
So, companies did try that approach, and
19 it was not particularly
productive.
20
DR. RUDORFER: We are now
going to turn to
21 Drs. Malone, McGough, Pfeffer, and
Ortiz, and then
22 move on to Question 2 more
specifically.
23
DR. MALONE: I am sorry, I
just stepped
24 out, so I may have missed things
that were just
25 discussed, but I was thinking that
looking at
344
1 agitation would be an important
thing if you think
2 about the way we use the recent
meetings on
3 antipsychotics and
agitation.
4
Agitation often leads to harming of self
5 or others, and it might be a proxy
for looking at
6 suicidal behavior. So, searching the
electronic
7 database for agitation, violence,
and trying to
8 construct an agitation -- I don't
know what to call
9 it -- but try to construct
agitation and see if it
10 does differ in those who are
having suicidal
11 ideation or having other such
problems.
12
The other thing, I end up currently
13 treating children with autism, and
I think this
14 whole activation syndrome is
something that anyone
15 who treats children with autism
worries about if
16 they are going to consider giving
an SSRI.
17
There is some sense in which I think you
18 could look at fairly quickly in a
controlled trial
19 whether populations other than
depressive
20 populations get agitation or get
activated, and
21 then get some information whether
these drugs in
22 children, in fact, cause this
activation syndrome.
23
DR. RUDORFER: Dr.
McGough.
24
DR. McGOUGH: This is really
a segue I
25 think to the labeling issue which
keeps coming up
345
1 again and again. First, as far as
off-label use
2 goes, child psychiatrists could
not treat severely
3 ill kids without off-label
prescriptions, there is
4 no doubt about
that.
5
Secondly, even in the absence of
6 scientific clinical trial
evidence, a physician
7 needs to be free in specific
instances to choose to
8 take the risk of using a medicine
even in the lack
9 of a controlled study. Again, there is no way
to
10 meet the needs of these really
severe kids without
11 this.
12
To your point, unfortunately, there aren't
13 enough child psychiatrists trained
and available to
14 do this, so it is left to other
practitioners, and
15 what I was really struck with,
hearing the stories
16 this morning, is many of the cases
we heard were
17 kids just naively given adult
titration regimens at
18 adult doses with no consideration
to slow
19 metabolizing, in Caucasian kids
particularly, with
20 no concern about the need to
monitor for akathisia
21 and early onset activation, so I
see we can't
22 restrict non-psychiatrist
prescribing, we now have
23 pediatricians, family docs,
nurses, psychologists,
24 all of whom will be prescribing
these medicines.
25
There has to be some way to really notify
346
1 people or put people on notice
that at least in the
2 absence of efficacy data, you have
to be very
3 concerned about safety, and if
there is any
4 labeling tweaking to be done, that
is what I would
5 want to see put
in.
6
DR. RUDORFER: Dr.
Pfeffer.
7 DR.
PFEFFER: I have a number of
questions
8 that have to do with the analysis
issues and
9 perhaps my concern is having heard
the families and
10 the sense of their urgency, if
while the Columbia
11 group is evaluating the
suicidality question, if
12 one might look at the data in a
variety of other
13 ways that might inform us about,
for example, who
14 improved and who didn't
improve.
15
Who improved within the placebo group and
16 who improved within the treated
group, and what are
17 the predictors of that or vice
versa, what are the
18 predictors of a poor outcome, and
we might find
19 that that might give us some very
important clues
20 as to the way that this
population are
responding
21 to the
drugs.
22
The question also that I have, and I
23 assume it must have been done, but
I am not sure,
24 and that is whether or not
randomization really
25 worked, and especially did
randomization work, for
347
1 example, in the suicidality
issue.
2
I don't know if that has been looked at,
3 and certainly once Columbia group
looks at the
4 definition of suicidal behavior,
it will be looked
5 at again, but that would be an
important question
6 to also look
at.
7
Then, if I might contribute some
8 information, for example, I know
in the venlafaxine
9 studies, they were doing blood
levels of
10 venlafaxine because they were
looking at the
11 question of slow metabolizers or
not, so I wonder
12 if that data might be able to be
looked at to, to
13 give us some clues about issues of
metabolism.
14
DR. RUDORFER: Thank
you.
15
Dr. Ortiz.
16
DR. ORTIZ: My comments, I
think are in
17 response to a couple of things
that Dr. Chesney
18 brought up. As far as levels in psychiatry,
what
19 we certainly know is that the
Sinemet kinds of
20 medicines, which are dopaminergic,
can cause
21 psychosis, and it is at different
doses for
22 different individuals, the same
thing with
23 amphetamines, they also can cause
psychosis.
24 Again, it is not predictable in
each individual.
25
I would also like to follow up on your
348
1 suggestion to specify the adverse
effects and the
2 descriptions of them a little
better.
3
As a psychiatrist, when I am watching
4 someone that I am concerned about,
that may be
5 developing hypomania or mania, I
am watching how
6 their speech patterns change, I am
watching their
7 activity levels, I am monitoring
their sleep, and I
8 think a little more precision in
those kind of
9 descriptions might be
helpful.
10
DR. RUDORFER: Dr. Andrews
will ask the
11 final question related to Question
1.
12
DR. ANDREWS: I have some
concerns about
13 the exploration of this activation
syndrome in the
14 context of the existing clinical
trial data.
15
First of all, as has been said, we may not
16 know what the elements of that
syndrome are, but in
17 addition to that, do we know
whether the elements
18 of that potential syndrome were
collected
19 diligently, frequently, and
similarly across all of
20 the studies, and I think that
needs to be addressed
21 before going into that
expedition.
22
If not, I
would encourage the FDA and the
23 analysts to look at more objective
endpoints, which
24 I think are the ones that were
established for
25 suicide events.
349
1
I have a bit of concern that the study may
2 not answer all of the questions
because of the
3 issue that was raised earlier
regarding
4 generalizability. These patients may not
resemble
5 the patients who are treated with
these drugs.
6
They are probably treated in a different
7 way in terms of dose titration in
the context of a
8 clinical trial, and in the context
of a clinical
9 trial, patients tend to be monitored more
10 carefully, so that perhaps those
at highest risk of
11 suicide or suicidal ideation might
have been
12 identified earlier with other
symptoms and
13 withdrawn from drug or had drug
titrated down.
14
DR. RUDORFER: Thank
you.
15
I think we will come back to some of these
16 issues. The sense I have from the
committee is that
17 while people have reservations
about the
18 limitations of the existing
database, the sense
19 seems to be that we would endorse
going ahead with
20 the Columbia reclassification, but
with some
21 additional
measures.
22
Dr. Laughren had also specifically asked
23 us about the appropriate
categories in terms of the
24 definition of "possibly suicide
related" and
25 "suicide attempt," and I wonder if
anyone has any
350
1 feedback for the FDA on those
questions.
2
Dr. McGough.
3
DR. McGOUGH: I was just
speaking from
4 experience and also the work Dr.
Shaffer showed.
5 You know, my view about cutting is
that it is not a
6 suicidal behavior, and others
might disagree, but
7 that would be my approach to
that. It would be
not
8 to classify cutting or superficial
cutting
9 certainly as a suicidal
behavior.
10
DR. RUDORFER: Dr.
Chesney.
11
DR. CHESNEY: I was
interested again this
12 morning to hear in a number of
instances that
13 people took a drug, took a dose
and then found
14 themselves in jail and did not
know what had
15 happened in the
interim.
16
How is that described in psychiatric
17 terms, is that confusion of
thought or absence of
18 presence, or is that something
that you could pull
19 out? That seems a fairly profound confusion
to
20 just absent oneself from the
situation and yet do
21 some fairly striking
things.
22
DR. LAUGHREN: It is
phenomenologically an
23 amnestic syndrome of some
sort. I did not see
that
24 in these trials. At least it was not described
as
25 such.
351
1
DR. GOODMAN: Also,
phenomenologically, it
2 would be a dissociative or fugue
state.
3
DR. CHESNEY: Was that asked
for in the
4 trials? Was that a question that was on the
--
5
DR. LAUGHREN: No, I am sure
it was not.
6
DR. LESLIE: I wanted to add
two comments.
7 One is on the Question No. 1,
which is I think part
8 of this is a process question of
where we go from
9 now. When I look at Dr. Hammad's variables
that he
10 has listed, I think there are some
that are missing
11 and it would be good to
redistribute that list to
12 the committee for
review.
13
For example, I only see after
14 discontinuation. I don't see on an increase
of
15 dose or decrease of dose. The issue of
family
16 history has come
up.
17
I
think all of us or there is a good
18 majority here that are concerned
about aggressive
19 instances, and some of the family
stories this
20 morning were not of kids who were
feeling down.
21 They were of kids who acted
suicidally because of
22 impulsivity, and not because of a
suicidal
23 symptomatology that had been
ongoing.
24
So, I think those things are important and
25 I also worry about what is hidden
in some of the
352
1 other neurological, et cetera,
categories that are
2 listed.
3
So, again, I don't know the process here
4 and how you all feel about doing
this, but I think
5 redistributing this list for some
suggestions of
6 some of the risk factors and
things that might be
7 important to be looking at, as
several of the
8 speakers have said, would be
important.
9
I also wanted to say that I am impressed
10 that the American Academy of Child
and Adolescent
11 Psychiatry has been here and other
groups, but
12 there is no one here from the
American Academy of
13 Pediatrics, representing the
American Academy of
14 Pediatrics, although several of us
are
15 pediatricians and on that
committee, and there is
16 no one from the National
Association of Nurse
17 Practitioners, and there is no one
from the
18 American Academy of Family
Practice Doctors, and
19 reaching out to those
organizations on an official
20 level, since so many of us are the
ones that are
21 giving those medications, would be
an important
22 step to be
taking.
23
DR. LAUGHREN: In terms of
the lists of
24 variables, all committee members
have that. It
is
25 attached to a memo that I
wrote. We would be happy
353
1 to accept suggestions at any
point, it wouldn't
2 have to be at today's meeting, of
additional
3 covariates that you think might be
important to add
4 to this database, so please free
to do that.
5
DR. RUDORFER: Dr.
Gorman.
6
DR. GORMAN: If all of these
15 studies
7 that we are going to re-review
were not intent to
8 treats, analysis based on intent
to treat, we would
9 not be able to answer Dr.
Chesney's questions.
10
DR. RUDORFER: Dr.
O'Fallon.
11
DR. O'FALLON: One process
question. Do
12 you have data for all the patients
in all of those
13 studies? Do you have the detailed data for all
of
14 the patients in all of the
studies?
15
DR. LAUGHREN: What we have
right now are
16 in terms of data sets. We have the data sets
for
17 the variables that we specifically
asked for.
18 Again, those are listed in an
appendix to my
19 review. So, that is what we have in terms of
an
20 electronic data set for all
patients, but it is
21 limited to those variables that we
asked for.
22
DR. TEMPLE: Just with
respect to intent
23 to treat, we expect to see all
patients randomized
24 who at least got some
treatment. It is typical
in
25 symptomatic treatments not to
include people who
354
1 don't get a treatment. You can debate that, but
it
2 is usually not a big loss, but
anybody who was
3 treated should be in those
analyses.
4
DR. PERRIN: It does seem,
having read
5 that list of variables on the way
down this
6 morning, that there are some
important gaps.
They
7 do include again some of the
factors Dr. Pfeffer
8 mentioned before which are really
in the social
9 environmental phenomena that might
influence rates
10 of responsive treatment or might
influence rates of
11 suicidal
behaviors.
12
It does seem like you don't have a lot of
13 sort of data over time. It is almost like
an
14 adverse event reporting system, if
I am reading the
15 data set right. In other words, you don't have
a
16 lot of information on other
response to treatment.
17
We have heard, for example, a lot of
18 discussion without a lot of
evidence that the first
19 week or two or three of treatment
is really
20 critical, so one would wonder a
lot about what kind
21 of things happened during that
time that you do
22 have data on, and you talked about
the notion that
23 maybe the next clinical trials
might be a
24 withdrawal
trial.
25
Again, there is a moderate amount of more
355
1 anecdotal than good evidence base
that withdrawal
2 is a very high-risk time, as well,
for kids on
3 SSRIs, and again there, having
some sense of what
4 happens relatively immediately in
that two or
5 three-week time would be extremely
helpful, but I
6 have a feeling you don't have
those data for even
7 the start-up
time.
8
DR. LAUGHREN: Could you say
a little bit
9 more about how you would
characterize that early
10 response? Are you talking about looking at
formal
11 assessments, HAM-D, and so
forth? I mean
clearly,
12 we have that. What we might not have is
more
13 anecdotal information about
particular ways in
14 which a patient didn't do
well.
15
DR. PERRIN: Well, then,
maybe you do have
16 it, but on what periodicity do you
have things like
17 the HAM-D?
18
DR. LAUGHREN: Every week,
you know, early
19 on
certainly.
20
DR. PERRIN: Then, you may
have the
21 information,
okay.
22
DR. RUDORFER: As I
understand the
23 situation, Dr. Laughren's Question
3 on patient
24 level data analysis, I think we
have been
25 discussing essentially on
important covariates that
356
1 should be considered in the
re-analysis.
2
Dr. Laughren, would you want us to address
3 anything else specifically on that
before we turn
4 to future
directions?
5
DR. LAUGHREN: No, but again
let me just
6 reiterate if committee members, as
you continue to
7 look at this list, if you have
additional ideas,
8 please feel free even after this
meeting to submit
9 them, because we want this to be
as comprehensive
10 as it can be. So, if there are
important
11 covariates we have left out, let
us know.
12
DR. RUDORFER: Dr.
O'Fallon.
13
DR. O'FALLON: Looking at
that list again
14 with fresh eyes after this
morning, you don't have
15 any data that will help you to get
at the
16 temporality of the various
things.
17
For example, I look at that dose, and you
18 are looking at the max of the
mods, and things like
19 that, but you don't have -- you
know, there is no
20 way in your data set then to get
at whether the
21 incidents occurred when the dose
was raised,
22 lowered, or
discontinued.
23
So, one of the key questions is not going
24 to be able to be
assessed.
25
DR. LAUGHREN: That is
something that we
357
1 clearly have that
information. We don't have
it
2 now, but we could get that
information and add it
3 to the
model.
4
DR. RUDORFER: Dr.
Katz.
5
DR. KATZ: I have a question
of
6 clarification on Question 1, I
guess it is, which a
7 lot of people have been talking
about, trying to
8 look at these other behavioral
symptoms that are
9 not explicitly suicide related,
like the
10 stimulation syndrome, so called,
or an activation
11 syndrome.
12
Again, you have seen what we have done to
13 try and capture the explicitly
suicide related
14 events. You know, we had these text strings,
I
15 think we had 15, we had to go back
and forth with
16 the sponsors and ask them to look
at their verbatim
17 terms, you know, that took some
time. But we
spent
18 a lot of time trying to figure out
exactly how to
19 ascertain those
cases.
20
Is it the committee's desire for us to
21 attempt to recreate that process
with regard to
22 this sort of stimulation syndrome,
in other words,
23 look for multiple different sorts
of terms that
24 might be subsumed reasonably under
this syndrome,
25 in other words, try to cast as
broad a net as
358
1 possible?
2
DR. RUDORFER:
Yes.
3
DR. KATZ: Is that a general
sense of the
4 committee?
5 DR.
RUDORFER: Yes, the sense of
the
6 committee is
affirmative.
7
Dr. Laughren.
8
DR. LAUGHREN: Bearing in
mind that going
9 back to search the database
involves a fair amount
10 of additional time, now, we could
proceed with our
11 analysis based on the data that we
have now, and in
12 parallel, go back and ask for
additional searches
13 for other kinds of events like
this activation
14 syndrome if it can be better
defined. That
is
15
something we clearly could
do.
16
I wouldn't want to hold up the suicidality
17 analysis waiting for that
additional searching
18 because that does introduce a lot
of additional
19 time to go back to companies and
ask them to search
20 again.
21
DR. RUDORFER: Dr.
Temple.
22
DR. TEMPLE: I just want to
be sure I
23 understand. I think everyone's
expectation is that
24 there will be evidence of an
activation syndrome or
25 hyperactivity or those things
because the drugs are
359
1 labeled to do
that.
2
What use would one make out of that if it
3 wasn't linked to some or one of
the suicidal terms?
4 I mean I guess it is more
information and that is
5 never bad, but is it more than
that, would it help
6 us understand
things?
7
DR. RUDORFER: I think if I
may speak for
8 the committee, as I understand the
discussion and
9 the concerns, there are two
issues.
10
One is that the activation or agitation or
11 akathisia may be what is actually
more accessible
12 both to the patient and to the
family and to the
13 clinician in terms of it seems,
again going back to
14 some of the cases we heard this
morning, it sounded
15 as if we heard more instances of
an individual
16 complaining of akathisia-like
symptoms as opposed
17 to volunteering suicidal
ideation.
18
I think that there is concern that the
19 akathisia may be what is driving
self-destructive
20 behavior at least in some cases,
and that might
21 actually be more informative for
the clinician to
22 be watching for than actual more
overt suicidality.
23
I also wonder if, in fact, don't we need
24 that information to see if in this
database there
25 is a link.
360
1
DR. TEMPLE: So, you think it
would be
2 useful. I mean obviously if it sort of went
along
3 with suicidal thinking and
behavior, that would be
4 certainly of interest as a
possible early signal of
5 that
consequence.
6
Suppose there isn't any link to suicidal
7 thinking and all you found was a
reasonable
8 estimate of the rate of that in a
pediatric
9 population, do you think that
would be useful all
10 by itself? You could then say how likely it is
and
11 you would know
that.
12
DR. GOODMAN: I think the way
I would
13 approach it, as you described, as
two parallel
14 processes where you continue the
work, looking for
15 the signal and suicidality. You
then develop some
16 criteria that help describe this
activation
17 syndrome which may occur in a
subset of
18 individuals, and then you would
test the validity
19 or clinical meaningfulness of it
by then plugging
20 it back into seeing whether it is
those individuals
21 that are more likely to go on to
suicide as defined
22 by the first part of your
study.
23
So, I would agree -- one way of saying
24 that -- I agree that for the
purposes of our
25 discussion, it would be more of an
academic
361
1 exercise and not worthwhile unless
we could then
2 find that that subgroup in which
there is an
3 activation syndrome are also more
likely to go on
4 to be the ones that were
identified as exhibiting
5 suicidal
behavior.
6
DR. RUDORFER: Dr. Hudak and
then Dr.
7 Gorman.
8
DR. HUDAK: I have a question
and a few
9 comments.
10
The question involves the quality of the
11 data that you currently have for
analysis.
12 Basically, the 15 studies that are
presented here
13 involved 7 drugs, and I am not
knowledgeable about
14 these drugs and pharmacological
companies, I
15 presume at least 7 drug companies
are doing these
16 things. They are using different protocols,
they
17 have different outcome measures,
and they have
18 different data acquisition tools,
and all those
19 differences, and so
forth.
20
The question I have specifically, the
21 information that was presented in
Appendix 2,
22 looking at the difference between
the "possibly
23 suicide related" versus the
"suicide attempts," as
24 I understand it, that in this
population of kids
25 who might be sick, you are going
to have more
362
1 suicide-related type reporting,
because that is
2 thoughts and behaviors in excess
of suicide
3 attempts, which is just behavior,
I mean the data
4 that was
presented.
5
Looking at the information here, there are
6 a number of these studies that
basically, within
7 both the drug group and the
placebo group, the
8 suicide related thought and
behavior is exactly
9 equal to the suicide attempt,
which I find
10
inconsistent.
11
Is this the final plumbing of the data, or
12 is this before the word strings
were done on the
13 other data?
14
DR. LAUGHREN: This is one of
the problems
15 that I was alluding to
earlier. When we sent
out
16 this request in July of last year,
we asked
17 companies to follow basically the
same algorithm
18 that Glaxo had used in looking at
the Paxil data,
19 which included, first of all, a
general search for
20 any term suggestive of possibly
suicide related,
21 and then an attempt to subgroup
patients from that
22 larger set who had any indication
of self-harm.
I
23 mean that is how it was
defined.
24 What we
found is that companies, in
25 carving out that subset of suicide
attempt, in some
363
1 cases appeared to count every case
as a suicide
2 attempt even though, if you looked
at the
3 individual cases, there was not
any clear
4 indication of self-harm, and that
was one of the
5 reasons why we felt it was very
important to have
6 these data completely reclassified
by an outside
7 group.
8 Basically,
our position is that neither
9 one of these categories, either
possibly suicide
10 related or suicide attempt, as it
has been carved
11 out and defined by the companies,
is particularly
12 meaningful, and that is
specifically the reason why
13 we want to have an outside group
look at this broad
14 group of events that were captured
as possibly
15 suicide related and help us figure
out what kinds
16 of bins to put those
into.
17
As you saw from Dr. Posner's presentation,
18 we will very likely end up with
different
19 categories and different data than
what we have
20 here. I mean this table is really a
very
21 preliminary table and we have very
little
22 confidence in what these numbers
mean because we
23 are not confident in what the
numerators are.
24
DR. HUDAK: I understand, but
even within
25 the Paxil studies, there are three
studies, and two
364
1 of them show no difference, and
one would think
2 that the studies were constructed
in somewhat the
3 same way and the query was done in
somewhat the
4 same way, and therefore at the
end, even going back
5 and having Columbia group look at
this, you may
6 have very imperfect data to look
at.
7
DR. LAUGHREN: That is
undoubtedly true,
8 and that is a problem that we
can't fix with these
9 studies. You know, if ascertainment was
poor,
10 there is no way to fix it at this
point.
11
DR. HUDAK: I have two
additional
12 comments. One is with respect to this
general
13 issue here. I think the big picture that I
take
14 away from this is the really
unexplained doubling
15 or tripling of suicide rates in
particularly
16 vulnerable populations that
occurred over the past
17 15, 20 years, which is really
quite impressive.
18
So, whatever socioenvironmental type
19 etiology there is to this is a
very significant
20 public health issue. To put this sort of
into
21 context, this is a doubling or
tripling. When
we
22 have a one-point difference in
infant mortality, we
23 have major committees sort of
looking at why this
24 occurs.
25
Infant mortality over the past 20 years
365
1 has gone down very substantially,
but differences
2 in infant mortality on the order
of 1 in 1,000,
3 which is about 10 percent of the
entire infant
4 mortality rate, are treated very
significantly.
5 And this is a huge problem, and I
guess with one
6 teenager and one incipient
teenager is something
7 that is dear to my
concern.
8
The other comment I have is in relation to
9 looking at treatment and the
amount of
10 prescriptions that are written,
and so forth. I
am
11 struck by the fact that we have so
much drug
12 prescription done in a population
that the efficacy
13 is not
established.
14
I fight that every day in the nursery, to
15 come around and see patients on 10
drugs, of which
16 maybe 2 have been shown to be
effective and trying
17 to withdraw therapy, but it must
be -- I have no
18 problem with they are children who
are clearly very
19 ill and anything that can be done
should be done,
20 and I agree with that, but on the
other hand, there
21 must be a large population of
children -- a lot of
22 the people who spoke this morning,
the picture that
23 was presented of their child or
someone they knew
24 was not someone who was very, very
ill.
25
It was someone who had relatively minor
366
1 type findings, who were put on
these drugs with
2 terrible consequences, and I agree
with every
3 speaker who said that something
needs to be done to
4 educate practitioners and the
public that these
5 things may not at all be
benign.
6
The fact that we don't find these things
7 that are reported among the
audience and the
8 controlled trials is not
surprising. It may be
a
9 very, low incidence phenomena that
you are not
10 going to find unless you have got
randomized
11 controlled trials, you know,
10,000 or more.
12
But each of these events, each of these
13 anecdotes, and I have heard enough
of them to think
14 that, you know, you hear enough of
these anecdotes,
15 there must be some truth in
it. I mean I
am
16 willing to believe that there is
an idiosyncratic
17 reaction that some patients have
with these drugs,
18 and I think that warning needs to
go out in the
19 very strongest terms from the
Agency as soon as
20 possible.
21
DR. RUDORFER: If we can hear
from Dr.
22 Gorman and Dr. Chesney,
please.
23
DR. GORMAN: I would like to
pick up on
24 the thread of where we are data
mining. One of
the
25 things that struck me in one of
the slides that was
367
1 put up was that in August, there
was the request
2 from the pharmaceutical companies
to relook at
3 their data and present it to the
FDA.
4
Within a month, one of the pharmaceutical
5 companies, I am not sure they
looked at their data,
6 but they decided to change their
labeling and
7 withdraw it from the
market.
8
I would ask the FDA to investigate what
9 signal that pharmaceutical company
found in their
10 data that made them want to change
their label
11 without going through the FDA, and
ask other
12 pharmaceutical companies to look
in their data in
13 the same
way.
14
DR. RUDORFER: Dr.
Laughren.
15
DR. LAUGHREN: Yes, can I
just respond to
16 that. That company was Wyeth and the drug
is
17 Effexor and Effexor XR. Having gotten our
request
18 in July, they did go back and look
for suicidality,
19 and they also looked for
hostility, and they found
20 a signal, and on their own, as I
explained, they
21 are allowed to do that on their
own if it
22 strengthens labeling under changes
being effected.
23
What they did is to add mention of that
24 signal in the Pediatric Use
section of their label.
25 They did not contraindicate the
drug. They did
368
1 send a letter out along with that
label change
2 recommending that clinicians not
use the drug in
3 pediatrics, but the labeling does
not in any way
4 contraindicate it. It simply mentions the
signal,
5 and it is the same signal that we
have seen and are
6 currently
evaluating.
7
You know, we have their analysis, I showed
8 it to you, in fact. The question is if you go
back
9 and do the kinds of work that we
are now proposing
10 to do in terms of looking at the
actual events that
11 got included under those broad
categories, what
12 signal will you
see.
13
That is really the question, and that is
14 why we have not acted
independently to approve that
15 label change, but it is basically
the same data.
I
16 mean there is nothing we haven't
seen. Again,
it
17 is not as if the drug has been
pulled from the
18 market. They have simply added mention of
that
19 signal in one sentence in their
label.
20
DR. RUDORFER: Dr. Chesney,
please.
21
DR. CHESNEY: This is in
response to the
22 question from the FDA about why
look at activation
23 syndrome if it is not known
whether it is directly
24 related to
suicidality.
25
But what I heard this morning or the way I
369
1 interpreted what I heard this
morning is that the
2 activation syndrome is associated
or can be
3 associated with very violent and
very hostile
4 behavior. Whether that results in anybody's
death
5 or not, several of the families
said that that
6 became an extremely difficult
issue to live with.
7
Where we are dealing with a drug with no
8 apparent benefit, it seems to me
that any risk
9 becomes incredibly important, so
that is one
10 additional reason that I would say
it is important
11 to look at this activation
syndrome that some of us
12 have just learned more about this
morning.
13
DR. LAUGHREN: Can I just
respond to that?
14 Again, we are very happy to do
that. It would
be
15 extremely helpful if the committee
could come up
16 with a little bit more definition
of what that is
17 to help us in searching for
it.
18
But independent of finding it in this
19 database, if there is a view that
this syndrome is
20 so well described and does exist,
put together the
21 case. Send us literature, whatever else, and
it is
22 possible to make labeling changes
about clear
23 events that are idiosyncratic in
some way.
24
Again, the problem here has been that the
25 events we are looking at are part
and parcel of the
370
1 disease. If there is an activation syndrome
that
2 is unusual in its nature, and is
not part of the
3 disease that is being treated, it
could be
4 described in some way in labeling
if there is
5 enough even non-controlled data to
support the
6 existence of that syndrome,
especially if it can be
7 linked to, as you suggest,
hostility and violence
8 and
suicidality.
9
DR. RUDORFER: Dr.
Trontell.
10
DR. TRONTELL: Thank
you. I have a
11 question for Dr. Posner and
perhaps other members
12 of the committee because of
looking at your
13 proposed reclassification of the
cases.
14
I have a concern, as we have all been
15 discussing, that a very large
number of cases may
16 well fall into the indeterminate
category using the
17 very clear definitions you laid
out for us.
18
Is there any mechanism you can suggest in
19 that category that there might be
some
20 classification broadly, you know,
low, medium, or
21 high, that might allow some
sensitivity analysis?
22
I am a little concerned that data that
23 have been volunteered, you know,
since this wasn't
24 a structured inquiry into
potential suicidal
25 behavior, might otherwise be lost.
371
1
DR. POSNER: I think it was
suggested
2 before that we do a level of
certainty variability
3 and analysis, and I think that
that is a very good
4 point and something that we will
take into account
5 when we are doing those
classifications.
6
DR. RUDORFER: Dr. Maldonado
is next,
7 please.
8 DR.
MALDONADO: This is a quick
question.
9 I am not trying to generate more
work for the
10 people who are doing this work,
but I also have the
11 concern that Dr. O'Fallon had,
that these data may
12 not yield what you are looking
for.
13
Actually after hearing the comments in the
14 morning of some of the
testimonies, it appears that
15 some of these reactions were very
similar in adults
16 also, not only in
children.
17
I understand that the signal is much less
18 evident and that is probably why
adults have been
19 excluded, but since the database
in adults, I
20 assume it is much larger and the
disease appears to
21 be less heterogeneous, I don't
know if there will
22 be a value in looking
systematically into that data
23 to see if there is a
signal.
24
But again not knowing the data, it may not
25 be warranted, but that is
something that might
372
1 actually help to understand. I am not talking
2 about only suicides and suicide
attempts, I am
3 talking about all the other
signals, the wide net
4 that has been proposed here that
appears to happen
5 also in
adults.
6
DR. RUDORFER: We are going
to hear from
7 Drs. Wang, Leon, and Fost, and
then look towards
8 the future.
9
DR. WANG: I just wanted to
follow up in
10 terms of the utility of studying
this
11 akathisia-like symptom. I think there is
actually
12 a lot of utility particularly if
you focus on sort
13 of the synchrony of change, not
just whether there
14 is a link, but also if there is,
you know,
15 presumably this akathisia-like
syndrome or
16 activation is just more frequent,
so you should
17 have some power to study it, but
see if there is a
18 time relationship, because there
are so many
19 questions raised about, you know,
these potentially
20 abrupt onsets of suicidality after
developing some
21 kind of activation-like
symptom.
22
Anyway, I would argue that there is some
23 utility in studying
it.
24
DR. RUDORFER: Dr.
Leon.
25
DR. LEON: A point of
clarification. Dr.
373
1 Laughren said the HAM-Ds or
whatever severity
2 rating is available from the
trials. Are
those
3 available for each week of the
trial or just for
4 endpoint, and are those available
at the item
5 level?
6
DR. LAUGHREN: They are
available by week,
7 and they are available by item
level. What I
was
8 pointing out earlier is that
companies did try to
9 do a similar analysis with the
suicidality item
10 from the HAM-D, Item 3, similar to
what has been
11 done with adults, and it did not
generate a signal
12 in general.
13
DR. LEON: But do they look
at the
14 agitation item? I wouldn't expect the suicide
item
15 to be very sensitive, and I expect
it to be even
16 less sensitive in kids who are
probably less
17 inclined to disclose their
ideation.
18
DR. LAUGHREN: I think we
probably already
19 know that there is an excess of
anxiety and
20 agitation both in adults and
children with SSRIs.
21
The question is what is it linked to, and
22 that is why we need help in trying
to define the
23 syndrome that everyone is talking
about and may
24 well be a real thing, but we
already know about
25 agitation by itself.
374
1
DR. LESLIE: I think part of
what you may
2 be raising, though, is using it as
an independent
3 variable, and not as an outcome
variable. I
mean
4 one thing would be is this is a
sign of increased
5 aggression on the item, on the
HAM-D or increased
6 irritability linked then later as
an independent
7 variable or a predictor variable,
so not as an
8 outcome variable, but as an
independent variable.
9
DR. LAUGHREN: We already
have agitation
10 in the model. That is one of the
variables,
11 agitation on drug as opposed to a
baseline
12 variable. We have already included that in
the
13 model. So, we should be able to look at
that.
14
The question is are there other things
15 like that, that might be combined
in some way to
16 look at as some sort of a
stimulation syndrome or
17 activation syndrome other than
just agitation by
18 itself.
19
DR. MALONE: Do you have
hyperactivity in
20 the model?
21
DR. LAUGHREN: I am not sure
that
22 hyperactivity is a term that was
even coded for.
I
23 would have to go back and look at
the dictionaries
24 and see what preferred terms were
used.
25
Are you thinking of hyperactivity as a
375
1 term for subsuming other
investigator terms or as a
2 descriptive term in itself? I am not sure what
you
3 mean by
"hyperactivity."
4
DR. MALONE: Increased motor
activity. In
5 addition to them just being
described as agitated,
6 they may be described as having
increased motor
7 activity, sleeplessness, all as
part of a syndrome.
8
DR. LAUGHREN: Or
restlessness?
9
DR. MALONE: Restlessness,
yes.
10
DR. LAUGHREN: Again, to the
extent that
11 committee members can put these
thoughts together
12 and help us identify something to
look for, it
13 would be very
helpful.
14
It doesn't have to be now.
Again, you can
15 think about this, and if you want
to send us your
16 thoughts about this, we will be
happy to entertain
17 them. This is the time to do it, because now
is
18 the time, if we are going to ask
for additional
19 variables, now is the time to do
it.
20
Dr. Fost and then Dr. Pfeffer.
21
DR. FOST: Thank you. I have some
22 comments that have to do with
Questions 5, 6, and
23 7, and I think they cover all
three issues.
24
There have been some comments both in the
25 public session and among the
committee and the FDA
376
1 people that there are two problems
here.
2
One is the possibility of causing harm to
3 children by prescribing these
drugs that may induce
4 suicide, and the other problem is
that we may be
5 scaring people away from
prescribing them and there
6 may be inadequate
prescribing.
7
That is presented as if they are sort of
8 commensurate or symmetrical, but I
think that is
9 not quite right. There is a reason for the
first
10 principle of first do no
harm. It is almost
the
11 whole raison d'etre of the
FDA.
12
The reason for that is that it is widely
13 thought that it is more important
not to harm
14 people than to fail to help
people. There is
an
15 infinite number of people we maybe
can help, and we
16 can't do all of it. It is unclear whether we
can
17 do it, but we know we shouldn't
harm people.
That
18 is our first
responsibility.
19
What is odd about this situation is that
20 we may be doing both. That is, there is not
just
21 concern about causing harm to
children, but there
22 is tremendous ambiguity about
whether anyone is
23 being
helped.
24
So, as several people have said, if there
25 is any risk of harm, even if it is
a very small
377
1 risk, it is not worth it if there
is nothing on the
2 benefit side of the
scale.
3
So, it seems to me equally urgent to try
4 to get some better information
about the benefit
5 issue, as well as the harm
issue.
6
Now, Bob Temple said that withdrawal
7 studies can't tell us anything
about harm, which I
8 agree with, but they can tell us a
lot about
9 benefit. In fact, they may be more powerful
than
10 prospective trials in showing
benefit.
11
So, it seems to me encouraging, however
12 you can get it done, getting some
withdrawal trials
13 to occur might take us a long way
towards assessing
14 the benefit issue. That can be done and it is
not
15 all that expensive to
do.
16
That seems to me equally urgent as
17 whatever can be done mining the
database to find
18 out about the harm. So, that is the first
point.
19 I think both of those are
important.
20
Second, in terms of what to do while we
21 are waiting for these things to
happen, while it is
22 correct that this long-standing
section of the
23 label that says be especially
careful when you
24 start people on treatment can be
interpreted to
25 mean they might get worse.
378
1
I don't think an ordinary person, it is
2 all counterintuitive, but I don't
think it occurs
3 to most parents and maybe not even
to doctors who
4 aren't really highly informed
about this, that that
5 may happen, that an antidepressant
can make you
6 more depressed or at least more
suicidal.
7
I think that word needs to get out as soon
8 as possible, first, that that is a
real
9 possibility, that the British FDA
thinks it is a
10 very real possibility, that the
FDA, the American
11 FDA is very concerned about it,
seriously concerned
12 Dr. Laughren has said several
times, that the level
13 of concern that exists among
everybody in this
14 room, public and committee members
and FDA, is not
15 adequately out
there.
16
For doctors, maybe psychiatrists, I can't
17 speak for them, but I doubt that
pediatricians are
18 aware, or family practitioners,
the level of
19 concern about this potential
problem.
20
So, it seems to me while we are waiting,
21 it would be very important to get
that word out
22 through the AAP and the AAFP,
through national
23 meetings, through pediatric news,
through
24 newsletters, through panel
discussions,
25 presentations at national
meetings, and so on, and
379
1 second, to parents, so that when
they make what are
2 ideally collaborative decisions
with their doctors
3 about whether to put their
children on these drugs,
4 they understand completely that
there is at least
5 serious concern and that while it
is not a settled
6 issue and FDA is looking into it,
and you may
7 withdraw the serious concern by
the summer, or you
8 may enhance it, but I don't think
that is so
9 terrible to say we are looking at
it, it may take
10 us another 6 or 12 months to
figure it out, but
11 while we are waiting, you should
be very alert to
12 the risk of these drugs, you
should be very alert
13 to this activation syndrome in
your children, here
14 are some signs of
it.
15
We don't know for sure whether it leads to
16 suicide or not, but there is a lot
of smart people
17 who think it may very well, so you
need to be
18 hypervigilant about
it.
19
Oh, and a last point. Just
to pick up on
20 something Skip Nelson said a
couple of hours ago,
21 there is only one drug that has
really been shown
22 to be effective in children, and
while you haven't
23 disproven efficacy, it hasn't been
really well
24 established either for all the
other drugs, so it
25 seems to me at least part of the
education campaign
380
1 to physicians is if they are going
to prescribe
2 anything, why not prescribe the
one that we know
3 the most about and have the most
confidence about.
4
That is not to say they may not also cause
5 the suicidal problem, but at least
we have efficacy
6 data for fluoxetine that is
stronger than for the
7 other, so why mess around with
these other drugs
8 for which there is less
encouraging data on the
9 efficacy
side.
10
DR. RUDORFER: Drs. Nelson,
O'Fallon, and
11 Pine,
please.
12
DR. NELSON: I want to just
make the
13 observation that that point about
fluoxetine
14 complicates how you might then
design a trial going
15 forward to look at the efficacy of
the other drugs,
16 because you need to evaluate the
alternatives that
17 the child would not be
on.
18
So, if you are proposing to start off with
19 an open-label, non-randomized
treatment of a drug
20 that has already been shown to not
be effective in
21 your short-term trials, and not
put that child on
22 fluoxetine, unless that child is a
non-responder or
23 has had an adverse effect to where
you think the
24 profile of the drug you are going
to put them on
25 would have some advantage, it is
not clear to me
381
1 that that would be a trial that
would get through
2 5052 on your IRB in evaluating
whether it ought to
3 go forward.
4
DR. O'FALLON: I recall that
Dr. Murphy
5 told us this morning that FDAMA
was needed in order
6 to basically motivate the drug
industry to do the
7 studies of these in the
children.
8
When I first went on the subcommittee, I
9 was appalled to realize that a
great many of the
10 doctors feel they pretty much have
to prescribe off
11 label because there isn't anything
on the label for
12 an awful lot of different
things.
13
So, I think that harm, being able to
14 identify harm in children may
actually be more
15 important than being able to
identify benefit,
16 simply because the physicians are
often having to
17 -- are often having to work off,
you know, just try
18 to figure it out on the
fly.
19
So, given that fact, one of the things
20 that really bothers me is the fact
that the
21 exclusion criteria are trying to
get rid of kids
22 who are taking more than one drug
for whatever
23 reason, but the kids out in the
community who are
24 getting it are generally on more
than one drug.
25
I think that your future studies have to
382
1 include children who are on other
medications, as
2 well. They probably would have to be
stratified
3 and treated carefully, but you
should be getting
4 the data on adverse events in those
populations, as
5 well, because the physicians need
to know what bad
6 things can
happen.
7
I think placebos are needed because you
8 aren't going to be able to sort
out the stuff that
9 is coming off of the disease from
the stuff that is
10 coming off of the treatment if you
don't have a
11 placebo for at least some part of
the time.
12
So, the forward studies, I mean there are
13 a lot of things that you have got
to do for future
14 studies, but it seems to me you
must be looking at
15 these things in
multi-polypharmacy, or whatever you
16 call that, group of patients, as
well.
17
DR. RUDORFER: Dr.
Pine.
18
DR. PINE: I have a couple of
comments in
19 light of a couple of things that
have been said
20 over the last few
minutes.
21
The first thing is in discussing the data
22 on efficacy, I think it is
important to point out
23 two things, the first of which is
that a number of
24 people have noted that the data
are quite
25 discrepant for fluoxetine relative
to the other
383
1 SSRIs in pediatric major
depression.
2
Non-psychiatrists might not be aware that
3 that is highly unusual. The data in adults, to
the
4 extent that SSRIs have been
compared, really do not
5 find that, and I think that one
possibility is that
6 kids are very different, and
fluoxetine works, and
7 the other SSRIs
don't.
8
Another possibility is that maybe there
9 are systematic differences in
terms of how the
10 studies were done, and I think it
is important,
11 particularly from a labeling
perspective, not to
12 jump too quickly to say, well,
fluoxetine is okay
13 and nothing else is, number
one.
14
Number two, we spent a lot of time talking
15 about the efficacy data for major
depression.
As
16 was said in a number of
presentations throughout
17 the morning, that particularly in
young children,
18 major depression is not the
leading condition for
19 which medications are prescribed,
it's anxiety
20 disorders.
21
When one looks at the efficacy data for
22 the anxiety disorders, for the
SSRIs, one gets a
23 very different picture, at least
to the extent that
24 those data have been made public
and have been
25 published, that the efficacy data
really looks much
384
1 stronger
there.
2
So, I think again it is very important to
3 not rush to judgment in terms of
saying that SSRIs
4 have no benefits for children who
present with
5 various types of psychiatric
disorders, because the
6 fact of the matter is that a high
proportion of
7 individuals who present with major
depression will
8 also have anxiety, and I think it
is very important
9 to look at that
issue.
10
Two other quick points. You
know, I think
11 that there are problems with the
withdrawal design,
12 and the FDA mentioned them. Probably the
biggest
13 one is it doesn't do much for
clinicians, for
14 patients, or for parents to answer
the specific
15 question if my child is depressed
right now, and
16 they need treatment, is it better
to give them an
17 SSRI or not. That is really the question that
we
18 need to
answer.
19
The last brief
comment, you know, I know
20 you guys are asking a lot about
could we better
21 define what this activation
syndrome is.
Something
22 that we need to consider very
carefully is not only
23 is it known at least among
psychiatrists that this
24 syndrome occurs, but usually it is
mild. So,
25 usually, at least to the extent
that it has been
385
1 studied in trials, the activation
syndrome that
2 occurs is relatively
mild.
3
So, to the extent that you are going to
4 look at it, it will be very
important to not only
5 assess the type of behaviors that
are manifest, but
6 to all say, well, what is the
difference between a
7 mild syndrome which might be
relatively common and
8 a severe syndrome which might be
relatively rare.
9
DR. RUDORFER: Dr. Temple,
would you like
10 to respond to
that?
11
DR. TEMPLE: Partly respond
to a number of
12 things that have come up. Actually, I wanted
to
13 ask Dr. Fost something
first.
14
The proposed addition to labeling about
15 the possibility of an immediate
deterioration,
16 would that, in your view, be based
on the results
17 of the controlled trials that we
have heard about,
18 or on the observation from various
personal
19 experiences that this seems to
occur?
20
I ask that because, as you have heard, the
21 first of them were a little
uncertain what it says,
22 and the second is confounded by
the difficulty that
23 some of the consequences that have
been described
24 are potential consequences of the
underlying
25 disease, as well.
386
1
That doesn't mean we couldn't say watch
2 out without necessarily acclaiming
the state of the
3 evidence for it. As you pointed out, we already
do
4 say this is a time to be careful
when you start
5 therapy, but I am just interested
in what you think
6 the basis for expanding that would
be.
7
DR. FOST: Yes, I think there
are multiple
8 reasons why the FDA called this
difficult meeting
9 today, which is very challenging
to put together
10 and very stressful for a lot of
people, but there
11 are several streams of data that I
am guessing
12 triggered
it.
13
First, there are the data from the trials
14 themselves and the reexamination
of it that is
15 going on, and the British
conclusions from it, so,
16 first, it is
that.
17
Second, it's, as Dr. Hudak pointed out,
18 this epidemic of suicide and what
is causing it,
19 and maybe -- it happens to be
concurrent with the
20 rise of SSRIs -- maybe that has
got something to do
21 with it.
22
DR. TEMPLE: Wait, you must
have seen
23 different data than what I
saw. What I saw
was
24 that in recent years,
approximately coinciding with
25 the SSRIs, the rate of suicide is
going down. I am
387
1 not saying that proves anything,
but I don't see it
2 -- you didn't show it going
up.
3
DR. FOST: So be it. The public
concern,
4 I mean the increasing number of
anecdotes, I mean
5 obviously, you think that is
important or you
6 wouldn't have spent so much time
on it listening to
7 it today.
8
I mean I think there are several things
9 that trigger it, but if nothing
else, the data
10 alone, I mean the original trials
themselves have
11 stimulated concern among
scientific people.
12
DR. TEMPLE: As you heard, we
have
13 considerable reservations about
what the state of
14 the trials themselves mean at the
moment. I am
not
15 saying this is a bad idea, I am
just trying to
16 figure out the basis of it,
because if we propose
17 something, we will certainly be
asked.
18
DR. FOST: I accept that you
are uncertain
19 about it and that is why you are
going to a lot of
20 trouble to look at it much more
carefully and in
21 much more detail, but while you
are looking, I
22 think sharing this concern, given
the seriousness
23 of it if it turns out that way, is
a relatively low
24 cost thing to
do.
25
DR. TEMPLE: I just wanted to
also say
388
1 something about randomized
withdrawal studies.
2 They are not the whole nine yards
obviously.
3
I don't think most people would say that
4 it is a good state to have only
one possible drug.
5 Prozac is a fine drug and
everything, but it stays
6 with you more or less permanently,
when you stop
7 it, it is very hard to get off,
has a very long
8 half-life with active
metabolites.
9
If there were other drugs that were
10 effective, it would be useful to
know that.
Now,
11 at the moment, you can't say that
there are any
12 other effective
drugs.
13
The interest in a randomized withdrawal
14 study is that you take people who,
in one way or
15 another, through off-label use,
are on a drug
16 already, and you put people into a
trial because
17 they seem to be doing well, not
because they seem
18 to be doing badly, and because the
current standard
19 of therapy isn't to keep kids on
therapy forever,
20 at some point you take them off
and see how they
21 do.
22
Therefore, a randomized withdrawal study
23 approximates or may approximate
clinical practice,
24 and that would be the case for
saying that it's an
25 ethically designed trial. Obviously, people are
389
1 going to look closely at all this
and see if they
2 agree with everything I
said.
3
But it can tell you that a drug -- again,
4 you taper the drug slowly, you
don't do an abrupt
5 withdrawal or anything silly like
that -- it can
6 tell you I think that the drug was
having a
7 favorable effect. It confirms the
clinical
8 observation that led people to
keep the patient on
9 the drug in the first place. So, I wouldn't
rule
10 it out.
11
DR. RUDORFER: I wonder if I
could
12 interject a comment on the
labeling. We
have,
13 under Question 5, a quotation from
the usual
14 labeling about watching out for
the risk of suicide
15 early in
treatment.
16
I am thinking, in that small paragraph,
17 the second sentence reads,
"Prescriptions for Drug
18 X should be written for the
smallest quantity of
19 tablets consistent with good
patient management, in
20 order to reduce the risk of
overdose."
21
I am wondering if that space could be
22 better served. I think that is a legacy from
the
23 tricyclic era and I don't think
clinicians today
24 really worry so much about their
patients
25 committing suicide by
antidepressant overdose.
390
1
I am wondering if instead we had a
2 statement that encompassed two
thoughts, one, that
3 patients should be monitored
frequently early in
4 treatment, and, two, that any
change in behavior,
5 particularly early in treatment,
should be reported
6 to the clinician promptly, to
avoid getting into
7 issues of causality, which we have
not settled
8 since we don't have all the data
yet, but I think
9 -- correct me if I am wrong,
committees -- but I
10 think what we are saying is we
want to put a speed
11 bump in the road, that, in fact,
the sense of the
12 committee is that clinician should
take these
13 medications more seriously, and
not dispense them
14 overly liberally with inadequate
monitoring.
15
I think our state of knowledge is such
16 that we don't have the data we
want in terms of
17 showing efficacy and in terms of
some of the
18 adverse effects, notably
suicidality, obviously,
19 that the analysis is very much
underway and we are
20 saying maybe there are other kinds
of data to look
21 at, but I think the concern that
many of us felt
22 today was that the way SSRIs and
other newer
23 antidepressants are being used now
is such that the
24 warnings, as they exist in the
current labeling,
25 are not adequate and/or not being
taken seriously.
391
1
My final thought is I wonder if it's time
2 to reconsider the bolded warning
about avoiding
3 combinations with MAO inhibitors,
which again I
4 think that is a very important
interaction to
5 avoid, but I am not sure how
relevant that is to
6 practice
today.
7
Dr. Fost.
8
DR. FOST: I just want to add
I think that
9 last sentence adds to the
confusion about that
10 paragraph, because the way I read
it, frankly, is
11 your patient is depressed, may be
suicidal, you
12 have just started him or her on
treatment, be
13 careful how many pills you give
him because it may
14 take a while for the treatment to
kick in and
15 during that time he may take too
many of them.
16
It makes it look as if the message is
17 don't give your patient too many
pills until he is
18 over the hump, he or she. So, I agree
completely
19 with your sentiment. I mean maybe that
is
20 important, too, but these are not
major causes of
21 death, overdose of these pills we
have heard.
22
So, it seems to me the more important
23 issue is watch for this other
thing where the
24 patient may kill himself in some
other way.
25
DR. NELSON: To continue on
the labeling,
392
1 looking through most of the
labels, it says simply
2 that efficacy has not been
established.
Even
3 though that is a true statement, I
think most
4 general physicians and
pediatricians have been
5 socialized into thinking that
means that the
6 studies have not been done, where
the reality here
7 is they were done and did not show
efficacy.
8
So, I would say you need to actually say
9 that, in fact, the studies were
done and didn't
10 show efficacy, not that it has not
been
11 established, because that is often
read as the
12 studies weren't
done.
13
DR. RUDORFER: We have time
for Dr.
14 Malone, Dr. Glode, and Dr. Irwin,
and if we stay
15 longer than that, we will have to
pass the hat for
16 rent, so we may have to wrap
up.
17
DR. MALONE: I will just try
to be brief.
18 I wanted to reiterate what Dr.
Pine had said, that
19 a lot of this discussion is about
efficacy in
20 depression, but there is a lot of
data about
21 efficacy in anxiety
disorders. In fact, three
of
22 the drugs are labeled I think for
OCD, which is an
23 anxiety disorder in
children.
24
The second thing is if you are doing a
25 discontinuation study, if the
problem is that you
393
1 have such a high placebo response
rate that it is
2 hard to separate drug from
placebo, and you have a
3 lot of placebo responders in your
study group and
4 then you do the discontinuation,
might it be
5 difficult to find an
effect.
6
DR. TEMPLE: Can I comment on
our
7 experience. That is not our experience. As Tom
8 said, at least half of all
conventional depression
9 trials in adults fail to
distinguish drug from
10 placebo. This includes only drugs we believe
are
11 effective because they are
successful in other
12 trials.
13
When you do the other, when you do a
14 randomized withdrawal trial, I am
aware of only one
15 drug that has ever failed to be
successful in that
16 setting. The reasons are fairly obvious. One, you
17 are only putting in people who do
well. It is
an
18 enriched population for people who
are likely to do
19
well. It is almost -- you know, okay, that's
one.
20
The second is that the support system that
21 probably helps the placebo
response in the acute
22 episode isn't there here. These are just
people
23 out in the community, they aren't
seeing anybody or
24 chatting with anybody. I mean they might be,
but
25 they are generally not.
394
1
So, the history is that those trials are
2 much more successful, much more at
showing
3 effectiveness. Tom can I am sure elaborate, but
I
4 think we have seen only one fail
out of a lot.
5
DR. MALONE: I am not sure,
though, that
6 the placebo response rates are the
same in adults
7 as they are in children. That would be my
only
8 concern.
9
DR. RUDORFER: Dr.
Glode.
10
DR. GLODE: I just wanted to
add my
11 support to the recommendations, if
I understood
12 them correctly, by Ms. Bronstein
and Dr. Fost.
13
I am impressed, if again I have these
14 numbers right, that there were 8
million
15 prescriptions in adolescents for
these drugs in
16 2002, so between now and June,
let's say another 4
17 or 5 million prescriptions may be
written, and
18 these may or may not be for
children who were the
19 same as the 3- to 4,000 children
with major
20 depression who were studied, again
without knowing
21 the exclusions for all of those
studies, if
22 suicidal children were
excluded.
23
Then, one comes to the risk of
24 overinforming people because I am
going to support
25 additional information to be
provided to parents,
395
1 patients, and providers, so that
what is the risk
2 of informing versus the benefit of
informing.
3
So, the risk of informing, as mentioned,
4 is that parents or patients could
refuse to take
5 the medicine that might possibly
help them,
6 although again we have the limited
efficacy data.
7
The benefit of informing them is that then
8 if you gave them the right
information, they would
9 re-present to their provider when
they develop
10 these symptoms and be re-evaluated
as opposed to
11 here is your two weeks of samples,
you know, I hope
12 you do well.
13
So, it seems to me that the benefits of
14 informing them probably outweighs
the risks of
15 informing them, and my own advice
to the FDA would
16 be to immediately request that
information be
17 provided to parents and patients
at the time the
18 drug is prescribed. You know, that just gives
them
19 more information about this and
ask them to
20 re-present
--.
21
DR. RUDORFER: Dr.
Irwin.
22
DR. IRWIN: I would argue
that the
23 patients may be ahead of the curve
than the
24 clinicians are, and I am a person
who specializes
25 in caring for adolescents, I run a
large adolescent
396
1 medicine program at the University
of
2 California/San
Francisco.
3
I would argue that most of the
4 pediatricians who prescribe these
agents are not as
5 familiar as the psychiatrists are
about the side
6 effects. I think in the way that pediatricians
--
7 when I was in training, you know,
you treated
8 everybody that walked through the
door who had a
9 red ear -- now, we don't do
that. We basically
do
10 a lot of watchful
waiting.
11
What I heard today from patients and
12 parents, as they stood up and
talked about issues,
13 that many of them went to primary
care physicians,
14 and there was not any watchful
waiting, in fact,
15 there was immediate response, and
the immediate
16 response was based upon I think
inadequate
17 information that is going to
clinicians who are
18 acting in good faith and really
committed to
19 improving the lives of young
people, of which,
20 known in an adolescent medicine
clinic, a primary
21 care clinic, about 1 in 5 kids
that walk through
22 the door have a behavioral
disorder, so you are
23 really confronted with a big
problem.
24
So, I think it is imperative I would say
25 that the FDA get something out to
clinicians as
397
1 quickly as possible, and it can be
done through a
2 variety of ways that have been
mentioned here,
3 because I think those are the
individuals that are
4 really acting in ways that we need
to really try to
5 encourage them to be acting in a
more responsible
6 manner when we are coming up with
what really the
7 issues are.
8
Thanks.
9
DR. RUDORFER: Dr. Leslie, do
you have a
10 word, and the we will wrap
up.
11
DR. LESLIE: I wanted to echo
what Dr.
12 Irwin was saying as a fellow
pediatrician, and also
13 comment that one of the large
pressures that many
14 of us in primary care are under is
that we cannot
15 access other types of mental
health services.
16 There aren't mental health
providers to see kids or
17 they are not able to get services
through managed
18 care.
19
So, many primary care providers are trying
20 to do what they can to help
families and children
21 by giving these medications. So, the other
thing
22 we need to do -- and I am not sure
what the role of
23 the FDA in this is -- demand
parity for mental
24 health
services.
25
DR. RUDORFER: Thank
you. I think we have
398
1 been identifying some very crucial
issues. As
Dr.
2 Laughren pointed out in his
handout, the FDA does
3 not control the practice of
medicine, so that we
4 here have under the FDA's
jurisdiction a limited
5 part of the overall
scheme.
6
Nonetheless, I think the sense of the
7 committee is that the FDA has a
very important role
8 to play, and this challenge is an
opportunity to
9 further protect the health of
young people with
10 depression while the further
studies we discussed
11 proceed.
12
If I can sum up the sense of the
13 committee, I think I have 18
seconds, I can distil
14 this to two major
bullets.
15
First, we concur with the plan to have the
16 expert group at Columbia
re-analyze the data from
17 the efficacy trials that were
presented and some
18 ideas were
offered.
19
We could do this in a more formal way in
20 terms of other covariates, issues,
such as family
21 history, the activation or
overstimulation,
22 restlessness, akathisia spectrum,
we discussed as
23 useful information to
have.
24
It will be particularly helpful if it is
25 linked with the suicidality
measures, but we think
399
1 nonetheless that is important to
have established.
2
Correct me if I am wrong, committees, but
3 I think our sense is that we would
like in the
4 interim the FDA to go ahead and
issue stronger
5 warning indications to clinicians
regarding
6 possible risks of these
medications, which we don't
7 see as contraindicating their use,
but we think
8 such warnings are required to
elevate the level of
9 concern and attention that
practitioners use in
10 prescribing
them.
11
I think, as a group, we were recognizing
12 the limitations of uncontrolled
data. We were
all
13 concerned about the stories we
heard of the actual
14 use of these very powerful,
potentially very
15 effective medications, but in many
instances, being
16 used without adequate
monitoring.
17
DR. TEMPLE: I would just add
to your
18 summary, information to physicians
and to parents.
19
DR. RUDORFER: Thank
you. I would
now
20 like to turn the mike over to Dr.
Chesney
21 representing the Pediatric Drug
Subcommittee.
22
DR. CHESNEY: I just wanted
to thank the
23 FDA for bringing this issue to all
of us and for
24 being so open and listening and
for asking us to
25 continue to provide them with
additional
400
1 information.
2 I
think it really brings home to all of us
3 the importance of looking at all
drugs very
4 carefully in children. I also, again on behalf
of
5 the Pediatric Committee want to
thank all the
6 parents and children and
individuals who came to
7 share their experiences with us
today.
8
DR. RUDORFER: Dr.
Katz.
9
DR. KATZ: I would like to
thank very much
10 the committee. I think this is a very
complicated
11 and important issue and through
all of that, I
12 think ultimately, your
recommendations have been
13 very clear, and I think we have a
very good
14 understanding of what you think we
should do and
15 how we should proceed at this
point.
16
I also would like to thank the families
17 for coming forward and telling us
your stories.
18 That was courageous and we know it
was painful, but
19 I believe we heard you, I believe
the committee
20 heard you, and we appreciate it
very, very much.
21 DR.
RUDORFER: In closing, I would like
to
22 thank the members of the two
committees, I would
23 like to thank the FDA staff. It is obvious what
24 time, effort, and hard work has
gone into this
25 important issue, we appreciate
that, and I want to
401
1 thank everyone in the audience who
came,
2 particularly people who told us
their painful
3 stories.
4
The FDA staff can attest to the fact I
5 kept arguing about the time
limit. I am sorry,
but
6 we would probably still be in the
open public
7 hearing if we didn't have that red
light.
8
Thanks all for coming and obviously, this
9 discussion is to be
continued.
10
Get home safely.
11
[Whereupon, at 6:05 p.m., the meeting was
12 adjourned.]
13
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