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