1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
JOINT MEETING OF THE
CDER PSYCHOPHARMACOLOGIC DRUGS
ADVISORY COMMITTEE
AND THE
FDA PEDIATRIC ADVISORY
COMMITTEE
Holiday Inn Bethsda
2
PARTICIPANTS
PSYCHOPHARMACOLOGIC DRUGS ADVISORY
COMMITTEE MEMBERS:
Wayne K. Goodman, M.D., Chair
Jean E. Bronstein, R.N.,
M.S.
(Consumer Representative)
James J. McGough, M.D.
Philip S. Wang, M.D., M.P.H., Dr.P.H.
Lauren Marangell, M.D.
Dilip J. Mehta, M.D., Ph.D.
(Industry Representative)
Delbert G. Robinson, M.D.
Daniel S. Pine, M.D.
Barbara G. Wells, Pharm.D.
Bruce G. Pollock, M.D., Ph.D.
PEDIATRIC ADVISORY
COMMITTEE MEMBERS:
P. Joan Chesney, M.D., Chair
Deborah L. Dokken, M.P.A.
Michael E. Fant, M.D., Ph.D.
Richard L. Gorman, M.D.
Robert M. Nelson, M.D., Ph.D.
Thomas B. Newman, M.D., M.P.H.
Judith R. O'Fallon, Ph.D.
Victor M. Santana, M.D.
CONSULTANTS AND GUESTS (Voting):
Norman Fost, M.D., M.P.H.
Charles E. Irwin, Mr., M.D.
Laurel K. Leslie, M.D., F.A.A.P.
Steven Ebert, Pharm.D. (Consumer
Representative)
James M. Perrin, M.D.
Cynthia R. Pfeffer, M.D.
Gail W. Griffith
(Patient Representative, Voting)
Robert D. Gibbons, Ph.D.
Tana A. Grady-Weliky, M.D.
Richard P. Malone, M.D.
Irene E. Ortiz, M.D.
Matthew V. Rudorfer, M.D.
3
PARTICIPANTS
(Continued)
GUEST SPEAKERS AND GUESTS (Non-Voting):
Kelly Posner, Ph.D.
John March, M.D., M.P.H.
Samuel Maldonado, M.D.,
M.P.H.
(Industry Representative
Barbara Stanley, Ph.D.
Madelyn Gould, Ph.D., M.P.H.
FDA PARTICIPANTS:
Robert Temple, M.D.
Russell G. Katz, M.D.
Thomas Laughren, M.D.
M.
Dianne Murphy, M.D.
Anne Trontell, M.D., M.P.H
Anuja M. Patel, M.P.H., Executive Secretary
4
C O N T E N T S
Call to Order and Opening
Remarks,
Wayne Goodman, M.D. 6
Introduction of Committee 9
Conflict of Interest Statement,
Anuja Patel, M.P.H. 20
Overview of Issues:
Dianne Murphy, M.D., Director, Office
of
Pediatric Therapeutics,
Office of the Commissioner 25
Russell Katz, M.D., Director, Division
of
Neuropharmacological Drug Products,
DNDP, CDER 34
Regulatory History and Background,
Thomas Laughren, M.D., Team Leader,
DNDP, CDER 46
Recent Observational Studies of
Antidepressants
and Suicidal Behavior,
Diane Wysowski, Ph.D., Division of
Drug Risk
Evaluation, Office of Drug Safety,
CDER 62
Brief Report on TADS Trial,
John March, M.D., M.P.H., Duke
University 74
Committe Discussion on TADS Trial 93
Characteristics of Pediatric
Antidepressant Trials,
Greg Dubitsky, M.D., Medical Officer,
DNDP, CDER 107
Classification of Suicidality Events,
Kelly Posner, Ph.D., Columbia
University 117
OCTAP Appraisal of Columbia
Classification
Methodology,
Solomon Iyasu, M.D., M.P.H., Team
Leader,
Office of Counter-Terrorism and
Pediatric
Drug Development 140
5
C O N T E N T S
(Continued)
Results of the Analysis of Suicidality in
Pediatric
Trials of Newer Antidepressants,
Tarek Hammad, M.D., Ph.D., M.Sc.,
M.S., Senior
Medical Reviewer, DNDP, CDER 152
Comparison Between Original ODS and DNDP
Analyses
of Pediatric Suicidality Data Sets,
Andrew Mosholder, M.D., M.P.H.,
Division of
Drug Risk Evaluation, ODS, CDER 200
Citalopram and Escitalopram Product
Safety Data,
Jeffrey Jonas, M.D., Forest
Laboratories, Inc. 219
Sertraline Use in Pediatric Population: A
Risk/Benefit Discussion,
Steven J. Romano, M.D., Pfizer,
Inc. 232
Wyeth Pharmaceuticals, Joseph S. Camardo,
M.D. 247
Open Public Hearing 255
Summary by the Committee Chair 444
6
P R O C E E D I N G S
Call to Order and Opening
Remarks
DR. GOODMAN: I wish to welcome you to
this two-day joint session of the
Psychopharmacologic Drugs Advisory Committee
and
the Pediatric Advisory Committee, being
held on
September 13th and 14th here, at the
Holiday Inn in
Bethesda, Maryland.
I am Wayne Goodman, Professor
of
Psychiatry at the University of Florida,
today
wearing my hat as chair of the advisory
committee.
As you settle in, please take this
opportunity to
put into silent mode your cell phones and
any other
devices that emit sounds in the audible
range of
human beings.
Some of you may be surprised not to see
Matt Rudorfer in this seat but we
arm-wrestled for
the position and he won.
[Laughter]
In all seriousness, his term
has ended but
we are fortunate to see him return as a
voting
consultant to the committee.
7
I have some official language
to read to
you.
All committee members and consultants have
been provided with copies of the background
materials, from both the sponsors and the
FDA, and
with copies of letters from the public
that we
received by the August 23rd
deadline. The
background materials have been posted on the
FDA
website.
Copies of all these materials are
available for viewing at the FDA desk
outside this
room.
We have a very large table, a
full house
and important topic today so I would like
to start
with a few rules of order. Please speak directly
into the mike when called on. We will be keeping
track of individuals at the table who
wish to speak
and we will call upon them in order.
FDA relies on the advisory
committee to
provide the best possible scientific
advice
available to assist us in the discussion
of complex
topics.
We understand that issues raised during
the meeting may well lead to
conversations over
breaks or during lunch. However, one of the
8
benefits of an advisory committee meeting
is that
the discussions take place in an open and
public
forum.
To that end, we request that members of the
committee not engage in off-record
conversations on
today's topic during the breaks and
lunch.
Whenever there is an important
topic to be
discussed there are a variety of
opinions. One of
our goals today and tomorrow is for the
meeting to
be conducted in a fair and open way where
every
participant is listened to carefully and
treated
with dignity, courtesy and respect. Anyone whose
behavior is disruptive to the meeting will
be asked
to leave.
We are confident that everyone here is
sensitive to these issues so understand
that these
comments are as a gentle reminder.
We look forward to a productive
and
interesting meeting. This is an unusual meeting in
that we have two advisory committees
represented
here, Psychopharmacological Drugs
Advisory
Committee, chaired by myself, and the
Pediatric
Advisory Committee, chaired by Joan
Chesney, to my
left. We will now go around the table and have the
9
committee introduce themselves, starting
on my
right.
Please indicate your expertise and
affiliation. We will start in that corner, over
there.
Introductions
DR. TEMPLE: Bob Temple.
I am the Office
Director, ODE I.
DR. KATZ: Russ Katz, Division Director,
Division of Neuropharmacological Drug
Products,
FDA.
DR. LAUGHREN: Tom Laughren, phychopharm.
team leader, in the Neuropharmacological
Division.
DR. MURPHY: Dianne Murphy, Office
Director, Office of Pediatric
Therapeutics.
DR. TRONTELL: Anne Trontell, Deputy
Director, Office of Drug Safety.
DR. FANT: I am Michael Fant, University
of Texas Health Science Center in
Houston. My
expertise is neonatology and
biochemistry.
DR. PFEFFER: Cynthia Pfeffer. I am a
child psychiatrist at Weill Medical
College of
Cornell University, and I have expertise
in
10
depression suicidal behavior in children
and
adolescents.
DR. FOST: Norm Fost, University of
Wisconsin, Professor of Pediatrics,
Director of the
Bioethics Program and Chair of the IRB.
DR. ORTIZ: Irene Ortiz, University of New
Mexico, Albuquerque VA. My expertise is in
depression in the elderly.
DR. MALONE: Richard Malone, Drexel
University College of Medicine, and my
area is
child psychiatry.
DR. NELSON: Robert Nelson, Children's
Hospital of Philadelphia and the
University of
Pennsylvania. My expertise is in pediatric
critical care medicine and ethics.
DR. PERRIN: Jim Perrin, Professor of
Pediatrics, Harvard Medical School and
Head of the
Division of General Pediatrics at the
Mass. General
Hospital.
I have shortened my expertise as being
in general pediatrics.
DR. GRADY-WELIKY: Tana Grady-Weliky,
Associate Professor of Psychiatry at the
University
11
of Rochester School of Medicine and
Dentistry. My
expertise is in mood disorders and women
across the
reproductive life cycle and medical
education.
DR. EBERT: Steven Ebert, Department of
Pharmacy of Meriter Hospital and School
of
Pharmacy, University of Wisconsin,
Madison.
DR. GIBBONS: Robert Gibbons, Professor of
Statistics and Professor of Psychiatry
and Director
of the Center for Health Statistics at
the
University of Illinois, Chicago. I only do math!
DR. PINE: Danny Pine, child and
adolescent psychiatrist, National
Institute of
Mental Health intramural research
program. I am a
clinical child psychiatrist.
MS. BRONSTEIN: Jean Bronstein,
psychiatric nurse, Stanford University
Hospital,
the consumer representative.
DR. RUDORFER: Matthew Rudorfer, National
Institute of Mental Health. My areas of expertise
are mood disorders and
psychopharmacology.
MS. PATEL: Anuja Patel, Advisors and
Consultants Staff, Executive Secretary
for the
12
Psychopharmacologic Drugs Advisory
Committee.
DR. CHESNEY: Joan Chesney, the University
of Tennessee, in Memphis, and Professor
of
Pediatrics, and my specialty is
infectious
diseases.
DR. MCGOUGH: Jim McGough, Professor of
Psychiatry, UCLA. My area is child and adolescent
psychopharmacology.
MS. GRIFFITH: My name is Gail Griffith
and I serve as the patient rep. on this
committee,
and I would just like to take this
opportunity to
say why I am here. First, I am not a medical
professional; I am a consumer. I have suffered
from major depression since I was a
teen. Second,
I have a son who suffers from major
depression and
three years ago, at age 17, after he was
diagnosed
and placed on a regimen of
antidepressants he
attempted suicide by overdosing
intentionally on
all his medications. He nearly died. So, I know
this illness. I know what it does to adolescents.
For the record, I would simply
like to
state that I have no professional ties to
any
13
advocacy group or any patient
constituency. I also
wish to affirm that I have no ties to any
pharmaceutical company, nor do I hold any
investments in pharmaceutical
manufacturers. My
sole responsibility is to ensure that the
interests
of concerned parents and families are
represented
at this meeting.
DR. MARANGELL: Lauren Marangell, Baylor
College of Medicine. I specialize in adult
interventions in mood disorders, both
unipolar and
bipolar.
DR. ROBINSON: I am Delbert Robinson. I
am from the Albert Einstein College of
Medicine, in
New York, and I specialize in psychotic
disorders
and anxiety disorders.
DR. LESLIE: Laurel Leslie. I am a
behavioral developmental pediatrician at
Children's
Hospital, San Diego and my area of
expertise is in
children's mental health services
research.
DR. IRWIN: Charles Irwin. I am a
professor of pediatrics at the University
of
California, San Francisco. I am in charge of the
14
Division of Adolescent Medicine at the
University,
which is a multi-disciplinary program
that cares
for adolescents and trains large numbers
of
individuals caring for teenagers, and my
research
is in the area of risk-taking during
adolescence.
MS. DOKKEN: I am Deborah Dokken. I
reside in the Washington, D.C. Metro
area. I do
not have a specific institutional
affiliation, and
I have for several years been involved in
parent
and family advocacy and health care.
DR. NEWMAN: I am Thomas Newman. I am a
professor of epidemiology and
biostatistics in
pediatrics at the University of
California, San
Francisco, and a general pediatrician.
DR. WELLS: I am Barbara Wells. I am a
professor and Dean of the School of
Pharmacy at the
University of Mississippi. My expertise is in
psychiatric pharmacotherapy.
DR. POLLOCK: I am Bruce Pollock. I am a
professor of psychiatry, pharmacology and
pharmaceutical sciences at the University
of
Pittsburgh. I head the Division of Geriatric
15
Psychiatry at the university.
DR. O'FALLON: Judith O'Fallon, Emeritus
Professor of Biostatistics from the Mayo
Clinic,
with 30 years of experience particularly
in cancer
clinical trials but clinical trials
methods.
DR. SANTANA: Good morning.
I am Victor
Santana.
I am a pediatric hematologist/oncologist
at St. Jude's Children's Research
Hospital in
Memphis, Tennessee.
DR. WANG: I am Philip Wang, Harvard
Medical School. I am a psychiatrist and
epidemiologist and those are my areas of
expertise.
DR. GORMAN: Richard Gorman, a practicing
pediatrician for 20 years in the
Baltimore suburbs,
Chair of the American Academy's Committee
on Drugs,
and representing the American Academy of
Pediatrics
at this table.
DR. MALDONADO: Sam Maldonado. I work at
pediatric drug development at Johnson
& Johnson. I
am one of the industry representatives to
this
committee.
DR. MEHTA: Dilip Mehta, retired industry
16
executive and industry representative on
the
Psychopharmacologic Drugs Advisory
Committee.
DR. GOODMAN: Thank you, all, for being
with us these two days. Our session today is the
second of two planned advisory committee
meetings,
convened to address recent concerns about
reports
of suicidal ideation and behavior
developing in
some children and adolescents during
treatment of
depression with a selective serotonin reuptake
inhibitor, an SSRI, or other newer
generation
antidepressants. Our goal is to gather information
from a variety of sources and
perspectives to help
us understand this complex situation, and
ultimately to offer the best possible
recommendations to the FDA.
I would like to thank the many
groups,
individuals and families that submitted
written
statements in advance of the meeting,
many of which
were quite informative as well as
moving. A major
portion of today's meeting will be
devoted to a
four-hour open public hearing during
which dozens
of people from around, and even beyond,
the country
17
will have the opportunity to present
their own
personal or professional experiences and
ideas
about the relative risks and benefits of
antidepressant medication in children and
adolescents. Although the necessary consideration
of the clock will permit only a short
time at the
microphone for each speaker, I can assure
you that
the committee welcomes and values input
from all
viewpoints and feels it is essential to
our work
that all voices be heard.
The committee's task is more
difficult
than usual. Our review is not confined to whether
one agent is safe and effective based
upon the
corresponding clinical trials submitted
to the FDA.
We are faced, instead, with assessing
efficacy and
safety for nine drugs that represent more
than one
chemical class of antidepressants, all of
which are
already available on the market.
Although the cornerstone of the data
under
examination is derived from randomized
clinical
trials submitted to the FDA this time,
following a
reclassification of the adverse events,
we find
18
ourselves turning to information from a
wide
variety of sources, in particular to
inform
ourselves about the drugs' possible
benefits in
this population. However, once we open our minds
to consideration of data originating
outside
randomized clinical trials we rest upon a
slippery
slope in which variations in
interpretation are
introduced according to the weighting
each member
places on the merits of the source.
For me, the difficulty in
assessing the
balance between benefit and risk is
multiplied by
the nature of the adverse events under
scrutiny.
Psychiatrists grapple, for the most part,
with
illnesses that produce significant
morbidity and
more rarely mortality except from
suicide. Nothing
in my experience is more tragic than the
loss of a
child to suicide. To think that I might prescribe
an agent that contributed to that outcome
is
unbearable.
Equally unbearable is to think that I
did not do enough to prevent it. This is the
essence of the dilemma before us.
We may not have all the data we
would
19
like, especially to assess long-term
benefit. We
can make recommendations about what
research should
be conducted, but we will be faced at the
conclusion of business tomorrow to make
recommendations based upon what we know
at this
cross-section in time. In deliberating on the
safety of antidepressant treatment in
children, let
us not forget the toxicity of the
underlying
disease.
Major depression remains an
under-diagnosed, under-studied and
under-treated
serious disorder among many thousands of
our
nation's youth, leading to considerable
suffering,
disability and heartbreak in many
families.
I believe that all of us in
this room
share the desire to alleviate the suffering
from
this disorder through the successful use
of
interventions that are made available to
all those
who need them. Despite the daunting task before
us, I remain hopeful that with a fair and
open-minded review of the evidence this
advisory
committee will constructively address the
issues
and ensure that interventions for this
serious
20
disorder meet high standards for both
effectiveness
and safety.
Now I will ask Anuja Patel,
executive
secretary for the advisory committee, to
review
some of the ground rules for this
committee and the
public hearing.
Conflict of Interest
Statement
MS. PATEL: Good morning.
Before I
continue, I would like to notify you of a
correction on the roster attached to the
agenda.
The following consultants, Dr. Robert
Gibbons, Dr.
Matthew Rudorfer, Dr. Richard Malone, Dr.
Tana
Grady-Weliky and Dr. Irene Ortiz will be
added to
the roster. Amended copies of the roster will be
available later this morning at the
information
desk outside this ballroom.
As you know, we have a very
full open
public hearing today, and in the interest
of both
fairness and efficiency we are running it
by some
strict rules. To make transitions between speakers
more efficient, all speakers will be
using the
microphone and podium in front of the
audience.
21
Each speaker has been given their number
in the
order of presentations and when the
person ahead of
you is speaking, we ask that you move to
the nearby
next speaker chair. Individual presenters and
families have been allotted three minutes
for their
presentations. The one consolidated presentation
has been given five minutes. We will be using a
timer and speakers who run over their
time will
find that the microphone is no longer
working. We
apologize for the need for the strict
rules, but we
wanted to be fair and to give as many
people as
possible an opportunity to participate.
The public may submit comments
after this
meeting directly to the FDA's Division of
Dockets
Management. Instructions for submitting electronic
and
written statements are available at the
registration desk outside this room. The docket
will remain open until July 29,
2005. Thank you
for your cooperation.
I would like to read the
meeting statement
into the record now. The following announcement
addresses the issue of conflict of
interest and is
22
made a part of the record to preclude
even the
appearance of such at this meeting. The topics to
be discussed today are issues of broad
applicability. Unlike issues before a committee in
which a particular company's product is
discussed,
issues of broader applicability involve
many
industrial sponsors and products.
All special government
employees and
invited guests have been screened for
their
financial interests as they may apply to
the
general topics at hand. The Food and Drug
Administration has granted particular
matters of
general applicability waivers under 18
USC
208(b)(3) to the following special
government
employees, which permits them to
participate fully
in today's discussion and vote: Jean Bronstein,
Dr. Joan Chesney, Dr. Wayne Goodman, Dr.
Lauren
Marangell, Dr. James McGough, Dr. James
Perrin, Dr.
Bruce Pollock. In addition, Dr. Philip Wang has
been granted a limited waiver that
permits him to
participate in the committee's
discussions. He is,
however, excluded from voting.
23
A copy of the waiver statements
may be
obtained by submitting a written request
to the
agency's Freedom of Infection Office,
Room 12A-30
of the Parklawn Building.
In addition, Dr. Judith
O'Fallon and Dr.
Victor Santana have financial interest
under 5 CFR,
Part II, Sec. 40.202 that are covered by
a
regulatory waiver under 18 USC 208(b)(2).
Because general topics impact
so many
entities, it is not practical to recite
all
potential conflicts of interest as they
may apply
to each member, consultant and guest
speaker. FDA
acknowledges that there may be potential
conflicts
of interest but, because of the general
nature of
the discussion before the committee,
these
potential conflicts are mitigated.
With respect to FDA's invited
industry
representatives, we would like to
disclose that Dr.
Dilip Mehta and Dr. Samuel Maldonado are
participating in this meeting as industry
representatives, acting on behalf of
regulated
industry.
Dr. Mehta is retired from Pfizer and Dr.
24
Maldonado is employed by Johnson &
Johnson.
With respect to all other
participants, we
ask in the interest of fairness that they
address
any current or previous financial
involvement with
any firm whose product they may wish to
comment
upon.
Thank you.
DR. GOODMAN: We will now proceed with a
series of formal presentations that will
bring us
to 11:45 a.m. and then a 15-minute
discussion
before lunch. In the interest of time, I would
like to ask my fellow committee members
to restrict
their questions after each presentation
to issues
of clarification only. There will be time, 15
minutes, for some discussion between
11:45 and
12:00 and tomorrow there will be a great
deal of
time for discussion and consideration of
the
questions before us. So, please, if you have
questions about clarification, you can
ask them
after each presentation but restrict it
to those
kinds of issues.
With that, I would like to
introduce Dr.
Dianne Murphy, of the FDA, who will be
followed by
25
Dr. Russell Katz, also of the FDA.
Overview of Issues
DR. MURPHY: Good morning and welcome to
this very important discussion. Before we begin
today's important deliberations, I would
ask us to
step back and see the broader context in
which this
meeting is occurring. I am going to spend a few
minutes trying to describe that for you.
There are four points I hope
you take from
this short presentation. One is that the majority
of medicines given to children in this
country are
prescribed off-label and have not been
studied in
all the pediatric populations in which
they are
used.
Second, because of new
legislation and
regulations since 1998, FDA has seen an
increase in
products that are used in children being
studied in
children.
Third, for the first 100
products,
involving over 200 studies conducted as a
result of
the new legislation, FDA has found that
approximately one-fourth of the time
there was a
26
need to change the dose, a new
pediatric-specific
adverse event was described or the
product was not
found to be efficacious despite the fact
that it
was efficacious in adults.
Fourth, part of the reason we
are here
today is because we are finally studying
the
therapies that are being given to
children.
Children deserve the same level of
evidence that is
required for adults to determine that
their use by
them is safe, effective and properly
dosed. They
are
a heterogeneous group who undergo rapid
metabolic, hormonal, physiologic,
development and
growth changes in comparison to us,
adults, who are
rather static and tend only to
deteriorate.
Over the last two decades FDA
has actively
supported, along with the American
Academy of
Pediatrics and many other groups, the
efforts to
encourage development of information and
appropriate use of therapies in the
pediatric
population.
Very quickly, and this is important
to
understand, again, the context in which
some of
27
this information has been brought to you,
in the
last decade we have made tremendous
progress. In
1994 the agency published an approach
that it hoped
would help foster and encourage
development of
therapies that we be used in
children. Congress
passed legislation in 1997 which is
referred to as
the exclusivity or the incentive to
develop studies
on products that are being used in
children.
In 1998 the FDA published the
Pediatric
Rule, which was an effort to say that if
a sponsor
is going to develop a product in adults
and that
same disease occurs in children, or
condition, that
product in most circumstances and certain
conditions would be required to be
studied.
We are going to go more into
the 2001
adoption by FDA of Subpart D, Pediatric
Ethics
Regulations, and I wanted to bring up the
Best
Pharmaceuticals for Children Act, which
you will
hear referred to as BPCA, because it
renewed the
congressional legislation of '97 and is
important
in that, again, it is the renewal of the
incentive
to study products that are being used in
children.
28
Another congressional
legislative
activity, the Pediatric Research Equity
Act, in
essence confirmed FDA's authority to
require
studies in children in certain
circumstances.
In the last decade,
particularly really
since 1997, the FDA has issued over 290
written
requests to sponsors asking them to study
products
in children because these products are
being used
in children. We have had submitted to us over 110
products, involving over 220 studies in
children,
and have now more than 76 new labels that
have new
pediatric information from these studies.
The major depressive disorders
were
included in the written requests that
were issued,
and written requests were issued for the
products
you
see listed here, Prozac, Zoloft, Remeron, Paxil
Effexor, Celexa and Serzone. Those studies were
all conducted under this program or in
response to
this program.
This is a list of some of the
programs and
activities that are in place at FDA to help
ensure
the quality and ethical conduct of
studies and the
29
approach to pediatrics. This is really focusing
mostly on the drugs component of
this. But there
is, at the Commissioner's level, an
Office of
Pediatric Therapeutics. This was enacted by the
Best Pharmaceuticals for Children Act in
2002 and
first staff were hired last year. We now have in
place an ethicist whose focus is
pediatric ethics.
You will hear a little bit more about the
Pediatric
Advisory Committee and Subpart D
referrals in a
minute.
You just heard about the exclusivity
process which has been important in
making sure
that trials do get conducted. I will spend a few
moments at the end talking about
disclosure
requirements that are unique to pediatric
studies
that are conducted under exclusivity.
This is another meeting,
actually in a
long series of meetings that have
occurred to
ensure the scientific and ethical quality
of
activities involving studies that are
being
conducted in children. Since 1999, the Pediatric
Advisory Subcommittee has had, including
today's
meeting, over ten meetings that have
addressed over
30
ten scientific issues, three ethical
issues and, in
addition, starting last year, began
having specific
safety reviews of products that have been
approved,
again under the exclusivity provisions,
so that all
adverse events that occurred in the year
after
product was granted exclusivity were
reviewed.
Again, this is just to inform you of the
ongoing
pediatric activities that are occurring
at the FDA,
some of them.
The new advisory committee, I
should say
full Pediatric Advisory Committee is
meeting for
the first time today. It was
chartered this year
and is mandated to include patient and
family
organizations, and its mandated
responsibilities
include safety, labeling disputes and
Subpart D
referrals and general pediatric issues.
The first Subpart D ethics
panel met this
past Friday and will report to this
committee on
Wednesday. I will tell you a little bit more about
that.
It is important to understand
that Subpart
D, which is part of the Common Rule, was
those
31
extra protections for children applied to
only
federally funded activities until
recently. In
2000, the Children's Health Act required
FDA
regulated products to be in compliance
with
additional protections for children that
are
embodied in the Subpart D of the Common
Rule.
Subpart D is fundamentally a
referral
process.
There is much more to it but it is a
process for IRBs when they are unsure
they can
approve or under which regulation they
should
approve a study involving children. The Pediatric
Ethics Subcommittee reports to the Pediatric
Advisory Committee and this is a public
process.
The disclosure of the studies
that are
conducted in children is distinct for
studies that
are conducted in children under the
exclusivity
provisions of BPCA. I mention this because it is
unusual in the FDA if a product is not
approved
that those studies would be
disclosed. However, we
now have, again under BPCA, a requirement
that
within 180 days of submission of a
pediatric study
a public summary of the medical and
clinical
32
pharmacology reviews will be posted. There are now
41 pediatric summaries posted at this
website.
Basically, you can go to the FDA page and
get there
by going to the Center for Drugs or
pediatric
summary\summary review.
The summaries of Effexor,
Paxil, Serzone,
Celexa, Zoloft and Remeron are available
on the
pediatric summary review site. As you know, and
will hear, Prozac is the only
antidepressant that
is approved for use in children, and it
is posted
up on FDA's site for approved
applications. That
URL is provided for you here and in your
handouts.
The new pediatric data has
taught us that
our knowledge of pediatric therapeutics
is in its
infancy; that we must study children if
we are to
understand pediatric-specific adverse
events and
reactions or if a product is going to
work in
children.
The pharmacokinetics in children has
proven to be more variable than
anticipated. The
submitted studies that we are receiving
are
teaching us that we need to know more
about
pediatric endpoints, pediatric trial
designs and
33
how to conduct these trials, and that we
will need
to change some of our trials as we move
forward.
Ethical issues require reassessment from
a
pediatric perspective. Therefore, at this point no
longer shall each child be an experiment
of one in
which not much knowledge is gained.
As we move forward, it will
require our
careful attention if we are to discover why
children are behaving differently. If children are
to be appropriately treated, we will need
to know
more than how to correct those things or
describe
adverse events. We are going to need answers to
such fundamental questions as to why
children react
differently, what are the metabolic,
physiologic
events that are occurring that
necessitate
different dosing, or why is there a
therapy that
works in adults and does not work in
children. Our
public policy must be more knowledge to
replace our
ignorance. Thank you, and we look forward to your
discussion.
DR. MARANGELL: Dr. Murphy, a quick
question, when the FDA requests a study
can you
34
specify methodology and assessments that
you would
like to see included?
DR. MURPHY: When FDA requests a study we
do put in that written request the trial
design,
the number of patients, the adverse
events--you
know, under exclusivity all of that does
go into
the written request.
DR. GOODMAN: Thank you, Dr. Murphy. Now
Dr. Katz?
Overview of Issues
DR. KATZ: Thank you, Dr. Goodman, and
good morning. I would like to welcome you to this
joint meeting of the Psychopharmacologic
Drugs
Advisory Committee and the Pediatric
Advisory
Committee.
As you know, we are here to
present to you
and to ask for your guidance in
interpreting the
results of our analyses of the
relationship between
antidepressant drug use and suicidal behavior
in
controlled trials in pediatric
patients. This
meeting is in follow-up to the meeting of
these two
committees held in February of this
year. At that
35
meeting, as you recall, we presented to you
and
obtained your endorsement of our plans to
perform
these analyses.
At this point I would like to
very briefly
recap how we arrived to this point. As you know,
we first became aware of a possible
relationship
between antidepressant drug use and
suicidal
behavior in pediatric patients in May of
2003 when,
in response to our request for further
clarification of their data,
GlaxoSmithKline, the
manufacturer of Paxil, submitted data to
us that
suggested such a link for that drug. As a result
of this submission, the agency issued a
public
statement recommending that this drug not
be used
in pediatric patients with depression,
and
independently we asked all other
manufacturers of
antidepressant drugs to resubmit the
relevant data
from controlled studies with their drugs
in
pediatric patients.
Based on our review of this
data, we
issued a statement informing prescribers
that there
was a potential relationship between all
of these
36
drugs and suicidal behavior, and that
these drugs
should be used with caution in these
patients.
However, at that time we also
noticed that
the data submitted to us from the various
companies
was not reported to us in a form that
would permit
definitive analyses. Specifically, each company
classified various behaviors as being
suicide-related adverse events in their
own
idiosyncratic manner. This led to questions about
whether or not these events were, in
fact,
suicide-related and, in addition,
prevented
meaningful comparisons between drugs in
this class.
For this reason, we decided
that an
independent assessment of these possible
events by
experts in suicidology would be the most
appropriate way to definitively answer
the question
of whether or not any, all or none of
these drugs
increased the risk of suicidal behavior
in
pediatric patients. Let me just add that by
definitive analyses I mean analyses that
make the
best possible use of the available data.
It was at this time that we
brought the
37
issue before you. At that meeting we presented you
with our plans to submit blinded
narrative
descriptions of possible suicide-related
events to
a group of independent experts, to be
coordinated
by Columbia University, whose task it
would be to
classify these events as being suicide-related
or
not.
Although no formal vote was taken, this
committee fully endorsed this effort and
agreed
that the data in hand at that time did
not permit
definitive analyses to be done.
The committee also recommended,
based in
part on the data in hand but also, I
believe
importantly, on the basis of testimony
from members
of the public who had suffered the
tragedy of loved
ones who had committed suicide while
taking these
drugs, that the agency should ask
sponsors of these
products to warn prescribers that
patients being
treated with these drugs, especially at
the
beginning of treatment, should be closely
watched
for the emergence of signs and symptoms
that might
suggest a worsening in their clinical
state.
Since that February meeting a
number of
38
important things have happened. Based on your
advice, the agency drafted, and all of
the sponsors
of these drugs have adopted, language in
product
labeling warning about the possibility of
significant behavioral changes at the
outset of
treatment with these drugs in both pediatric
and
adult patients, and the prescribing
community and
the public have been informed of these
changes.
Critically, this warning made
clear that
the possibility of worsening and a
possible
increased risk of suicidal behavior at
the outset
of treatment could not necessarily be
attributed to
the drugs because the data did not permit
such a
definitive conclusion. Nonetheless, it was
considered appropriate and prudent to
inform
prescribers and patients and their families
that
changes in behavior could occur with the
onset of
treatment.
Also, the Columbia group has
completed
their task of reclassifying the potential
cases of
suicidal behavior and, importantly, we
have
completed our reanalyses of these
data. As
39
promised at our February meeting, we are
now ready
to present to you the results of these
analyses.
At this point I would just like
to give
you a brief overview of the agenda for
today's and
tomorrow's session. First Dr. Tom Laughren, of the
Neuropharmacology Division, will provide
you with a
more detailed account of the regulatory
history and
events that have brought us here this
morning. He
will be followed by Dr. Diane Wysowski,
of the
agency's Office of Drug Safety, who will
briefly
present the results of some recently
published
epidemiologic studies relevant to this
question.
We have provided the committees with
copies of
these published materials. Although, of course, we
consider our reanalyses of the controlled
data to
be the primary source of data on which
your
discussions and recommendations will be
based, we
thought it important to present at least
briefly
the available relevant epidemiologic
data.
Next, Dr. John March, of Duke
University,
will present a brief report of the
Treatment for
Adolescent Depression Study, or TADS
trial, a
40
recently completed trial that evaluated
the effects
of fluoxetine in adolescents with
depression. As
you know, fluoxetine is the only drug
approved in
the United States for the treatment of
depression
in pediatric patients and, as you will
see, these
data make an important contribution to
our overall
assessment of the problem before us.
Dr. Greg Dubitsky, again of the
Neuropharmacology Division, will then
present an
overview of the design of the pediatric
trials from
which the data for our analyses were
derived. This
exploration is important because
similarities and
differences in design elements among
these trials
can have important implications for
whether or not
these data can be examined as a whole, or
whether
they must be considered separately.
Then, Dr. Kelly Posner, of
Columbia
University and the primary person
responsible for
coordinating the blinded reclassification
effort,
will present to you the methodology her group
used
to produce what we now consider to be the
definitive data on which we have based
our
41
reanalyses.
Because the reclassification of
these
clinical events was the critical activity on which
all subsequent analyses and decisions
will have
been based, and because by its nature it
involved
subjective assessments of the primary
data, we felt
strongly that it was appropriate to
ensure that the
methodology used by the Columbia group
could
reliably and reproducibly yield similar
results
when applied by an independent
group. For this
reason, agency scientists performed such
an
independent reclassification of a
percentage of
these cases, utilizing the Columbia
classification
schema, and Dr. Solomon Iyasu, of the
agency's
pediatric group, will present the results
of this
independent audit of the Columbia process.
At that point, Dr. Tarek
Hammad, of the
neuropharmacology group, will then
present the most
critical results of his extensive
reanalyses of the
data as reclassified by the group of
outside
experts.
These analyses look at the data for
individual drugs, as well as across all
drugs, and
42
will provide the data on which the
committee
subsequent discussions will be based.
Finally, the last formal agency
presentation will be given by Dr. Andrew
Mosholder,
of the Office of Drug Safety. Dr. Mosholder's name
is undoubtedly familiar to you. Dr. Mosholder was
the agency reviewer who had, prior to the
February
advisory committee meeting, performed
analyses on
the cases as submitted, that is, the
non-reclassified cases, and had concluded
that
these drugs did, in fact, increase the
risk of
suicide-related behaviors in this
population. As
you know, Dr. Mosholder did not present
his
conclusions at the February meeting,
although the
data on which his analyses were based
were
presented and we noted at that time that
some in
the agency had already reached a
definitive
conclusion on this question.
There has been since that
meeting
considerable public discussion and
controversy
related to the fact that Dr. Mosholder
was not
given the opportunity to present his
conclusions at
43
that meeting. The reasons for our decision at that
time were straightforward. As I have discussed
today and as we have discussed publicly
on numerous
occasions, we had decided that at the
time of the
February meeting the data had not been
submitted in
a form in which we could reliably agree
that the
events described as representing
suicide-related
behavior did, in fact, represent such
behavior.
We, therefore, felt that conclusions
reached on the
basis of analyses that relied on these
descriptions
could no, in turn, be considered
completely
reliable.
We felt, and still feel, that presenting
conclusions based on potentially
unreliable
analyses could have led to errors in
either
direction, that is, resulted in a
conclusion that
the drugs were dangerous when they really
were not,
or resulted in a conclusion that the
drugs were
safe when they were not. A mistake of either kind
could have, in our view, disastrous
consequences.
For this reason it was, and remains, our
view that
these decisions must be based on the most
reliable
44
analyses possible. Now that the definitive
analyses have been done, however, Dr.
Mosholder
will present his own analyses and conclusions,
with
particular attention to a comparison
between his
results and Dr. Hammad's.
Following lunch we will hear
brief
comments from several of the
pharmaceutical
companies who have antidepressant drug
products on
the market, and the day will end with the
open
public hearing. A total of 73 members of the
public have signed up to make
statements. As you
have heard and as in the February
meeting, we will
again need to limit the statements from
the public,
this time to three minutes per
individual. We
recognize that this is not much time and
we
apologize for the limit but it would be
impossible
for all those who wish to make statements
to do so
without imposing this limitation. We appreciate
your understanding on this point and, as
you have
heard, anyone who wishes may submit
written
testimony to the docket.
Tomorrow the committee will
discuss the
45
data you will have heard. We, of course, look
forward to this discussion and in
particular to
your answers to the questions we have
brought to
you and which we have provided in your
background
packages.
We are, in brief, interested in your
views on our approach to the
reclassification
effort and, critically, whether you
believe that
the analyses establish that one or more
of the
drugs studied increases the risk of
suicidality in
pediatric patients. Importantly, if you do
conclude that there is a signal for
suicidality,
whether for one or more of these drugs,
we need to
know what additional regulatory action,
if any, you
believe should be taken.
The results of our reanalyses
are complex
and their interpretation is not
immediately
obvious.
They raise difficult questions, not only
about the fundamental meaning of the
results of the
analyses for each drug, but also about
the
comparability of the various treatments
and,
therefore, whether it is appropriate to
consider
the drugs as a class for which any
conclusion
46
reached should globally apply or whether
the drugs
must be considered individually. Further, the
question of any further regulatory action
is also a
thorny one and must take into account the
consideration of the lack of available
effectiveness data for all of the drugs,
except
fluoxetine, although the absence of this
effectiveness data is not easily
interpreted
either.
Because of the complex nature
of the
evidence and because of the extraordinary
importance for the public health of the
decisions
that we need to make, we are turning to
you, the
experts, for guidance on these
matters. We thank
you in advance for your efforts.
DR. GOODMAN: Thank you, Dr. Katz. I
would like to invite Dr. Tom Laughren to
come to
the podium.
Regulatory History and
Background
DR. LAUGHREN: Thank you, and I would also
like to welcome everyone to the meeting
today. I
am going to begin by briefly giving an
overview of
47
events leading up to today's
meeting. I am then
going to talk about the key elements in
the
division's exploration and analysis of
the
pediatrics suicidality data. I will then spend a
little time talking about our March 22nd
public
health advisory and the subsequent
labeling changes
that have now been implemented. Then I am going to
spend a little time talking about the
effectiveness
data.
I did this at the last meeting; I will do
this again because I think it is
important to have
these data in mind since they are an important
part
of the context of this discussion about
pediatric
suicidality. Then I am going to quickly go over
the questions and the issues for which we
are going
to be seeking feedback tomorrow. I think it is
important that you have these questions
in mind as
you hear the talks this morning.
This slide lists a number of
the people at
FDA who have been involved in looking at
these
data.
As you can see, these people come from
various sections of the agency. It is a long list,
and really the point of this slide is
that we take
48
this matter very seriously and we have
invested a
lot of effort into trying to understand
these data.
You heard earlier about the two
laws,
FDAMA and BPCA, that give FDA authority
to grant
additional market exclusivity for
companies which
do pediatric studies. The point of this slide is
that most of the data that we are dealing
with this
morning come from these types of studies,
in other
words, studies that were done to obtain
additional
marketing exclusivity. However, we have also
included in our analysis data from a
ninth
antidepressant drug, Wellbutrin, that was
not
studied for exclusivity. That was one study in
ADHD.
We are also including in our analysis data
from the TADS trial that you will hear
about in
more detail later in the morning from
John March,
from Duke.
As Dr. Katz pointed out, this
issue first
came to our attention based on a review
of the
Paxil supplement. In that review, the reviewer
noticed that events suggestive of
possible
suicidality were subsumed, along with
other
49
behavioral events, under the preferred
term
"emotional lability." This led FDA to issue a
request to the sponsor, GSK, to explain
this coding
practice.
Ultimately, that resulted in a report to
FDA, in May of last year, on pediatric
suicidality
with Paxil. As Dr. Katz pointed out, that report
did suggest a signal of increased
suicidality in
association with drug use, particularly
in one of
three depression trials in that program.
What I am going to do in this
slide is
very quickly run through subsequent
events that led
us up to the February advisory committee
meeting.
So, in June of last year we issued a
public
statement cautioning about the use of
Paxil in
pediatric patients with depression. In July we
issued requests to sponsors of eight
other
antidepressant products to ask them to
give us the
same kind of summary data that GSK had
provided for
Paxil.
In September of last year we
held an
internal regulatory briefing at FDA. The purpose
of this was to brief upper management
about this
50
signal.
The two points that I took away from that
meeting from the standpoint of the
division's work
were, number one, there was general
agreement that
it would be important to try and classify
these
events since many of them were not
clearly related
to suicidality and we felt it would be
very
important to do a rational
classification.
Secondly, there was sentiment that we
ought to try
and obtain patient-level data
information, beyond
the summary information, in order to try
and
explain differences among trials and
between
programs.
In September and October we
began to get
responses to our July requests. Also, in October
we issued requests to sponsors for the
patient-level data sets that I mentioned
earlier.
Also in October, we decided to go outside
of FDA to
get a classification of these cases
accomplished.
Then, again as Dr. Katz mentioned, in
October we
issued a second public health advisory,
this time
extending the cautionary language to all
current
generation antidepressants. Finally, in November
51
and December, having looked at the
responses to the
July request for summary data, it
occurred to us
that we may not have obtained all of the
relevant
events and so we sent additional requests
to have a
broader search for events that we would
then try
and get classified.
That brings us up to the
February advisory
committee that we held. At that
meeting you
advised us to basically continue with our
analysis
of the data but, in the meantime, to go
ahead and
make some labeling changes. In March of this year
we issued a public health advisory
announcing the
changes that we had requested. In the meantime,
the classification of the cases was
ongoing by the
Columbia group. Those were completed in June of
this year. Then, in August of this year we
completed our analysis of the pediatric
suicidality
data.
In this slide what I am doing
is basically
summarizing what I think is the major
contribution
of the division to this effort. Again, we went to
a lot of effort to try to ensure
completeness of
52
case findings, that we had a complete set
of events
to have classified. We then worked with Columbia
University to have these events
classified.
As an aside, I would like to
mention that
this effort, conducted by Kelly Posner
and her
group at Columbia and the very
exceptional group of
outside experts that they assembled to do
this,
represents a very substantial effort that
has not
only helped us to understand these data
but I think
will have implications for the field in
terms of
developing a standard approach to
classifying these
kinds of data, and also will lead to
guidance
document that, hopefully, will improve
ascertainment for suicidality, which was
a very
significant problem in these trials.
Finally, the third effort that
we were
involved in was, again, in obtaining the
patient-level data sets that allowed us
to try and
explore for confounding and effect
modification, in
essence, to try to explain some of the
striking
differences we were seeing in the signal
across
trials within programs and across
programs.
53
As mentioned, at the February
advisory
committee you advised us to go ahead and
strengthen
labeling, in particular for monitoring
for
suicidality, while we were completing our
analysis.
We did this and we announced the request
that we
were making in a March 22nd public health
advisory.
The changes in labeling that we
requested
have now all been implemented for the ten
drugs of
interest.
I would add here that our plan is to
extend the standard language to all
antidepressants, not just the current
generation
and, in fact, that has already been done
for some
of these drugs. We are waiting to do it for the
others until we work out the final
standard
language, which will be based on advice
we get from
you at this meeting.
What I want to do in this slide
is to very
quickly go over the labeling changes that
have been
implemented now. This slide focuses on the advice
for clinicians who are using
antidepressants for
treating any condition really, whether in
adult of
pediatric patients. So, the advice is as follows,
54
first of all, we are asking clinicians to
closely
observe patients who are being treated
with
antidepressants for clinical worsening and
for the
emergence of suicidality, especially at
the
beginning of therapy but also at times of
dose
change.
Secondly, we are asking
clinicians to
consider changing the therapeutic regimen
in
patients whose depression is either
persistently
worse or whose emergent suicidality is
severe,
abrupt in onset, or was not part of the
patient's
presenting symptoms.
Finally, we are also asking
clinicians to
observe for the emergence of other
symptoms as
well, for example, anxiety, agitation,
panic
attacks, insomnia, irritability,
hostility,
impulsivity, and so forth. The idea here is that
there is a belief, not really solidly
empirically
established but a belief that many of these
events
may represent precursors to emerging
suicidality.
So, we are also asking clinicians to be
alert to
these symptoms.
55
This slide focuses on advice
for families
and caregivers that also is included in
labeling.
We are asking those folks to also be
alert to the
emergence of these same symptoms and to
report
those symptoms to healthcare providers if
they
emerge.
Now I want to turn to briefly
describing
the efficacy data for the 15 short-term
trials that
we looked at in our review of these
pediatric
supplements. I am going to be focusing on primary
outcomes in those trials. I also want to spend a
little time talking about the difficulty
in
interpreting negative findings in this
setting and
again I want to note that although I am
not going
to be talking about the TADS efficacy
data, you
will be hearing about the TADS efficacy
data from
John March a little bit later in the
morning.
This is kind of a busy slide
but basically
each row in this table represents a different
trial.
Again, there was a total of 15 trials.
This is color-coded so you can separate
the
different programs. There were seven programs.
56
Paroxetine had three trials. The rest all had two
trials.
The column to look at is the far column
where I have summarized the results on
the primary
endpoint.
Basically I have characterized
the results
as follows: Where the p value on drug versus
placebo on the primary endpoint was less
than 0.05,
I am calling it positive. As you can see, that
applies to the two fluoxetine trials and
one of the
citalopram trials. If the p value fell between
0.05 and 0.1 I am characterizing it as a trend.
That applies to one of the sertraline
trials and
one of the nefazodone trials. If the p value was
greater than 0.1 on that primary endpoint
I am
characterizing it as negative. That applies to all
the remaining trials. So, basically what you have
here is three out of 15 trials meeting
FDA's
standard for being positive.
The other point I want to make
on this
slide is that this represents FDA's view
and I
think it is a reasonable standard,
however, it is
not the only standard. To illustrate that, I want
57
to talk about two published papers, one for
study
329, the paroxetine trial, a paper that
was
published by Keller in 2001. That paper
characterized that trial as a positive
study, the
argument being that although it failed on
the
primary endpoint it succeeded on all the
secondary
endpoints. So, the authors of that paper
considered it a positive trial and many
in the
community also considered that a positive
study.
Secondly, there was a paper
published on
the two sertraline trials by Wagner et
al., in
2003, that was based on a pooling of the
two
trials.
Individually those trials did not make it
but if you pooled them you got a
significant p
value.
Again, many in the community view that as
evidence of effectiveness of sertraline
in
pediatric depression. This does not meet FDA's
standard but the point is that different
folks have
different views of the same data.
Now I want to talk a little bit
about the
problem of interpreting negative findings
in this
setting.
First I want to turn to adult depression
58
trials for drugs that we believe
work. Llooking at
trials that on face should work, about half
the
time those trials fail. If that failure
rate can be
extrapolated to the pediatric population,
the
expectation in two study programs and
most of these
programs were two study programs--the
expectation
is that three out of four times you would
fail to
get two positive studies. So, perhaps it shouldn't
have come as such a surprise that many of
these
programs failed. On the other hand, the fact that
the
overall success rate, again according to FDA's
standard, is only 20 percent success is
clearly a
concern.
Other factors to think about in
looking at
negative trials in this setting is, first
of all,
the history of antidepressant trials in
pediatric
depression. If you go back to the tricyclic era,
there were 12 trials comparing tricyclics
with
placebo in this population. All of them failed.
There are many interpretations of that. One, of
course, is that these drugs simply don't
work in
that population.
59
Another might be that there is
even
greater heterogeneity in this population
of
patients captured under the diagnostic
criteria for
major depression than we see in
adults. That would
work against getting positive trials.
Another factor to think about
is the
somewhat unusual regulatory context in
which these
studies were done. Ordinarily, when companies do
studies they only benefit if they get a
positive
trial.
In this setting they would win in terms of
getting exclusivity whether the trial
succeeded or
failed.
I don't know whether or not that was a
factor in the conduct of these trials but
it is
another thing to think about.
Finally, at the time that we
issued
written requests for these programs we
were not
routinely asking for phase 2 dose-finding
studies
as we are now. That, again, maybe a factor. It is
possible that the dose was not right in
some of
these trials.
In any case, the bottom line in
terms of
efficacy is that I think there are plausible
60
reasons for failure to find efficacy
other than the
obvious one that maybe the drugs don't
work. On
the other hand, a very important point I
believe is
that even though most of these programs
have failed
to meet FDA's standard for approval, this
is not
the same thing as saying that we have
proof that
the drugs have no benefit. The drugs may have
benefit that has simply not yet been
demonstrated.
On the other hand, the failure to
demonstrate
benefit clearly is a concern, especially
when we
have a risk, as we have now seen, of
emerging
suicidality. So, the burden is clearly on those
who believe that these drugs do have
benefit to
show that benefit. Tomorrow I am going to talk a
little bit about some possible designs
for looking
at longer-term benefits with these drugs.
Now what I would like to do is quickly
move through the questions that we are
going to be
asking you to discuss and comment on
tomorrow.
Again, we think it is important that you
have these
in mind as you hear the presentations
this morning.
First of all, we are going to
ask you to
61
comment on our approach to classifying
the possible
cases of suicidality and our subsequent
analyses of
the resulting data for the now 24
trials--again,
the additional trial is the TADS trial.
The question then would be do
the
suicidality data from these trials
support the
conclusion that any or all of these drugs
increase
the risk of suicidality in pediatric
patients? If
the answer to that question is yes, to
which of
these nine drugs does that risk
apply? In other
words, is this a class effect of all
antidepressants? Does it apply to certain
subclasses within this broader class or
only to
specific drugs?
If you believe there is a class
risk or a
risk that applies only to certain drugs,
how should
this information be reflected in the
labeling for
each of these products? What, if any, additional
regulatory actions do you think we need
to take?
Finally, again we would like
you to
consider what additional research might
be needed
to further delineate the risks and the
benefits of
62
these drugs in patients with pediatric
depression?
Thank you very much.
DR. GOODMAN: Thank you, Tom. I imagine
people have questions but I want to try
to catch up
this morning to make sure that we have
time for all
the presentations. So, I will ask you to hold your
questions and I would like to invite the
next
speaker, Dr. Diane Wysowski, who will be
looking at
data from different sources other than
clinical
trials.
Recent Observational Studies of
Antidepressants
and Suicidal Behavior
DR. WYSOWSKI: Good morning.
In this
presentation I will be reviewing recent
studies of
antidepressants and suicidal behavior and
briefly
discuss their methods, results and
limitations.
I reviewed two types of
studies,
ecological and patient-level controlled,
observational studies. Ecological studies show
increasing antidepressant use and
simultaneous
decreasing suicide rates. However, such
correlations do not necessarily imply
causality.
63
Findings of ecological studies can be
merely
coincidental. Numerous factors such as changes in
risk factors, social and economic
changes, more
available counseling, changes in gun
access and
choice of a less lethal means of suicide
in
children and adolescents may coincide
with
decreases in the suicide rate in children
and
adolescents.
Ecological studies don't show
which factor
or
factors are responsible for an observed trend.
Furthermore, an increased relative risk
of suicide
with antidepressants in children and
adolescents
may coexist with a decreased suicide
rate. To
better examine causality, we turned to
patient-level controlled studies, such as
observational studies, in clinical
trials.
For the rest of this
presentation I will
be focusing on two patient-level
controlled,
observational studies. The first is the Jick study
that was published this July in The
Journal of the
American Medical Association. It is a matched case
control design based on patient
prescriptions and
64
diagnoses obtained from the United
Kingdom's GPRD,
the General Practice Research Database,
for the
period 1993-1999. The GPRD is a database of
medical records from general
practitioners of more
than three million patients in the United
Kingdom.
For this study subjects were 10
through 69
years of age. Exposures studied were the most
widely used antidepressants in the U.K.,
amitriptyline, fluoxetine, paroxetine and
dothiepin. Dothiepin was chosen as the reference
category.
From data on these antidepressants
users, the investigators identified 555
cases of
nonfatal suicidal behavior, defined as
ideation or
attempts.
They identified 17 cases of suicide.
From the base group of antidepressant
users, the
investigators matched the cases with more
than 2000
controls who did not develop suicidal
behavior.
The researchers then compared the
suicidal cases to
the non-suicidal controls for initiation
of each
antidepressant.
Controlling for age, sex,
calendar time
and time from first antidepressant
prescription to
65
onset of suicidal behavior, the range of
relative
risk for nonfatal suicidal behavior was
0.83 to
1.29 for the antidepressants compared to
dothiepin.
None of these risks were statistically
significant.
Paroxetine, with a relative risk of 1.29
and a 95
percent confidence interval of 0.97 to
1.7, had
borderline statistical significance.
Similar results were obtained
for those
10-19 years old. No statistically significant
association was found between each
antidepressant
and completed suicide. No statistically
significant association was found between
stopping
an antidepressant and nonfatal suicidal
behavior.
The relative risk for nonfatal
suicidal
behavior and suicide were highest for
patients
first prescribed an antidepressant within
1-9 days,
versus 90 days or more, before the
suicidal
behavior of the case in the same time
period for
the control. For nonfatal suicidal behavior the
relative risk for antidepressant use
within 1-9
days was 4, with a 95 percent confidence
interval
of 2.89 to 5.74. For suicide the relative risk for
66
antidepressant use within 1-9 days was
38, with a
wide confidence interval of 6.2 to 231.
Reviewing the limitations of
this study,
the results are only as good as the GPRD
data.
There are concerns about possible missing
data,
possible incomplete ascertainment and
misclassification of patients, and
possible
uncontrolled biases among the
antidepressant drugs,
such as selection by severity of
depression. There
were no interviews of cases and controls
so
medication compliance is not
systematically known.
There was no unexposed group, and the
antidepressant risks are only in
reference to the
dothiepin group.
FDA asked Dr. Jick and colleagues
to
reanalyze their results with
amitriptyline as the
reference category. They kindly responded to our
request, and asked that their
interpretation of the
results be presented verbatim to the
committee. If
the committee wishes to see these
supplemental
analyses I will be glad to present them
in the
question and answer period.
67
Other limitations of the study
include the
fact that suicidal ideation is a more
subjective,
softer diagnosis than suicide attempts
and the
risks were not examined separately. This was a
study of mostly adults and there is
limited
information on children and adolescents.
Finally, the investigators
excluded
patients with a history of 11 other
neuropsychiatric diagnoses, calling into
question
the representativeness of the patients
compared
with those in clinical practice.
Another patient-level
controlled study
examined the relationship between
antidepressants
and the risk of suicide attempt by
adolescents with
major depressive disorder diagnoses. The study was
done by investigators at the University
of Colorado
School of Pharmacy and Medicine. Robert Valuck was
the principal investigator. It was presented as a
poster at the International Society of
Pharmacoeconomics and Outcomes Research
meeting,
this past May.
It is a retrospective cohort
study of paid
68
medical claims data from the PharmMetrics
Integrated Outcomes Database of 70
managed health
plans for the period 1995 through March,
2003.
Paid claims data include health care
provided in
which costs are incurred, such as for
prescriptions, doctor visits, emergency
room visits
and hospitalizations.
The investigators identified about
16,000
adolescents aged 12-18 with the first
major
depressive disorder diagnosis. They classified
patients into cohorts by antidepressant
prescription, those who received none
over the
entire follow-up period, which was the
reference
group, and those who received SSRIs,
tricyclic
antidepressants or other antidepressants
within 30
days of diagnosis. They followed the cohorts for
at least 6 months.
The researchers used a Cox proportional
hazards regression analysis to control
for some 14
covariates and to examine the
multivariate
relationship between antidepressant use
and time to
suicide attempt. The majority of patients, 78
69
percent, had no antidepressant filled in
the 6
months after diagnosis; 15 percent had
SSRIs filled
within 30 days of diagnosis. And, 209, 1.3
percent, of the 16,000 patients made at least one
suicide attempt in the follow-up period.
The investigators concluded
that
antidepressant treatment with any class
of drugs
did not increase the risk of suicide attempt.
Antidepressant use for less than 6
months, compared
with use for 6 months or more, was
associated with
a statistically significant 3-fold
increased risk
of suicide attempt. Females, those who received
psychotherapy within 90 days of major
depressive
diagnosis, patients with substance abuse,
schizophrenia or another mental health
disorder,
patients with more chronic diseases and
those in
the Midwest and West were independently
at greater
risk of suicide attempt.
Dr. Valuck and co-investigators
recently
expanded their study to include 24,000
eligible
patients with a new diagnosed major
depressive
disorder.
This expanded study is currently being
70
reviewed for publication. The researchers added a
propensity matching adjustment to control
for
predictors of treatment and to achieve
greater
balance among the antidepressant
groups. The
proportion of suicide attempters, 1.4
percent, was
about the same proportion as in their
smaller
study.
In this expanded study the
hazards ratio
for SSRIs compared to no treatment was
1.58, not
statistically significant. The hazards ratio for
tricyclics was not estimable due to small
numbers
and it was 1 for the other antidepressant
category.
The hazards ratio for multiple
antidepressants was
1.43, also not statistically
significant. The risk
of suicide attempt declined with longer
use of an
antidepressant. Compared with patients having less
than 8 weeks of use, those with equal to
or greater
than 6 months of use had a statistically
significant decline in the risk of
suicide attempt.
Concerning the limitations, the
results
are only as good as these paid claims
data. There
are concerns about possible missing data,
possible
71
incomplete ascertainment and
misclassification of
patients, and possible uncontrolled
selection
biases by antidepressant group. There were no
interviews of patients so we don't have
systematically collected information on
medication
compliance. There are no data on the outcomes of
the attempts. We don't know how many of the
attempters died, and there is no
information on
suicides.
Also, there is no information on
individual antidepressants. There were differences
in study results between the poster and
the
expanded study, although this is probably
due to
the larger size of the expanded study.
In conclusion, although most of the
results for the individual
antidepressants or
classes of antidepressants were not
statistically
significantly associated with suicidal
behavior, I
do not believe that the Jick and Valuck
studies
completely rule out a possible increased
risk of
suicidal behavior with antidepressant
use. The
studies reviewed were in agreement in
showing that
the risk of suicidal events occurred
statistically
72
significantly closer to diagnosis and
onset of
antidepressant treatment. The studies did not
provide data about the characteristics of
patients
who did not respond to antidepressants or
whose
illness worsened with them. The studies had actual
or potential methodological limitations.
I conclude that more definitive
studies,
perhaps large randomized, controlled
trials of
sufficient length, are needed concerning
the risk
of suicidal behavior and suicide as
related to
antidepressant use in children and
adolescents.
With so much at stake, children and
adolescents,
their parents and physicians and society
in general
deserve to know which therapies and which
individuals work best for treatment of
depression.
Thank you.
DR. GOODMAN: Thank you very much, Diane.
My preference would be that you present
those
additional Jick data tomorrow. I don't think we
have time for it today. Would that be an agreement
by the committee as well? So, I think we are in
accord on that, if you could prepare to
present
73
that data tomorrow to us. There is one question,
yes, we will allow that.
DR. PINE: I am wondering if you could
clarify in the Valuck 24,000 patient
study, if you
looked at the association in the less
than 8-week
treatment versus no treatment group. Did that
confidence interval exclude 1? I mean, I saw that
you gave less than 8 weeks versus
prolonged
treatment but I didn't see an odds ratio
for less
than 8 weeks versus no treatment.
DR. WYSOWSKI: I don't think that I have
those data. I don't think that they did that
analysis.
Their results are still being considered
for publication and we just got an
abstract. You
saw the poster in your package. Then, when they
did the expanded analysis they only gave
us an
abstract of the results. So, we don't have a lot
of detail on the expanded study.
DR. GOODMAN: Dr. Fost, you had a question
also?
DR. FOST: One of the theories of why
suicide behavior might be increased
shortly after
74
prescribing is that the patients are at
the worst
then and that is why they are started on
prescriptions. If that were true, one might expect
to see increased suicidal behavior in the
week or
two before prescribing. Do either of these studies
allow for that analysis?
DR. WYSOWSKI: I believe the Jick study
did look at that. Actually, no--no, I don't see
any information on that; it is just
after.
DR. FOST: And the data set doesn't allow
itself for that reanalysis?
DR. WYSOWSKI: Well, it may.
I don't know
whether either investigator has
information on
that.
DR. GOODMAN: I think that was an
excellent question. Now I would like to invite Dr.
John March, from Duke University, to
present
results from the TADS trial.
Brief Report on TADS
Trial
DR. MARCH: Thanks, it is a pleasure to be
here and I would like to begin the
presentation by
thanking the committee for inviting the TADS
team
75
to present the TADS data, and also thank
the FDA
for the comprehensive and thoughtful way
that it is
approaching this question of enormous
public health
importance.
The TADS trial, the Treatment
for
Adolescents with Depression Study, is an
NIMH-funded comparative treatment trial,
and I am
going to present efficacy and safety data
from the
stage-1 outcomes that were published in
The Journal
of American Medical Association several
weeks ago.
We have a detailed safety paper in
preparation. We
have a methods paper which has been
published and a
baseline paper which looks at the sample
composition in press, and those of you
who are
interested in the TADS trial are referred
to these
papers for further information.
As I mentioned, this is a study
funded by
the
NIMH, coordinated by the Department of
Psychiatry at Duke University and the
Duke Clinical
Research Institute, the DCRI. It has had the
benefit of oversight and consultation
from numerous
consultants, a scientific advisory
board. The
76
NIMH, DSMB participants included 12 sites
from
around the United States. Lilly provided
fluoxetine under an independent
educational grant
to Duke University, had no input into the
design of
the study, the conduct of the study, the
analysis
of the data or the preparation of the
manuscript.
My sense is that the major credit for
this work, as
for all of the research on which we base
evidence-based practice, goes to the
children and
families who are willing to participate
in
research.
Without their participation, we would
have no evidence at all.
The overall objective of the TADS
trial
was to examine the effectiveness of
medication and
cognitive behavioral psychotherapy alone
and in
combination for the acute and long-term
treatment
for adolescents with DSM-IV diagnosis of
major
depression. The design of the trial was a
balanced, randomized, controlled study
that was
masked by use of independent evaluators;
four
groups, placebo, cognitive behavioral
psychotherapy, fluoxetine and their
combination,
77
and the study involved 36 weeks of
treatment, of
which I am going to present the stage-1
data for
the first 12 weeks of treatment. We also have a
year of naturalistic follow-up and we
have recently
been funded to follow these youngsters
out into
young adulthood. That data will not be discussed
today.
Now, it is important, in
understanding the
generalizability of the data, to know a little
bit
about the sample composition. The inclusion
criteria included outpatients, both boys
and girls
age 12-17, with a DSM-IV diagnosis of
major
depressive disorder and an IQ greater
than or equal
to 80.
Youngsters with severe conduct disorder or
substance abuse, other than nicotine,
pervasive
developmental disorders, thought
disorder, bipolar
disorder, or history of suicidality or
homicidality
were excluded from the trial.
Because suicidality is the question at
issue today, I thought it important to
say a little
bit more about these exclusion criteria,
kids were
excluded if they had a hospitalization
within the
78
previous 3 months or if they were
considered to be
high risk, which meant a suicidal event
of some
sort within the past 6 months, the
presence of
active intent or plan, or if they had
suicidal
ideation in the context of a family which was
so
disorganized that we felt that even with
the
intensive monitoring in the TADS trial
framework
that it would not be reasonable to enter
them into
a randomized, controlled research study.
This was a moderate to
moderately severely
ill population. We had 439 kids, as you can see,
randomized equally into the 4
groups. The total
sample on the Children's Depression
Rating Scale
had a CDRS scale score of 60. That, again, is a
mean score of moderate to moderately
severely
depressed, with a range from mild to
severe
depression. The T score for that mean score is 75.
That means that these kids were more than
2
standard deviations out from normal with
respect to
severity of depression. The sample was multiply
comorbid, as is characteristic of
patients in the
clinical samples. This was the first major
79
depressive episode for about 90 percent
of the
sample.
Ten percent of the sample had had more
than one depressive episode. The mean duration of
major depression was 42 weeks. Again, over 50
percent of the sample was comorbid for
another
mental disorder, both internalizing and
externalizing disorders; 14 percent of
the sample
had ADHD and half of those kids were on
concurrent
psychostimulant treatment.
So, unlike the industry-funded trials,
the
TADS sample is largely representative of
patients
who are treated in clinical practice with
major
depressive disorder. As you might expect, given
the severity of illness and the pattern
of
comorbidity, these youngsters suffered
significant
functional impairment. This is the children's CGAS
rating and you can see that the mean CGAS
score was
between 40-50, so significant functional
impairment
associated with mental illness in this
patient
population.
What did we learn in the
trial? This is a
take-home efficacy message. Four groups, again,
80
began at a CDRS raw score of 60. These are random
regression analyses looking at the
adjusted or
predicted means at baseline, week 6 and
week 12 of
treatment. Actually, all 4 treatments showed
significant improvement, a characteristic
of major
depression. The placebo group and the cognitive
behavioral psychotherapy group were
superimposed,
one on top of the other. There is no additional
benefit from receiving cognitive
behavioral
psychotherapy, either in the slope term
or at the
end point, over receiving placebo. There was
significant benefit from fluoxetine
alone, and the
largest effect was associated with the
combination
condition. The combination condition beat the CBT
condition and the placebo condition on
all 4
efficacy measures. Fluoxetine beat these CBT on
all 4 measures and placebo and placebo on
3 of the
4 measures.
If we look at the impact of
treatment
using effect size calculations, the mean of
the
control condition minus the mean of the
placebo
condition, divided by the pooled standard
81
deviation, the effect size for the
combination was
close to 1. This is a very large effect. For
fluoxetine it was around 0.6, a moderate
to large
effect.
For CBT there was no difference between
CBT and placebo, effect size calculated
relative to
placebo.
If we look at response rates,
defined as a
clinical global importance measure rated
by the
independent evaluator of much improved or
very much
improved, 71 percent of the combination
kids
improved; 61 percent of the
fluoxetine-treated
patients improved; 43 percent of the
cognitive
behavioral psychotherapy treated patients
and 35
percent of the placebo-treated patients
improved.
Combination statistically was no
different than
fluoxetine. CBT was no different than placebo.
The two drug-containing conditions were
superior to
the two non-drug-containing conditions on
responder
analysis.
If we look at the effect size
calculated
as
a derivative of the odds ratio of improvement
for the active treatments relative to
placebo for
82
the responder analyses, the results
parallel the
analyses on a scale or outcome variable,
the
Children's Depression Rating Scale. The effect
size for combination was 0.8, almost 0.6
for
fluoxetine, and about 0.2 for cognitive
behavioral
psychotherapy. So, again, clear superiority for
the
drug-containing conditions, with the largest
effect reserved for the combination of
medication
management and CBT.
Now, of interest here are the
safety
outcomes from the TADS trial. Although we spent an
enormous amount of time and energy on
measuring
adverse events, particularly measuring
the impact
of the treatments on the potential for
harm, I
think it is important to point out that
the study
did not have safety as a primary outcome. With 439
subjects randomized to 4 conditions, it
is easy to
see that for these outcomes the study is
clearly
under-powered.
It is I think important to
separate
ideation from behavior. Despite the exclusion, we
had significant suicidal ideation in the
TADS
83
sample.
This is looking at the Reynolds Adolescent
Depression Scale, item 14, and 7.5
percent of the
sample exhibited a score of 4 or above
which is the
threshold for clinical investigation on
the RADS.
CDRS item 6, serious suicidal ideation,
the kind of
suicidal ideation that leads you to
consider
hospitalization, 2 percent of the sample
met CDRS
item 13 criteria for severe suicidal
ideation. On
the suicidal ideation questionnaire 2
measures, the
SIQ flag which is to prompt clinical
investigation,
or elevated scores on any one of the
items on the
SIQ
that would also prompt suicidal ideation, 29
percent and 10 percent of the sample
respectively
on these measures exhibited clinically
significant
suicidality. So, although suicidality was an
exclusion criterion, there was plenty of
suicidal
ideation exhibited in the TADS sample at
baseline.
Now, as expected, suicidal
ideation
occurred across all 4 groups taken in the
aggregate. One sees here, looking at the CDRS item
13 score, in this case greater than 1, or
SIQ
score, SIQ flag greater than 31,
significant
84
suicidal ideation at baseline. It came down at
week 6 and was significantly reduced
overall at
week 12.
This is the aggregated data across all 4
treatment groups.
Random regression analyses
looking at
between group differences on the SIQ,
although it
looks like these groups might be different
at
baseline, in fact there were no
statistically
significant differences on the SIQ in all
4
treatments.
One sees a different result
than we found
in the pattern for depression. This is placebo;
this is fluoxetine; this is CBT and this
is
combination. The take-home messages here are
three.
First, as we saw in the previous slide,
suicidal ideation improves with treatment
irrespective of which treatment one
gets. Second,
fluoxetine and placebo are indistinguishable with
respect to suicidal ideation, either with
respect
to the slope or at entry, indicating that
fluoxetine, at least on average, is not
provoking
suicidal ideation. Finally, the only treatment
85
which separated from placebo with respect
to
reducing suicidal ideation was the
combination of
fluoxetine and CBT. So, here the combination
offers a significant advantage over
medication
monotherapy.
Moving on to behavior, using a
comprehensive adverse event monitoring
procedure,
we looked at the incidence of three kinds
of
harm-related adverse events. Harm-related events,
the broadest category, were defined as
harm to
self.
This could involve no suicidal ideation,
ideation or attempt. Or, harm to others which
required aggressive ideation or actual
behavior
involving harming another person or
physical
property.
These events are subsumed one within the
next.
So, a suicide-related event, which is a
subset of harm-related events, involves
harm to
self, either ideation or attempt. Then we had
suicide attempts themselves. What differentiates
harm-related events from suicide-related
events is
primarily one subject with aggression and
7
subjects, I believe, who exhibited
self-injury
86
without ideation, primarily cutting.
These are the actual rates of
harm-related
and suicide-related events divided by
treatment
group.
One sees that there is a larger number of
harm-related events and suicide-related
events in
fluoxetine-treated kids relative to
placebo-treated
kids.
The combination group is intermediate
between harm-related and suicide-related
events,
intermediate between fluoxetine and
placebo. The
cognitive behavioral psychotherapy group
was
roughly comparable to the placebo group.
If you look at children who
received drug,
that is, combining the fluoxetine and the
combination groups and comparing them to
the
placebo group, 10 percent, 22 of those
fluoxetine-treated kids exhibited a
harm-related
event; 7 percent exhibited a
suicide-related event;
and the rates of these events overall
were quite
low, 7.5 percent of 439 kids, or 33 kids
had a
harm-related event, 24 of 439 kids, or
5.5 percent
exhibited a suicide-related event.
I think it is very important as
we move
87
through this discussion to understand
that the base
rates of these events are extremely low
relative to
the rates that we see for benefit.
If we look at the odds ratios
calculated
from the actual rate data, the relative
risk is 1.5
for combination, 2 for fluoxetine, less
than 1 for
CBT.
Those is calculated relative to placebo.
For
the collapsed category of fluoxetine and
combination the relative risk is slightly
greater
than 2.
This is the only statistically significant
relative risk in which the confidence
interval
crosses 1. That is largely because these events
are so rare so the power is quite low to
identify
these events. In fact, the power for detecting a
20 percent difference is about 10
percent.
For suicide-related events
there are no
statistically significant differences
although, as
you can see from the graph, the odds
ratios pretty
closely track the odds ratios for
harm-related
events.
The take-home message from this
presentation actually is in this
table--no, it is
88
in the next table. This is the table that looks at
the suicide attempts in the trial. We had 7 of
them out of 439 kids, or slightly less
than 2
percent of the sample, Two fluoxetine-treated
kids, 4 combination-treated kids, 1 CBT
and no
placebo-treated patients made a suicide
attempt.
There probably is an imbalance in
randomization
which may in part be responsible for
this. There
were more kids with an elevated SIQ flag
randomized
to the drug-containing than the
non-drug-containing
conditions so it is not clear what to
make of this
data.
Here I think is where the
take-home
message lies relative to safety. This is looking
at the benefit/risk ratio using analyses
for the
number needed to treat and number needed
to harm.
What we see here is fluoxetine compared
to placebo,
in the first column; combination compared
to
placebo; and the collapsed category, SSRI
versus no
SSRI. The absolute benefit increase is calculated
as the control, the experimental event
rate minus
the control event rate. So, it is the absolute
89
benefit increase for receiving the
treatment. The
absolute risk increase is calculated,
again, as the
experimental event rate minus the control
event
rate, that is, the risk increase
attributable to
the treatment over the placebo condition
in
absolute numbers.
The NNT and the NNH are the
reciprocal of
the absolute benefit increase and the
absolute risk
increase respectively, 1 over the
absolute benefit
increase or 1 over the absolute risk
increase.
These are defined as the number of
patients for
benefit that would need to be treated to
find one
patient who had benefit over the benefit
occurring
from the control condition or, in the
case of the
NNH, the number of patients who would
need to be
treated to find one patient who would be
harmed
over treatment with the control
condition. So, it
is a nice metric that combines both the
absolute
rate and the magnitude of the effect.
One sees clearly here that 27
percent of
patients benefit from treatment with
fluoxetine,
with an NNT of 4 which is a large effect;
27
90
percent of patients benefit from treatment
with
combination, with an NNT of 3, again a
very large
effect; for SSRI versus no SSRI,
combining the
categories, 31 percent of patients
benefit, again
with an NNT of 3.
The absolute risk increase for
a suicidal
event with respect to fluoxetine is 4.7
percent as
compared to placebo; 2 percent for
combination over
placebo; and 3 percent for the combined
category.
NNH is number of patients that you would
need to
treat with the active treatment to find
one patient
who would be harmed over the control
condition of
21, 50 for the combination condition and
4 for the
collapsed categories.
From a clinical point of view,
these
patients would be easy to pick out in a
crowd,
easily identifiable who is getting better
and who
is not getting better, active treatment
versus
control.
These effects are so small and so
uncommon that one could not possibly pick
out
patients who would be harmed by the
medication
versus patients who would commit these
91
suicide-related event behaviors with
placebo
treatment. If you calculate the NNT to NNH ratio
looking at benefit to risk, one sees
clearly here
that the benefit tilts in favor of the
treatment,
and particularly the combination
treatment.
So, we conclude that the
combination of
fluoxetine and CBT is the most effective
treatment
for adolescents with major
depression. Fluoxetine
alone is effective but not as effective
as the
combination of the two treatments. CBT alone is
less effective than fluoxetine and not
significantly more effective than
placebo. We also
conclude that placebo is acceptable in
randomized,
controlled trials of adolescent major
depression
and, in fact, is essential for looking at
the
adverse event outcomes, at least in this
study.
Suicidality decreases substantially with
treatment.
The improvement in suicidality is
greatest with the
combination and least for fluoxetine
alone.
Fluoxetine does not increase suicidal
ideation.
Suicide-related adverse events which are
uncommon
may occur more often in
fluoxetine-treated
92
patients.
CBT may protect against suicide-related
adverse events in fluoxetine-treated
patients.
Taking both risk and benefit into
account, the
combination of fluoxetine and CBT appears
superior
as a short-term treatment for major
depression in
adolescents.
Now, the most practical
clinical trialist,
the kind of trial models that are used in
other
areas of medicine--cardiology, oncology,
infectious
disease for example, would much prefer a
large
simple or practical clinical trial in
2000 subjects
to a meta-analysis of 10 under-powered
subject
trials.
So, it is our sense from looking at the
FDA data and also the TADS data that we
have a
significant signal for drug treatment
relative to
suicidality but the evidence is not conclusive. In
fact, a definitive study has not been
done and we
would, as a field and as consumers of
this
information, much benefit from a
placebo-controlled, practical clinical
trial
comparing fluoxetine to another SSRI,
perhaps
sertraline or citalopram. This trial could be run
93
easily on the child and adolescent
psychiatry
trials network, which is a clinical
trials network
that we are now putting in place to run these
kinds
of trials in the pediatric
population. Thank you.
DR. GOODMAN: Thank you, John. My first
question is will you be here tomorrow?
DR. MARCH: No.
DR. GOODMAN: Oh, you won't? That may
affect my subsequent questions because I
am sure,
besides myself, there will be a number of
questions
for you.
I don't know if we have time to take them
all right now. I wonder if there is any other
option, Anuja. What time do you leave today, Dr.
March?
DR. MARCH: Noon.
Committee Discussion on TADS
Trial
DR. GOODMAN: I am going to ask a
question.
My understanding in looking at your
results is that on the categorical
measures of
response fluoxetine is superior to
placebo.
However, if you look at a comparison of
the mean
scores on the CDRS fluoxetine is not
superior to
94
placebo.
Is that correct?
DR. MARCH: The slope term on the random
regression analysis for the CDRS, the p
value was
0.08 for fluoxetine versus placebo. Fluoxetine was
statistically significantly different
than CBT but
not placebo.
DR. GOODMAN: So, from a standpoint of
FDA, if this trial had been submitted to
the FDA
and you didn't have the CBT group, it
seems to me
that it might be classified as a negative
study.
DR. MARCH: It would have been classified
as a negative study using the CDRS as the
primary
endpoint, the slope term.
DR. GOODMAN: Do you have any comments
about the methodology or outcome measures
we are
using and whether we are using the most
appropriate
ones in your opinion?
DR. MARCH: Well, I think it is actually a
very important question. If you look at the
fluoxetine outcomes on the predicted
endpoint, the
week 12 endpoint on the CDRS predicted by
the CDRS
slope, on the clinical global improvement
measure
95
dichotomized and on the Reynolds Adolescent
Depression Scale fluoxetine was
statistically
better than placebo. It was simply a near miss on
the slope term, which probably relates to
the way
the random regression analyses handle
standard
errors.
So, my sense of the story that the data is
telling us is that fluoxetine--and also
if you look
at the effect size calculations--the
story the data
is telling is that fluoxetine is an
effective
treatment and it would be a mistake to
consider
this a negative trial. On the other hand, the
technical definition used by the FDA
would require
that the study be considered negative.
DR. GOODMAN: Dr. Perrin?
DR. PERRIN: On the other side of the
equation, you made comments that the
sample was
somewhat different from some of the
trials that
have been sponsored by industry. Could you be a
little bit more specific about what the
differences
are, and how they might have affected the
results,
and what are the implications for
meta-analyses of
these studies?
96
DR. MARCH: I think it is a very important
question, and we have a paper that is in
press in
The Journal of Child Medicine Psychiatry,
the
"orange journal," which
describes the TADS sample
in some detail and compares the TADS
sample to
epidemiologic samples and to treatment
samples,
both on the pharmacotherapy side,
primarily the
industry data sets, and also the
cognitive
behavioral psychotherapy trials, of which
there are
13 published at this point. In general, our sample
is not substantially different from
either the
epidemiologic or the treatment seeking
samples,
with the caveat that we are slightly
sicker and
slightly more comorbid, particularly
relative to
the CBT samples.
So, given that the range of
depression
goes from mild to severe and half the
sample is
comorbid, there are plenty of patients in
the data
set who resemble the mildly ill patient
all the way
up to the severely ill, multiply comorbid
patients.
So, I think the result of the TADS trial
is
generalizable to the total sample.
97
With respect to meta-analyses,
it would be
better to have a very large sample including all
these variations, but by combining the
data sets
one gets a better picture, I believe, of
the total
variation in the patient population than
simply
using the industry data sets which tend
to exclude
the more complicated and clinically ill
patients.
DR. GOODMAN: Dr. Newman, did you have a
question?
DR. NEWMAN: Normally when you use a
continuous outcome you have greater power
than when
you dichotomize. I assume that is why you
specified that as the endpoint at the
beginning of
the trial. A reason why you might not is that the
medication helps maybe a majority but
actually
harms a minority and then you could
actually see
that if you dichotomize the percent to
improve is
statistically significantly greater in
the
fluoxetine group but the mean may not be
significantly greater because there are
some people
who are harmed and they drag the mean
down, whereas
they have no effect on the dichotomized
variable.
98
Did you look to see whether there was
evidence that
the variation in the standard deviation
in the
effect size differed between the two
groups and
might have been greater with fluoxetine?
DR. MARCH: That was actually the point
that I made, that the standard errors are
larger in
the fluoxetine-treated group than in the
combo or
the placebo--
DR. NEWMAN: Actually, not just the
standard errors but the standard
deviation, meaning
that, in fact, there are some people who
are harmed
by it and that diminishes the apparent
benefit when
you average.
DR. MARCH: It would be impossible to look
at the standard errors or the standard
deviation
and make a judgment about harm because
there is a
fair amount of variability data point to
data point
which is intrinsic to the disorder. Some patients
get better; some patients deteriorate.
We do have in the safety paper
a whole set
of analyses looking at shifts, which I am
not
confident enough in to have wanted to
present
99
today.
We will try to examine what percentage of
patients are getting worse with respect
to ideation
and behavior, and how that relates to
treatment
classification and also how it relates to
other
adverse events like mania activation,
anxiety
disinhibition and so on. I think the secondary
paper is going to shed a fair bit of light
on these
questions.
DR. GOODMAN: Dr. Pfeffer?
DR. PFEFFER: I have two questions. One
is were there any differential dropout
rates in the
samples?
This also relates to the question of
compliance in the different
treatments. My last
question is these were intent-to-treat
analyses?
DR MARCH: All very good questions. The
analyses are all intent-to-treat. Although I
didn't present the data, if we look at
observed
cases analyses, those who were still on
their
assigned arm at any given assessment
point or
completer analysis, the results are
exactly the
same.
About 10 percent of the kids in each
treatment overall dropped before the
week-12 data
100
point.
Another 10 percent were what we call
prematurely terminated. That is, for ethical
reasons.
They received an out of protocol
treatment at some point during the first
12 weeks
of the study. There were no statistically
significant differences across treatment
groups in
either the rate of dropping out or the
rate of
receiving an ancillary treatment, that
is, a
premature termination.
You will see this afternoon
when FDA
presents its analysis of the TADS data
that the
odds ratios for being harmed by receiving
fluoxetine are greater than we presented,
or I
presented this morning on behalf of the TADS
team.
That is because the FDA data set excluded
those
kids who were prematurely terminated and
received
another treatment. That actually represented two
kids in the placebo group and that, in
turn,
inflated the odds ratios in the FDA
results versus
the TADS results. So, there is some method
variance in there which accounts for the
differences between the two findings.
101
DR. GOODMAN: Dr. Gorman?
DR. GORMAN: Does analysis of your data
set allow interpretation of the time of
onset of
treatment to behaviors that we are
studying today?
DR. MARCH: That is a very good question
and, in fact, one that we will address in
the
secondary paper. I can tell you that the majority
of the events occurred within the first 6
weeks but
not within the first 2 weeks. But I don't have
that data presented in slide form so I
can show it
to you, but it will be in the safety
paper that we
are currently preparing.
DR. GOODMAN: So you don't know what the
differential rates are between the groups
at this
point, particularly between fluoxetine
and placebo?
DR. MARCH: In terms of time?
DR. GOODMAN: Yes, in terms of the early
events.
DR. MARCH: My general impression, looking
at the data, is that the fluoxetine
events occurred
early and the placebo events occurred
later, which
is kind of what you would expect given
what we know
102
about the compounds. But I
wouldn't want to cite
chapter and verse or have you base your
decisions
based on that because we haven't
completed the
final analyses of the data.
DR. GOODMAN: Dr. Rudorfer, you will be
the penultimate questioner.
DR. RUDORFER: If I can go back to the
characteristics of the patients for a
moment, we
will be looking at a number of studies
that were
submitted to the FDA by various sponsors,
and it
seems to me that the TADS inclusion
criteria go
beyond DSM-IV in terms of length of
illness and
degree of dysfunction in various spheres
of life.
Could you comment on that?
DR. MARCH: Sure, it is a very good
question.
That is, the exclusion criteria included
requirements that were designed to ensure
a stable
baseline.
So, we required at least six weeks of
mood disorder symptoms that crossed two
or three
contexts--home, peers in school--which,
of course,
are not required in the DSM-IV
criteria. This was
done in part to minimize the chance of a
placebo
103
response and to ensure that we had a sick
patient
population that would be both ethical to
randomize
and would offer some opportunity for the
combination treatment to separate from
the two
monotherapy conditions.
I think we actually designed a
very good
experiment, and looking at a 35 percent
placebo
response rate did exactly what we had
intended to
do.
But in that sense, this population is sicker
perhaps than what is seen in the industry
data sets
and certainly sicker than what is seen in
the CBT
data sets on average.
DR. GOODMAN: I will permit two final
questions and that is it, one from Dr.
Pine and
then Dr. Fant.
DR. PINE: I want to return to the first
question from Dr. Goodman as far as how
this study
would be evaluated from an FDA
perspective. My
sense from reading the paper is that
there were two
primary outcome measures and three
analyses, and
two of the three were positive so that
the CGI
analysis done categorically was positive,
the CDRS
104
analysis done categorically was positive,
and it
was only the third analysis, the CDRS
continuous
measure, that was not positive.
So, my take on that from an FDA
standpoint
of, you know, do the primary outcome
measures make
it or not is that it would be closer to
positive
than negative. Do I have that right?
DR. MARCH: You have it partially right.
There is a CDRS slope analysis, and
whether that is
positive or negative depends on whether
you treat
the intercept term as random. I mean, there is a
fair amount of method variance on a
subtle level
that can tilt these things one way or the
other
when it is a near miss. There is a CDRS endpoint
analysis based on the predicted or
marginal mean.
There is a categorical analysis, logistic
regression, and there is a self-report
scale which
was included, the Reynolds Adolescent
Depression
Scale, which was included because the CBT
literature relies heavily on patient
self-report.
Three of those four measures, all but the
CDRS
slope analysis, were positive for the
105
fluoxetine-placebo comparison. The CDRS slope
analysis, again, was a p value of 0.08, a
near
miss.
So, I think the take-home
message is
actually in the effect sizes, not in
whether you
are looking at p values or not. Clearly,
combination and fluoxetine have larger
effect
sizes, meaningful effect sizes relative
to placebo
as contrasted to CBT.
DR. FANT: For the sake of the study I
know it was necessary to exclude certain
patients
to optimize the conditions for the study,
but I
think in real-world practice a lot of the
patients
who were excluded would be patients who
would be
prescribed medication under various
conditions. Is
there any reason, from your standpoint or
perspective, to think that that
population of
patients may be at a different risk for
fulfilling
suicidal attempts, ideation, and carrying
it
through to the ultimate result, or may be
affected
differently by the medication than
patients that
are not excluded from the study?
106
DR. MARCH: That is a very good question.
That is, is there some issue to believe
that there
would be a differential treatment
response in
patients who would be excluded,
particularly
excluded for harm to self or others, as
compared to
the TADS sample of patients? I don't know of any a
priori reason to believe that there would
be a
differential treatment effect relative to
the TADS
sample.
I do think it is quite clear from the
treatment and epidemiologic literature
that they
would be at higher risk for adverse
harm-related
outcomes but whether they would be more
at risk
than, say, the TADS sample patient I
don't think we
know.
My guess as a clinician is probably not.
We are actually doing an
NIMH-funded study
called the Treatment of Adolescent
Suicide
Attempter Study, in which we are
comparing a
medication algorithm to cognitive
behavioral
psychotherapy to the combination--no
untreated
control condition obviously in this
sample--to try
to understand something about treatment
for this
particular patient population precisely
because
107
they have been excluded from these other
trials,
and we need additional data on their
care. So,
that trial is now under way and should be
completed
in the next couple of years.
DR. GOODMAN: Thank you very much, John.
The final question that I will take the
chairman's
privilege to ask is do you have data that
you
haven't presented yet on long-term
outcome based on
this trial?
DR. MARCH: The final subjects in the
trial are out in a naturalistic follow-up
window so
that 36-week data is in the can, but that
data set
has not been cleaned and locked yet. We expect it
will be cleaned and locked and ready for
analysis
in the spring, and we hope to have that
data in
press by this time next year.
DR. GOODMAN: Thank you very much, John.
DR. MARCH: Thank you.
DR. GOODMAN: I would like to ask our next
speaker to come forward, Dr. Greg
Dubitsky.
Characteristics of Pediatric
Antidepressant Trials
DR. DUBITSKY: Good morning.
You just
108
heard about the TADS trial from Dr.
March. I would
like to now go on and briefly summarize
the other
studies that were included in the FDA's
primary
analysis of suicidality.
I do want to emphasize that my
review and
this presentation are really descriptive
only. I
am not going to touch on efficacy
outcomes or
safety outcomes. The discussion of the risk of
suicidality in these trials with be
presented later
this morning by Dr. Hammad.
The study pool, again excluding
the TADS
study, consisted of 23 placebo-controlled
studies
which were conducted between 1984 and
2001. Each
study was done with one of nine different
antidepressant drugs and studied patients
with one
of five different diagnostic indications;
major
depression, obsessive compulsive
disorder,
generalized anxiety disorder, social
anxiety
disorder or attention deficit disorder.
These studies all had some
features in
common.
They were all randomized, double-blind,
placebo-controlled. They utilized a parallel group
109
design and a flexible dosing regimen.
I did prepare a handout to go
with this
talk which should be in your packets, at
least for
the advisory committee members. It consists of two
tables which summarize some of the design
characteristics of these 23 studies. Table 1 has
some basic study information, to include
the
diagnostic indication, the age range that
was
studied, number of patients by treatment
group, the
duration of double-blind treatment, and
the dose
range that was used in the particular
study.
I would like to point out
though that I
don't intend for everybody to read this
and
memorize it; this is really for reference
for later
this morning when you hear about the
analysis of
these trials.
The second table in the handout
includes
some information on screening and
exclusionary
criteria.
Some of the studies used very extensive
diagnostic screening. I have indicated those in
the table. I have also indicated information on
whether there was a placebo lead-in, and
also
110
whether certain exclusionary criteria were
employed
in the various studies to include whether
people
were excluded who had a history of
treatment
resistance, current suicide risk, history
of a
suicide attempt, bipolar disorder, or
family
history of bipolar disorder.
My review of these studies did
include a
number of other variables. I have listed in these
two tables the most relevant ones but in
my review
that is on the Internet I do describe
some other
characteristics which you might be
interested in,
such as the location and number of sites,
whether
stratified randomization by age group was
utilized
and other exclusionary criteria such as
homicidal
risk or the presence of psychotic symptoms.
There were a few notable
differences
between these studies that I would like
to point
out.
One study with Prozac, HCCJ, was a very small
study.
It was the smallest of the 23 studies, with
only about 40 patients and it was
terminated early.
Only one of the 23 studies
included an
active control arm. That was study 329 with Paxil
111
in major depressive disorder. That included an
imipramine control arm. The others only had a
placebo control.
Two of the studies did include
inpatients
as well as outpatients, the Celexa study,
94404,
and Wellbutrin, 75.
Last, I did want to point out
that three
of the studies did use a rather extensive
diagnostic screening of the patients,
much more so
than the other studies, Prozac studies
X065 and
HCJE, and Paxil study 329. Those three studies
were done in major depressive disorder.
One other difference involves
the
treatment options after patients
completed the
acute phase of double-blind
treatment. This was
quite variable across the trials. In eight studies
there was a taper of acute treatment
before
discontinuation. Seven other trials just abruptly
discontinued treatment, and there was no
provision
for continued treatment. Five trials did allow for
continuation of open-label treatment, and
in three
trials patients could continue
double-blind
112
treatment.
However, this was also very
variable
within trials. For instance, in Paxil 329
responders could continue double-blind
treatment
but non-responders were tapered off
treatment.
This variability in the follow-up
treatment
following the acute phase made it very
difficult to
do any analysis of suicidality-related
events post
double-blind treatment.
I would like to point out that
none of
these studies was specifically designed
to assess
suicidality. Suicide attempts and ideation were
detected only through routine safety
monitoring,
that is, through treatment emergent
adverse events
and through suicide-related items on
various
depression scales, such as the HAM-D and
the CDRS.
One problem with this is that often
descriptions of
possibly suicide-related events were
rather vague
or incomplete and often made it difficult
to reach
a classification.
I have no specific conclusions
since this
is really a descriptive review and
overview of the
113
studies.
I think one of the important questions
that arises from this information though
is whether
any of these differences in design
characteristics
could contribute to any observed
differences in
suicidality risk that we observed across
these
studies.
That is a question that will be addressed
later this morning by my colleague, Dr.
Hammad.
So, that is all I have.
DR. GOODMAN: Thank you for being concise
and providing us with an outstanding
handout for
our reference. We have one question. Dr.
Rudorfer?
DR. RUDORFER: Thank you.
Could you
clarify, of the 23 trials how many were
submitted
in response to the pediatric exclusivity
rule?
DR. DUBITSKY: I don't have the exact
number.
I believe most of them were but some of
them were submitted well before pediatric
exclusivity took place or came into
effect. I
don't have the exact number off the top
of my head.
DR. GOODMAN: Dr. O'Fallon?
DR. O'FALLON: Asking the question in a
114
somewhat different way, the data that you
have for
this reanalysis, does any of that data
come from
outside, beyond the data that was
submitted to the
FDA?
That is, were you able to go in and obtain
data from studies that were never
submitted to the
FDA for approval or whatever?
DR. DUBITSKY: Well, to my knowledge,
there was one study that had not been
submitted as
part of an efficacy supplement or an approval
package.
The other ones, I believe, were.
Dr.
Hammad actually requested data sets for
all these
studies.
Correct me if I am wrong, but I believe
we had relatively complete data sets to
allow
reasonable analysis for all these
studies.
DR. O'FALLON: But I am asking whether
there are, as some are claiming, studies
that were
done but were never submitted to the
FDA. Are
there any of those data here, if they
exist?
DR. DUBITSKY: There are some studies that
are not included in this analysis, but
those are
mainly open-label continuation studies of
the acute
studies.
Also, there were a number of pediatric
115
pharmacokinetic studies but I think for
obvious
reasons we didn't include those in the
analysis.
But, to my knowledge, I think we have
everything.
DR. GOODMAN: Dr. Laughren, do you also
want to respond to the question?
DR. LAUGHREN: I think I can respond to
that.
The vast majority of these programs were
submitted under pediatric exclusivity so
the
companies were required to submit every
scrap of
data they had as part of those
supplements. The
only trial here that was not submitted as
part of
an application, in terms of a company
trial, was
the ADHD study for Wellbutrin. The other study
that we have included safety data for is
the TADS
trial and, of course, that was also
independent.
But those are the only two trials of the
24 that we
looked at that were not submitted as part
of an
application.
DR. GOODMAN: Dr. Marangell?
DR. MARANGELL: How many of the studies
excluded family history of bipolar
disorder?
DR. DUBITSKY: Let's see, actually I think
116
I
have that in table 2. I don't know the
number
off the top of my head. It looks like about ten of
the studies excluded a family history of
bipolar
disorder.
DR. MARANGELL: Thank you.
DR. GOODMAN: Dr. Perrin?
DR. PERRIN: You are saying basically that
the extensive diagnostic screening
occurred only in
three studies, I believe. Is that right?
DR. DUBITSKY: I am sorry?
DR. PERRIN: The extensive diagnostic
screening occurred only I think in three
studies--one of the points that you
made. Does
that give us some information about the
potential
diagnostic heterogeneity and also raise
questions
about whether entrance into these studies
of
children, ages 7-17, might not have had
MDD in the
MDD studies? My last related question is, since I
am not a psychiatrist at all, what do we
know about
the ability to distinguish bipolar disorder
from
MDD in the 7-17 year-olds?
DR. DUBITSKY: Well, it is true that in
117
looking across all 23 studies, those
three studies
did stand out as far as using more
extensive
diagnostic criteria. I believe that it certainly
is possible that we might have more
confidence that
those patients did actually have the
diagnosis
under consideration. Whether that is actually true
or not, I don't know and I don't know any
good way
of figuring that out.
I am not a child psychiatrist
so I can't
answer your last question about the
ability to
diagnose.
I understand it is very tricky though.
DR. GOODMAN: Thank you again. I would
like to ask Dr. Kelly Posner to come up
to the
podium to present. Dr. Posner is from Columbia
University and she will be talking to us
about the
reclassification of the clinical trials
data
according to suicidality.
Classification of Suicidality
Events
DR. POSNER: I would like to start by
introducing my expert work group from
Columbia that
included myself, Dr. Maria Oquendo, Dr.
Barbara
Stanley and Dr. Madelyn Gould. Dr. Stanley and Dr.
118
Gould are here with me today. Our statistical
consultant was Mark Davies.
Why was reclassification needed? The
problem is that the field is challenged
by a lack
of well-defined terminology and common
language to
refer to suicidal behavior, and this was
reflected
in the lack of standardized language used
in the 25
trials in question. That is why there was
difficulty in interpreting the meaning of
all of
these reported adverse events that
occurred in
these trials. So, AEs that should have been called
suicidal may have been missed and there
may have
been AEs that were inappropriately
classified as
suicidal.
Here are some illustrative
examples of the
difficulties in adverse event labeling in
the
field.
I want to make sure to note that these
labels have nothing to do with the labels
the
sponsor gave these events, but just
original
investigators at the site. Again, they are extreme
examples just to reflect the problem.
You see the first one, it says
patient
119
attempted to hang himself with a rope
after a
dispute with his father. Investigator did not
consider this event to be a suicide
attempt but
called it a personality disorder in this
10
year-old patient.
The second one is one we have
all heard a
lot about. The patient is reported to have engaged
in an episode of auto-mutilation where
she slapped
herself in the face, called a suicide
event. Then,
the patient took 11 tablets impulsively
then went
to school--called a medication error.
So, how do we address this
problem? Well,
a common set of guidelines needed to be
applied and
we needed to look at the data
consistently across
trials using research-supported
definitions and
concepts that had reliability and
validity. We
also needed to broaden the range of
adverse events
that we were looking at. This was for two reasons.
The first one is to avoid bias in
readings. We
wouldn't have wanted the expert raters
only to have
had what the sponsors had identified as
possibly
suicidal.
Also, to identify suicidal events that
120
may have been missed.
So, what was included in this
broadened
range of events? Of course, the events originally
identified by the sponsors as possibly
suicide
related, all accidental injuries which
included
accidental overdoses, and serious adverse
events
which includes life-threatening events
and all
hospitalizations.
Why did we need experts in
suicide? Well,
you all heard about the limited
information
provided in the narratives, particularly
frequent
lack of stated suicidal intent. So, only experts
in suicide would have allowed for
inference based
on
details of behaviors and related clinical
information.
This is the list of our very
distinguished
international panel of experts. I will just read
their names very quickly, Drs. Bautrais,
Brent,
Brown, Van Herringen, King, Mazark,
O'Carroll,
Rudd, Spirido and Miller.
So, what was the Columbia
classification?
I want to move to this slide because it
goes
121
through the definitions which I will just go
through briefly. Suicide attempt, of course, which
is defined as a self-injurious behavior
associated
with some intent to die. Intent can be stated or
inferred by the rater. It is important to know
that no injury is needed.
Then there was preparatory
actions towards
imminent suicidal behavior. So, the person takes
steps to injure himself but is stopped by
self or
other, anything beyond the threshold of a
verbalization but not quite making it to
a suicide
attempt.
Then we had self-injury
behavior, intent
unknown.
These are cases where we know there was
some self-injury but we don't know what the
intent
was.
So, the associated intent to die is unclear
and cannot be inferred.
Self-injurious behavior with no
suicidal
intent is the next category. That is where, again,
we know there was deliberate self-harm
but there
was no intent to die so behavior is
intended to
affect other things. This is what we think of
122
self-mutilation typically.
Suicidal ideation was the next
relevant
category, which can be passive or active
thoughts,
passive thoughts of wanting to be dead or
active
thoughts about killing oneself.
Then we had all the other
categories.
That is essentially one rating, anything
other than
deliberate self-harm or something
suicidal. That
could include accidents, psychiatric
events or
medical events.
Finally, we had not enough
information,
which meant that there was insufficient
information
for a rater to be able to say whether or
not there
was some deliberate self-harm or
something
suicidal.
The scheme is laid out
conceptually here
for you.
I think it helps make a little more sense
of it.
The blue boxes refer to what you will hear
later as the FDA's primary outcome. These are
ratings that are considered definitively
suicidal,
suicidal behavior and suicidal
ideation. You see
codes 1, 2 and 6. Suicide attempt, preparatory
123
actions and ideation. The next are non-suicidal
events, all the other events and the
self-injurious
behavior without suicidal intent, and
then
indeterminants. The green boxes are what will be
referred to as the sensitivity analysis,
things
that could have been suicidal but there
is no way
to know.
So, what was done? The classification
methodology involved, of course, choosing
the
expert panel who had expertise in
adolescent
suicide and suicide assessment, based on
reputation
and publications. They had no involvement in
industry youth depression trials in
question, and
no expert rater was employed by Columbia
University.
We had a training
teleconference to review
classification parameters, then training
reliability exercise to ensure
appropriate
application of classifications. All case
narratives were blinded to any
potentially biasing
information, and I will review that in a
minute.
There was random distribution of 427
events to 9
124
expert raters. Each case was independently rated
by 3 raters. Each rater received approximately 125
events to rate, and any group of 3 raters
shared
only 5 cases. All ratings were reviewed for
quality assurance and identification of
non-agreement cases. Consensus teleconferences
were held for any disagreement cases, and
there was
double data entry for quality assurance.
Now, what was the consensus
process I
referred to? If ratings did not have unanimous
agreement, then a consensus discussion
was held.
Each case was discussed by the three
raters
involved only. Discussion of each case was led by
an expert other than those originally
assigned the
case.
The goal of the discussion was to reach 100
percent agreement. If 100 percent agreement could
not be reached, the case then became
indeterminate.
Sometimes the original majority opinion
did not
always end up as the final consensed
classification. In other words, if there was a
minority rating, sometimes that ended up
being the
final outcome.
125
Now, what was rated? Blinding of event
narratives to avoid bias included--we
received the
narratives from the FDA blind to all
potential drug
identifying information. This included drug name,
company sponsor name, patient
identification
numbers, whether they were on an active
or placebo
arm, and any and all medication names and
types
because there could be associated
treatments that
might bias somebody or tip them off as to
what drug
was
being talked about and, of course, primary
diagnosis. We also did some additional blinding of
potentially biasing information which
included the
original label of the event given by the
investigator or sponsor and serious or
non-serious
labels.
Rating guidelines--how was the
classification scheme applied? We wanted the
experts to apply concepts using their
clinical
expertise and judgment; to use their
experience to
integrate clinical information and infer
when
appropriate. We wanted them to have a reasonable
certainty in order to commit to a rating,
and
126
rating was based on what was probable,
not what was
possible.
The guidelines for intent
inference
involved inferring if something was
clinically
impressive, and I am going to give you an
example
of that in a moment, or using two smaller
pieces of
clinical information. The clinical information
that could inform inference of intent
included
clinical circumstances. That could be method used,
number of pills; past history of suicide
attempt;
past history of self-injurious behavior
or
self-mutilation; and family history of
suicide or
suicide attempts.
Now, here is a case example of
inferred
intent, what we call clinically
impressive
circumstances. This is the first time you are
actually seeing one of these real
narratives. In
this case clinical impressiveness
actually
overruled stated intent, so you see the
subject
attempted suicide by immolation. Her siblings
doused the flames immediately. She was left with
minor burns on her abdomen and on her
left
127
shoulder.
The subject admitted she was angry with
her parents for going away and leaving her
alone at
home because she was fearful. The subject admitted
that she had acted impulsively and had
not intended
to kill herself.
Here are more examples. This is another
example actually of clinically impressive
circumstances which was ultimately called
a suicide
attempt.
It is also important to know that we had
no idea what the sponsor ratings were but
both
these cases were consistent with what the
sponsor
had said as well.
This case involved a 16
year-old who
claimed to have ingested 100 tablets of
study med
after a fight with her mother. The patient
informed her mother. The mother brought her to the
ER.
The patient reported feeling shaky.
Emergency
room physician said she was slightly
tachycardic
with a pulse of 100. The tox. screen was negative
but the patient did have some illness and
she
stayed in the ER until she was
asymptomatic, and
then was later admitted to the psych. unit.
128
Another example of a suicide
attempt, a
patient age 17 took an overdose of 20
tablets. In
the father's opinion the overdose was 5
tablets.
The patient didn't have any symptoms of
an
overdose, not even nausea, but it was
classified as
a suicide attempt, of course.
More overdose examples. You see in this
first example there were 113 tablets and
it
exemplifies how medication types were
blinded so
you see all the different numbers
there. Then, the
next one is patient aged 15, impulsively
slit her
wrist following an altercation with her
mother.
Finally, age 17, attempted suicide by
taking 8
tablets after a fight with her father,
whom she
considered harsh and rejecting.
Now, these are examples of
self-injurious
behavior, intent unknown. So, this is where we did
some harm but we just don't know
why. A patient
aged 10 had superficial scratches, left
arm,
scratched herself with scissors. That was all the
information that was there essentially.
Patient, aged 14, ingested or
simulated
129
ingestion of 2-3 cigarettes. The patient was
reported as feeling tired and playing a
theatrical
role.
Subject, aged 9, reported he had ingested 4
of his brother's tablets on a dare. Finally,
patient, aged 10, swallowed a small
amount of
after-shave lotion while angry. It is hard to know
what to make of those without
information.
Examples of preparatory
actions, age 16,
tried to hand herself and was prevented
from doing
so by her family. The next case, age 18, a voice
commanded him to jump from the roof. Although he
went up, he did not jump. Next one, age 10, held a
kitchen knife to her neck while alone but
did not
cut herself. Event was not witnessed. Finally, a
patient, age 18, was noted to be hostile,
hopeless
and helpless and had written suicide
notes. As I
said, anything beyond a verbalization was
considered a preparatory action,
including writing
a suicide note.
These are good examples of
self-injurious
behavior, no suicidal intent. In the first case
the patient stated there was increased
family
130
tension.
She made superficial cuts on her wrist
with an Exacto knife. The patient and mother
reported the cuts weren't deep and they
looked like
cat
scratches. Patient adamantly denied any
suicidal gestures or intent. She stated she only
wanted a release and that cutting and
hitting her
legs offers her a release.
The second case, denied
suicidal thoughts.
The first time she cut herself was age
16. She
stated she did it for attention. Today her cutting
was more spontaneous. She reported that
cutting
gives her a good weird feeling.
So, what were the results? This slide
just refers to what we are talking to in
our
results, or referring to, and there were
427 events
but some patients had more than one event
so we
ultimately, in the reliability data, used
378
cases.
We employed the same severity hierarchy
that the FDA used. So, we just took the most
severe event for cases that had multiple
events.
Expert rater consensus--only
two of 427
cases had no agreement among the three
raters. So,
131
each rater had a different rating in only
two
cases.
Fifty-nine cases had agreement among two of
three raters, and those had to go to
teleconference. There were no cases in which
consensus was not able to be reached
during the
teleconference and they, of course, had
that
option.
Now, discordant cases between
the sponsor
and Columbia classifications, there were
40 out of
the 427 cases in which the sponsor and
the Columbia
classification differed. Twenty-six new cases were
identified that had not been identified
by the
sponsor as possibly suicide-related. There were
two new cases of self-injurious behavior
without
suicidal intent that had been labeled
something
other than deliberate self-harm, and 12
cases were
originally called possibly suicidal and
were
changed to something other than possibly
suicidal.
Here it breaks it down for you
further.
Of the 26 new possibly suicide-related
events, one
was a suicide attempt; one was a
preparatory act;
13 were ideation events; four were intent
unknown
132
acts; and seven were not enough
information to say
whether there was deliberate self-harm.
Here is an example of one of
the newly
identified suicidal events. This is a preparatory
act.
The patient, age 11, held a knife to his
wrist and threatened to harm
himself. The patient
was hospitalized with an acute
exacerbation of
major depressive disorder. The reason we have this
is because, as I mentioned before, every
hospitalization is a serious adverse
event so that
is why this preparatory act was caught.
The events that were changed
from suicidal
to something other included two changed
to
psychiatric; one changed to an accident;
and nine
changed to self-injurious behavior with
no suicidal
intent.
Again, our famous example, a patient
reported to have engaged in an episode of
auto-mutilation where she slapped herself
in the
face.
The event resolved the same day without any
intervention.
These are actually the kappa,
the
agreement between the sponsor and
Columbia. So,
133
Columbia's classification of possibly
suicide-related and the sponsor's
classification of
possibly suicide-related, the kappa was
0.77. You
see in the 2 X 2 table that the numbers
correspond
to the numbers that I just went through
with you.
Now, if you want to look
somewhat more
specifically or at least what we think is
more
specific, we did a comparison of what
Columbia said
was definitively suicidal and what the
sponsor said
was possibly suicidal, and the kappa was
0.69.
Here are the reliability
results of the
ratings with the nine expert raters. The median
ICC was 0.86 and what the FDA will refer
to as the
primary outcome variables, you can see
the numbers
here, suicide attempts is 0.81;
preparatory
actions, 0.89; suicidal ideation, 0.97.
Where do we go from here? We need to
improve our adverse event reporting for
suicide-related events by developing
consistent
terminology; developing guidelines for
classification of suicidality so that
adequate
information is provided by the clinician;
134
utilization of research assessment tools,
what
questions to ask, how to ask, and what
measures aid
this; finally, hopefully, that will lead
to
improved, more valid identification and
documentation of suicidality.
DR. GOODMAN: Thank you very much. Dr.
Chesney?
DR. CHESNEY: Thank you.
This is a little
bit of thinking outside the box, but we
heard at
the February meeting a number of examples
of
homicidal behavior. I wonder if, in your
speciality, homicidal behavior is ever
identified
as being self-injurious primarily to
affect
circumstance or to affect an internal
state.
DR. POSNER: No, that did not represent
any of those self-injurious, no suicidal
intent
ratings.
So, the classifications that you are
referring to, internal state and
circumstance, are
not synonymous at all with the cases that
had
homicidal ideation or any kind of
aggressive
behavior.
It doesn't mean that it couldn't be
looked at in another analysis but it
wasn't
135
represented in these cases.
DR. CHESNEY: I guess my more general
question, I just wonder in the bigger
question,
homicidal behavior outcome is bound to be
bad and
self-injurious, and if it is just another
factor
that we should consider in this whole
picture.
Thank you.
DR. GOODMAN: Dr. Robinson?
DR. ROBINSON: Do you know how many of the
events led to hospitalization and how it
breaks
down in terms of your classification?
DR. POSNER: Dr. Laughren, do you know?
DR. LAUGHREN: I don't have that figure
off the top of my head. There were a substantial
number of events leading to
hospitalization, I
believe somewhere in the ballpark of
maybe 40
percent.
I don't have the exact number. It
was a
common outcome.
DR. POSNER: It is important to know that
we were very narrowly just looking at
obtaining the
most appropriate label for the particular
event in
question, and we didn't have any of the
surrounding
136
information or follow-up information in
this
particular piece of the project.
DR. GOODMAN: Dr. Wang?
DR. WANG: I have a question. Do you know
how many of the sponsors originally
submitted
reports that were categorized as
serious? The
reason I am asking is to get a sense of
how many
cases may not have been originally
reported. I
know you had these serious cases sent to
you for
adjudication, just to check in case there
were
cases that were being missed in what the
sponsors
were reporting, but did you look as to
how many
cases were not considered serious by the
sponsor,
jut
to give us a sense of how many may be sort of
out there in the non-serious pool?
DR. POSNER: Again, we were blinded to
sponsors' classifications throughout the
entire
process.
I don't know if somebody from the FDA can
answer that question for you.
DR. LAUGHREN: Again just a ballpark
figure, I think it is probably somewhere
in the
vicinity of maybe 65-70 percent. But you have to
137
understand that a designation of serious
is a
judgment that is made by the sponsor
fairly
subjectively. I mean, there are criteria for
regulatory serious. It is fatal, life-threatening,
seriously disabling, leading to inpatient
hospitalization. But even though, you know, that
on face appears to be fairly definitive,
sponsors
in many cases, in my view, made the
judgment that
if it was considered to be suicide-related
it was,
by definition, serious.
So, if you look at many of the
narratives
that were classified as serious, I think
no
reasonable person looking at those would
consider
that, in a common sense notion, as a serious
event.
But the point is that that
designation--how that
judgment was made varied from sponsor to
sponsor.
So, you know, some of them classified
many more of
the events as serious than other
sponsors. But the
answer to the question is that overall
roughly
two-thirds of these events that were
included in
the analysis were designated as
regulatory serious.
DR. GOODMAN: Ms. Griffith?
138
MS. GRIFFITH: I have a question about
cutting specifically. It seems to me that most of
the examples of cutting fall into
self-injurious
behavior, intent unknown or
self-injurious behavior
with no intent. I am just curious as to are you
confident that the reporting that you
received and
reviewed actually got to whether or not
there was
intent or no intent, and how subjective
is the
reporting likely to be?
DR. POSNER:
Again, as you can see,
cutting is a method that is used both in
suicidal
behavior and self-injurious behavior
without
suicidal intent. If you remember the conceptual
scheme, there was the category
self-injurious
behavior, intent unknown, because cutting
can be
used both ways. I forget the exact number but
there were 20-something cases in which
they cut but
we don't know if it was suicidal or
not. That is
why we had to come up with a category
just to
categorize and deal with that issue. The FDA will
point out that the included that in the
sensitivity
analysis so just in case all of those
were
139
suicide-related events, they have those
numbers.
DR. LAUGHREN: If the question you are
asking were the narratives lacking in
detail, they
absolutely were. These were not by any sense
complete descriptions. Ideally, many more
questions would have been asked when
these events
occurred to help flesh them out. That is why it
was necessary to use inference as one
approach to
try and get at intent because intent was
not
included for the vast majority of these.
DR. POSNER: Which is why only experts in
the field could have been able to infer
from the
surrounding information. The narratives were
limited with respect to suicidal intent
often but
there was significant surrounding
information for
the expert raters to be able to infer
from in many
cases.
DR. GOODMAN: Thank you, Dr. Posner. I
would like to welcome Dr. Solomon Iyasu,
from the
FDA, who will be presenting what I think
is a
vetting of the sample to establish
reliability and
validity of the classification system.
140
OCTAP Appraisal of
Columbia
Classification
Methodology
DR. IYASU: Good morning.
I am going to
be speaking about the appraisal that we
did
regarding the classification scheme of
Columbia
University.
In my discussion today I will give you
a
brief background and then give you what
the
objectives of the FDA audit or appraisal
were.
Then I will describe briefly the methods
that were
used and also present the results of the
audit and,
finally, discuss the limitations and the
strengths
of the methodology and give some
conclusions
regarding our appraisal.
I just want to make clear that
the
objective of the FDA appraisal of the Columbia
methodology was really to assess how
reproducible
or reliable the methodology is. The objective was
not to assess the validity of the
methodology or
the scale as we cannot really test it
against a
gold standard which is not available
right now.
So, I just wanted to make sure that the
audience
141
understand that this is really to assess
reliability.
Just like Columbia, we reviewed
all the
sponsor-submitted event narratives. They included
all the original ones as well as the
subsequently
requested narratives. The FDA team also reviewed a
computerized line-listing of these event
narratives
and from the review we drew a sample from
those
that were appraised or rated by Columbia.
In our methodology we grouped
the event
narratives that were submitted into four
predefined
strata, and then we selected event
narratives from
the various strata via a stratified
simple random
sampling scheme. We over-sampled for difficult to
classify and reclassified events.
Stratum 1 is defined as events
reclassified by Columbia to non-suicidal
or other
events.
Stratum 2 was defined as events newly
identified or classified by Columbia as
possibly
suicide related or other categories. Stratum 3 is
events that were difficult to classify as
defined
as events with discordant initial
independent
142
ratings by the Columbia reviewers. Then the last
stratum was events that are the
straightforward
cases that were concordant among all
reviewers in
the Columbia rating.
We had 64 sample records out of
423. You
notice that it is only 423 because some
events were
in active control and were not included
in our
review, unlike the Columbia group. We included 2
events in stratum 1. We over-sampled and took
one-third each from stratum 2 and 3, and
then from
the last stratum, which were the
straightforward
cases, we only sampled one-tenth.
This slide just shows how collaborative
this process was. There was a planning group that
included individuals from the Division of
Pediatric
Drug Development and the Division of
Neuropharmacologic Drug Products, and then
the
Office of New Drugs. Clinical reviewers who served
as independent reviewers of the case
narratives
included two individuals, pediatricians,
from the
Office of Counter-Terrorism and Pediatric
Drug
Development, and then from the Division
of
143
Neuropharmacologic Drug Products one
pharmacist and
one other psychiatrist. None of these clinical
reviewers had previously been involved in
the
review of any of these narratives or the
trials.
We had a consensus process, similar to
what
Columbia did, that was facilitated by a
psychiatrist who was also not previously
involved
in any of the reviews.
Basically, we wanted to replicate the
training that was given to the Columbia
reviewers
so we had Dr. Kelly Posner provide a
similar
two-hour teleconference training to all
the review
team regarding the suicidality scale.
Each sampled event was randomly
assigned
to three of four reviewers for
independent and
blinded review. Therefore, each reviewer had 48
events to review, and we received a total
of 192
reviews from the four reviewers that we
had.
Reviewers were similarly blinded to
treatment
assignment, sponsor, diagnosis and also
to the
final Columbia ratings.
The planning group also wrote a
memo
144
outlining the procedures of the review to
all and
provided this to the audit team
members. Reviewers
were not allowed to discuss the events
among
themselves or with colleagues during the
independent review period. However, we did allow
reviewers to call Dr. Kelly Posner to
clarify the
classification scale or to obtain
clarification on
the scale, but no discussion of specifics
of any
case was allowed during this process.
We also required reviewers to
record on
the rating form if they consulted with
Columbia
during the review process. For recording the
ratings, we used a modified and pre-coded
rating
form which is shown here. The only difference is
that this is pre-recorded and includes
all the 12
event categories. At the bottom of the form is
where they would indicate if they did
consult with
Columbia.
The reviewers and the rating
scores were
returned to me in sealed envelopes and
these were
key-entered into an Excel database. Then we
identified the discordant ratings and
then these,
145
similar to the Columbia group, were taken
to a
consensus meeting which was facilitated
by a Board
certified childhood and adolescence
psychiatrist
who was external to the Division of
Neuropharmacologic Drugs, who was actually
from the
Division of Scientific
Investigations. This
individual had not been previously
involved in the
review of these records, as I mentioned
before.
The final consensus ratings
were again
entered into an Excel database and
compared to the
final Columbia ratings. Then, finally, discordant
ratings between FDA and Columbia were
discussed by
teleconference basically to understand
the reason
for the differences.
How did we assess the
concordance of
ratings among FDA reviewers, as well as
between FDA
and Columbia? With definition of concordance for
categories 1 through 3, 6 and 10 and we
required
that there be an exact match between the
two
reviewers. Then, for categories 4, 5 or 11, which
all describe essential self-injurious
behavior with
no suicidal intent, we considered them as
146
equivalent rating. We didn't need to differentiate
between these three. Lastly, categories 7, 8, 9 or
12, essentially other categories,
non-suicidal and
non-self-injurious behavior, are
considered
equivalent rating.
What were the results? Among the FDA
reviewers, of the 64 that were rated, 47
were
concordant among the three
reviewers. We had 17
that were discordant. These were taken to the
consensus meeting and, similar to
Columbia, we also
arrived at consensus ratings for all 17
events.
Once we got the final ratings
by the FDA
reviewers for the 64 sampled events, then
we
compared them to the final Columbia
ratings and 57
out of the 64 were concordant, which
gives us an
agreement rate of about 89 percent, with
a kappa of
0.84.
We did look at the discordant ratings, which
were number 7. We assessed severity hierarchy to
sort of analyze where the ratings
differed. In
general, compared to Columbia, the FDA audit
team
classified six out of the seven events
with a
higher severity score than Columbia, and
one event
147
was a lower severity. I must point out that three
of the six that were rated higher were
events that
were classified as not enough information
or other,
so not really pertinent to the
suicidality events.
I will point out now the limitations. In
this audit neither the quality of the
narratives
nor the clinical source material for the
narratives
were evaluated. Secondly, the validity of the
Columbia classification method was not
assessed as
this was not the objective, and there is
also no
gold standard to compare it to.
The strengths are that despite
the
differences in expertise and experience
between the
two groups of reviewers and the short
time line
that we had for training and review, and
finally,
more importantly, intentionally
over-sampling is
difficult to classify events for review,
we
achieved a very high level of concordance
between
the reviewers.
Therefore, from this activity
we concluded
that the Columbia suicidality
classification
methodology is robust and reproducible
when used by
148
a non-expert group to classify a similar
group of
events.
Finally, I would like to
acknowledge the
team of auditors who participated in this
review
from OCTAP, DNDP, DSI and OND, and also I
would
like to acknowledge the contribution of
Kelly
Posner in terms of the training and
classification
scales.
Thank you.
DR. GOODMAN: Thank you very much. I
would now like to take a short
break. I am sorry,
I missed somebody who had a question.
DR. PERRIN:
Thank you. I just wonder
whether you know whether the five or six
discrepancies between the Columbia review
and the
FDA review might have been highly
represented among
the cases that were considered cutting in
the last
presentation, or were ones that were
reclassified
by Columbia as non-suicidal from the
original
industry reports.
DR. IYASU: Well, there were seven
discordant ratings, as I mentioned
before. Three
of
them were classified by the FDA reviewers to a
149
10, which is not enough information, from
a
category that was other. So, if you look at the
severity hierarchy it sort of went
towards the more
severe hierarchy because 10 represents
not enough
information; not sure whether there is
deliberate
self-harm or self-injurious
behavior. So, when you
are not sure you put them in that
category.
In the other cases, I actually
have a
slide to show the cases that were
discordant. I
talked about the cases where not enough
information
was classified from a 12 and 7. But for those that
were important, critical elements in
terms of the
suicidality event, there were four and
the FDA
group rated one as a suicide attempt from
a
Columbia group that was self-injurious
behavior,
intent unknown. Then there was a second one,
self-injurious behavior according to the
reviewers,
and a 10 which was not enough information
from
Columbia.
Finally, there was a suicide ideation
versus psychiatric.
But we don't consider this to
be critical
in terms of numbers because the objective
was not
150
really to test the validity of one
classification
as opposed to another one. It was really to test
how reproducible it was so we are not
really making
a statement as to which one really
measures
suicidality.
DR. POSNER: The final case that you
didn't talk about, the negative severity
bias, was
one in which your raters called it
self-injurious
behavior, intent unknown and we called it
a suicide
attempt--
DR. IYASU: Exactly.
DR. POSNER: --which was the only suicide
attempt and we rated it as more
severe. I think,
you know, it is just worth noting all of
them.
DR. IYASU: Yes, that is right.
DR. GOODMAN: Thank you.
I wish to remind
the committee members not to discuss any
elements
of today's presentations among yourselves
during
the break. We will reconvene promptly at eleven
o'clock so that doesn't give you much
time to get
back here for a very important
presentation by Dr.
Hammad.
151
[Brief recess]
DR. GOODMAN: Anuja Patel has some
clarification points for tomorrow's
agenda.
MS. PATEL: We have been receiving a lot
of inquiries regarding the times for
tomorrow's
meeting and I just want to clarify that
the Federal
Register Notice does state that the
meeting will
begin promptly at eight o'clock in the
morning, and
it is scheduled to end at approximately
5:00 p.m.
tomorrow.
If you look at the agenda, it is pretty
much deliberations for tomorrow. There is no
saying whether we will end earlier or
not. So, if
you are making flight arrangement plans,
I do
encourage you to go ahead and make your
arrangements for after five o'clock just
to be
safe.
So, I just wanted to make that clarification
for tomorrow's agenda. Thank you.
DR. GOODMAN: I am hoping that, at the
current rate, we will be able to break
for lunch at
12:15.
So, that is my intermediate goal this
morning.
I would like to introduce our
next
152
speaker, Dr. Hammad, from the FDA, and
this is one
of
the key presentations before the committee this
morning, involving a reanalysis of the
clinical
trials data following the
reclassification of
suicidality.
Results of the Analysis of
Suicidality in Pediatric
Trials of Newer Antidepressants
DR. HAMMAD: Good morning, everyone. I am
here today to share with you the results
of our
analysis of suicidality in pediatric
trials of
antidepressants. These are the elements that I
will cover in my presentation. After a brief
statement of our objective, I will
describe the
data that we requested and then I will
give you the
highlights of the findings before I go
over some of
the limitations of the current
investigation. Then
I will give you an overall summary of the
findings.
Our objective was to
investigate the
relationship between antidepressants and
pediatric
suicidality based on the adverse events
reported,
as well as the suicidality item scores in
pertinent
depression questionnaires. So, it is important to
153
keep in mind that we will be dealing with
two
different sets of outcomes, and I will draw
your
attention to that again at the
transition.
First, our data came from 25
clinical
trials in nine drug development programs,
in
addition to the TADS trial. Here is a list of the
drugs and number of trials involving each
drug. At
first glance you will notice that there
are
differences between the available trials
for each
drug, which have an implication actually
for our
ability to observe the event of interest.
Here are the indications that
these trials
were conducted in. As you can see, the majority of
trials were done in depression
patients. Two
trials were excluded, one because it was
a relapse
prevention trial and the other was simply
uncontrolled. So, we ended with 23 available
trials in addition to the TADS
trial. All trials
were comparable in design. They were all parallel,
controlled trials.
Although trials started in the '80s, I
think one trial or two, the majority were
conducted
154
in the late '90s and TADS was, of course,
in '04.
The duration of treatment ranged from
4-16 weeks.
In the next section I will
focus on the
findings first for outcomes based on the
adverse
events, the ones that you see here. I will go over
them in detail. Then, the ones that were based on
the suicidality scores.
That is the first set of
outcomes. These
are four outcomes that we examined; these
are the
main outcomes we examined. The first outcome we
called suicidal behavior and it included
cause 1
and 2 from the Columbia
classification. You can
see here the details of what 1 means and
what 2
means.
As you notice, this will stay up all the
time so you will be able to have a chance
to go
back and see what everything means.
The second outcome was suicidal
ideation.
It includes code 6. You have 33 events here and 45
events here. Putting them together, we came up
with outcome 3, which was the primary
focus of the
analysis.
This is simply the combination between
number 1 and number 2. It had codes 1, 2 and 6.
155
So, it ended up with 78 events.
The so-called outcome 4, to
construct that
we added two more types of events, code 3
and code
10.
Just to remind you, code 3 meant suicidal
injury with intent unknown, and code 10
meant there
was some injury but there was no
information to
help determine what the intent was. So, this is
sort of considered the worst-case
scenario and it
was used in the sensitivity analysis for
the
primary outcome. The reason we chose this as a
primary outcome--it was chosen a priori--is
because
it is the most pertinent and the one
least likely
to be subject to dilution because of
misclassification.
I will take you step by step
over the
events from the time that we sent them to
the
Columbia group. We sent them 427 adverse events.
We ended with 260 that were coded as
"other" that
are not really pertinent to the
analysis. Don't be
surprised by the magnitude of the
number. The
reason is because we cast a very wide web
to start
with to be able to capture every possible
event.
156
So, we ended with 167 potential events
with those
particular codes.
Those events boil down to 141
unique
patients because many patients had more
than one
event.
Among those, we chose the most severe
events.
For example, if a patient had an event
that was coded as 6 and an event that was
coded as
4,
then this particular patient would be labeled
with the most severe event.
Among those, we ended up with
21 that were
not eligible. The eligibility here is determined
by when the event occurred. If it occurred within
the double-blind period, then we
considered it
eligible.
If it was outside, then it was not
eligible.
So, we ended with 120 eligible.
Among
the eligible, we had 109 that were
pertinent, that
were suicidal related. You notice what is missing
from here are codes 4, 5 and 11 which are
self-injury but the intent is known not
to be
suicidal.
So, they were not pertinent to the
analysis.
We ended up with 109. You notice
a few
discrepancies between some of the numbers
because
157
it depends on if we are looking in the
window or
outside the window. So, don't worry about the few
discrepancies here and there.
I showed you on the previous
slide how we
ended up with 109 events. These 109 events were
not exactly the same events that the
sponsor
reported initially. So, in this light, I will walk
you through the disposition of the
sponsor original
events.
We started with 115 possibly
suicide-related events as reported by the
sponsor.
Now, we took out 11 because they were not
pertinent. Just to remind you, being pertinent or
not had to do with how it was coded by
the Columbia
group.
So, they were coded as non-suicidal.
The
15 were taken out of consideration
because they
were not eligible. Some of them were suicidal but
they were not within the double-blind
period. So,
we ended with 87 pertinent events. To those we
added 29 new events from broader search
and
classification. However, only 22 were pertinent.
Others were not pertinent to the
analysis. So, we
ended up with 109 events.
158
Before I go on with the
results, this is a
list of caveats that I would like to draw
your
attention to because they have important
implications on the interpretation of these
findings.
There is always the possibility of a
chance finding because we are dealing
with post hoc
analyses with multiple outcomes,
complicated by
having many sub-analyses. So, keep in mind that
there is always the possibility for a
chance
finding.
It is also difficult to compare
across
drugs, unfortunately, because of the low
power of
individual trials and the differences in
the
databases among the trials, which is the
point I
mentioned earlier for each drug. So, it will
affect our chance of observing the event
of
interest.
In addition to this, there is the
potential role for differences in the
level of
ascertainment of events and completeness
of
narratives between trials or between
development
programs.
Mind you, the sponsor actually is the
one that puts together the narratives
based on the
159
case report form so you would expect to
find some
variability here also.
Having said that, I will go on
with the
rest of the analysis. The investigation followed a
standard approach for examining the
effect
modification and confounding in the
variables that
we asked for. First, the effect modification--this
was slightly harder to do but by
modification I
mean that the effect of the drug is
actually
modified by another variable. For example, if the
drug was more risky among the males
versus females,
then the gender variable modified the
effect of the
drug and this would have important
implications if
it was true.
Before I go on, it was
difficult to figure
out if there was interaction or not, so
my approach
was to look if there was any inconsistent
finding
across the trial when I stratified by the
variables
of interest. As you can imagine, we have very
small numbers of events. But that is in this
particular outcome. Other outcomes had more
events.
160
The variables that I focused on
were the
age group, gender and history of suicidal
attempt
at baseline. But none was found to meaningfully
impact the risk estimates so there was no
effect
modification to report so I am not
reporting any.
In examining the confounding we
were
concerned about the possibility of
perhaps some
randomization failure at baseline. So, there might
be some randomization failure that might
be
responsible for the observation we have
because we
have very few events. So, if this was true, then
adjusting for these imbalances would have
made a
difference in the risk estimate.
We examined several variables,
at least 17
variables, but the exact number of
variables
differed between trials because some
trials had
missing information about some variables
so it was
not exactly the same number of variables
for all
trials.
Again, none was found to meaningfully
impact the risk estimates and I am not
going to
present any. I think the purpose of these
two
slides is to show you the process that we
went
161
through.
In the next section I will go over
suicidal behavior or ideation which,
again, are
codes 1, 2 and 6, by drug. I will do it drug by
drug.
Then, at the end of that section I will give
you a summary of all the drugs in one
table so you
can have a snapshot of the whole picture.
I will start with Celexa. I ordered them
alphabetically. This graph has a lot of
information so I would like to take a minute to
orient you with the graph. First, this section
will have the name of the outcome that we
are
trying to evaluate. In this case it is suicidal
behavior or ideation. In the upper corner, here,
we have the name of the drug and the
indication of
the trials. Here it will give you the modeling
approach.
The value of this section is to know the
study number. It is sort of redundant, you again
have the indication and the drug
name. This
section will draw your attention to the
actual
relative risks, risk ratios, with the
confidence
intervals. This section gives you the percent
162
weights which reflects the relative
contribution of
each trial of these two, for example, for
the
overall estimate of risk. So, this trial had more
weight in getting the overall
estimate. This
actually is a standard approach for
meta-analysis,
and it takes into consideration both the
sample
size and the number of events.
Just as an example for how to
read the
graph for this trial, that is the number
of the
trial, 94404. The size of the box, if you notice,
is slightly larger than this one because
this
reflects the percent weight. So, all you need to
do is just look at the graph and get a
lot of
information.
Notice that the relative risk
is more than
1.
For those who are not familiar with relative
risk, it is simply the ratio of the risk
in a drug
over the risk in the placebo group. As you can
imagine, if it is 1 then the risk is
equal. So, if
any relative risk is 1 it would fall on
this red
line.
It will not be red in other graphs but I
made it here to emphasize it. Now, if you see the
163
trial estimate on your right-hand side,
this means
the drug is worse. If you see it on the left-hand
side, that means the placebo is
worse. So, in this
case, this is saying that the drug is
slightly
worse in one trial and not exactly the
same in
other trials. So you can see immediately the
divergent results.
Now, one last thing to keep in
mind is
that this is just an estimate and that is
why we
provide the confidence interval. It sort of
reflects the amount of information we
have and
simply means that if we are to repeat
this trial or
the sampling process 100 times, 95
percent of the
time the true effect of the drug will be
somewhere
between these two extremes. So, it is important to
put keep in mind that this is just an
estimate.
I will move on with Paxil. It will be
much quicker. With Paxil, notice that all the
trials are on your right-hand side, which
means
that all of them have a relative risk of
more than
1.
Overall it is 2.65, but the confidence interval
is just at 1, the lower limit. Notice here that
164
this graph contains all indications. Later on in
the summary I will separate the depression-based
trials and non-depression trials.
For Prozac this graph shows you
the
results I have in my briefing
document. As you can
see, there is not much going on in all
the trials,
and the overall estimate is almost 1.
But after I finished my report
we received
information from the TADS trial and, as
you can
notice here, I am only using two arms of
the four
arms that you heard abut this morning,
only the
Prozac and the placebo because these were
the two
arms that were really blinded. Again, the events
were sent to the Columbia expert group
and we ended
up with 9 events total in the Prozac
group and 2
events in the placebo group. So, I ran the
analysis again and I added the TADS
trial. Note
that based on these numbers the TADS
trial is the
only trial that you have in all the 24
trials that
has a confidence interval that does not
include 1.
It has a considerably different picture
than the
sponsor-conducted trials. As you can imagine, the
165
overall the risk will increase.
Zoloft had three trials, one in
OCD and
two in depression. As you can imagine, when we
take the OCD from the consideration, the
overall
estimate will actually be different; it
will be
higher.
For Effexor we had four trials,
two in
anxiety and two in depression. The two in anxiety
did not have anything going on, but the
two in
depression really had the highest
estimate in all
the trials, and overall actually
represents the
only overall for a drug that does not
include 1.
This is kind of a busy slide
but it gives
you a snapshot of the whole picture so I
would
rather have it on one slide instead of
giving it to
you on two slides. I will try to orient you with
this slide. This gives you the overall relative
risks of suicidal behavior or ideation by
drug.
This column has the brand name
alphabetically. The
first group is SSRI. The first column here shows
you the results in the depression trials
and the
last column shows you the results in all
166
indications in all trials, regardless of
indication.
For example, let's take
Celexa. You will
notice that the numbers here and there
are the
same.
That is because Celexa only had two
depression trials. It did not have any
non-depression trials. Luvox did not have
depression trials but it had one OCD
trial. So,
this really gives you a snapshot of all
the
findings in all the drugs whether by
being a
depression trials or overall.
Notice that Paxil did not
change much.
Prozac did not change much whether you
look at
depression alone or depression and other
indications. Zoloft, as I told you, if you take
out the OCD trial the overall estimate
slightly
increases. Then, Effexor, if you take the MDD
trial it is considerably increased actually
whether
you actually just focus on the depression
or
overall.
Both estimates do not include 1 in their
confidence interval. Remeron, again is the same
because it had one trial with
depression. We did
167
not have any events in with Serzone, so
nothing is
reported here. Wellbutrin did not have a
depression trial and it did not have an
event in
the only trial it had, which is ADHD.
The overall observation here is
that all
relative risks were more than 1 but, of
course, as
I mentioned earlier, there is always the
possibility for a chance finding because,
as you
can see, the majority of numbers really
overlap and
they include 1 in their confidence
intervals,
except for Effexor.
One thing that you observed in
the slide I
showed for drug by drug is that we
observed
differences between trials even within
the same
drug within the same development
program. So, we
tried to examine some of the trial design
attributes to try to understand where
these
differences come from. But none was found to
consistently explain the observed
differences in
the risk estimates between trials whether
within or
between development programs. For example, you
might find a trial that excluded placebo
168
respondents and had a signal, and also
find a trial
that actually included those and also had
a signal.
So, there was really no consistent
pattern. So,
there is a chance that what we are
observing is due
to some attributes that we have not
captured, like
how rigorously the trial was actually
implemented
and how closely the investigators were
actually
following the instructions of inclusion
and
exclusion criteria, and so on.
Now, every time you lump things
we might
lose some valuable information. So, after I did
the overall analysis for suicidal
behavior or
ideation I did an analysis for the
components of
all outcomes which you can see on this
other slide
as outcome 1 and outcome 2.
This is again a slide which
gives you an
idea of what is going on in all the drugs
that have
events.
First, again this just shows you the drug
name.
Here is the relative risk of the suicidal
behavior alone; then suicidal ideation
alone; and
then I repeated again the combination for
ease of
comparison. If you notice, for example, with
169
Celexa the behavior was slightly more
frequent in
the drug but the ideation was slightly
more
frequent in the placebo group. But if you look at
the combination you find that there is a
slightly
diminished signal if you compare it to
the first
outcome, which is the suicidal
behavior. It is
slightly more when you look at
ideation. So, it
really depends on what outcome you really
can trust
more.
Perhaps you can say that behavior is more
readily captured and that ideation is
something
that might be missed. However, the first three
drugs are showing this pattern. When you go to
Zoloft, for example, it reverses itself
and you
have more ideation in the drug group than
the
behavior.
Anyway, of course, all this can just be
due to chance findings because everything
is
actually overlapping but I thought you
might be
interested in knowing what exactly is
going on
behind the scenes of a combined outcome.
The sensitivity analysis, as I
mentioned,
we actually added three events coded 3
and 10 to
the pool of codes already in suicidal
behavior or
170
ideation, 1, 2 and 6 as the sort of
worst-case
scenario.
I have here the results, again, all
trials, all indications and just SSRIs in
depression trials. As you can see, there is not
much difference between 1.95 and 2.19. All the
confidence intervals did not include 1,
which means
they were all significant. Again, perhaps there is
some difference here but it still did not
meaningfully change our perception that
there is
risk going on.
This is a different way to look
at the
risk estimates. We actually also did an analysis
by the risk difference that is different
from the
way we just presented. The analysis of risk
difference estimates the absolute
increase in the
risk of the event of interest due to
treatment. It
is simply the risk in that group minus
the risk in
the placebo group. The overall risk difference for
SSRIs in the patient trials ranged from
2-3
percent, actually 2 percent for outcome 3 and 3
percent for outcome 4. So, that is the range that
we have here.
171
This can be interpreted as out
of 100
patients treated we might expect 2-3
patients to
have some increase in suicidality due to
short-term
treatment because what we have is just a
short-term
treatment, and that is beyond the risk
that occurs
with the disease being treated.
Now, this is a different
section now. We
are moving to the outcomes based on the
suicidality
scores, which is totally different from
the one
that I just presented so far. There were two
outcomes.
One is worsening of the suicidality
score and it was simply defined as an
increase in
the item score of pertinent depression
questionnaires relative to baseline,
regardless of
subsequent change. Emergence was defined the same,
except that the patient had a normal
baseline
score.
As you know, these
questionnaires are
actually collected regularly as part of
the
efficacy judgment. We are only capturing here sort
of the subscore that is pertinent to
suicidality.
For worsening, again, the same
approach
172
was used as for effect modification and
confounding, and here we had a considerably
larger
number of events, but again none was
found to
meaningfully impact the risk estimate.
This graph shows you all the
trials that
we have, and simply shows that there is
not much
going on overall. It is almost 1, the relative
risk.
There are only 3 trials that have some
suggestion that there might be some
signal going on
there.
Interestingly, these trials also show the
signal with the other set of outcomes.
Now, the emergence--just to remind you,
they are identical, except this one which
required
the patient to be normal at
baseline. Again,
effect modification and confounding were
examined
but none was found to meaningfully impact
the
estimates.
Here the same picture
holds. In the
majority of trials there is nothing going
on,
except for a few trials that have a
suggestion of a
signal and, again, those trials show the
signal in
the other set of outcomes and here the
overall was
173
really not consequential.
I did many other analyses, as
you can see
in my briefing document. But in the interest of
time I am not including them in my
presentation. I
tried to focus on the highlights of the
findings,
and none of what I did present changed
the
conclusion about the risk. But I will quickly go
over the other list of things that were
done and I
can answer any questions about those.
I also did another sensitivity
analysis
examining the effect or the modeling
approach. I
also did an analysis of the co-called
completers
analysis in which I stratified by
discontinuation
and I looked at the signal within those
that
discontinued and compared that to those
that
completed the study.
Also, I did the time-to-event,
both
survival curves, and I estimated the
hazard
functions for all the SSRIs put
together. I am
sure a question will come up about the
timing of
the events. The finding of Dr. Jick's group did
not hold.
There was no initial increase in the
174
risk and chances that their finding was
confounded
by indication.
I also did some preliminary
look at the
so-called activation syndrome. The issue was
raised at the last AC. Then I did some post hoc
power analyses to just show why none of
the trials
really had power to detect a signal on
its own or
even within the same drug. So, I can share with
you any of these if you have any
questions.
Anyway, before I conclude, I
have a very
few slides left. The limitations, again just to
recap what I said before, what we are
dealing with
here is post hoc analyses with multiple
outcomes
that in addition involved many subanalyses,
therefore, caution is warranted in the
interpretation of the findings.
As you saw, there were observed
differences between drugs but the
differences in
themselves are no a limitation but our
ability to
tease out where these differences come
from is the
limitation. They can be due to chance findings
because most of the confidence intervals
actually
175
overlap.
They can be due to true differences so,
in effect, there is no class effect. Also, they
can simply be because we don't have much
opportunity to observe the outcome. Because the
database sizes are different, they can
simply
reflect differences in the level of
ascertainment
of events and completeness of
narratives. As I
mentioned earlier, the sponsors put
together the
narratives so there might be some
differences
there.
Also, there might be some differences in
the trial design attributes that we were
not able
to capture or quantify.
Now, just a quick reminder that
we are
dealing here with short-term exposure and
we don't
have any information on the risk beyond
16 weeks.
It might increase; it might
decrease. It is very
difficult to extrapolate.
Medication non-compliance might
have
influenced the occurrence of the events
of
interest. However, the
determination of
non-compliance was suboptimal in the way
it was
defined and the way it was assessed
actually. Some
176
companies did it post hoc; some had
pre-planned it
in the protocol. It was very difficult to really
get hold of ascertainment of the
non-compliance.
Again, after everything is said
and done,
it is important to know that the observed
rate of
suicidality associated with the use of
antidepressants might not reflect the
actual rates
among patients in the general
population. Because
we are dealing with volunteers we have
the
volunteer bias. We have the whole logistics of
conducting the trial, the very close care
for
example that patients take and the
detection bias
that can result from that. So, it is important to
appreciate this issue.
Most trials were conducted with
a flexible
dosing scheme, eliminating our ability to
examine
the dose effect. So, none was examined.
Now to give you an overall
summary of the
findings, the broader search for adverse
events in
various drug development programs and the
blinded
classification process identified many
new events
and also eliminated several events that
were not
177
appropriately classified. It is important to note
that there were no completed suicides.
The next point is that many
individual
trials had a relative risk of two or more
for
suicidality and some confidence intervals
of
overall estimates did not include 1. I think the
key here is not really the statistical
significance, because of the caveats I
mentioned,
as much as the consistency. You can see most of
the trials falling on your right-hand
side of the
graph, which means that there is some
suggestion of
signal coming from many trials even
though none of
them was really significant perhaps.
The next point is that the
sensitivity
analyses did not yield a meaningful difference
in
the evaluation of the estimated
risk. This gives
more confidence in the finding that we
might really
be dealing with some real finding.
None of the examined covariates
was found
to be an effect modifier or to
meaningfully impact
the risk estimates as a confounder. But, mind you,
this might be simply a function of power
because
178
there might be some slight imbalance but
the sample
size is not large enough to really detect
it or
detect its effect.
Among the examined trial design
attributes, none was found to
consistently explain
the observed differences in the risk
estimates
between trials. But I believe they can partially
perhaps explain some of the differences,
as I am
sure you saw in my briefing document.
My last point is that no signal
was
observed in the outcomes based on the
suicidality
scores, unlike what we saw with the
adverse events.
I have like 70 backup slides so
if you
have any questions, feel free.
DR. GOODMAN: Thank you, Dr. Hammad. I am
sure you will be here tomorrow so I would
ask the
committee members to limit your questions
to
clarification because we will have an
opportunity
to ask additional questions tomorrow as
we
deliberate over the questions that are
posed to us.
With that in mind, Dr. Marangell?
DR. MARANGELL: It doesn't appear that you
179
included family history of bipolar
disorders.
DR. HAMMAD: No.
DR. MARANGELL: How come?
DR. HAMMAD: This was an attribute of the
trial.
It is not patient-level data so what I have
is that this trial did this or didn't do
that and
none of the actual attributes explain any
of those
differences anyway. So, the non-inclusion was
because they were not patient-level data;
they were
trial-level data, and it really did not
make much
difference. You can see that some excluded and had
a signal and some did not exclude and
still had
signal.
DR. GOODMAN: Dr. Leslie?
DR. LESLIE: I just wanted to make sure of
the SSRI alone analyses and the
activation syndrome
analyses, if we can do that tomorrow. Since one of
our questions is to think about these
drugs as a
whole versus certain classes versus
specific
medications, I just want to make sure we
can do
that.
DR. GOODMAN: Dr. Perrin?
180
DR. PERRIN: As I understand it, the
nefazodone sample, which is about 450
kids in the
MDD trials, has zero events noted. Can you help us
understand why that might be true, and
what might
be different about those trials and those
sample
selections compared to the other trials?
DR. HAMMAD: I have not reviewed the
actual protocols of the trials. That is something
that Dr. Rabitsky did so perhaps he can
comment on
that tomorrow.
DR. GOODMAN: Dr. Gibbons, do you have a
question?
DR. GIBBONS: First, I think you have done
a great job. Apparently getting four degrees in
your lifetime was a good benefit! I have a couple
of general questions and lots of specific
questions
which I will hold for tomorrow. But the most
general question is this, most of your
analyses
focused on the relative risks, which
really in some
ways goes away from the idea of using the
patient-level data and using
patient-level
characteristics or covariates.
181
Now, I think you have done a
very nice job
of conditioning on things using
stratification, but
the analyses, even though in some sense
are similar
for the time-to-event, the survival kinds
of
analyses which do make use of the individual
patient-level data--it seems to me those
would be
much stronger because they adjust for
time at risk.
The relative risks ignore the
differential time--a
study was conducted for the differential
time that
an individual within a study
participated, whereas
that is exactly the time-to-event
analysis. So, I
would just like your general comments on
that.
DR. HAMMAD: The first thing was to
actually make sure if there was any
imbalance in
the exposure time between trials, and I
did not
find much difference in the actual time
for every
trial between placebo and
intervention. In spite
of that, I realized that the
time-to-event can
answer other questions, other than taking
into
account imbalance between both. That is why I did
it both ways actually. They are giving more or
less similar conclusions. I didn't see that there
182
was that much difference in conclusions
whether we
looked at it as relative risk or as
time-to-event
analysis.
DR. GIBBONS: Just one follow-up question
to that, one of the things you see
throughout your
analysis is that if you condition on
prior history
of suicide attempts or ideation, what you
find is
that the effects tend to go away. So, the
development of new suicidal effects or
worsening of
suicidal effects shows absolutely
nothing. When
you conditioned on prior history the risk
ratio
went down to 1.2 essentially for those
people who
didn't have a prior history. What is your sense of
this kind of what you bring to the table
and then
the effect of the drug?
DR. HAMMAD: I think this actually draws
our attention to the fact that when you
are dealing
with a patient that is at higher risk to
start with
you might expect the drug to be--I don't want
to be
more risky because quantitatively the
difference is
not significant, the difference you are
referring
to.
There is some trend towards that but if you
183
actually look at within trial you find that
it goes
both ways. Sometimes it is more in those patients;
sometimes it goes the other way. So, I don't think
actually there was much meaningful--that
is why I
used, if you noticed, the word
"meaningful"
difference. I don't think this particular
covariate, which I believe is the single
most
important risk factor, plays much of a
role in
modifying the risk estimates.
DR. GIBBONS: Thank you.
DR. GOODMAN: Dr. O'Fallon?
DR. O'FALLON: I am interested in the
missing data essentially. That is the thing that
is bothering me all through this
retrospective
analysis.
There are two issues that I am concerned
about.
One of them is how many of the patients
had, in essence, missing follow-up? I mean, they
disappeared from the study and,
therefore, they
could have had an event that was never
observed or
recorded.
What percentage of missing data
disappeared? I know you talked about last
follow-up carried forward and that sort
of thing in
184
your analyses.
DR. HAMMAD:
Not in my analyses.
Actually, I don't have information in my
database
about the lost to follow-up. However, we did
something that is sort of similar that
sort of
talks to the same idea. When I stratified by
discontinuation, those that end up as
discontinuing
without us really capturing them, you
would expect
that among those who discontinued,
because we know
they discontinued--among those the signal
would be
greatly diminished. They would look as if nothing
is going on--
DR. O'FALLON: Yes.
DR. HAMMAD: --but when I stratified by
that, as a matter of fact there was a
tendency for
the majority of trials to observe a
signal among
those that discontinued, which simply
sort of means
that those that have events usually
discontinue but
it sort of allayed anxiety about the fact
that we
might be losing or missing information.
DR. O'FALLON: Yes, but I am still worried
about the fact that there are some that
could have
185
dropped out and then had an event and it
was never
recorded.
So, you may be missing events.
DR. HAMMAD: Sure.
DR. O'FALLON: The other part of it was
that I am concerned about the timing of
events with
respect to dose changes. I realize, again, with
the retrospective analysis you may not
have the
information in your database, but that is
one of
the issues here, whether the events are
occurring
in connection with a dose change of any
sort, and
can you get at that or not with your data
set.
DR. HAMMAD: No, we can't.
The issue of
the non-compliance, as I mentioned, is to
some
extent similar to dose change. I mean, it doesn't
matter who changed it, the physician or
the patient
decided not to take it. I don't think we can
capture that, unfortunately.
DR. GOODMAN: Dr. Robinson?
DR. ROBINSON: I understand that on the
Paxil trial 329 there was an active
control. I
think it was imipramine. Could you tell us was
there a difference between imipramine and
Paxil in
186
terms of--
DR. HAMMAD: No, I have not compared it to
Paxil actually.
DR. GOODMAN: Could you repeat the
question, please?
DR. ROBINSON: The Paxil trial 329 had
another active antidepressant as a
control and I
believe that was imipramine, and I was
asking if
there had been any comparison of the
effects of
Paxil and the imipramine cell.
DR HAMMAD: I did not do a formal
comparison but if you look in my review,
on page
101, you will see that there were two
events in the
active control and four events in the
SSRI and one
event in the placebo in this particular
trial, with
the sample size almost identical. So, it gives you
an idea that it was about half of the
ones observed
on Paxil but double the ones observed on
placebo.
DR. GOODMAN: Dr. Santana?
DR. SANTANA: Based on your expertise in
this area, and I confess that I am not a
behavioral
scientist, can you give me some general
sense, if
187
you look at these outcomes in adults are
the
relative risks for these outcomes the
same when
these drugs are used, or is this a
universe that is
particular to pediatrics, based on the
data that
you know of?
DR. HAMMAD: No, I am not aware of any
data that actually looked at this
particular
question among adults.
DR. GOODMAN: You said that you have not
examined those data in adults?
DR. HAMMAD: No, I don't have
that.
DR. GOODMAN: Is there somebody from the
FDA who can respond to that
question? Tom?
DR. LAUGHREN: Yes, the adult data have
not been looked at with the same level of
scrutiny.
But there are a couple of things I can
tell you.
First of all, this issue first came to
our
attention with Prozac back in the early
'90s, and
based on reports, from spontaneous
reports of
suicidality events in association with
Prozac, the
company went back and looked at all their
controlled trials for Prozac, looking at
them in
188
two different ways.
One thing they looked at are the item
scores, roughly the same thing that we
did here,
and they did not find any signal for
excess risk on
the item scores, as we did not here. They also
looked at event data and they did not find
any
signal with event data either.
Now, they didn't go back and
try to
reclassify the events in the same way
that was done
here.
But subsequent to the Prozac experience, all
subsequent NDAs for all antidepressants
were looked
at in the same way. The companies did an item
analysis and they looked at their own
event data,
using their own approaches to
classification. With
all these subsequent NDAs, we have never
seen a
signal for excess suicidality, either
looking at
event data or looking at item data.
In addition to that, we now
have a much
larger database for completed suicides in
adult
data that we are currently looking
at. Based on
the analysis that we have done to date,
we have not
seen a signal for excess completed
suicides in a
189
very large adult database. I mean, this comprises
I think 240 trials, over 40,000
patients. But,
again, none of these data in terms of
event data,
short of completed suicide, have been
looked at
with the same level of scrutiny for
adults.
DR. GOODMAN: Tom, let me follow-up to
that question. When you say that there has never
been a suicide signal, I take that to
mean a
greater rate in the drug versus placebo
group.
What is the denominator there? How many studies
are we talking about in adults?
DR. LAUGHREN: Again, this has only been
looked at by individual programs so it is
however
many trials exist in the different
databases, and
generally, you know, we are talking
about--this is
ballpark again, I don't have the numbers
in front
of me but generally we are talking about
anywhere
from probably 4-10 trials per drug. So, it has
been looked at within individual
programs. It may,
in fact, be larger than that if you include
trials
for indications other than
depression. You know, I
am just giving rough estimates here. So, it has
190
not been looked at across programs the
way we have
looked at it here for the pediatric
data--complete
suicides has been but not the event data
or the
item data.
DR. GOODMAN: One final follow-up
question, from me at least, on these
data, I don't
imagine that you have stratified in the
adult data
by age, such that you would look at
whether there
is a relatively increased risk of
suicidality in
the younger adults versus the older.
DR. LAUGHREN: I don't believe that has
been done.
Again, these NDAs came in over a period
of 10-12 years. I don't recall that being done.
DR. GOODMAN: Dr. Pollock?
DR. POLLOCK: Just a quick question for
Dr. Laughren, the 40,000 database that
you spoke
of, was that what was published in the
Kahn report
in The American Journal of Psychiatry,
2003, or has
this been published?
DR. LAUGHREN: No, I believe it is a
larger database than Kahn included in his
analysis
that was done several years ago. So far it has
191
only been published in abstract form, a
little over
a year ago. It is an analysis that we are still
working on but basically so far we have not seen a
signal.
DR. POLLOCK: Thank you.
DR. GOODMAN: Dr. Rudorfer?
DR. RUDORFER: Yes, I have a
question/comment for both Dr. Hammad and
Dr.
Laughren.
It seems to me that one issue that we
are up against that is unique here,
unlike the
adult data, is the relative dearth of
positive
efficacy in these trials so that the
Celexa data
that we just saw are particularly
interesting
because, as I understand it, those are
the only set
of studies where there is one positive
efficacy
trial and one negative. As I understand the
suicidal risk ratio, there is an inverse
relationship so that the study that was
done in the
U.S. and showed positive efficacy had a
suicidal
risk ratio less than 1 and the study that
was done
in seven different countries--we can talk
about
that tomorrow--and had negative efficacy
result
192
showed a suicidal risk ratio greater than
1.
So, I wonder if there is any
way we have
for working around that issue, namely, if
we are up
against a couple of dozen studies that
maybe were
not done very well, or not done very
seriously, or
were not done in the right people, and
then we are
looking at adverse effects but in the
context of a
drug that is not doing what it is
supposed to be
doing.
DR. GOODMAN: Was that rhetorical?
DR. RUDORFER: That was the comment.
DR. GOODMAN: Well, thank you very much.
Dr Pfeffer?
DR. PFEFFER: You gave us relative risks
and the confidence intervals very rarely
reached 1.
What would be the power or the size of
samples
necessary to show the effects with more
assuredness?
DR. HAMMAD: I have one in my backup
slides that I can share with you.
DR. NEWMAN: While he is getting that,
could I make a comment?
193
DR. GOODMAN: Okay.
DR. NEWMAN: When you have randomized,
double-blind trials the main thing that
you worry
about is lack of power. Most of the errors will
leave you being unable to show a
difference. So,
it is relevant I think to look not just
at the
confidence interval but what the p values
were for
these estimates when you pool all the
trials
together.
That is what I was just doing with my
spreadsheet. I don't know if Dr. Hammad did that
or not, but for the confidence interval
that is
furthest from 1 the p value is about 5
times 10
-5.
So, the probability that these are chance
findings
is very, very low. The confidence intervals are
far from 1, at least for the outcome that
is most
impressive.
So, I think to think that these
are chance
findings is not a viable explanation,
even given
the number of subgroups and even given
the
differences in the trials. Most errors will be in
the other direction, will be false
negative. This
also addresses what you have on the slide
but if
194
you calculated the p values for the
difference
between the risk ratios and 1, you know,
the p
values for the pooled estimates.
DR. HAMMAD: No.
DR. NEWMAN: Well, I can share my
spreadsheet.
Just from the confidence intervals
and the width of the confidence intervals
you can
do that.
DR. HAMMAD: No, I didn't do that. I
thought the confidence interval gives you
more
information.
DR. NEWMAN: Yes, well, I disagree. I
think if you are talking about chances
and
explanation, how low the p value is, is
actually
very relevant and something that most
people around
the table can understand, and they are
very low.
DR. HAMMAD: But they are not equivalent
to each other actually. So, you might have two
confidence intervals that hardly overlap
and then
the p value is not significant, or the
reverse.
So, I thought that the confidence
interval would
give you more information, that is all.
195
Back to your question, it
actually depends
on the incidence in the placebo
group. The red is
assuming an incidence of 1 percent in the
placebo
group and the blue is assuming an
incidence of 5
percent in the placebo group. So, for example, if
you want to design a trial to be able to
detect a
relative risk of 3 or more, then you
would actually
need around 200 patients per group here
and around
800 patients per group there. So, it depends on
your assumptions of how many events would
occur in
your placebo group. And, one of the limitations in
this particular effort is the great
variation even
in the rate in the placebo group. So, it would be
hard to really plan for the future, but
that is
your range.
DR. GOODMAN: Dr. Pine and then Dr.
Gorman, and those will be the last
questions for
the speaker.
DR. PINE: I wanted to return to the
summary by Dr. Laughren and ask two
questions about
it.
It sounded like a meta-analysis of 40,000
patients as opposed to a bunch of
individual
196
studies, I just wanted to confirm that I
understood
that correctly, that you were talking
about a
global meta-analysis, number one.
Then, number two, I notice that
you
started your comment by stating that
those studies
have not been looked at with the same
level of
detail as the studies and analyses that
have just
been presented, oon the one hand. On the other
hand, I wondered if the level of review
was
comparable to kind of the first-pass
review from
the pediatric studies where there
appeared to be a
signal on more fine grade analyses. Was that
meta-analysis comparable to the initial
pediatric
one or not?
DR. LAUGHREN: Let me again distinguish
between the analysis that is focusing on
completed
suicides in adults. That is a very different
matter from the analyses that the
individual
companies did, looking at either event
data or item
data.
I would say, in answer to one of your
questions, that probably the quality of
the
analyses looking at event data and item
data were
197
comparable to the initial data that we
got from
Paxil in that sense. But, again, none of those
data have been reclassified using the
more critical
approach that we have used for these
data, but
probably comparable to what we have seen
for Paxil,
and from that standpoint may have some
validity,
the fact that we never saw anything in
any of those
trials.
The adult completed suicide
data--Tarek
can speak more to that than I can, but
that is a
completely different thing. That is something that
we have done based on data that we have
obtained
from companies and a relatively small
number of
completed suicides. I think the total number of
completed suicides in that 40,000 patient
database
is only about--what?--30, Tarek?
DR. HAMMAD: Around 30, yes.
DR. LAUGHREN: Would you characterize that
as a meta-analysis?
DR. HAMMAD: Yes, it is because we had a
couple of hundred trials that were all
pooled
together, but the analysis was not the
trials; it
198
was the actual patients. So, it is slightly
different. And, there were only eight trials that
were actually positive--not positive,
that had some
event in one of the arms. All other trials did not
have anything at all. So, it is sort of
controversial to take findings from eight
trials
and pool them with others and then try to
get a
conclusion. But even with those eight trials, our
statistical group did a review and they
found no
signal, even focusing on those eight
trials alone.
DR. GOODMAN: Dr. Gorman?
DR. GORMAN: This question is motivated by
trying to answer some questions for the
agency
tomorrow.
When you looked at the relative risks of
the suicidal scores that were used, you
found them
to be not predictive of the behaviors
that you may
be observing. But we don't generally think of
screening tests or predictive tests in
terms of
relative risk; we usually think of them
in terms of
sensitivity and specificity. Can you reanalyze
your data for us to see if these scores
actually
predict the behaviors you then observed?
199
DR. HAMMAD: I have this in my review. I
did a sort of clustered relation between
the two
types of events regardless of the
treatment between
the worsening and between outcome 3,
which is the
primary focus. In some trials there was a
significant association; in some there
wasn't. So,
in some trials it was predictive to some
extent; in
some trials it wasn't. But the word predictive
implies that one is occurring before the
other and
we don't have this exact timing
associated in the
data.
DR. GORMAN: I was more interested in the
patient-level data. Were the ones that actually
participated in behaviors that were ranked
in
outcome 3, in fact, predicted by the
screening
tools that we use?
DR. HAMMAD: But this assumes that you
know the outcome occurred and then you
have the
screening tool before it, but we don't
know that.
The
finding is not in my database.
DR. GORMAN: Thank you.
DR. GOODMAN: Thank you, Dr. Hammad. We
200
look forward to further interrogation of
the
data--not you but the data--tomorrow.
DR. HAMMAD: Thank you.
DR. GOODMAN: Now I am pleased to
introduce Dr. Andrew Mosholder, from the
FDA.
Comparison Between Original ODS and
Current DNDP
Analyses of Pediatric Suicidality
Data Sets
DR. MOSHOLDER: Thank you very much.
[Applause]
Thank you. I was asked to present a brief
comparison of the original analysis done
in the
Office of Drug Safety with the current
analysis
that Dr. Hammad just presented. I will present
that and then I will touch on two or
three
additional points that were covered in
the March
consult document that is in your briefing
packages
that weren't really part of the analysis
we just
heard, just to supplement that. So, during this
talk I will refer to the ODS analysis as
the
original one that I completed, and then
the
Division of Neuropharmacological Drug
Products
analysis as the one that Dr. Hammad just
presented
201
to you.
This is just to orient you to
the ODS
analysis.
It was the same trials as in the DNDP
analysis, with the important exception
that the
TADS data has been added to the DNDP
analysis. The
events were determined from the responses
to the
July, 2003 data requests. Dr. Laughren mentioned
these requests earlier, but just to
amplify on
that, last July the agency asked all the
sponsors
of the drugs in question to essentially
reproduce
the analysis that GlaxoSmithKline had
done for
their Paxil pediatric trials. This involved
basically two components. One was an electronic
search of specific terms in the adverse
event
databases for those trials, then followed
by a
manual review of all the serious adverse
events in
those trials. These were the data that I used for
the ODS analysis.
I chose to emphasize the
sponsor
identified suicide-related events, that
were
identified by the means I just described,
that were
also classified as serious adverse events
and I
202
will show you the exact definition of
that in a
moment.
This, of course, predated the Columbia
University reclassification.
There are some differences in the analytic
methods.
This just gives a brief summary.
In the
ODS analysis person-time was used as the
denominator rather than the number of
patients.
The post-treatment window for including events
was
30 days versus 1 day in the DNDP
analysis. Events
during down-titration I included in the
ODS
analysis.
Also, in the Mantel-Henzel calculations
Dr. Hammad's analysis employed a
correction for
zero cells, whereas my method did not.
To give you an overview of the
data set
for the analysis, there was a total of
roughly 2200
drug-treated patients and 1900
placebo-treated
patients.
This yields a total exposure of about
407 patient-years for drug, almost 350
patient-years for placebo. Just to remind people,
patient-year is a unit of exposure. It is a
cumulative measure so that it could be
represented
by one patient receiving the drug for a
year; two
203
patients receiving a drug for six months;
12
patients for a month, and so forth.
As we have heard, one of the
limitations
of these data is that they are all
short-term
trials so that there is no implication
that there
is any year-long treatment data
here. In neither
treatment group were there any completed
suicides.
Then, there was a total of 74
sponsor-defined
suicide-related events with drug; 34 with
placebo;
and then a subgroup of those, 54, were
serious and
24 for placebo were serious.
This slide gives the definition
of
seriousness. It has already been mentioned this
morning but, basically, if the event is
fatal,
life-threatening, involves
hospitalization, is
disabling or is a congenital defect it is
considered to be a serious event
according to the
FDA regulations. Now, in this case the events
would fall under these two categories
since there
weren't any completed suicides, as has
been
mentioned, and the other two categories
aren't
relevant.
204
Each sponsor determined whether
the
adverse event was serious, and that is
routine in
the conduct of clinical trials. I will show you
the comparison between the outcome that I
emphasized, which is serious suicide-related
events, to the Columbia University
outcome 3, as we
see over here, which is the suicidal
behavior/ideation. The reason for concentrating on
seriousness was to eliminate some of the
events
that were of questionable clinical
importance, such
as superficial self-cutting or the girl
who slapped
herself.
Cases like those were not part of the
serious events by and large.
So, this gives the comparison
for those
two categories. For the ODS serious
suicide-related events there was a total
of 78, and
61 of these were also eventually
classified by
Columbia University as definitive
suicidal
behavior/ideation. Of the remaining 17 cases, 13
were considered self-injurious behavior with
unknown intent, which is over here. So, they were
not part of outcome 3 essentially because
the
205
intent was unknown. Then, conversely, for the
Columbia University category--and this is
ignoring
the time following double-blind treatment
so that
this is a somewhat higher number because
events
occurring after treatment discontinuation
are being
shown here--there was a total of 95 in
that
category.
As I said, 61 overlapped with
the previous
category.
There were 18 new cases disclosed by the
expanded search algorithm that you head
about
earlier.
Then, there were 16 sponsor-defined
suicide-related events which did not meet
criteria
for seriousness so that they were not
included in
the ODS analysis but they were considered
to be
definitive suicidal behavior/ideation by
the
Columbia University team.
First I am going to show the
results of
relative risk for both analyses, and
first for
individual drugs. These are the drugs for which
both analyses were able to calculate a
relative
risk.
Just to orient you, first of all, let me
point out this is a logarithmic scale
because some
206
of the confidence limits are quite broad
here.
Then, I have highlighted the value of 1
here to
remind you that values above 1 indicate a
risk with
drug and below 1 indicate a protective
effect of
the drug.
For the ODS analysis the values are on
the left and the DNDP are on the right.
First of all, we see that just
in general
the new relative risks from the DNDP
analysis fall
within the confidence limits of the
previous
results.
So, from that standpoint there is
agreement. Then, if you look at particular cases,
some are similar; some are a little
different. For
sertraline the value decreased just
slightly--let's
see, this is 2.5 to 1.5 based on the
addition of a
single placebo case. For paroxetine, 2.2 versus
2.7. Venlafaxine actually showed
an increase, 1.8
to 5 and the confidence limit, you see,
just
touches 1. Fluoxetine in both cases is just below
1.
However, with the inclusion of the TADS data
you see that the new relative risk for
fluoxetine
is 1.5.
Then, for citalopram, 2.5 versus 1.4.
Next we are going to look at
some
207
groupings of trials. First, on the left are SSRI
major depressive disorder trials. Again, the value
here, 1.9; the new analysis, 1.4. The confidence
limit extends below 1 in this case. But then,
again, with the addition of the TADS data
the
relative risk is 1.7. Then, for the category of
all trials the relative risk is 1.9
versus 1.8.
Then, with the addition of the TADS data,
just
below 2.
You see in all cases that the confidence
limit excludes 1.
That concludes a brief overview
of
comparison of the two analyses. I just wanted to
touch on three additional topics. First is the
incidence rate difference analysis. Secondly, and
this has already come up in the
discussion, there
is one case in which we have direct
comparison to
adult data, and that is for
paroxetine. Finally, a
little bit of data on treatment
discontinuation
events.
This is an analysis of rate
differences.
This is a little different from what you
have been
seeing.
Again, the events are per patient-year
208
but, of course, as I said, there is no
implication
that patients received the drug for longer
than the
short-term trials. Here I have highlighted zero
because, as you realize, a value above
zero would
indicate a risk of the drug because it is
drug
minus placebo. A value below zero would indicate a
protective effect of the drug. This is actually
statistically a rather crude method. This is a
simple totaling of the data for each
drug's
clinical trial database.
But with those things in mind,
we see
first of all that the pattern is that in
every case
here for the individual drugs, except for
fluoxetine, the risk difference is
positive,
indicating an excess rate on drug
compared to
placebo.
For fluoxetine I did not have the TADS
data so one would expect, as we have seen
with the
addition of that data, that the
fluoxetine risk
difference would likely be above zero as
well. For
fluvoxamine there were no events. Unlike the DNDP
analysis, there was one event for
nefazodone,
giving us a positive value.
209
So, for the individual drugs,
those you
see, the confidence limits are rather
broad. For
the set of all MDD trials the rate
difference is
about 0.09 events per patient-year. For all trials
it is somewhat lower. Taking this one as the worst
case, that translates to one excess
serious
suicide-related event for about every 12
person-years of treatment with the
drug. In
summary, this is just a slightly
different way to
look at the same data set.
This is a summary of the
analysis that
GlaxoSmithKline did in which they applied
the same
search algorithm to their adult clinical
trial
database that had found the signal in the
pediatric
trials.
First of all, I need to point out, of
course, that these events are not
reclassified.
These are simply the sponsor-defined
suicide-related events. These are, again, rates
per patient-year. There are a couple of things
to point out. First of all, if we look at the
placebo rates we see, first of all, that
in major
depressive disorder compared to all
indications the
210
rate is a bit higher, and that is true
for the
pediatric group as well. That is not unexpected,
given the association of suicidality with
major
depressive disorder which is being
diluted in the
larger pool of trials with other
indications.
Secondly, we see that actually
the placebo
rates comparing adult and pediatric data
sets are
actually rather comparable, similarly for
the MDD
trials, not too dissimilar.
Third, we notice that for the
adult trials
the rates between drug and placebo are
really not
that discrepant. That could, of course, mean that
some drug-treated patients are getting
worse and
others are getting better but there is no
net
imbalance. Also, I should point out that, of
course, these trials are not designed to
measure
impact on suicidality because, as we
know, most
suicidal patients are excluded from these
studies.
But be that as it may, there doesn't seem
to be
much discrepancy in the rates for the
adult
studies.
However, for the paroxetine
pediatric
211
trials that is not the case. You see that there is
an excess for the MDD trials, and also in
the
larger pool of all trials which did reach
statistical significance. So, it is not perfect
data but I think it suggests, at least to
me, that
there could be a difference between the
pattern of
these events for pediatric patients and
adults.
Finally, this is just to look
at the
possibility that drug discontinuation plays
a role.
These are going back to the serious
suicide-related
events now. This is all trials, all indications.
As you recall, in the DNDP analysis
events were
included up to one day after the end of
double-blind treatment. Here that is extended out
to up to four weeks. This shows the pattern. We
see that there is sort of this cluster
here in the
first week. In fact, all those occurred within the
first four days of treatment
discontinuation.
It may not be projecting real
well, but
paroxetine accounts for the largest
number. Five
of the nine events were in the paroxetine
trials.
Not too much is really seen in the
subsequent
212
weeks.
Again, it is just a suggestion.
This is
not perfect data but suggests that there
may be
some phenomenon happening early in the
period after
treatment discontinuation.
In conclusion, both the
original ODS
analysis and the current DNDP analysis
indicate an
association of suicidal adverse events
with
antidepressant drug treatment in this set
of
short-term placebo-controlled clinical
trials.
Thank you.
DR. GOODMAN: Thank you very much. Any
questions? Dr. Rudorfer?
DR. RUDORFER: Thanks.
Andy, a question
about your discontinuation data, did you
get the
sense, or could you tell from the data
whether
there were discontinuation issues during
the course
of the trial? I mean, some of the data we have
seen suggest that in some of the trials
adherence
could have been a problem and I am
wondering,
particularly with paroxetine which you
showed was
being problematic after the end of the
trial, if a
child in the study is taking the drug
only
213
intermittently wouldn't they be exposed
to repeated
discontinuations?
DR. MOSHOLDER: Yes, of course, that is
true.
I think that has been hard to capture in the
clinical trial data though. I think in some cases
patients were discontinued by the
investigator if
they admitted to not having taken their
medication
in several days, but that might not
always be the
case.
So, it is very hard, at least in the data I
looked at, to really get a sense. It was much
easier to look at what happened when
double-blind
treatment was known to have been
discontinued.
DR. RUDORFER: Right.
Just as a
follow-up, I am wondering if that could
play a role
in the difference you noted between the
pediatric
and the adult data for paroxetine, that
is, if
medication use is more continuous in the
adult
samples than in the pediatric ones.
DR. MOSHOLDER: That is a hypothesis. I
don't know if there is any data that
directly
compares compliance for pediatric and
adult
patients.
I think we know that compliance could
214
always be better, wherever one looks, but
whether
it is really worse in the pediatric group
or not--I
think people suspect that but I know if
that has
been documented.
DR. GOODMAN: Dr. Fant?
DR. FANT: Yes, I was struck by your
fluoxetine data when you included the
TADS trial,
you know, showing more concern than the
previous
trials had shown, and it really makes me
wonder,
with the inclusion of children with other
coexisting comorbidities and other
medications on
board, whether or not this may be
pointing to a
subset of kids, maybe in a distinct
minority but
who may be at higher risk for potential
adverse
events related to these medicines. It is just a
comment.
A question, when you looked at
the TADS
data, when you included that, did you
look at all
of the kids who were given the drug or
did you
split it up into how they looked when
they were
given the drug alone or given the drug
plus CBT?
DR. MOSHOLDER: I think I have to defer
215
this to Dr. Hammad who gave me those
results so I
could include them here.
DR. FANT: Since CBT seemed to suggest
perhaps an enhanced effect on efficacy.
DR. HAMMAD: In my presentation I actually
mentioned that I did not include CBT
patients. The
two arms were excluded because they were
not really
blinded.
I only included the blinded ones.
DR. GOODMAN: Dr. Temple?
DR. TEMPLE: I was just going to mention
that before the TADS data came in one of
our
explanations for why Prozac might have
been
different is that it is not so easy to
discontinue
with its several week half-life. Now that the TADS
data seem to go in the same direction,
the
discontinuation hypothesis seems less
strong.
DR. GOODMAN: Dr. Gibbons?
DR. GIBBONS: In your person-time analysis
how did you handle people who had
multiple events?
DR. MOSHOLDER: I took the first event.
DR. GIBBONS: So, they counted just once?
DR. MOSHOLDER: Right.
I believe Dr.
216
Hammad took the clinically worst event; I
took the
first event. As a practical matter, that didn't
involve large numbers.
DR. GIBBONS: Great!
DR. GOODMAN: Dr. O'Fallon?
DR. O'FALLON: In your discontinuation
data, is there any chance that in that
week-1 group
there are people who were discontinued
because they
were doing badly? In other words, are these people
who went all the way to the end of the
planned
analysis and then had an event? I mean, you are
looking at this event in the week after
they
discontinued therapy. Were they
the ones who
completed the therapy or were they
possibly having
their therapy discontinued because they
weren't
doing well?
DR. MOSHOLDER: Yes, I don't have the
numbers on that to break it down by
whether they
were prematurely discontinued or
completed the
intended length of treatment. I believe it is a
mixture of both but I can get you those
numbers.
DR. GOODMAN: Last question?
217
DR. PINE: Yes, I found the direct
comparison of the data for paroxetine in
the adults
and children very helpful, and I was
wondering if
that was volunteered by the company or
was there a
specific request and, if the latter, are
there
plans to do comparable analyses for other
agents?
DR. MOSHOLDER: Well, by way of answering,
I can say it is included in my March
memorandum and
it was a submission that actually I
believe went to
another regulatory agency which FDA was
copied on.
As far as whether neuropharm. is asking
other
sponsors, I will defer to one of the
people from
neuropharm. for that.
DR. LAUGHREN: Yes, we don't have any
current plans to do this in terms of
adult data.
Since we have this fairly large database
with
completed suicides which, after all, is
the event
that is of greater interest right now we
are
focusing on that.
DR. GOODMAN: Momentarily we will break
for lunch. Before we do so, this is the last call
for registered open public hearing
speakers to sign
218
in.
We are going to reconvene and, hopefully, be
seated and ready for presentations by
1:15. We
have three presentations that need to be
given
before we begin the public hearing at
2:00. For
the benefit of the committee members
sitting around
the table, there are reserved places for
you at
lunch in the restaurant in the
lobby. A final
reminder once again, we are not to
discuss matters
that are germane to our deliberations
during our
break.
[Whereupon, at 12:26 p.m., the
proceedings
were adjourned for lunch, to reconvene at
1:15
p.m.]
- - -
219
A F T E R N O O N P R O C E E D I N G S
DR. GOODMAN: We are about to hear three
presentations from representatives of the
pharmaceutical industry. We are going to get
started with the presentations. Our first speaker
is representing Forest Laboratories.
Sponsor Presentations
Citalopram and Escitalopram Product
Safety Data
Forest Laboratories
DR. JONAS:
Good afternoon. My name is
Jeffrey Jonas, and I am the vice
president for the
central nervous system therapeutic area
at the
Forest Research Institute. Thank you for allowing
me to address you today.
I will be presenting some new analyses
today based on our three studies of
pediatric major
depression. Two of these studies you have already
seen involving citalopram. Another involves a
recently completed study of escitalopram,
the
S-isomer of citalopram which we believe
to be the
active component, also in pediatric major
depressive disorder.
220
I will be presenting an
analysis of the
SREs, presenting an integration of these
three
studies.
Then I will discuss our Lundbeck study,
European Union study 94404 which was
conducted by
our licensor, Lundbeck, and talk a little
bit why
we think this study is distinct from our
other
studies and, indeed, from most of the
other studies
under consideration today. Finally, I will be
concluding with some exploratory
analyses, looking
at some alternative explanations for
SREs, in
particular, an examination of activating
adverse
events and a look at responder analyses
of patients
with and without serious suicide-related
activities
and events.
As I mentioned, there are three
completed
placebo-controlled studies in pediatric
major
depressive disorder, two with citalopram
and one
with escitalopram. The citalopram studies are
MD-18, which was a U.S. study looking at
children
and adolescents, conducted in outpatients
in the
United States. The second study is a European
Union study, 94404. This is a study of adolescents
221
only that enrolled both inpatients and outpatients.
The escitalopram study, MD-15,
studied
children and adolescents and in most
respects was
similar in design and implementation to
the U.S.
citalopram study MD-18. This study was recently
completed. The safety data were just recently
submitted to the FDA, in May, and the
efficacy data
were completed afterwards, sometime in
June, and
then submitted to the FDA. We will be presenting
integrated analyses for this study with our
other
two studies, but I should point out that
the SREs
were not reclassified by the Columbia
group.
The escitalopram study was an
8-week,
double-blind, flex-dose study, basically
conventional design. It studied patients with
DSM-IV major depressive disorder. Of note,
patients who were at high risk for
suicidality were
excluded and this study studied only
outpatients.
I will be focusing on safety
today but I
just want to highlight the efficacy
results of
these three studies. Study MD-18 in citalopram was
a positive study utilizing as its primary
endpoint
222
the CDRS-R. Study MD-15 also had the same
endpoint.
This was a negative study. I
should
note, however, that recent analyses have
shown
clear trends in the adolescent
subpopulation in
MD-15.
Also of note, both of these studies had
similar decreases in the CDRS-R of about
22 points,
the differentiating feature being the
placebo
response in MD-15 which was largely
driven by the
placebo response in the children's
group. Study
94404 utilized the K-SADS and this was a
negative
study.
This slide now shows the SREs
for the
three studies combined. The middle row shows you
the data for MD-15 which is the recently
completed
study in escitalopram. We analyzed the study using
the FDA-provided algorithms that were
used in the
other studies for the analyses we have
been
discussing today. In the study there were three
SREs, two in placebo and one in
escitalopram. None
of these was categorized as SAEs.
As you can see here, for both
the U.S.
studies the risk for an SRE was greater
in the
223
placebo group than in the escitalopram
group. The
reverse was true in the European Union
study.
Overall, however, the risks for placebo
or active
treatment are roughly comparable when all
three
studies are combined.
This slide depicts that in
terms of
relative risk. As you can see, the confidence
intervals all cross unity and, again as
you can see
for the U.S. studies, the relative risk
for an SRE
is greater for the placebo patients
rather than
patients on active drug, and the reverse
is true
for patients in the 94404 study.
Dr. Hammad, in his report, did
comment
that in most respects our European study
was
dramatically different or differed in
almost every
respect from our U.S. studies. So, we spent a
little time looking to see if we could
understand
some of these differences.
We think the most important
differentiating features involve the
inclusion and
the exclusion criteria utilized in the
U.S. and the
E.U. studies. This slide shows some of the major
224
differences. For example, inpatients could be
enrolled in the E.U. study. I should point out
that most of these inpatients were
complex
psychiatric cases with many psychosocial
stressors,
many coming from dysfunctional families,
many on
multiple medications. In addition, patients could
have recent psychiatric hospitalizations,
even
suicidality, could be included in the
study, and
patients with a history of suicide
attempts, even a
recent one, could also be included. About 15
percent of the patients in the European
study were
inpatients. About a fifth had a history of
psychiatric hospitalization and about a
third had a
history of a suicide attempt.
Few other studies of the
studies we have
looked at today had these features. In addition,
the complex nature of the inpatients may
have made
it hard to have successful randomization
balance in
these studies. In particular however, we think the
features of including inpatients and
patients with
significant psychiatric hospitalizations
may have
been a major differentiating feature of
this study
225
from the other studies we examined today.
We, therefore, did a somewhat
straightforward analysis and simply
looked at
relative risk in 94404, excluding the
patients who
had a history of hospitalization or who
were
inpatients at the start of the
study. As you can
see, when you do this analysis the risk
for SREs is
similar between placebo and citalopram.
Looking at the relative risk,
we now see
an analysis that in some ways makes these
three
populations and three studies comport
more closely
to each other. Here you see that overall the
relative risk for an SRE is greater for
placebo
than for drug.
If one accepts the possibility
that
medication may not be the only factor or
a factor
in inducing SREs, one must look for other
explanations. One common theory is that patients
experience activating adverse events in
association
with SSRI treatment. This has been postulated also
in relationship to other therapies but
today we are
speaking about SSRIs. In particular, there is a
226
theory that SSRI treatment induces early
stage AAEs
that, in turn, are precursors to
SREs. As a
corollary, there is some clinical theory,
I would
says, that patients sometimes have to get
worse to
get better, and that is, patients who are
responding to treatment undergo an
energizing
effect that may be confused or may be
heralded as
an activating adverse event--so-called
getting
worse to get better.
Regardless of how we postulate
the role of
AEs, we thought this was worthy of
examination.
So, we cast a broad net at looking at AEs
in our
studies in order to make sure that we
basically
subsumed any adverse event that might be
considered
to be activating.
This slide presents the risk
data for the
three studies. As you can see, overall there is
not very much difference between active
therapy and
placebo.
We also conducted other
analyses looking
at activation adverse events. We looked at the
pattern of onset and we found no
difference between
227
drug and placebo. We also noted that the large
majority of patients who have AAEs do not
go on to
develop SREs. Conversely, if one looks at patients
with SREs, we found that if one looks for
close
proximity of AAEs to the SRE there is
very little
difference between the drug and placebo
groups.
Taken as a whole, we found no
preferential
relationship between AAEs and medication
therapy.
This slide shows the relative
risk for
developing AEs in drug versus
placebo. As you can
see, in the two U.S. studies the relative
risk was
actually greater than in the European
study, 94404,
and we found this to be an interesting
finding.
You may recall that the signal for SREs
in the U.S.
studies was weaker than in the 94404
study where
the risk of SREs was felt to be greater
for drug
treatment. This is not what one would expect if
one thought that SREs were associated
with AAEs.
As a result, we feel that there is not
very good
data in our data set to suggest a
relationship
between AAEs and SREs.
Finally, we explored what we
thought was
228
perhaps a more parsimonious explanation
for SREs,
that is that patients who develop SREs
are simply
patients who are not responding to
therapy, whether
they are being treated with drug or
placebo. We
hypothesized that SREs were simply
associated with
the course of depression, exacerbation of
depression or clinical deterioration
rather than
associated with medication treatment.
We conducted a series of
analyses to look
at this question. The one I am going to show you
now compared the course of response in
patients
with and without SREs using the change
from
baseline in a primary efficacy measure.
the K-SADS.
This is the data from study 94404,
looking
at all the patients who had SREs. There are a
number of points to make. First, there is good
separation between the groups. However, the groups
here are patients with and without
SREs. The top
two lines represent patients who had
SREs; the
purple, patients on placebo; the blue,
patients on
citalopram. This is an LOCF analysis and I should
point that if you plot this with the OC
analysis
229
the curves are virtually the same. Approximately
50 percent of these patients went on to
completion,
likely, of course, because these patients
could be
hospitalization in this study even during
the
course of the study.
If you look at this slide, this
suggests
to us that it is lack of response that
may be
responsible for the development of SREs,
regardless
of treatment group, rather than a
distinct effect
of medication.
We have done a number of other
analyses
looking at this theory and some of them
are still
in development. However, if you look, for example,
at the patients in this study who were
classified
by the Columbia group as having SREs, of
the nine
patients on citalopram with SREs, none
met
protocol-defined endpoints for
response. In the
patients on placebo, there were
five. Only one met
protocol-defined criteria for response.
Considering that in this study both the
placebo
group and the active treatment group had
protocol-defined measures of response at
60
230
percent, we think this is an interesting
difference
and we, again, think that these data
suggest that
it is exacerbation of depression,
regardless of the
treatment group, that may play an
important factor
in the development of SREs.
In conclusion, we found that
the numerical
rate of SREs in the two U.S. studies was
lower in
active drug groups versus placebo. In the E.U.
study, when one corrects for patients who
might not
have been included in the U.S. studies, this
removes the signal for SREs from that
study.
We found no evidence overall of
an
increased rate of AEs in the active drug
group
relative to placebo, and really no
evidence
suggesting that AAEs were etiologically
related to
the induction of SREs.
Finally, our data suggest that
patients
with SREs were typically poor responders
whether
they received placebo or active
drug. Thank you
very much.
DR. GOODMAN: Thank you.
DR. MCGOUGH: Did you elicit your
231
activating AEs by structured interview or
rating
form, or was it simply open-ended
questioning?
DR. JONAS: The AAEs in the European study
had a questionnaire and we actually got
our AAEs by
searching the data strings for the
preferred terms
in the studies.
DR. MCGOUGH: How about in the U.S.
studies?
Was there a structured rating to elicit--
DR. JONAS:: No, in the U.S. it was
spontaneous.
DR. MCGOUGH: Because there is good work
that shows that you get under-reporting
of AEs if
you don't have a structured instrument.
DR. GOODMAN: Dr. Fant?
DR. FANT: Your second conclusion or
summary point is that patients with SREs
are
typically poor responders, suggesting
that it had
more to do with their non-responsiveness
than the
drug itself. Based on your data, can you exclude
the possibility that there is something
about the
makeup of those patients that the
introduction of
altered chemistry might predispose
certain
232
behaviors in those particular patients?
DR. JONAS: We looked to see--
DR. FANT: --which may coexist with
non-responding in general.
DR. JONAS: We looked to see, when we did
these analyses and, as I say, some of
these are
still ongoing, whether or not there were
any
differences between the groups in terms
of pattern,
onset and so forth, and we just found
none. It
simply looked as though this was a
pattern that was
common to patients whether they received
placebo or
drug.
So, we had no clue, for example, of any
prognostic factors that might herald
this. if I am
answering your question.
DR. GOODMAN: Thank you very much, Dr.
Jonas.
Our next speaker will be representing
Pfizer Pharmaceuticals.
Sertraline Use in Product
Population:
A Risk/Benefit Discussion,
Pfizer, Inc.
DR. ROMANO: Thank you very much. My name
is Steve Romano. I am the therapeutic head for
psychiatry in our worldwide medical
organization.
233
That is not the name you see on your
agenda.
Charlotte Kremer is a colleague of
mine. The title
there though is mine.
What I am going to be talking
about today
briefly is sertraline use in the
pediatric
population and I am going to talk a bit
about a
risk/benefit discussion. Of course, I also want to
say that I appreciate the opportunity to
address
this joint committee.
There are some critical points I think
that are worthwhile considering in the
assessment
of risk/benefit for any antidepressant
for use in
pediatric patients and adolescent
patients with
MDD.
Clearly, MDD is a very serious illness.
It
affects many children and adolescents in
the U.S.
and is associated with suicidal behavior.
Unfortunately though, physicians have
limited
approved treatment options for pediatric
patients
with MDD.
Pfizer believes that the risk/benefit of
antidepressant use in pediatric
depression should
be assessed on an individual product
basis, and
this is for a number of reasons.
234
Antidepressants do differ with
regard to
chemical structure, pharmacological
profile,
pharmacokinetics, adverse events and
discontinuation symptom profiles, and I
think that
all of them may potentially translate into
a
differential effect in the real
world. Also, in
support of this, as a result of the
studies
reviewed in the FDA analysis, they do
vary from
drug to drug. We believe that approaching this
issue as a class effect might jeopardize
or at
least fail to highlight potential
beneficial
treatments for children or for some
children and
adolescents with MDD.
The suicide-related behavior in
MDD in the
pediatric population is a huge medical
concern and
a public health concern. It is the third leading
cause of death in adolescents 15-19 years
old. The
annual present prevalence rate of MDD in
children
is roughly 2-3 percent but about 2-3-fold
that in
adolescents. The diagnostic criteria, as we all
know, clearly clarify suicidality as a
part of the
disorder itself and that is clearly
captured in our
235
diagnostic nomenclature, DSM-IV for
instance.
In one study, it is important
to note that
suicidality in depressed children and
adolescents,
at the time of study entry was quite
significant,
in fact, about 1/10 individuals had a previous
suicide attempt and up to 66 percent, or
about
two-thirds of the patients, actually had
a previous
history of suicidal ideation. I say this because I
think the latter may very well complicate
our
ability to evaluate suicidal ideation in
clinical
trials.
It is frequent and it is very difficult to
assess the intent. Suicide attempts are a much
clearer manifestation of potential
suicidality.
We are now shifting to the
Pfizer
sponsored placebo-controlled trials. These are the
trials done in pediatric patients with
sertraline.
As you can see, there are approximately
five
studies.
The three studies I am going to talk
about are the first three, a study in OCD
and two
studies identically designed in major
depressive
disorder.
Those are the three studies that have
contributed to the analyses that you are
going to
236
review today, or have reviewed to this
date.
The last two studies, one a
PTSD study
that is being conducted in response to a
pediatric
request, and the last, a non-IND OCD
study, are
both continuing and are blinded so they
have not
contributed to any events that you are
going to see
in any of the analyses and I am not going
to talk
anymore about those today.
What I do want to point out
though is that
all of these studies include both
children and
adolescents in the age range of
6-17. There is, by
the way, and it is worth noting one
NIMH-sponsored
study that Pfizer has provided sertraline
to, and
it is not so dissimilar from the TADS
study that
was reported this morning. It is called the POTS
study and it is looking at OCD
patients. We do
understand from communication from John
March, and
this is personal communication, that
there were no
events in any of the arms of that study
that looked
at CBT, sertraline, a combination as well
as
placebo, and that is a randomized
trial. That has
been submitted for publication but is not
yet in
237
press.
That was not a Pfizer sponsored study.
I
just share that for completeness.
The main discussion today,
obviously is in
MDD but I do want to show you that, in
fact, we
have met the rather rigorous criteria for
a
regulatory submission and an indication
in OCD in
children.
This just shows that in our study, the
ITT analysis, LOCF, change from baseline
to
endpoint.
We did show a robust difference, a
statistically significant difference
between drug
and placebo for OCD. We have been on the market
for OCD and have had an indication in OCD
since
1997.
Turning now our attention to
the studies
in major depression, we used the CDRS as
the
primary outcome measure and the primary
efficacy
analysis was a change on scores from
baseline to
endpoint in the ITT population, the LOCF
analysis.
As you can see, in both individual
studies, study
1001 and study 1017, neither study showed
a robust
separation from placebo although, as Dr.
Laughren
pointed out this morning in his summary
of all the
238
trials, study 1001 on the primary
analysis of the
change score on CDRS did show a trend of
0.8.
But, interestingly, we did have
an a prior
defined analysis which was a pooled
analysis of
those two identically designed trials,
and that was
also reported in an article by Wagner in
JAMA about
a year ago. In that particular pooled analysis, in
fact, we showed separation from placebo
on both the
primary outcome measure of the CDRS
change score,
as well as on the responder analysis, the
categorical analysis of those patients
who met a
greater than 40 percent change in CDRS at
endpoint.
Now, I think the interesting
point to
highlight is really when we look at this
data, why
is it that we are not seeing a more
robust or
significant difference between drug and
placebo in
pediatric patients with depression? In other
words, it doesn't mirror that which we
see in
adults.
And, I think this slide is somewhat
helpful in clarifying, at least for the
sertraline
database, what might be contributing to
that.
This is looking at the
placebo-controlled
239
pediatric MDD studies with sertraline,
but at this
case we are looking at the CDRS responder
rate, the
categorical analysis. I have it divided, on the
left for children and on the right for
adolescents.
I think the important point here is that
the
placebo response in both children and
adolescents
is quite high but it is even more
significantly
elevated in children. We did include children in
all of our trials and in both MDD
studies. So, as
you can see, there was a separation in
the
adolescent subgroup. This is a post hoc
subanalysis. There is separation on this
particular indicator of
improvement--there is not,
but both placebo and drug showed significant
improvement on both subgroups.
Just for completeness, you saw
the
presentation of the item 13 score this
morning in
previous presentations, this is just to
highlight
that item 13 of the CDRS, which is suicidal
ideation score, did improve in patients
with major
depression in our sertraline clinical
trial
database from baseline to endpoint. As you can
240
also see though, there is no significant
difference
between active treatment, in this case
sertraline,
and placebo but both groups showed
improvement from
baseline to endpoint. I think the fact that
children can get in, present for their illness
and
actually get treated and are seen on some
regular
basis does impact on a child's outcome.
Let's move specifically to talk
about the
events of suicidal attempts and suicidal
ideation.
None of what I am showing you is
new. This is in
the briefing documents and was included
in the
analysis that the FDA and Columbia have
done. I
think it is also important to point out
that the
FDA analysis is consistent with the
Pfizer
analysis.
In other words, no events were relabeled
or significantly changed. They did not find new
events.
So, this really is consistent with the
analysis that was done by both FDA and
Columbia.
What I want to show now is
suicide
attempts first. We feel strongly that we need to
look at suicide attempts separately from
suicidal
ideation.
Suicidal attempts are a much clearer
241
and--it is a much clearer indicator of suicidality.
As you can see here, for patients in the
MDD trials
as well as the patients in the OCD trial
the rate
for suicide attempts was quite low. In fact, it
was exact in the case of subjects
experiencing
these events in MDD. We had two patients in the
MDD trials who received sertraline and
reported an
event that was classified as a suicide
attempt. We
had two subjects in the placebo group,
although one
of those subjects contributed two events
of
suicidal attempt. But the incidence rate based on
the subject numbers is the same and as
you can see
by the confidence intervals, they overlap
zero.
There is no difference. In the OCD study there
were no events in either the placebo
group or the
sertraline group and in the combined, as
you can
see, we are showing the exact
incidence. Looking
at suicidal ideation, again, in this case
this is a
very common adverse event and it is quite
difficult
to assess intent around suicidal
ideation. So, we
really do feel it is worth looking at
them
separately and not combined. Again, as you can see
242
here for MDD and OCD, there was a
relatively low
rate of events across these studies. In the MDD
studies, again, we were looking at the
pooled
analysis of those two MDD trials. There were three
patients on sertraline for a rate of
1.6. There
were no patients on placebo that
experienced the
event of suicidal ideation during the
course of
those MDD trials.
In the OCD trial, which was a
12-week
short-term trial, we see that there were no
events
in the sertraline group but one event out
of 95
patients in the acute phase of that
particular
trial.
As you can see, neither in MDD nor in OCD
or for sertraline or placebo was there a
statistically significant difference
across the
groups, and that is true also for the
combined
analysis.
Now, one of the issues that has
arisen as
being very important to consider is, is
there a
temporal association between the onset of a
particular event, like suicide attempt or
ideation,
and the initiation of double-blind
therapy or
243
titration of drug during the course of
the study.
This is looking at all the cases of
suicidal
ideation and suicide attempt for
sertraline and for
placebo in our trials, both the MDD
trials and the
OCD trial, so for those three trials.
As you can see, if you look to the far
end, the last column, day of event, the
day of
double-blind therapy, in fact in
sertraline-exposed
patients none of these events occurred in
the first
week or two of exposure to drug, and
there was no
pattern of response that was based on
changes or
titration of drug during the course of
the therapy.
For placebo, there were two patients in
the first
week and a half, one in depression and
one in the
OCD trial, where the event was associated
with
initiation of treatment but in this case,
of
course, we are looking at placebo.
So very importantly, there was
no specific
pattern in time of event. It was fairly random.
There was no association between time of event and
dose increases. I think more importantly as well,
when we get down to the narrative level
most of
244
these events were actually associated
with some
psychosocial stressor or precipitant that
was
captured.
In summary, for the
placebo-controlled
pediatric studies with sertraline we can
say that
sertraline is effective and safe in the
treatment
of pediatric OCD, and we were granted
that
indication about eight years ago. The a priori
pooled analysis of the sertraline
clinical studies
in pediatric MDD did demonstrate a
statistically
significant effect on the CDRS but,
admittedly, the
benefit relative to placebo was
modest. The effect
size was relatively low, and there was a
high
placebo response, as I showed you
previously. That
was primarily driven in the subpopulation,
children
ages 6-11.
There were no completed
suicides in any
pediatric study with sertraline. You are well
aware of that. There were also no statistically
significant differences between
sertraline and
placebo in placebo-controlled studies of
MDD or OCD
with respect to suicide attempts, as I
just showed
245
you, or suicide ideation. Again importantly, no
temporal association was seen between
onset of
double-blind therapy or dose increases
and
suicide-related events, either suicide
attempts or
suicide ideation.
So, just to highlight the
points that we
really think are very important to
consider are the
fact that this is a very serious illness;
that
physicians really do have limited
approved
treatment options for the treatment of
pediatric
patients with MDD; and that the
risk/benefit of
antidepressant use in pediatric depression
should
really be assessed on an individual
product basis
for the reasons I mentioned earlier. Again, I
think it is worth underlining that
approaching this
issue as a class effect might jeopardize
or at
least limit the likelihood of clarifying
some
benefit in some population of patients
with MDD in
the pediatric group.
Lastly, I just want to
highlight a
position of Pfizer's, we currently feel
that class
labeling for monitoring during treatment
with
246
antidepressants accurately reflects the
risk of
suicidality in adult as well as pediatric
patients.
We
think that such labeling should be applied to
all medications indicated for the
treatment of
depression and simply not just to the
SSRIs or
SNRIs, and I think we heard earlier from
Tom
Laughren that that may, in fact, be a consideration
of the FDA's as well.
We also feel that if the FDA
does consider
a label change necessary that product
specific
labeling would be most beneficial to
prescribers
and patients. I guess an example of that might be
the inclusion of specific event rates of
suicide-related behavior for the
placebo-controlled
clinical trials, and perhaps the best
place for
that would be in the adverse section of
the label.
We do this for other dimensions of
tolerability
like weight, for instance, and that has
been very
helpful to our prescribers and I think it
might
actually clarify potential risk as well
as a
possible benefit in some patients treated
with
sertraline.
Thank you.
247
DR. GOODMAN: Thank you, Dr. Romano.
Questions from the committee? If not, I would like
to proceed with our next speaker who will
be
representing Wyeth Pharmaceuticals.
Wyeth Pharmaceuticals
DR. CAMARDO: Good afternoon. I am Dr.
Joseph Camardo. I am head of medical affairs for
Wyeth, located in Pennsylvania. Wyeth developed
and has marketed venlafaxine, brand name
Effexor,
since 1994 and I want to start by
expressing my
appreciation for the opportunity to speak
before
the committee.
As we have heard today, mental
illness,
including depression in pediatric
patients, is a
complex medical condition and it is
associated with
the risk of suicide. More than two million
children and adolescents in this country
suffer
from depression in one form or
another. Physicians
need to treat individual children and
they have
cautiously used the newer
antidepressants,
including venlafaxine, even though most
are not
indicted in the pediatric population.
248
Wyeth has never labeled or
recommended
venlafaxine for such use but we, and
other
manufacturers, have conducted clinical
studies of
antidepressants in children. However, despite all
of our research efforts many of the drugs
that have
been very beneficial in adults have not
been proven
to be effective in clinical studies in
pediatric
patients.
The studies of antidepressants in
children have shown an apparent increase
in
suicidal thoughts and possibly suicidal
attempts
which is a concern for us, for the
patients, for
the parents and for the physicians. Thankfully, no
child committed suicide in any of these
studies.
It is important that we learned about
these effects
and now we need to make use of this
information
that is the subject of this meeting. I want to
take just a few minutes to describe
Wyeth's point
of view.
The first is that we should make use of
this information that was gleaned from
these
studies and provide this information to
physicians.
In our pediatric clinical studies there
were
increased reports of hostility and
suicide-related
249
events, such as ideation and
self-harm. We, at
Wyeth, updated our label and we provided
our
pediatric safety information to over
450,000
healthcare professionals in 2003 in a
"dear
healthcare provider" letter.
Studies with other
antidepressants,
carried out by other pharmaceutical
companies in
pediatric patients, have shown similar
adverse
events.
As an industry, we should continue to
provide safety information broadly and in
a
consistent way to physicians, and the
information
should be similar for all
antidepressants.
Second, although the FDA's and
the
Columbia University's cross-study
analyses were
done carefully, one cannot conclude that
a
difference among the drugs has been
demonstrated.
This is largely due to limitations
inherent in the
various study designs, and I think you
heard a lot
about these caveats from Dr. Hammad
already. The
reviews, by necessity, included post hoc
analyses
with multiple outcomes and no statistical
corrections. They are complicated by the lack of
250
statistical significance for many of the
subanalyses. This increases our level of
uncertainty. So, we have to exercise caution if we
try to draw definitive conclusions about
the true
relative risk of these events.
Also, these trials were
designed for
efficacy and were not sufficiently large
to detect
differences in the less frequently
reported events.
Moreover, the studies did not include a
direct
comparison of one antidepressant with
another.
There was insufficient commonality among
the
studies to make valid comparisons. For example,
the studies we venlafaxine did not
exclude patients
with treatment resistance, history of suicide
attempt or homicidal risk, but some of
the trials
with other medications did exclude these
patients.
Therefore, while we recognize that there
were
larger risk ratios reported for
venlafaxine than
for some other products, we do not, on
the basis of
these observations, believe it is
appropriate to
advise that a physician could apply
special
precautions for one antidepressant and
not the same
251
special precautions for another.
Third, it would, in our
opinion, represent
good medical judgment to allow physicians
to use
these products in pediatric patients if
they
believe the products to be necessary, and
if they
determine that other ways of treating
depression
are unsuccessful. Companies should provide
warnings.
Prescribers should be fully aware of the
risks and fully capable of identifying
and managing
suicidal thoughts, hostile behavior and
suicide
attempts.
The parents should be well informed of
these risks as well in order to recognize
the
emergence of these symptoms.
Let me summarize our point of
view.
First, we should continue to provide
information to
physicians about what we have learned in
our
studies about suicidal thoughts, suicide
attempts,
and we need to emphasize the need to be
vigilant.
Second, the information we
provide should
be consistent for all of the
antidepressants since
the data do not allow us to distinguish
among them
for the appearance of this particular
risk.
252
Third, we should keep these
products
available to physicians to use when
needed,
according to their expert judgment,
because
depression in children is a complex,
serious
problem and it may be extremely difficult
to treat.
I want to thank you for giving
Wyeth the
opportunity to present our position.
DR. GOODMAN: Thank you very much. Any
questions? Yes?
MS. GRIFFITH: I appreciate the time you
took, and I don't mean to pose a hostile
question
to you but as a parent, looking at the
data that
Dr. Hammad gave us, it is so dramatically
different, the presentation for effects
and the
overall risks of suicidal behavior and
ideation. I
mean, it wasn't just a couple of points
difference,
you know, 8.84 as opposed to 1.37 for
Celexa; 2.15
for Paxil. I am not a clinician but that would
alarm me as a parent and I don't quite
understand
how you excuse a result that is so
dramatic.
DR. CAMARDO: I purposely acknowledged the
risk, and your question is not at all
hostile,
253
first of all, and we in fact believe that
notification of the risk is critically
important to
any physician who is trying to use the
product. I
don't want what I said to be
misinterpreted as not
being forthcoming about the risk and the
differential risk observed. I just am recommending
that we be cautious about treating one
drug as so
dramatically different from another that
you could
apply a warning or precaution in one case
and not
in another case when we have seen that
one trial
can be different another; one condition,
such as
anxiety, could be different from
depression; and
sometimes the differences in the way the
studies
were done may lead to differences in the
outcomes.
So, I think we just need to be careful
about
believing that we have distinguished
between the
drugs on the basis of magnitudes of
effect that
might be suspicious when you look at them
carefully.
DR. GOODMAN: Dr. Fant?
DR. FANT: Could you just reiterate the
comment you made about differences in
exclusion
254
criteria in your studies and some of the
other
studies with the other drugs? If I am remembering
your comment correctly, and validate this
for me, I
think you said you included kids who
potentially
had more problems that were excluded in
other
studies.
DR. CAMARDO: I am actually basing what I
say only on the basis of what I know
about our own
studies.
In fact, Dr. Hammad outlined in his
review some differences between different
studies,
and that information is only available to
me from
that review.
But having said that, we did include,
for example, children who had not
responded to
other antidepressants. I don't know if that is
true in the other studies or not. We have included
in the venlafaxine studies children who
actually
may have had a previous suicide
attempt. Our only
exclusion criteria were if the child was
considered
to be a high risk of suicide. So, I only know a
little bit about those.
DR. FANT: Now, if you went back and
excluded those kids in your group and
reanalyzed
255
the data using different exclusion
criteria, how
would the risk look?
DR. CAMARDO: I don't know the answer to
that question. It is a very good question but I
can't answer it.
DR. GOODMAN: Any other questions? If
not, we are going to take a very brief
break but I
am asking people not to leave the
room. You can
just stretch as we prepare for the open
public
hearing.
I am going to hand the microphone over to
Anuja Patel.
MS. PATEL: I would like at this time for
all registered open public hearing
speakers to make
sure they are sitting in the reserved
open public
hearing section on the left-hand side of
the
audience, which is the committee's
left-hand side,
just to help us be more efficient in
recognizing
the registered speakers. Thank you.
[Brief recess]
Open Public Hearing
DR. GOODMAN: We are about to begin. I
would like everybody to find their
seats. For the
256
next four hours we will be holding the
open public
presentation portion of the meeting. Let me begin
by making a statement. Both the Food and Drug
Administration and the public believe in
a
transparent process for information
gathering and
decision-making. To ensure such transparency at
the open public hearing session of the
advisory
committee meeting, FDA believes that it
is
important to understand the context of an
individual's presentation. For this reason, FDA
encourages you, the open public hearing
speaker, at
the beginning of your written or oral
statement, to
advise the committee of any financial
relationship
that you may have with any company or any
group
that is likely to be impacted by the
topic of this
meeting.
For example, the financial information
may include a company's or a group's
payment of
your travel, lodging, or other expenses
in
connection with your attendance at the
meeting.
Likewise, FDA encourages you at the
beginning of
your statement to advise the committee if
you do
not have such financial
relationships. If you
257
choose not to address this issue of
financial
relationships at the beginning of your
statement,
it will not preclude you from speaking.
We have approximately 70
speakers in the
next four hours who will each be
allocated, for the
most part, three minutes a piece. To describe the
process more clearly to you, let me turn
the
microphone to Igor Cerney, who is the
Director of
the Center for Drug Evaluation and
Research
Advisors and Consultant Staff.
DR. CERNEY: As Dr. Goodman has said,
everyone will have three minutes, except
for one
group that has a consolidated
presentation which
will be allowed five minutes. When you have 30
seconds left the green light which has
been on your
timer will turn yellow and that is your
wrap-up
time of 30 seconds. Then, when you are out of time
the light will turn red. It will flash, it will
beep, and will cut the sound off
automatically at
that point. So, that is just letting you know what
the ground rules are for the open public
hearing.
Thank you.
258
DR. GOODMAN: At first blush, it may seem
insensitive to cut off the sound but we
have to
achieve the right balance between giving
an
individual an opportunity to express his
or her
opinion but also ensure that there is
sufficient
time for everyone here who wants to
speak. We are
not going to be making exceptions in the
timing.
It is going to be a relatively automatic
process so
please gauge your presentation to ensure
that you
have reached the high points before the
mike is
turned off.
I also apologize in advance for
addressing
each of you by a number. The data I have here, at
least the most valid data, just gives me
a number
of
each speaker presentation and then I ask you,
when you get to the podium, to introduce
yourself.
No surprises here, we are going to be
starting with
speaker number one. I would appreciate it if you
would stand up to the microphone.
DR. DUCKWORTH: Good afternoon. My name
is Ken Duckworth and I am a Board
certified child
and adolescent psychiatrist. I work part-time as
259
the medical advisor to the National
Alliance for
the Mentally Ill, also known as
NAMI. NAMI has
220,000 people who have serious mental
illness or
have people in their families who have
serious
mental illness. Because I work for NAMI, they have
paid for my trip here but I do no work
for the
industry of any kind and I get my income
from
clinical practice and taking care of
patients.
NAMI would like to start by
saying we
believe there is sufficient reason to
demand better
research, which I think is evident from
your
conversations today. It is very clear that the
studies don't answer all the questions
that
parents, doctors and teenagers need. We
feel that
longitudinal research is one of the
things that is
missing from this conversation. We know that it is
hard to do and expensive but we feel that
it is an
incredibly aspect of this work.
The TADS study is a very
important and
good start, but it is only a start. We still don't
know so many aspects of the risk/benefit
assessment
that parents and doctors need to make
when they
260
make decisions about whether to start a
compound, a
medication or psychotherapy on an
adolescent who
walks into the office with
suicidality. In that
TADS study 20 percent of the patients
were
presenting with suicidality before they
entered the
study.
To me, this is emblematic of the problem of
suicidality that is endemic to the
condition of
adolescent depression.
I just want to also say that
the
President's Freedom Commission has told
us that the
mental health system is a shambles. That is
important because if you think cognitive
behavior
therapy and thoughtfully applied
medications, with
good monitoring, is going to happen on a
routine
basis, there is not much evidence to
suggest that
the system is set up for that, and that
is
something that NAMI wants to acknowledge,
that you
know that the work force issues around
getting good
care for people is a major problem that
relates to
this.
Monitoring--monitoring is a
very important
piece of this whole conversation and I
would like
261
you to reflect on your success with
monitoring
clozapine for people with
treatment-resistant
psychoses. People with treatment-resistant
psychoses have a 10 percent chance of
killing
themselves. This is people with schizophrenia.
Your system for monitoring clozapine
enables me to
give people a medicine which is risky,
may save
their life and may cause the rare chance
of a
catastrophe. Your system for monitoring for this
rare thing enables me to prescribe this,
give good
informed consent, and the patients and the
families
make good decisions.
We also need to remember that
as you are
constructing whatever risk/benefit
information you
are giving to people everybody should
know what
akathisia is. Every person should
know if their
kid has a family history of bipolar
illness and,
finally, every person should know, and
you should
communicate to them, that untreated
depression also
kills people. Thank you.
DR. GOODMAN: Thank you very much, and I
welcome our next speaker, number two.
262
MS. TOTTEN: Hello.
My name is Julie
Totten, and I am the president and
founder of
Families for Depression Awareness. Regarding
financial disclosure, there is no
industry money;
we just took it out of our operating
dollars for
coming here today.
Families for Depression
Awareness--I would
like to speak on behalf of our members
who are
families coping with depressive
disorders, our
board of directors and our advisory
board. Many of
us have lost a family member to suicide
and I lost
my brother to suicide 14 years ago. He was
undiagnosed but afterwards, when I
learned about
depression, it was very apparent that he
suffered
from this condition.
I would like to make three
points. One is
that family care-givers are the ones who
need to be
active in monitoring treatment. Number two,
monitoring is the key issue and, number
three, more
monitoring advice is needed, first,
regarding
family care-givers. Families for Depression
Awareness is very pleased and
enthusiastic that you
263
have put out a warning that families,
patients and
clinicians all need to monitor depression
treatment
and
we are so glad that you have included family
care-givers, people like me who are in a
position
to help when patients are not capable and
doctors
are too busy, which is most of the
time. Please
make sure to include family
care-givers. They are
the ones who can make a difference.
Six months after my brother
took his life
I helped my father get diagnosed and
treated for
major depression. I am a family care-giver and I
am proof that family care-givers can make
a
difference if we are given a chance.
The second issue is that
monitoring needs
to be the main issue here. People with depression
need medical treatment and every person's
reaction
to medication is different and has to be
handled on
a case-by-case basis, as we all
know. So,
monitoring is what we need to focus on to
prevent
suicides right now. But the problem is that
families and patients do not know how to
monitor
treatment. So, families need more explicit
264
monitoring advice. They don't even know how often
to make a doctor's appointment.
Families for Depression
Awareness is
developing a depression treatment
monitoring tool
for medication, psychotherapy or both to
help
families and patients track their
symptoms, side
effects and treatment, and we would
welcome
collaboration.
We can only do so much and we need
your help. Please focus on family care-givers make
monitoring an issue right now,
immediately, and
help us develop more specific monitoring
advice.
Thank you.
DR. GOODMAN:
Thank you very much. I
would like to invite our next speaker,
number
three.
MR. WILKINS: Hello.
I am Ronnie Wilkins,
with the ACNP. Depression in youth, as you have
talked about today, is a serious
disorder. It
affects every aspect of a child's life
and
increases the risk of more drug, alcohol
use, adult
depression and suicide. Allowing to go untreated
delays improvement and it increases the
likelihood
265
of long-term negative outcomes.
Controlled trials have shown
that
fluoxetine is effective in the treatment
of
depression, and the recent data from the
NIMH-funded TADS trial provides further
support and
justification for the use of this
medication, In
addition, the TADS trial compared
fluoxetine to
cognitive behavior therapy and found some
evidence
that both CBT and placebo were inferior
to
treatment with fluoxetine alone.
The ACNP strongly supports more
research
comparing psychological and medication
treatment
for depression in children and
adolescents, more
methodologically sound research with
other SSRIs,
more studies of non-SSRI agents such as
tricyclic
antidepressants, and studies testing
strategies to
treat depressed children and adolescents
who have
failed treatment on an SSRI.
Depression as a significant
risk factor
for suicide is something to be concerned
about as
well.
Treatment of depression is likely to
decrease overall suicide rates. Epidemiological
266
data tends to support this view.
In over 4000 children and
adolescents
treated in controlled trials with
antidepressants
there have been no suicides, however,
there are
indications that there may be an increase
in
suicidal ideation and suicidal
behavior. Recent
data from the U.K. in adults are
consistent with an
increase in suicidal ideation during the
initial
phases of antidepressant treatment with
all
medication treatments. These uncontrolled
observations need additional rigorous
study in
depressed children and adolescents before
we will
have a final understanding of these
issues.
The ACNP supports the FDA
recommendation
that clinicians carefully monitor all
patients
treated with antidepressants for
worsening of
symptoms and emergence of suicidality, as
well as
for agitation and mania. This has always been good
clinical practice and adding that
information to
antidepressant labeling is highly
justified.
The TADS study also shows that
overall the
impact of treatment on depression
significantly
267
decreased suicidal ideation. It is important to
put into perspective that while some
adolescents
may demonstrate a worsening of suicidal
ideation,
up to 40-60 percent will demonstrate an
improvement
in suicidal ideation, and similar
proportions will
demonstrate a meaningful reduction in
other
symptoms of depression.
It is only through further
methodologically sound research that we
will
increase our understanding of
age-specific issues
of safety and effectiveness of both
medications and
psychotherapy in the pediatric
population.
Limiting clinician choices because of
lack of
available information would not be in the
best
interest of patients and it would be
unfortunate if
these controversies resulted in stifling
of
research just when more research is
needed.
DR. GOODMAN: Thank you very much.
Speaker number five, you have five
minutes.
MS. TRACY: I am Ann Blake Tracy, head of
the International Coalition for Drug
Awareness. I
am the author of "Prozac: Panacea or
Pandora." My
268
house is mortgaged to the hilt to pay for
the last
15 years that I have devoted to nothing
but
research on SSRI antidepressants and to
fund my
trip here.
I testified for twelve and a
half years in
court cases involving these drugs. Research on
serotonin has been clear from the very
beginning,
that the most damaging thing that could
be done to
the serotonergic system would be to
impair one's
ability to metabolize serotonin, yet that
is
exactly how SSRI antidepressants exert
their
effects.
For decades research has shown that
impairing serotonin metabolism will
produce
nightmares, hot flushes, migraines, pains
around
the heart, difficulty breathing,
worsening of
bronchial complaints, tension and anxiety
which
appear from out of nowhere, depression,
suicide,
especially very violent suicide and
repeated
attempts, hostility, violent crime,
arson,
substance abuse including cravings for
alcohol and
other drugs, psychosis, mania, organic
brain
disease, autism, anorexia, reckless
driving,
269
Alzheimer's, impulsive behavior with no
concern for
punishment, and argumentative behavior.
How anyone ever thought it
would be
therapeutic to chemically induce these
reactions is
beyond me, yet these reactions are
exactly what we
witnessed in our society over the past
decade and a
half as a result of the widespread use of
these
drugs.
Can you remember two decades
ago when
depressed people used to slip away
quietly to kill
themselves rather than killing everyone
around them
and then themselves, as they do while
taking an
SSRI antidepressant?
A study out of the University
of Southern
California, in 1996, looked at a group of
mutant
mice that had been genetically
engineered. In an
experiment that had gone terribly wrong,
they were
the most violent creatures they had ever
witnessed.
They were born lacking the MAOA enzyme
which
metabolizes serotonin. The end result is the same
as if they were taking an SSRI
antidepressant which
does inhibit the metabolism of serotonin.
270
This has been a national
holocaust. It
must end.
These are extremely dangerous drugs that
should have been banned as similar drugs
were in
the past.
As a society, we once thought LSD and
PCP to be miracle medications. We have never seen
drugs so similar to LSD and PCP as these
SSRI
antidepressants are. All of these drugs produce
dreaming during periods of
wakefulness. The higher
serotonin levels overstimulate the brain
stem
leading to a lack of muscle
paralysis. That was
seen clearly in the case of comedian Phil
Hartman
and his wife in the terrible
murder-suicide. Thank
you.
MS. GOLF: Thank you for allowing me to
speak here today. My name is Marion Golf. I am
here today with my other daughter. It was her twin
sister who was put on SSRIs.
I would like to ask all of you
a few
questions. Why is it easier to have
antidepressants prescribed to our
children than to
have antibiotics prescribed for
them? Why are
antidepressants handed out so easily to
our
271
children?
During the fall of 2002 my nine
year-old
twin daughter was diagnosed with an
eating disorder
by a doctor who never did a sufficient
medical or
psychological workup. Up to that point she had
been a happy and beautiful child, a sweet
child.
We told him that this was unlike her,
that it had
come on suddenly and severely. Instead, within a
week of seeing this eating disorder
specialist, she
was given Zoloft up to 75 mg, which was
then
switched to Paxil. At one point she was given 30
mg of Paxil and up to 10 mg of Zyprexa at
the same
time.
These drugs did not help her.
They made her
suicidal and abusive to herself and to
our family.
We almost lost our child twice.
My daughter was finally
diagnosed with
chronic Lyme's disease, in January of
this year.
Because of the delay in treatment she has
been on
intravenous antibiotics and continues in
this way,
but she has made incredible progress
while on these
antibiotics.
The antidepressants that were
given to my
272
daughter are dangerous. Would any of you prescribe
these medications for you own
children? Why are we
turning to drugs before we truly
understand the
problem?
My daughter could still be on these
mind-altering drugs if my husband and I
were not so
persistent in getting to the truth.
When a child presents with a
multi-systemic problem why isn't Lyme's
disease
ruled out first? Lyme's disease is the fastest
growing infectious disease in this
country...
DR. GOODMAN: Thank you for your
testimony.
[Applause]
Speaker number five?
MR. CHONILEWSKY: My name is Andrew
Chonilewsky. I am not affiliated with--
DR. GOODMAN: Could you bring the
microphone closer to you?
MR. CHONILEWSKY: Surely.
My name is
Andrew Chonilewsky. I am not affiliated with any
organization at all, just totally on my
own. If
you notice from slide one, this is the
name of my
273
ex-wife.
She is a VA psychiatrist currently
practicing. She is homicidal, suicidal. She is a
psychiatric drug user, mother, child
abuser and dog
killer.
This is what she is. I can
document
everything. It is certainly in the court records.
Nevertheless, she is still
practicing. That is her
workplace, where she is. I am not afraid of
exposure.
I would request slide two. I received
this, an affidavit in support of
preliminary child
protection order from the State of Maine
regarding
my son.
This is an affidavit made before Gail
D'Agostino, State of Maine, Department of
Human
Services, being duly sworn.
Next slide, please. This is rather
interesting. It comes down to, for all the talk
and all the minutia given psychiatric
drug trials,
regression analysis--I am rather reminded
in a
far-off time, in a far-off land of the
dialectics
of Marxism and class struggle. It is meaningless.
However, you have one of your colleagues
here, a
trained, Board certified psychiatrist
with added
274
qualifications in geriatric psychiatry,
and I am
inclined to believe this time what Dr.
Runden wrote
about herself in revealing her set of
depressions,
suicidal feelings regarding my child and
herself
for she planned to kill my child first,
then
herself, but there was a snowstorm that
she did not
expect so she did not. That is her reasoning.
Her comments are very
interesting. She
has forged my signature, forged
documents, perjured
herself, stolen, lied. She is a whore.
Nevertheless, I am inclined to believe
what she
writes in terms of her status, mental
status. I am
inclined to give her credibility for the
so-called
mentally ill, besides being
self-indulgent and
being control freaks...
DR. GOODMAN: Thank you.
Number six,
please.
MS. FURLOUGH: Hello.
My name is Susan
Furlough.
I am not affiliated with anyone.
This
is my son's letter to you. Good afternoon--
DR. GOODMAN: You need to bring the
microphone closer.
275
MS. FURLOUGH: Is that better? This is a
letter from my son. He says, good afternoon to
everyone.
My name is Ryan Furlough. Please
excuse
me for not being there in person for, at
present, I
am currently incarcerated. I was only 16 when I
started taking the antidepressant Effexor
XR. I
started out with a small dose of 75 mg
and over a
short period of time was up to 300 while
I was only
17.
While I was on the drug my depression got
worse, completely affecting all aspects
of my life.
Negative thoughts filled my mind night
and day. I
wasn't living at all; I was just
existing. I felt
like I was on the outside looking in on
life. I
believe that everyone hated me and
nothing seemed
to be right for me. I gave up on life and it
seemed like everyone else had no purpose.
Unfortunately, solving this
problem meant
the death of the best friend I ever
had. I felt
uncontrolled hate towards him because,
beyond my
comprehension to where I acted like I was
an
emotionless puppet, having someone else
pulling my
strings to what my fate would be. Now the worst
276
thing has happened and I can't fix it
now. I am
off Effexor XR and I can't understand
what I was
then.
This medication changed me, who I was then
and who I am now. There is no other Ryan there.
There is a new Ryan, the Ryan that used
to be there
before medicines. I know who I am now, just like I
did before.
As I said to you, it is too
late now. His
family and friends are forever
traumatized and my
own family feels the same way, except
they are
relieved that I am emerging from a dark
cloud of
Effexor.
I ask you to please take action and stop
these drugs now. Too many times have I read about
people like me having problems with
Effexor and
other antidepressants. Too many times have I put
the shoes on of the other cases similar
to mine,
knowing how much pain and suffering they
are going
through.
Too many times have I had to see people
die because nobody will take action.
It is sickening to know that
cases such as
mine will continue to show up, and unless
you do
something now more men, women and
children will
277
die.
Please don't let this continue to happen.
Other countries have started to pay
attention and
step up, shouldn't we do the same for our
children?
Thank you, Ryan Furlough.
As you have heard from my son,
many people
are suffering from these drug adverse
reactions.
These drugs change kind, gentle children
into
monsters.
Please listen now before it happens to
your family. You have the proof in front of you
from all the families that are in this
room today.
Even if the drugs can help some people,
it is not
acceptable to lose one more life. Doctors are
busy.
I am a registered nurse, I know that.
They
don't read everything they get. These drugs need
to be taken off the market to protect our
precious
children, and also to protect the young
adults that
are also having reactions, but nobody is
listening.
My son says to you stop the drugs now as
every day is a potential for another
death. My
life is forever changed...
[Applause]
DR. GOODMAN: Thank you very much.
278
Speaker number seven, please step
forward.
MS. VAN SYCKEL: Good afternoon. My name
is Lisa Van Syckel. The FDA and the pharmaceutical
industries have repeatedly stated that it
is the
disease, not the drug, that causes our
children to
become violent and suicidal. It wasn't the disease
that caused my daughter to viciously
mutilate
herself; it was the drug. It wasn't the disease
that caused my daughter to become violent
and
suicidal and out of control. It wasn't the disease
that caused her to scream the words
"I want to
die."
And, it sure as hell was not
the disease
that caused Christopher Pittman to kill
the two
people he loved the most, his
grandparents. He had
been on Zoloft just three weeks and he
was 12 years
old.
Christopher is now facing life in prison as
an adult.
I am asking everyone in this
room to help
me
to help Joe Pittman to save Christopher
Pittman's life. It is a life worth saving.
Christopher is an honor roll student,
doing well in
279
psychotherapy since he has been off the
medication.
Does he deserve life in prison because
you, as
adults, cannot accept responsibility to
tell the
truth, to come forward? I think it is time, ladies
and gentlemen, that you become adults and
you come
forward and you help this young boy.
Pfizer refers to me and others
as a
detractor of SSRIs and that I am
misinforming
legislators with oversight
responsibilities. As an
adult, I am considered fair game for verbal
attacks
but, ladies and gentlemen, Pfizer crossed
the line
the day they attacked a dead child. They viciously
attacked a dead child and you all know
it. And
you, ladies and gentlemen, as adults,
need to tell
Pfizer that they need to stop.
I would like to end by saying
thank you to
Congressman Mike Ferguson of New Jersey
who has
oversight responsibilities, who has spent
countless
hours with me and other family members in
showing
compassion. I thank him for his
assistance in
allowing me, and supporting me in my
pursuit for
congressional hearings because we need
criminal
280
charges to be filed against many.
I would like to end the rest of
my time in
a moment of silence for all of those
children and
adults who have lost their lives to
antidepressant-induced violence, homicide
and
suicide.
Thank you.
[Applause]
DR. GOODMAN: Thank you.
Speaker number
eight, please.
MR. LAGURRE: Good afternoon, ladies and
gentlemen. My name is Raul Lagurre. I am here on
behalf of my son, whose name I cannot
mention, and
all the other victims that shall remain
nameless.
The American government was formed to
protect and
serve and help the people, yet it has
failed us.
The FDA was formed to protect consumers
in showing
that the drugs we consume are, indeed,
safe but
they still allow companies to distribute
dangerous
antidepressant drugs on the market even
though
there are severe side effects to children
and
adolescents.
My son was under the influence of an
281
antidepressant drug and now he faces a
long prison
term and an innocent person was
hurt. Before he
took these drugs he was a gentle, lovable
kid who
never hurt himself or any other
person. Because of
this failure of a major drug company in
releasing
information on suicide effects of
antidepressant
drugs, I may lose my son to the
system. He is one
of
a thousand of victims who suffered severe side
effects, and continues to do so, yet this
company
continues to supply the market with them.
The FDA needs to step up,
protect the
consumer and crack down on these drug
companies
before more lives are lost. Thank you very much.
[Applause]
DR. GOODMAN: Speaker number nine?
MS. PULP: Distinguished committee
members, my name is Gloria Pulp and I am
here on
behalf of DBSA, the Depression of Bipolar
Support
Alliance.
We are a national patient-driven
advocacy organization, with more than
1000 support
groups throughout the country that assist
the more
than 25 million Americans living with a
mood
282
disorder.
Untreated depression is the
number one
risk for suicide among youth. With suicide as a
third leading cause of death among 15-24
year-olds
and the fourth leading cause in 10-14
year-olds,
medication treatment options for youth
are
absolutely critical. As an organization, DBSA has
been actively involved with the youth
population.
On the screen before you is the cover of
the "Storm in my Brain," a
publication compiled by
DBSA and the Child and Adolescent Bipolar
Foundation. As you can see, this art work, created
by young people with mood disorders,
graphically
displays the feelings they associate with
their
illness.
These illnesses, if left untreated, can
lead to tragic consequences.
DBSA does not believe there
should be
limits to therapeutic options open to
doctors and
families.
But we do believe that whatever
treatment is selected, whether it is
medication,
psychotherapy or support groups, parents
and
physicians need to be diligent in
monitoring
283
symptoms to avoid self-harm of all types.
Therefore, we support strict monitoring
of existing
and emerging treatment options.
DBSA appreciates and supports
the very
hard work of these two advisory
committees in
examining whether certain medications
increase the
risk of suicidality in adolescents. Like NAMI,
DBSA believes even further research is
needed and
that the results of clinical trials should
be made
available to the public.
We urge the National Institute
of Mental
Health to increase research on the proper
treatments for children. Depression and bipolar
disorder are real treatable medical illnesses
that
affect both children and
adolescents. While we
recognize that there may be consequences
or
occurrences where, without adequate
monitoring,
certain patients have responded
negatively to
certain medications, in many others they
have.
Take, for example, a woman
named Tara who
contacted the DBSA to say that after
trying a
number of medications her 12 year-old son
had found
284
a treatment that appeared to be
working. My child
never actually laughed until he was 12
years old,
she said.
Imagine what a joy when he finally did.
As FDA looks to potentially
regulate
certain medications, DBSA urges these
advisory
committees to look closely at the
successes as well
as the shortcomings in existing treatment
options
and act accordingly. We can help children quell
the storms in their brains.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number ten?
MR. VICKERY: Good afternoon. My name is
Andy Vickery. I am a trial lawyer from Houston,
Texas, and for the bulk of the last nine
years I
have represented the families of victims
of
SSRI-induced violence.
I have three separate and
different things
to share with you if my time
permits. First, when
I was here in February the written
materials and
the presentation I made expressed a
concern that
when you search the databases you are
looking for
285
the needle in a haystack--Eli Lilly's
words, not
mine--needle in a haystack because the
clinical
trials were not designed to capture
suicidality.
They use rating scales that have only one
item on
the rating scale even though there are
others that
are more refined and difficult to find
because we
know that there is a redistribution of
risk.
Tischer and Cole wrote about
this in '93.
Dr. Gordon Parker, from Down Under, wrote
to Lilly
about it in 1990. It may help some over here and
harm some over here. So, if you are looking for a
signal, you are looking for a needle in a
haystack.
Miraculously, in spite of that, you have
found the
needle but I still am concerned that you
are
looking the wrong way.
Lilly knew in 1990, when they met with the
FDA, the best way to answer this question
in a
scientifically proper way was through a
rechallenge
protocol, not through RCTs and not
through epi.
studies.
They pledged to the FDA that they would
conduct such a study. They never did it. You
never made them.
286
The second item I would like to
bring to
your attention is that in the interim,
since this
committee met last, the FDA has blessed a
new drug
on the market, duloxatine released just a
couple of
months ago. It is an SNRI. There are completed
suicides in the clinical trials,
including one of a
healthy volunteers, on February 7th of this year.
It was, nonetheless, approved. If you are going to
differentiate in the warnings, ladies and
gentlemen, that one needs a black box on
it.
Finally, I wish you could hear
from some
of the victims themselves. I only have 55 seconds.
I would tell you if I could--my name is
Christopher
Joseph Gangwich. Two weeks from today would be the
fourth anniversary of my death. I got the Paxil
because my girlfriend wasn't being nice to
me. I
went to my mom. They put me in the hospital. The
doctors increased the Paxil. A week later I was in
the hospital again--more Paxil. Four days later I
hanged myself in the closet. Before I did, I
carved a message, a message for you, the
words--"dying; help," in my own
groin--in my own
287
groin.
Ladies and gentlemen, kids are still dying.
Will you help them?
[Applause]
DR. GOODMAN: Thank you very much. Is
speaker number 11 here?
MS. SHARAV: My name is Vera Sharav, and I
am the president of the Alliance for
Human Research
Protection. In contrast to today's presentations,
every independent analysis of the data,
including
FDA's own, has corroborated King's 1991
report
describing the development of intense
self-injurious ideation and behavior in
six
children who received fluoxetine.
The Mosholder report, which was
embargoed
for six months and didn't see the light
of day
until we put it up on our website,
confirmed that
children exposed to an antidepressant are
twice as
likely to suffer suicidal-related adverse
events
compared to those given a placebo. Dr. Mosholder
identified 78 cases and recommended
discouraging
off-label pediatric use of SSRIs. Columbia's
reclassification identified 17 additional
cases.
288
The FDA and drug companies have
known the
risks and concealed them for over a
decade, and the
blinders are still on. Physicians and parents
continue to be deceived with false
assurances that
the drugs are safe and effective. FDA's excuses
for its inaction insult our
intelligence. Dr.
Temple maintains that both the data and
Mosholder's
interpretation were imperfect, and
behaviors
labeled suicidal could have been
accidents.
When a fire erupts, the fire
department
doesn't wait until it has absolute proof
of
causality before it acts. The committee's charge
is not to answer why or how the drugs
increase
suicide risk. Given that the drugs' failure in
controlled clinical trials to show an
effectiveness
for children, and given the link between
drug
exposure and increased risk of suicidal
behavior
has been scientifically established, the
committee's charge ought to be how to
best protect
children.
In addition to suicide risk,
SSRIs are
linked in children to stunted growth,
cardiac
289
abnormalities, mania and a tremendous
rise in manic
depression. How many children need to be harmed
before action is taken? Children's safety in these
trials is a concern as well. FDA's review
identified Prozac study HCJE as, quote,
one of four
trials with the largest number of
definitive...
[Applause]
DR. GOODMAN: Thank you very much. We are
skipping number 13 because the FDA is
superstitious--no, actually number 13 has
not
shown, and we are turning to number 14.
MS. TIERNEY: Hello.
My name is Jennifer
Tierney, and I have no financial ties to
anyone but
my husband--
[Laughter]
My daughter, Jamie, and I
attended the
last advisory meeting during which she
described
her experience on Effexor. Jamie was prescribed
Effexor for migraine headaches, not--and
I want to
emphasize--not for depression. She became suicidal
on Effexor for the first time in her life
and, to
make matters worse, when she tried
stopping Effexor
290
she suffered tremendous withdrawal
reactions.
Following the February PDAC, I
met with
members of HHS and Dr. Temple. I followed up with
a letter to the FDA which I cc'd to the
entire
advisory panel, detailing the history of
FDA's
failure to protect the public health
related to
antidepressants and suicidality.
I have returned today to make a
couple of
points.
First, I want to thank the panel from the
February meeting for actually listening
to us and
for taking us seriously about our
concerns.
Second, I would like to say that I am
appalled that
the FDA would not allow the maker of
Effexor to
place stronger warnings in its label, stating
that,
quote, in pediatric clinical trials there
were
increased reports of hostility, and
especially in
major depressive disorder suicide-related
adverse
events such as suicidal ideation and
self-harm,
unquote.
This is what the data shows, yet the FDA
will not allow it.
One has to ask whose interest
is the FDA
protecting here? I honestly do not know how the
291
individuals responsible for this can even
sleep at
night.
Now the U.K. has all but banned these drugs
in children and adolescents. Dr. Mosholder found
an increased risk of suicidal behavior in
children
and adolescents taking the drugs, which
certain
people within the FDA tried to
suppress. Now the
review by the Columbia group, despite its
flaws,
seems to confirm that risk.
Well, it doesn't take a rocket
scientist
to figure out that if a drug lacks
efficacy, which
has been a problem for the drug companies
in both
child and adult clinical trials, and it
has serious
risks such as suicidality, you probably
should not
be prescribing it to as vulnerable
population as
children and adolescents. The argument that one
doesn't want to deter people from taking
them
doesn't hold water when you consider the
lack of
efficacy.
But for those families who still argue
that drugs have been helpful to their
child, that
does not justify withholding warnings
that would
have helped my child and save lives.
One last comment I would like
to make is
292
that Pfizer's very personal attack on Dr.
David
Healy and the father who lost his 13
year-old
son--he hung himself while on Zoloft--is
nothing
short of reprehensible. It appears that Pfizer is
getting down and dirty. Dr. Healy is a pioneer
whose bravery and strength of character
has saved
lives.
As for the boy, even if Pfizer's facts were
accurate, the drug is...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number 15, please come forward to the
microphone.
DR. SALERIAN: Good afternoon. I am Dr.
Salerian.
I am a psychiatrist and medical director
of a private psychiatric clinic, and I
primarily
practice psychopharm.
As a society, we are wonderful
at
developing villains and heroes, and it is
impossible for me to sit in this room and
not to
realize that it is as if we had two
groups of
people, good people and bad people, and
depending
on what side you are taking, the other
side is the
293
enemy and we are questioning their values
and
integrity. The truth is, as a psychiatrist, I am
very ashamed of how poorly we have served
the
nation in terms of educating about the
dangers of
side effects of antidepressants, and this
is the
truth.
So, in that way, I personally apologize to
anybody--to mothers and fathers, whose
children
have been affected adversely by
antidepressants.
It is also true that depression
is a real
illness. It exists. It existed before
antidepressants. I grew up in Turkey and I can
tell you that even today not many people
take
antidepressants, but a good number of
people manage
to commit suicide or have miserable
lives. The
significant thing to know for all of us
is that
depression is a dangerous disease, so are
antidepressants.
Now, in terms of our approach
and the
numbers--recently I published an article
and
reviewed an article in Lancet about
antidepressants
and safety. My analysis is that we are making a
big mistake by not realizing that
depression is a
294
heterogeneous group of depressed kids and
adolescents; it is not just one
group. When a
child is depressed he may grow up and
develop
nothing; may grow up with a bipolar
illness; may
grow up and become an adult with
schizophrenia or
any other serious psychiatric
illness. Our current
technology and science is not enough to
differentiate one diagnosis, particularly
children
who present with depression and who are
dormant
candidates to become severely ill as
adults. This
itself causes tremendous vulnerabilities
and,
therefore, monitoring is essential to
prevent side
effects and dangerous consequences such
as suicide.
So, better monitoring would be my
advice. Thank
you.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number 16, please come forward.
MS. BOSTOK: Over ten years ago, in the
article,
"Antidepressant Drugs and the
Emergence of Suicidal
Tendencies," Harvard doctors
described nine
295
mechanisms by which antidepressants can
induce
suicidality. My daughter, Cecily, who stabbed
herself to death after three weeks on
Paxil,
exhibited behavior on antidepressants
that closely
fit these mechanisms. We need warnings for all of
them.
One,
energizing--antidepressants may
provide the energy to enable depressed
patients to
act on preexisting suicidal plans. The authors
affirm the relevance of this mechanism to
other
classes of antidepressants besides SSRIs
but state
that in no case was there evidence that
strong
preexisting self-destructive urges were
energized
by Prozac. Cecily had no history of suicidality.
She was not given Paxil for depression
but for
racing thoughts and her energy did not
improve.
Two, paradoxical
worsening--Cecily's mood
did worsen on Paxil.
Three, akathisia--in the last
days of her
life Cecily was jittery.
Four, panic anxiety--after
Cecily started
treatment she became very fearful upon
waking. The
296
last day of her life she came shrieking
from her
bedroom, terrified by the noise of a
plane--completely uncharacteristic.
Five, manic or mixed
states--although
Cecily had no confirmed diagnosis for
mood
disorder, she was being treated for
manic-like
symptoms.
Paxil was exactly the wrong medication
for her.
Patients should be closely monitored for
the emergence of mania which can enhance
violent
and aggressive behavior or a mixed state
can
augment suicide risk.
Six, sleep disturbances--on the
first
night she took an antidepressant she
walked in her
sleep.
She had never done this before.
There is
evidence she was sleepwalking when she
died. She
did not turn on any lights or make any
noise when
she stabbed herself at 2:00 a.m. Quote, Prozac
produced a dramatic increase in rapid eye
movement
even during non-REM sleep stages. It reduced delta
sleep, causing emergence of day terrors
similar to
unmedicated patients with a history of
suicidal
attempts.
297
Seven, suicidal
preoccupation--on the last
day Cecily confessed uncharacteristic
fears, and
after dinner stared strangely at her
knife. This
frightened me but I never dreamed she was
contemplating self-harm; she had never
done so
before.
Quote, strong obsessive, remarkably
violent suicidal thoughts emerged after
Prozac
treatment.
Eight, borderline
state--symptoms of
borderline disorder suggest a state of
serotonin
dysregulation. Cecily's autopsy revealed a very
high blood level of Taxol and, thus,
acute
dysregulation. Quote, patients who do not suffer
from borderline disorder may have
drug-induced
borderline reactions that include
emergence of
uncharacteristic aggression,
self-mutilation and
suicide.
Nine, EEG activity--Cecily said
when she
took a pill she felt like it was frying
her brain.
One study reported a...
[Applause]
DR. GOODMAN: Thank you very much.
298
Speaker number 17, please come forward to
the
microphone.
DR. FASSLER: Thank you.
My name is David
Fassler.
I am a child and adolescent psychiatrist,
from Burlington, Vermont. I am speaking on behalf
of the American Psychiatric
Association. No
pharmaceutical or other industry support
was used
in conjunction with my appearance here
today.
I would like to emphasize a few
key
points.
First, childhood and adolescent depression
are very real illnesses which affect
between 3-5
percent of all young people.
Second, these are extremely
serious
conditions with very significant
consequences.
Research tells us that over half of all
kids who
suffer from depression will eventually
attempt
suicide at least once, and over 7 percent
will
actually die as a result. Fortunately, effective
treatment is available. Medication, including the
SSRI antidepressants, can be extremely
helpful and
even life-saving for some children and
adolescents,
but medication alone is rarely an
adequate or
299
sufficient intervention for complex child
psychiatric disorders such as depression.
With respect to the SSRIs, I
would offer
the following comments and
observations. The
studies currently available do suggest
that the use
of these medications may be associated
with an
increased risk of certain suicide-related
thoughts
and/or behaviors in some children and
adolescents.
However, the data is far from clear.
For example, as we heard this
morning, the
same data indicates that there is no
significant
increase in the worsening or emergence of
suicidal
symptoms.
As you have also heard, concerns about
suicidal thoughts and behaviors early in
the course
of treatment are not new. They are also not
limited to the SSRIs, nor are they
limited to the
treatment of children and
adolescents. Thoughts
about suicide are also not uncommon,
especially
during the teenage years. According to the CDC,
one adolescent in six thinks about
suicide each
year.
Fortunately, the overwhelming majority of
young people who have suicidal thoughts
do not
300
actually commit suicide. But every suicide is a
tragedy and any increased risk of
suicidal thoughts
or behavior, no matter how small, must be
taken
very seriously.
However, based on the data
currently
available, most clinicians believe, and I
would
concur, that for children and adolescents
who
suffer from depression the potential
benefit of
these medications far outweighs the risk.
There is also general clinical
consensus
that all of the antidepressants are
effective for
some but not all children and
adolescents.
Research indicates that between 30-40
percent will
not respond to an initial medication,
however, many
of these young people will ultimately
respond to a
different medication.
Let me close with the following
specific
recommendations. First, we strongly support the
development of a national registry of all
clinical
trials.
Second, we support the
continuation of the
current FDA warnings with respect to SSRI
301
antidepressants. We believe the language is
appropriate and consistent with our
current
knowledge, understanding and scientific
data.
Finally, we fully support the
call for
additional large-scale research
studies. Thank
you.
[Applause]
DR. GOODMAN: Thank you very much for your
presentation. Speaker number 18, please come
forward.
MR. WOODWARD: My name is Tom Woodward.
My wife, Kathy, and I have four
children. Julie,
the oldest of our four children, took her
life on
July 22, 2003. Julie was a gentle and beautiful
young girl. She was only 17. She was deeply loved
and is truly missed by all who knew
her. Julie was
a normal teenager, dealing with normal
teenage
issues.
She had no history of self-harm or
suicide.
She was prescribed Zoloft and
we were told
that it was safe, very mild, extremely
effective
and essential to her getting better. Seven days
302
after taking her first Zoloft tablet
Julie hung
herself in the garage of our home. We have since
learned that Julie began experiencing
akathisia
almost immediately after taking the first
pill.
Julie never harmed herself in
her 17
years.
The only variable was seven days of Zoloft.
We are certain that Zoloft killed our
daughter.
The recent JAMA article stated that the
risk of
suicide is 40 times greater during the
first nine
days of treatment with an SSRI. I believe this is
a national crisis.
The drug industry has oversold
the
purported benefits of SSRI drugs and
aggressively
promoted their use. As the Spitzer lawsuit
confirmed, drug companies have purposely
misled the
public about the safety and efficacy of
their
drugs.
The problems associated with
these drugs
are particularly frightening in light of
the Bush
administration's new Freedom Initiative,
a program
designed to subject every school age
child in this
country to psychological testing. The way these
303
tests are designed, many children will
fail and
inevitably be prescribed an SSRI. Tragically, some
of these children will then go on to
mutilate
themselves, commit acts of violence, or
kill
themselves as a direct result of these
drugs. We
are too quick to medicate our children.
Our system of medical treatment
is based
on a sacred circle of trust. This trust has been
broken.
Children look to their parents to protect
and guide them. Parents seek out the advice and
counsel of physicians and mental health
professionals who, in turn, largely rely
on the
drug industry opinion leaders and the FDA
to allow
them to fulfill their role as informed
intermediaries. The drug industry has employed
tactics of deception, distortion,
misdirection and
manipulation.
Big PhARMA's money has
corrupted the
process and destroyed the sacred
trust. They buy
political influence that secures the
placement of
individuals within the FDA to do their
bidding,
such as Dan Troy whose mission is
clear--damn the
304
public and protect his former drug
industry clients
at all cost. Troy is more concerned with tort
reform than with children's lives.
Senior leadership at the FDA
drag their
feet and make Orwellian statements such
as, just
because these drugs have not been proven
to be
effective does not necessarily mean they
are
ineffective. This gibberish is an insult to the
American public and would be laughable if
the
consequences weren't so terribly tragic.
Drug industry CEOs at Pfizer
and those at
Glaxo and Lilly, senior leadership under
FDA--Troy,
Crawford, Temple, Katz and Laughren know
the truth
and therefore have blood on their hands.
I deeply appreciate the work of
this
committee. I know there are good people at the FDA
trying to do the right thing in spite of
the FDA's
current leadership. Implement class-wide, strongly
worded black box warnings immediately,
inclusive of
Prozac, not some carefully worded drug
industry
version designed to protect their
interests instead
of the public's. The FDA needs to be restored to
305
its vitally important mission of
protecting the
welfare of the American public.
[Applause]
DR. GOODMAN: Thank you.
Speaker number
19.
MS. MCDONALD: Good afternoon. My name is
Sheila McDonald. I am the vice president of the
Board of the Child and Adolescent Bipolar
Foundation.
The public is alarmed that
SSRIs may cause
children to become suicidal. What alarms us is
that untreated children, prepubertal
children and
teens with affective mood disorders are
already
suicidal at high rates. This is the crux of the
problem.
Just two days ago there was a
posting on
our website, and I quote a woman about
her 10
year-old son where she says, "I
thank God for each
and every pill, each and every day that I
don't
have to listen to my son, my little boy
say that he
wishes he was dead." She was talking about mood
stabilizers, not SSRIs but we come back
to the crux
306
of the problem, which is that untreated
children
are already suicidal.
I have prepared remarks. I think they
have been handed out to you, and this may
be a
little disjointed. I wanted to talk actually about
some testimony that we have heard this
morning. I
have two points on that. One is that the research
is not where it should be. It is not advanced
enough for us to be able to distinguish
between
children with major depressive disorder
and
children with bipolar disorder.
Secondly, as a lay person,
which I admit
that I am, many of these events I think
can be
explained perhaps by SSRI's triggering
disinhibition for children who perhaps
have
presented with a major childhood
depression
disorder but, in actuality it is bipolar
disorder.
This morning Dr. Laughren asked
the
committee what research is needed. In my prepared
remarks we urge that significant resources be
devoted to both the suicidality component
inherent
in certain pediatric brain disorders and
on the
307
efficacy and safety of medications used
to treat
these disorders in the pediatric
population. We
must realize that children are not short
adults.
What I think this morning's
testimony has
made clear is that research must be
devoted to
diagnosing appropriately the pediatric
psychiatric
disorders. All the presenters have made the
assumption--as I like to say, they have
put the
bunny in the hat. It is easy to pull the bunny out
once you put the bunny in--bunny in the
hat. Dr.
March says that his studies have excluded
bipolar
disorder.
Dr. Dubitsky speaks of the, quote,
potential influence of study design on
suicidal
risk.
Our children are ill. Our
children need
medical help and they are excluded from
these
studies, our children who have bipolar
disorder.
At this time we don't have a
magic
dip-stick to tell whether you have MDD or
BP.
Clinicians must be cognizant that an
episode of
childhood depression can signal bipolar
disorder
and that in certain cases antidepressant
use may
trigger or provoke mania. We do want amplified
308
warnings and monitoring, but we do oppose
any
attempt to ban the use of antidepressants
as they
can be an important and potential
life-saving tool
in the treatment box when carefully
monitored.
Thank you.
DR. GOODMAN: Thank you.
Speaker number
20?
DR. WALKUP: I am John Walkup. I am a
child and adolescent psychiatrist, on the
faculty
at Johns Hopkins. I currently have grant support
from Eli Lilly, Pfizer and Abbott, and within
the
past year I have received honoraria from
Lilly,
Pfizer and Janson. No one is paying for me to be
here and I don't represent anyone today
other than
myself.
I am a clinician and also a
clinical
investigator. I have conducted federally-funded
trials like TADS. I was a participant in TADS and
I have also participated in
industry-sponsored
trials
As a clinician, there is much at stake
today.
There are many, many children who have
benefited from appropriate assessment and
309
treatment, and I am afraid their stories
may get
lost if someone doesn't speak for them.
Prior to this controversy we
knew a lot
about depression, and one of the things
that we
knew about was the early risk for
suicidal ideation
early in the course of treatment. In addition, we
were also trained that medications, not just
SSRIs
but other medications, can cause
behavioral side
effects.
So, other antidepressants, the
tricyclics, antihistamines like Benadryl,
and
anti-malarials were recently reported in
the
newspaper. Anti-psychotic medications and
stimulants can all cause changes in
behavior. What
is unusual is the link between changes in
behavior
and suicidal acts that we do not
understand even
though changes in behavior are a part of
the
spectrum of drug effects.
With that said about suicidal
behavior, I
would like to talk a little bit about the
efficacy
trials.
It is very surprising to me as a clinician
that the clinical trials do not document
efficacy
of antidepressants in depression. When I look at
310
the clinical trials, there are two types
of
clinical trials. There are the federally-funded
trials and then there are the
industry-sponsored
trials.
If you look closely at the methodologies
for both, there are significant
differences in the
methodologies for the federally-funded
trials and
the industry-sponsored trials, with the
federally-funded trials having a much
higher
standard for ongoing quality assurance
and training
of investigators and participation.
My recommendations to the FDA,
as humble
as I can be, please don't make policy
based on
complex and rare events. It is a dangerous
precedent and it can do more harm than
good. If
you do go to a stronger warning, please
provide a
warning that clarifies but doesn't
magnify.
Magnification of the warning may actually
do more
harm than good to the kids who actually
need to
come to care.
Lastly, I would encourage the
FDA, as it
reviews future clinical trials in
children, to
think about those kinds of standards that
are set
311
through the peer review process for
clinical trials
in kids, and to incorporate some of those
quality
measures in those clinical trials. Thank you.
[Applause]
DR. GOODMAN: Thank you.
Speaker 21,
please come forward.
MR. TAYLOR: My name is Mark Taylor and I
am one of the victims, one of the many
victims of
the SSRI antidepressant era. I took 6-13 bullets
in the heart area at my high school when
Eric
Harris who was, in fact, on Luvox fired
at me.
They almost had to amputate my leg and my
arm. My
heart was missed by only one
millimeter. I had
three surgeries. Five years later I am still
recuperating.
I had to go through all this to
realize
that antidepressants are dangerous for
those who
take them and for all of those who
associate with
those who take them. I hope that my testimony
today shows you that you need to take
action
immediately before more innocent people
like me and
you get hurt or die horrible deaths as a
result.
312
As Americans, we should have
the right to
feel safe, and if you were doing your
jobs we would
be safe.
Why are we worrying about terrorists in
other countries when pharmaceutical
companies have
proven to be our biggest terrorists by
releasing
these drugs on an unsuspecting
public? How are we
supposed to feel safe at school, at home,
on the
street, at church or elsewhere if we
cannot trust
the FDA to do what we are paying you to
do? Where
were you when I got shot?
You say that these
antidepressants are
effective. So, why did they not help Eric Harris?
According to Eric, they helped him feel
suicidal.
He reported to his psychiatrist he was
having
psychotic reactions to the drug. They took him off
it.
He said he was doing great. They
put him back
on it.
He was having suicidal thoughts again.
These drugs help increase the rage in
people and
cause them to do things they would not do
anyways.
So, why do these so-called
antidepressants not make
him better?
I will tell you why. It is because they
313
don't work. We should consider antidepressants to
be accomplices to the murder.
MS. TAYLOR: Hello.
My name is Donna
Taylor and Mark did go through these
injuries.
Mark and I both know that had Eric Harris
not been
given the antidepressants both Zoloft and
Luvox the
nightmare at Columbine would never have
happened to
our family and our lives. But Columbine was only
the beginning of the
antidepressant-introduced
nightmare. I was also given antidepressants and
suffered side effects, including suicidal
thoughts
and horrible Paxil withdrawal.
To this day, four years later,
I am still
suffering adverse events. Many other members of my
family have been on antidepressants with
disastrous
results.
Where there was never a...
[Applause]
DR. GOODMAN: Thank you.
Speaker number
22, please come forward to the
microphone.
MS. WOODSACK: Hi, my name is Kin Woodsack
and my husband of almost ten years,
Woody, died of
Zoloft-induced suicide after being on the
drug for
314
five weeks, with the dosage increased
just prior to
his death.
He was prescribed Zoloft by his
general
physician for the diagnosis of
insomnia. He had
just started his dream job as vice
president of
sales for a start-up company two months
prior. He
was having trouble sleeping due to the
new stresses
of the job. Woody wasn't depressed, nor did he
have a history of depression or any other
mental
illness.
He was told the drug was safe and was
sent home and a three-week
Pfizer-supplied sample
packet automatically doubled the dosage
from 25-50
mg.
No cautionary warning was given to him nor me.
In fact, I was out of the country and
there was
nobody monitoring him the first two and a
half
weeks.
Shortly before he died, I found
him curled
up in a fetal position with his hands
like a vice
going, "help me; help me. I don't know what's
happening to me. It's like my head is outside my
body looking in. I'm losing my mind." This is not
just a children's issue. Adults are also dying
315
from SSRI-induced suicides.
As I was preparing for today
one thing
kept coming to mind, and that is the
outrageous
marketing of these drugs. These drugs were
originally designed for major depressive
disorder.
Now they are being prescribed for
everything from
mild depression, anxiety, shyness,
insomnia,
migraines. Just last week people were on the
"Today Show." Doctors were telling people they
could take two weeks on, two weeks off
because
having depression is so serious with
PMS. One drug
fits all?
Are these marketing based or are they
science based?
You know, my entire career has
been in
advertising and I just want to say thanks
to the
drug companies that are here because the
Harvard
Business School is actually doing a
study, one of
the case studies, which is all about the
marketing
of antidepressants. I have to say that children
who have died on these drugs matter. The adult
victims of this tragedy matter. Woody, my best
friend, matters. The time has come to do the right
316
thing.
We should never have been here today if the
right thing had been done 13 years ago
and the
follow-up safety studies had been done,
and if FDA
followed up with the drug companies.
Let's continue not to waste
hours of
precious time and lives. We have to fix the
problem.
The system is broken. We have to
do it;
people's lives are at stake. Thank you.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number 23, please come forward to
the
microphone.
MS. BARTH MENZIES: Thank you.
My name is
Karen Barth Menzies, and I am an attorney
with Baum
Headland.
We represent over 100 families whose
loved ones have committed suicide or
they,
themselves, have attempted suicide. You heard from
a few of them today.
Approximately half of those cases
involve
children.
We have been doing this for over 14
years.
Through the litigation process, our experts
see more evidence concerning the true
risks versus
317
the true efficacy of these drugs than
anyone
anywhere.
That includes FDA. Court-imposed
protective orders don't permit us to show
this
evidence to FDA or even the congressional
investigators or you.
This evidence shows, I can tell
you, that
the companies have known about the
serious risk and
the lack of efficacy since the mid
1980s. But
today I am not going to talk about
suicide risk.
Plenty of people are going to be
addressing that
today.
What I want to talk about is efficacy.
For purposes of illustration
and because
of what I have just heard earlier today,
I am going
to focus on Zoloft. Dr. Paul Lieber, former FDA
veteran of 20 years, who was principally
involved
in the investigation, analysis and
approval of the
SSRIs, wrote in a memo, from August of
1991, and I
quote, in recommending the approval of
Zoloft for
adults, I have considered the fact that
the
evidence marshalled to support Zoloft's
efficacy is
not as consistent or robust as one might
prefer it
to be.
Back in 1991, Dr. Lieber noted that
318
numerous countries around Europe have
already
rejected or were about to reject approval
of Zoloft
because Pfizer could not demonstrate
efficacy. It
was only until FDA approved Zoloft that
the rest of
the countries followed.
In 1991, Dr. Lieber stated, and
I quote,
approval of Zoloft may come under attack
by
constituencies that do not believe FDA is
as
demanding as it ought to have been in
regard to its
standards for establishing the efficacy of the
antidepressant drugs.
Just yesterday Dr. Lieber was
quoted again
in the "Denver Post" article,
stating, second
generation antidepressants were approved
by a
regulatory process that requires only
limited proof
of efficacy and safety. Dr. Lieber also quoted,
you are working in a sea of
ignorance. He
concluded, I do have some doubts about
these drugs'
values in the big picture.
The drug companies have been so
successful
in misleading the medical profession that
their
drugs are remarkably effective that it is
hard...
319
[Applause]
DR. GOODMAN: Thank you.
Speaker number
24, please come forward to the
microphone.
DR. GREENHILL: Thank you.
My name is
Larry Greenhill. I am a child and
adolescent
psychiatrist, from New York. I am speaking today
on behalf of the American Academy of
Child and
Adolescent Psychiatry and the American
youth that
they represent. This organization represents over
7000 child psychiatrists across the
country and has
supported my trip here today. I have also received
support for research from the
pharmaceutical
industry in the past but not for this
meeting.
In the brief time I have been
given I want
to focus on four points. Both I and the Academy
support education about depression, which
is a
serious illness which needs very good
treatment
immediately.
Second, the Academy supports
better
adverse event elicitation and safety
monitoring
procedures.
Third, the Academy supports the
formation
320
of a national registry of clinical trials
and,
finally, they support more prospective
research.
To get to the first point, the
Academy
finds untreated depression to be a
serious illness
which interrupts youth's normal emotional
development, undermines self-esteem,
interferes
with learning in school, and undermines
friendship
with peers. It afflicts many of the 500,000
adolescents who attempt suicide annually
in this
country.
Second, the Academy supports
the FDA's
more detailed evaluation of safety data
found in
the clinical trials of SSRIs we are
discussing
today; supports its Columbia
reclassification
project; and supports the public airing
of the
resulting data analysis.
We also agree with the FDA's
decision to
insert warning language into the package
instructions that accompany all
antidepressant
medications, alerting physicians and
families about
the need to monitor for signs of new
suicidal
thinking or activity during the early days
of
321
treatment.
Many child psychiatrists,
including me,
have found these antidepressants to be
helpful for
treating carefully diagnosed depressed adolescent
patients when these drugs are used in a
well-monitored treatment program. It is reassuring
that the analyses that we have heard
today fail to
find a single completed suicide among the
4400
youth who participated in clinical
trials.
Third, the AACP is pleased to
join the APA
in support of a national registry of
clinical
trials.
We believe that physicians and parents
must have all available knowledge about a
medication's safety and effective to make
informed
decisions about treatment choices.
Fourth, the Academy calls for
more
research on SSRIs to obtain more precise
estimates
of the risk of suicidal behaviors and
suicidal
ideation during treatment. The Academy supports
the funded research efforts now under
way, and we
encourage the FDA to support new data in
the future
using an incentive program. Thank you.
322
DR. GOODMAN: Thank you.
Is speaker
number 25 here? Okay, we will turn to speaker
number 26, please.
DR. DILLER: I have prescribed psychiatric
drugs to children for 26 years. I have written two
books on children and psychiatric
drugs. I have
appeared before Congress and the
President's
Council on Bioethics. But today I come before you
as a physician in private practice with a
report
from the front lines, news from the
primary care
pediatricians and family doctors, the
private
practice child psychiatrists and the
families of
the patients themselves.
I am here, representing the
views and the
reactions of a silent majority of
physicians who
aren't intimately connected financially
with the
drug industry. Here is what they are saying and
thinking:
The battle over the SSRIs in kids'
depression is over. The ongoing publicity and
negative reactions have already changed
the average
doctor's opinions and practices. No longer are
pediatricians, willy-nilly, prescribing
SSRIs for
323
minor mood swings and phobias. Even child
psychiatrists have become more careful to
whom they
prescribe. All the doctors have become aware of
the problems that may be developed in the
early
stages of SSRI treatment. They are warning the
families and following the children far
more
closely.
I think this is a very good
development.
However, many of the leaders in organized
psychiatry and academia are publicly
wringing their
hands--pediatric depression is untreated
they say.
Now even more families will refuse
medication. I
find this cavilling worry the height of
psychiatric
sanctimony. For years we were told to practice
evidence-based medicine and now, when
there is no
evidence for SSRI effectiveness and yet
higher risk
of suicidality, the leaders say,
"wait, not so
fast." I say, "where's the beef?"
That brings me to my major
point. There
is a growing credibility gap between the
front-line
doctors with the leadership and
researchers in
psychiatry. We simply do not know what to believe.
324
We are increasingly bewildered, skeptical
and
cynical.
The final blow was learning about the
eight negative SSRI studies in children
that were
never released to either the doctors or
the public.
This loss of credibility within
the
medical profession extends beyond
psychiatry into
all of medicine and the general
public. The blame
is clear.
The money, power and influence of the
pharmaceutical industry corrupts
all. The
pervasive control that the drug companies
over
medical research, publications,
professional
organizations, doctors' practice,
Congress and,
yes, even agencies like the FDA is the
American
equivalent of a drug cartel. It is long overdue to
make changes in the way we approve and
market
pharmaceutical drugs in this country.
Suppression of negative studies
in the
name of protecting stockholder interests
at the
cost of children's health highlights the
immorality
of an unfettered, unregulated
marketplace.
Specifically, we need true transparency
in
research.
We also need a more organized system of
325
follow-up by neutral third parties once a
drug is
released.
Let us not lose the momentum to reform
this moment gives us lest the tragedies
of the
families who appeared before us today go
in vain.
Thank you.
[Applause]
DR. GOODMAN: Thank you.
Speaker number
27?
MR. BUTLER: My name is Reese Butler, and
I am a survivor. I lost my wife, my best friend,
my life partner to a suicide on April
7th, 1998.
Her name was Kristin Brooks Roussel. It is my
belief, and the belief of many experts I
have met
since her death that her suicide was
preventable.
What began the chain of events
that led to
her suicide was a severe bout of
postpartum
depression treated with SSRIs, which
triggered what
is known as an SSRI syndrome. Kristin became
pregnant in July of 1997 and was taking
SSRIs on a
daily basis. She had been taking SSRIs for close
to five years. They worked.
They gave her peace
and very little depression.
326
The pregnancy was unplanned so
during the
first trimester she was still on the
SSRIs. As
soon as she found she was pregnant she
stopped
taking the drug. On December 7th we learned that
our baby daughter had many significant
birth
defects, one of them life-threatening to
our baby.
She immediately decided to terminate the
pregnancy.
After losing our baby she started down a
path that
led to her death.
A bipolar mom is 31 times more
likely to
suffer postpartum depression. The standard of care
is prescribing SSRIs. This can trigger an SSRI
syndrome when a bipolar patient is
prescribed SSRIs
without a mood stabilizer. The opinion of many
experts is that bipolar patients should
not even be
prescribed SSRIs at all due to the risk
of violent
behavior, both inward and outward, that
can be
caused by the SSRIs in a bipolar patient
without a
mood stabilizer.
The way the syndrome can
manifest is by
causing a mania that does not end on its
own. The
depressive side is abated but the drug
does not
327
stop the mania, which is a form of
euphoria that
can cause the patient to have an extended
high like
a runner's high. As a result, the patient may not
be able to sleep or sleep well. In the case of my
wife, she had sleep disturbances that
lasted
approximately two weeks. Her doctor switched the
SSRI she was on to another, hoping for a
better
effect.
In the end she became suicidal
and
homicidal. We were left with no choice but to
admit her to a psychiatric facility. There, they
administered trazodone to help her sleep.
Thirty-six hours into the stay she
managed to hang
herself on an electrical cord. Her last words from
her diary are chilling: "I am experiencing major
drug doubt feeling from the meds. This is
ridiculous. My body chemistry has changed so
dramatically from the SSRI and the additional
crap
on top of it. This sucks.
Reese, darling, I will
always love, Buddy too and Hank and Rich,
mom and
dad, etc.
This is no way for me to live. It
doesn't serve the world. I am becoming a chronic
328
insomniac due to the meds. I am being tortured. I
must leave now. Bye-bye, my love. I will always
love you, Kristin."
To say the SSRI caused her
death would be
unfair and inaccurate. The SSRI without a mood
stabilizer prescribed by a psychiatrist
who had
poor training in risk assessment and not
enough
concern about SSRIs in a bipolar patient
led to the
sleep deprivation which I believe led to
her
suicide.
As a survivor and a founder of
the Kristin
Brooks Hope Center, I ask that the FDA
require
educational materials about the risk
factors in all
prescriptions of SSRIs...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number 28?
DR. VOGEL-SCIGILIA: Thank you very much
for allowing myself, Dr. Suzanne
Vogel-Scigilia,
and my son, Anthony, to speak to you
today. It may
seem paradoxical that you see many more
families
who have concerns about these medications
than
329
children who have done well since
thousands of
children have had their lives saved by
these
medications and the suicide rate in our
youth has
dropped.
The view that this community
receives is
skewed towards the minority who claim
tragic
adverse events because families who are
doing well
don't have much motivation to be
here. Some can't
believe that antidepressant medication
access can
be restricted directly or indirectly by
your
committee's decision. Others are hesitant to
parade their children whose lives have
been saved
in front of this media circus.
Please do not make a decision
without
clear, reliable scientific evidence. The only
issue at hand here, in my opinion, is
whether there
is
credible evidence to show a danger. This
you
will have to decide, and I ask you not to
make a
hasty decision. In all my years as a physician, I
have never seen a warning removed on a
medication,
even later if evidence proves it should
be. If you
inappropriately release a strong warning,
either
330
due to true concerns or because of
intense pressure
from the other viewpoint, managed care
companies or
nervous physicians willingness to pay for
or
prescribe these medications may
decrease. This
will gravely harm far more children than
any number
who have appeared before the committee
thus far.
My father and husband are
pediatricians
who have prescribed psychotropic
medications for
two generations of children in Beaver
County
without adverse events. I am a practicing clinical
psychiatrist in the same area where there
are
woefully few pediatric psychiatrists and
most care
is done by other physicians. Some family
practitioners, pediatricians and
psychiatrists in
western Pennsylvania have told me they
may have to
stop prescribing if an inappropriate
warning, not
backed by reliable research, occurs due
to the
threat of malpractice in this
litigation-based
society.
Managed care companies also do not want a
suit when their attempts to protect
themselves may
lead to prior authorization processes or
other
barriers to access that may frustrate
families of
331
physicians.
The most chilling thing I have
heard to
day
is that since the initial hearing on your
committee occurred antidepressant
prescriptions for
children and adolescents have declined
ten percent.
One consequence of the prior warning is
that more
children are not receiving treatment that
they
need.
I hope that you think about these absent
children and their families when you look
at Tony
and I.
MR. SCIGILIA: Hello.
Ladies and
gentlemen of the FDA, my name is Tony
Scigilia and
I am diagnosed with bipolar
disorder. I currently
take Wellbutrin. My mother told me what was going
on today and I want to tell you that I
have been
taking several--I took several
antidepressant
medications. And, they consist of Zoloft, Prozac
and Effexor, and they have caused me no
side
effects, none however.
Please, help me preserve my
future. Don't
take away my medication. Thank you.
DR. GOODMAN: Thank you very much.
332
Speaker number 29?
MS. WINTER: Hello.
My name is Mary Ellen
Winter.
This is my husband Jeffrey.
Exactly 342
days ago we lost our daughter, Beth. Beth was only
22 years old and had recently graduated
from the
University of Rhode Island, in May,
2003. Beth was
looking forward to a career in
communication and
was experiencing some anxiety and having
trouble
sleeping when she consulted our family
physician.
He prescribed Paxil and said
she would
start feeling better in two weeks. Seven days
later Beth took her own life. Since October 7th,
2003 our family's life has been indelibly
altered
We, like most of you in this room, grew
up with
confidence in the strides made in
medicine and
accepted with faith antibiotics and
vaccinations
prescribed. We believed the FDA would always act
to protect our family's well being.
When my daughter went to our
family GP
last year, we trusted that our doctor was
well
educated and informed. We were wrong. We now know
that pharmaceutical sales is a high stake
business,
333
driven to increase shareholder
wealth. The
consolidation of pharmaceutical companies
like
GlaxoSmithKline has resulted in increased
sophistication in the quest to market and
distribute pharmaceutical products. Priority has
moved from health to profit. Not all doctors are
equipped to understand the marketing
targets they
have become. The FDA has allowed our daughter to
be the victim of a highly commercial
enterprise
that selectively releases clinical data
to maximize
sales efforts and seek only to gain
corporate
profits.
We quickly learned, after
Beth's death,
that Paxil and SSRIs in general are
highly
controversial and cases of suicidal
behavior are
well documented, yet the prescription
Beth received
contained no such warning. Beth was not told about
the hidden data or the clinical studies
or the
untold lawsuits that GlaxoSmithKline had
been
quietly settling. The bottle of Paxil that Beth
received only contained pills and had no
warning as
to the risk of suicide.
334
As residents of the State of
New York, we
thank our Attorney General, Elliot
Spitzer, for
addressing issues that the FDA has been
unwilling
to address.
[Applause]
In a few summer months, Mr.
Spitzer has
forced GlaxoSmithKline to release secret
clinical
data, and in the future GlaxoSmithKline
will be
required to perform under the terms of
the consent
agreement. We believe every state's attorney
general in this country should seek similar
action
against GlaxoSmithKline.
The FDA needs to regain their
leadership
position and restore lost respect and
integrity.
This will clearly require complete and
full
disclosure of the risk associated with
prescription
drugs regardless of the impact on
potential sales
and profit margins of the major
pharmaceutical
companies. This will also mean full and complete
disclosure of what the FDA knows to
Congress and
the American people about SSRIs.
If we, or Beth, knew the
information we
335
now know, Beth would have recognized the
side
effects when they were taking
effect. We know for
certain that Beth would have never hung
herself in
the home of her family whom she so
loved...
[Applause]
DR. GOODMAN: Speaker number 30, please.
MS. HATCHER: My name is Beverly Hatcher
and I want to tell you how Paxil
destroyed my
mother's life. She was a normal, healthy person
who loved life to the utmost. She loved to eat,
cook, travel and talk on the phone. She had a
smile for everyone that she met. She had no
history of mental illness.
In 1997, after my dad died, she
moved from
North Carolina to live with me, in
Virginia. She
soon found work but later chose to
retire. She
soon ran across another one of her
childhood
sweethearts. They began to travel everywhere.
This was life before Paxil. On August 18, 2003,
she was prescribed Paxil because of a
small bout of
depression that was due because of a
heart attack
of her closest cousin. She quickly transformed
336
into someone that began to complain of
having
constant bad dreams, having no appetite,
being
nervous, hearing voices. She stopped taking baths
at night and bit her nails down to
nubs. She said
she thought things were crawling all over
her and
that she was losing her mind. Nothing mattered
anymore.
These were not normal signs of normal
grief.
On September 2nd, 2003, the day
before her
daughter's birthday, she hung herself in
that
daughter's basement. This was 16 days after
starting Paxil. She was only 60. How did Paxil
get the FDA stamp of approval and make it
to
market?
How or why would any healthcare provider
prescribe such a medicine capable of
causing this?
As a nurse and healthcare provider
myself, we take
an oath to save life, not destroy it.
Are drug companies providing
the FDA and
healthcare providers all the facts about
Paxil?
No.
Drug companies are not telling the truth to
the FDA, healthcare providers and
certainly not to
consumers because they have figured our a way
337
around all the loopholes. In this case, the FDA's
guidelines are meaningless and they
contain even
bigger loopholes.
To the FDA, we will never
understand why
this had to happen to us. There is no excuse. It
was your job to protect my mother and not
the drug
company's profits. Because of this, we will be
motherless for the rest of our
lives. Nothing can
change that. When will enough be enough? Stop
taking innocent lives.
To the drug companies, and
especially to
the FDA, this T-shirt sums up how we, the
family of
Barbara Jean Darton, feel about
Paxil. The back
reads "cocaine is an illegal drug
that kills." On
the front it reads, "Paxil is a
legal drug that
kills." Don't put another family through this.
Remove Paxil from society. Until then, remember
the faith and the message of this T-shirt
and do
the right thing. Sincerely, in memory of my
mother, Ms. Barbara Jean Darton. Thank you.
[Applause]
DR. GOODMAN: Thank you.
We are now going
338
to take a brief break. We will reconvene in ten
minutes.
[Brief recess]
DR. GOODMAN: Please start gravitating
towards your seats. As soon as we receive a few
more committee members back from their
break, we
will recommence.
First let me reiterate my
apology that I
issued before. That is, we have a system that
basically, once we start up, is automated
and
sometimes the microphone is turned off on
people at
a very key moment in their
presentation. We have
to balance that with the desire to make
sure that
we are treating everybody uniformly. I think that
or the most part I am very pleased with
the way
this has been going, the respect that
everyone has
shown each other in the process. I need to remind
you that everyone has a chance to speak
who had
signed up. Really we should not have any outbursts
from the audience. If there is somebody who has
something to say, they should have had an
opportunity to be up at the podium. With that,
339
speaker number 31.
DR. SCHAEFER: My name is David Schafer.
I am a child psychiatrist and pediatric
at Columbia
University, and I have engaged in
research on
adolescent suicide since 1970. I have never
received any financial support from the
pharmaceutical industry, and my travel
expenses are
going to be reimbursed by an endowment
from the
University.
I am please to be able to make
this brief
statement because my main interest
professionally
has been in suicide prevention, and I
believe that
the decisions that will be arrived at by
your
committee will probably have an important
effect on
suicide prevention.
I would like to make three
points,
starting with the point that was referred
to this
morning, by Dr. Wysowski about the
coincidence
perhaps, or perhaps not, of the very
striking
decline in the youth suicide rate that
coincides
with the very striking increase in the
rate of
prescription of SSRI antidepressants to
340
adolescents.
Starting in 1964, the youth
suicide rate
started to increase, and increased in an
unstoppable fashion until about
1990. At that
point it stabilized and started to
decline in 1994.
This pattern was not confined to the
United States.
It was also found in most other developed
countries
where SSRIs are also available. The general
consensus is that SSRIs must be
considered as one
of the possible causes of this abrupt
change in a
pattern of mortality.
I think Dr. Wysowski said quite
clearly
that this is an ecological
situation. The fallacy
is there.
But I think it also was somewhat unfair
in not giving cognizance to the large
number of
analyses that have been done to try and
look at
alternative explanations for the
decline. Most
importantly, there has really been no
decline in
exposure to substance and alcohol abuse,
which is
recognized as one of the major risk
factors. There
has been a decline in other forms of
psychotherapy
during this period, rather than an
increase. And,
341
the rates have declined in many, many
countries.
Firearm suicide is almost unknown. And, the CDC
have recently produced data showing that
there has
been a significant switch from firearms
to hanging
in the United States during this
period. So, I
think that we do have to give serious
consideration
to the possibility that there is a causal
relationship.
The second point is that there
is another
whole area of research which has not been
discussed, which is toxicology analyses
in suicide
victims which have failed to show high
rates of...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number 32, please.
MR. MILLER: My name is Mark Miller. The
first thing I would just like to say in a
response
to a comment made earlier here this
morning is that
I would rather be scared to death by a
label on a
medication than be changed forever by the
death in
our family seven years ago.
Seven months ago my wife Cheryl
and I
342
stood here and shared our story. Our 13 year-old
son, Matthew, had committed suicide after
taking
Zoloft.
We shared how he had become akathistic on
the drug and, despite what Pfizer would
like to
have you believe about our son as they
attempt to
portray him in a letter posted on your
website, the
one indisputable fact that matters most
is that
Matt, our son, never attempted suicide or
self-harm
prior to taking Zoloft. In fact, in testimony that
Pfizer did not share with you, Matt
revealed to his
doctor before he ever took a pill that
suicide was
something that he could never bring
himself to do.
His doctor did not see suicide as a
threat. His
mother did not see suicide as a threat,
nor did I.
Yet, within a week, one week on the pill,
Matt
violently and with great difficulty took
his own
life.
Pfizer's strongly worded
50-page document
continues to show a pattern of how drug
companies
disparage victims and anyone else who
dares speak
out against them. Pfizer was so afraid of our case
going to trial where the facts could best
be
343
weighed by a jury that they tried to
discredit the
science of an internationally respected
expert. If
that is the case, the conclusions from
this science
are now being validated by regulatory
bodies around
the world. Months ago, in fact, they were
validated by your agency's own internal
review.
Health Canada, in the meantime,
has
demanded that Pfizer level with its
citizens. In a
warning on their own letterhead, Pfizer
Canada
admitted last May that Zoloft, quote, may
be
associated with increased risk of
suicidal ideation
in children under 18, unquote. Where is your
demand for a similar clear and
unambiguous warning
in the U.S.?
You have to go to page 13 of
Pfizer's new
38-page prescribing information for
Zoloft until
you read anything about the possibility
of suicide,
and even then there is no mention that
the drug may
be
associated with it, as they admit to in Canada.
That is a warning?
Are we to believe that children
in the
U.S. react differently to Zoloft than
Canadian
344
children?
Last year in Great Britain, as you know,
these drugs were banned for children
under 18. It
is very possible they could ban their use
for
anyone under age 30. Why, I ask, has the FDA,
contrary to your own mandate, allowed
negative
trial data to be so easily kept from
doctors and
the American public? Why haven't parents, like
Cheryl and myself and countless others,
been told
the truth about these medications? That is your
job, to make sure that we get the
information we
need to make careful, wise and informed
decisions.
We learned the hard way that these drugs
can kill.
Many of the people are testimony to that.
Ban these drugs...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 33, please come forward.
MR. FARBER: I am Donald Farber. I am an
attorney from Wren County,
California. I represent
antidepressant victims and there are a
lot of them,
believe me.
Dr. Hammad said this morning
that there
345
are no consistent patterns of trial
design. He
cited 12 variables. He is wrong.
There is a
consistent pattern of trial design, and
that is to
conduct them so that they don't detect
suicide at
the crucial times.
The Columbia project, though
interesting
and I am sure professionally stimulating,
does not
advance the knowledge necessary to know
whether
antidepressants are safe. The only real question
the world wants to know is do
antidepressants cause
suicide?
Congress asked Dr. Woodcock the question
last Thursday, and she said the jury is
still out.
Well, the jury has been out on that
question for 15
years.
We have heard the same rhetoric
the last
six months as we heard in 1991 with the
original
Prozac hearing. If you go back and read the
transcripts, it is the same thing. Everybody knows
why no progress has been made to answer
that
question.
The drug companies will not do the
clinical trials to specifically test the
suicide
hypothesis under any condition. If ethical
346
barriers are involved, as Dr. Temple
claimed in
"The Wall Street Journal" and
PBS, the FDA should
give as much attention to ensuring
clinical trials
are properly designed to test that
hypothesis as it
has to this Columbia project to bail out
the
industry.
While I have my opinion, the
public cannot
tolerate another 15 years of professional
ignorance
on whether antidepressants cause suicide
or not.
Test them right and find out the
answers. Thank
you.
[Applause]
DR. GOODMAN: Thank you.
Speaker number
34.
MR. ROUTHIER: I testified once already in
February and I am not happy about having
to do it
again.
My beloved wife of 18 years went to her
doctor sick with abdominal pains and was
coerced
into trying an unmarked sample of
Wellbutrin.
After a week of serious adverse reactions
and
insomnia, she shot herself. She was never
depressed, was a perfect wife and mother,
and
347
worked 25 years in the Department of
Public
Welfare.
The product information guide,
which she
was not given, states patients treated
with
bupropion have experienced psychosis, but
it is
impossible to determine the extent of the
risk.
How can any benefit be worth the risk if
risk is
impossible to determine? The list of side
effects--psychosis, mania,
hallucinations,
insomnia, agitation, suicidal ideation,
etc., etc.
GlaxoSmithKline's answer is we told you
so, and everyone knows the inherent
dangers.
Hundreds of cases were settled on Prozac
alone a
decade ago. Two main ingredients are fluoride and
hydrochloric acid, the most caustic, corrosive
substances known. These neurotoxins poison the
brain, triggering adrenaline, masking
symptoms.
Nobody can know what it is to lose the
most
beautiful, intelligent, strong, loving,
caring wife
of 18 years, incredible mother of two
boys that she
adored, my soul-mate. There was nothing ever wrong
with her until these damned pills. Which they want
348
to question and deny?
She left a legacy of love that was
witnessed by hundreds as the most
unselfish wife
and mother, sister, daughter, friend,
co-worker.
She left me and two sons with a need for
justice.
We all know this stuff is dangerous. Anyone
denying this, especially anyone in a
position to
make a difference, in the face of such
horrific
testimonies is an enemy of humanity.
After 18 amazing, wonderful
years, at 40
years old she became deathly ill for a
week and
then ended her pain. One week after the first
pill.
Then the autopsy found the gallstones.
Guess what, don't take poison, toxic
chemicals
while having a gallbladder attack. I absolutely
worshiped her and everyone told us we had
a rare
love.
Even our middles names are Mary and Joseph.
We were a match made in heaven. We were ripped
apart by a nightmare conspiracy no one
could
imagine.
My wife was murdered.
How many settlements have silenced
victims?
I don't care about any perceived benefit
349
when this stuff kills people. My wife was worth
the risk?
Other victims here were? Which
ones?
The FDA has to get off their ass and move
on this,
and make it clear it is children and
adults. Don't
try to minimize the numbers by dividing
groups.
There is plenty of proof. I call on everyone to
carefully investigate every episode where a
person
on these drugs had uncharacteristic,
uncontrolled
violence or suicide. I am aware of many. Don't
let them blame psychotic episodes on
depression.
Many are given these drugs for reasons
other than
depression, including my wife.
Look at the studies, the NDAs,
the
MedWatch reports, the settlements,
witnesses, read
the side effects. The body count is climbing and
we are sick of the coverups. The risks are too
great to be...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker number 35?
MS. MCBRIDE: My name is Sharon McBride
and I am a dental hygienist. I am here as a mother
350
and a friend--
DR. GOODMAN: Could you bring the
microphone closer to you?
MS. MCBRIDE: Sorry.
I am here at my own
expense as a mother and a friend. I am here today
to remind the committee of the serious
suicide
attempt of my then teenage daughter
shortly after
being prescribed the SSRI medication
Zoloft. After
seven years on Paxil, she is still
attempting to
recover from the problems incurred from
abruptly
stopping that medication.
I have only in the last three
weeks
learned of the higher suicide ideations
of the
other SSRI type medications that she has
been
prescribed. Two days after beginning Seroquel, my
daughter overdosed on that
medication. She denied
suicide attempt but had no explanation
for her
action.
She continues to have difficulties more,
in part, to the side effects of the
medications and
the devastation they have caused in her
life.
Liz Torklingson was a beautiful
high-spirited young lady who was a purist
and very
351
careful about what she put into her body,
only
eating organic foods and no red
meat. She did
suffer from a nagging depression and
became, over
time, convinced to try medication. She took
Serzone for a year but discontinued after
hearing
on the radio that it can cause long-term
health
problems.
Celexa was recommended as a healthier
replacement. Because of a bad cold, the dosages of
Celexa were forgotten and Sudafed was taken. Upon
resuming the Celexa, she quietly walked
into the
subway, entered into the dark tunnel, sat
down on
the track and let the train run over
her. One week
later came the FDA warnings about
antidepressant
medications but too late for Liz.
This morning I received an
email from my
neighbor in Arizona about her 13 year-old
daughter.
Erica was never suicidal while on Paxil,
although
we had some of the worst incidents with
her rages
and
meltdowns during the time that she was on
Paxil.
She was literally uncontrolled about home
school and church. Teachers in school and church
were not able to handle here. At one point in
352
school she had such a serious meltdown
that the
entire classroom had to be removed and
the school
officer was brought in to control the
situation.
Another time her behavior reached a point
of
kicking the teacher and aids resulting in
her
getting arrested. These incidents led to her
admittance into a behavior health
center. She was
admitted twice within two months.
This report is also similar to
the report
you heard from Todd Shivick about his 11
year-old
son Michael. Michael not only had these same type
of rage behaviors but made four suicide
attempts
while on Paxil. Now, one and a half years after
discontinuing Paxil, Michael, now 14, has
returned
to a normal teenage life, participating
in high
school activities.
I respectfully request that not
only
suicide ideation be investigated but also
these
personality and behavior changes in our
children
prescribed these SSRI medications. This affects
our homes, our society, our nation and
our future.
Thank you.
353
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 36, please.
DR. BREGGIN: I am Peter Breggin. I am a
psychiatrist without financial ties to
the drug
industry or anyone else.
It is gratifying to see the FDA
finally
considering, after ten years, data that I
produced
in talking back to Prozac and since then
in
numerous books, medical articles, peer
reviewed
articles, including the one I have given
the
committee. Some of my data comes from suits
against the manufacturer in which I have
been an
expert.
I have been involved now in dozens of
cases against the manufacturers and they
have, for
good reason, settled every single
one. In
addition, a number of criminal cases have come out
well for the defendants.
Dr. Laughren knows that he is
wrong about
the absence of any suicide signal in
adult cases.
By a 6:1 ratio there were more suicide
attempts on
Prozac compared to imipramine and
compared to
354
placebo in all of the clinical trials
used for the
approval of Prozac. Beasley, at Lilly, kept this
data initially from the FDA but I
disclosed it ten
years ago, in 1994, in the Westecker case
and it
has since then been published numerous
times.
The Prozac data would have been
much
worse, as Dr. Laughren knows, if Lilly had
not been
illegally medicating its patients by
actual memo
from Ray Fuller to all of his principal
investigators, empowering them to give
tranquilizers against the protocol for
these
patients, also, if Lilly had not been
hiding its
adult suicide events in the coding items,
innocuous
items such as "no drug effect"
in a suicide case.
This kind of thing makes the collection
of data, as
done in the present cases today, just
fraught with
risks of fraud about coding because
Lilly, we know
for sure, has coded with absolute ability
to hide
their data and I found it by going
through the
files, which the FDA doesn't do.
Again, in adults I have
reanalyzed suicide
data from other high profile SSRIs and
found adult
355
signals, but the data is sealed because
the cases
have been settled but the FDA hasn't
empowered me
to release that data or, in fact, ask for
it.
SSRIs cause suicide and
violence in the
early stages of treatment or during drug
changes
because of stimulation, euphemistically
called
activation. It is an amphetamine- or cocaine-like
effect, which the FDA has now recognized
by putting
out a list of agitation, hostility,
anxiety,
irritability, and so on, on its own
website,
symptoms wholly indistinguishable from
methamphetamine or cocaine...
[Applause]
DR. GOODMAN: Thank you.
Speaker 37,
kindly come forward.
MR. ORR: I cannot see my notes with the
lights off.
DR. GOODMAN: Somebody may be leaning
against the dimmer somewhere. That was probably
inadvertent. We won't start you until we get the
lights right.
MR. ORR: Thank you.
My name is Bruce
356
Orr.
I have no financial ties to anyone.
I am
from Charleston, South Carolina. I am a former law
enforcement officer, with approximately
20 years
experience. I am also a former director of a
children's ministry. I currently have a child in
my life whose meds. were switched three
times, in
four months, with three suicide attempts.
As a law enforcement officer, I
spent a
career combating illegal drugs and the
influence
that they had on our children. As supervisor of
the violent crimes and homicide division
of my
agency, I dealt with the aftermath of the
unnecessary violence associated with
these drugs.
Times have changed. There are still, and always
will be, crimes related to street drugs, but
more
and more I am seeing a pattern of
violence
associated with the excessive use, sudden
withdrawal from, or switching of
antidepressants
and, frankly, it is quite disturbing.
While we sit in this air
conditioned room,
looking at pretty charts, cops like I was
are
dealing with the blood and gore
accompanying these
357
suicides.
Have you seen the aftermath of a
suicide?
I have and I still do every night when I
go to sleep.
Our children are our hope and
our
investment in the future, and we sit here
today
hearing the cries of parents whose hope
and future
were destroyed by the very drugs they
thought would
help preserve it.
As I stated earlier, I was a
law
enforcement officer and a children's
church
director.
I was a pretty easy-going person but in
2002 I was placed on the antidepressant
Paxil for
post-traumatic stress disorder and major
recurring
depression. Prior to that time I was awarded
"Supervisor of the Month," in
line for promotion,
and had just received a medal for saving
a life.
After four months of horrible side
effects, my
doctor attempted to switch me from Paxil
to Remeron
and stopped abruptly in four days. During severe
withdrawal, I attempted suicide by
overdosing and
driving my truck into a parked car and
shoving it
through my home. I was subsequently charged and
358
eventually pled guilty to lesser charges,
and now I
am a convicted felon. I guess you could say Paxil
brought my career full circle, from cop
to
criminal.
Two years ago, as a 38 year-old
man, I
wanted to die in withdrawal. I recall laying on a
friend's bathroom floor and begging him
to kill me.
When he didn't do it I tried to do it
myself. I
cannot fathom what that must be like at
18, 15, 12
or even 10 years of age. The pain and mental
anguish is unbearable.
Something must be done about
these drugs
and the effects that they have on both
children and
adults.
If the drug companies withhold potentially
life-threatening information just to turn
a profit
something must be done. My family and my career
were forever destroyed but at least I
still have my
life.
I never would have thought that a little
pill, that ironically comes in
little-girl pink for
lower doses and baby-boy blue for larger
doses,
could alter my personality so
drastically, but it
did.
It is not worth another parent losing a child
359
over or, in my case, children losing a
parent over.
This medication cost me a year of my
children's
lives but I have them back now. I just wish that
some of these parents could say the same
thing.
Thank you.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 38, come forward, please.
MR. REED: Good afternoon. My name is
Jerry Reed and I am the executive
director of the
Suicide Prevention Action Network, SPAN,
U.S.A.
Suicide claims the lives of over 4000
young people
each year, making it the third leading
cause of
death for those between the ages of
10-24. In 2003
16.9 percent of high school students
seriously
considered attempting suicide, while 8.5
percent
made an actual suicide attempt.
Research shows that over 90 percent of
children and adolescents who die by
suicide have a
mental disorder. Among adults, psychotherapy and
antidepressants are regarded as the most
effective
treatments for depression, but only
limited
360
research has been conducted on the
efficacy of
antidepressants in children and
adolescents and the
studies that have been conducted thus far
have
three major problems: One, they have been too
short in duration. Two, they have excluded those
at highest risk for suicide and, three,
not all of
them have been published.
The limited evidence available
and the
shortcomings of the research conducted
thus far
underscore the need for continued and
improved
research.
Most suicide prevention is based on the
principle that suicide is generally
preceded by the
signs and symptoms of a mental illness or
other
behavioral or emotional problem which can
be
treated.
If we are to continue screening young
people, it is imperative that we have
safe and
effective treatments to provide to those
identified
at risk.
Since most young people with a
mental
disorder to not receive mental health
services,
prematurely prohibiting the use of
antidepressants
for young people with depression, one of
the most
361
widespread treatment methods, may
discourage a
significant number of people from seeking
out help
and ultimately do more harm than good.
As an organization comprised
mostly of
suicide survivors, we have heard the
stories of
mothers and fathers who sought out
treatment for
their children but were never educated
about the
risks associated with their loved one's
condition
or treatment. In survivor suicide support groups
nearly all parents who lost a child
report if they
had only known 30 days before the suicide
what they
knew 30 days after, their child's life
might have
been saved.
The fact is that most young
people
receiving treatment for depression or
other mental
illnesses do not get services from the
specialty
mental health sector but, rather, from
schools,
primary care providers, child welfare
services or
juvenile justice facilities. It is, therefore,
essential that everyone prescribing
antidepressants
to youth know about the need for
increased
monitoring and vigilance, particularly
during the
362
first weeks of treatment. All those involved with
the treatment of children and adolescents
with
depression should be forewarned about the
potential
risks and may be informed as to what
signs and
symptoms are indicative of potentially
serious
problems.
Patient education is a proactive action
that should be taken now. It is the least we can
do while the requisite research is
pursued.
Suicide has been a leading cause
of death
among young people for far too long. Any concerns
about the efficacy of antidepressants for
treating
young people with depression must be
addressed
immediately. SPAN, U.S.A. represents people who
know all too well the terrible tragedy of
suicide.
We must act now. There are too many lives at
risk...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 39, please come forward.
MR. COFFIN: Good afternoon. My name is
Chris Coffin. I am with Pinley law firm in
Plackman, Louisiana. I am standing before you
363
today in two separate roles, number one,
I am an
attorney who represents thousands of
individuals
whose lives have been negatively affected
by the
use of SSRIs. Some of them are parents who have
been misled about the safety and efficacy
of these
drugs.
Some of them are adults who have ingested
the drugs and experienced suicidality or
experienced severe debilitating
withdrawal symptoms
when they tried to reduce their dose or
terminate
the use of the drugs.
The second role I am in here
today as a
healthcare professional. I am also a practicing
registered nurse. I understand the risk/benefit
analysis that goes along with treatment
decisions.
I understand what it means to be a
provider who is
passionate about the care, in this case, of his
patients.
For the sake of my clients, my
patients
and for the sake of our colleagues as
healthcare
providers, I come to you with three
requests today.
Number one, take further action.
Contraindicate the use of SSRI drugs in
children.
364
I understand that you want to be
thoughtful and
careful in your analyses. I understand that you
want to consider all angles. At this point,
however, we now have the benefit of the
analysis
done by British regulators, by Dr.
Mosholder and by
the Columbia University group. Although the data
is not absolutely perfect because it was
not always
looking at suicidality, we do know that
the risk
outweighs the benefit. That seems very clear.
The second request I have to
you is to dig
deeper.
By dig deeper, I mean to look deeper into
the data.
Look further, beyond just the pediatric
issues.
Realize that there is far more data in the
halls of the pharmaceutical companies
than has been
presented to you. Because of litigation, my legal
colleagues and I have been able to look at
that
information and I think if you look you
will find
an abundance of information that will
further
educate you about the debilitating risks
of these
drugs.
Do not trust and do not be misled by the
pharmaceutical companies. Whether you take my
position or anybody's position in this
room, you
365
owe it to the American people to look
further into
the information that the drug companies
have within
their houses.
The third request I have of you
today has
been made by many others, and that is to
educate.
From a healthcare provider's standpoint,
I ask that
you go beyond the regular minimal
requirements that
FDA imposes on drug companies. Force the drug
companies to provide better education on
SSRI drugs
for children and adults. You will prevent serious
injury in the future if you do so. Thank you.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 40, please come forward.
MS. ERBER: Hi. I
am Alice Erber and this
is my family, Robert, Talia and Rachel
Steinberg.
We live in Palo Alto, California. My son, Jacob
Steinberg, died last year, on Wednesday,
July 23,
after being on Paxil for about a
month. He was 20
years old. Jake was going to be a senior at
college.
He played the piano, sang in the glee
club, was the entertainment editor of the
school
366
newspaper. He was involved with student
government. He was a great kid, so full of life.
He loved music, films and had many
friends.
In mid-June, Jake went to see
an
internist, whom he had never seen before,
to get a
referral for a hand specialist because
his hands
were sore from playing the piano. The internist
who saw him for 30 minutes prescribed
Paxil because
he bit his fingernails and the doctor
thought it
might help with that. Jake had been taking
Wellbutrin for anxiety and mild
depression for
about six months. He was doing fine on Wellbutrin.
The internist told him that it was okay
to take the
Paxil with the Wellbutrin.
Jake had begun a six-week
internship in
New York City in June and he was not
going to be
supervised by a doctor. He went on a trip with my
husband to Israel for two weeks in July,
and felt
sick and had diarrhea. My husband was concerned.
I talked to Jake on Saturday before he
died. He
told me he was staying up late; he wasn't
sleeping.
He left me a great phone message on the
day that he
367
died.
In the morning he sounded fine.
He talked
to his sister at lunchtime and they had a
good
talk, but before he hung up he complained
to her
that his stomach hurt. Then, on that afternoon, on
Wednesday, July 23, we found out that he
killed
himself.
They said at work he started
acting
bizarre.
He started having erratic behavior and he
ran through the building, throwing his
clothes off
and fighting the office security guard,
and ending
up throwing a chair through a window and
jumping to
his death from the 24th floor of a
Manhattan office
building.
What a horrible way to die.
We went to get his body the
next day and
the detective said he found two empty
bottles of
Paxil and Wellbutrin. When the autopsy report came
back it showed that there was Paxil and
Wellbutrin
in Jake's body but not in overdose, just
a regular
amount.
We are sure that the Paxil caused his
death.
He had the symptoms of akathisia.
We also
think Paxil and Wellbutrin may have
created a manic
psychotic episode.
368
We want to tell our story to
make sure
that if he had not taken Paxil he would
be alive
today.
The public and the doctors need to know
these suicides in young people. Tomorrow is Jake's
birthday.
He would be 22 years old. We are
here
in his memory, making sure this does not
happen
again.
He was impulsive and out of character.
We
know he did not want...
[Applause]
DR. GOODMAN: Thank you.
Sorry for your
loss.
Speaker 41, please.
MS. WEBB: I am here because three years
ago my daughter was suffering some symptoms
that
the doctor felt represented depression
and started
her on samples of Paxil. I trusted this decision
as a mother and based on my medical
background as a
registered nurse.
Unfortunately, she did have an
obvious
worsening of symptoms. Were we aware that the
antidepressant could be the cause of
this? No, we
were not.
I am here because I agree that the FDA
needs to require further studies to be
done to see
369
if it is true that certain
antidepressants increase
the risk of suicidality.
When I learned that I would
have the
opportunity to speak before this
committee I wasn't
sure what I would say. So, I replayed an audiotape
of a confrontation with my then 17
year-old
daughter during the time she was taking
these
antidepressants. We could not believe the changes
we saw in our daughter in the very short
time she
had started on the antidepressants. It was
unbelievable--the rage, anger, the
hostility she
exhibited that night. She ended the night by
cutting her wrist. Now I am learning that the
changes we saw in our daughter, more
likely than
not, were the side effects of the
antidepressant
she was taking at the time.
Yes, we did report a worsening
of symptoms
shortly after she started the Paxil. The doctors
only changed her to another
antidepressant, Zoloft.
She then continued to worsen and they
continued to
increase the dosage until she began to
further harm
herself with self-mutilation, cutting,
overdose,
370
numerous things. We were fortunate to get her help
in the right environment with counselors
who spent
many hours with the children. She was taken off of
the strong antidepressants and, within a
short time
none of the staff could believe she had
done while
she had been on Paxil and Zoloft. She continued
there, getting counseling, and returned
as the
child we knew before she took these
antidepressants.
Why did we not know about these adverse
side effects that are now being reported
in
children?
Was it possible the drug companies may
have been aware of these adverse side
effect? If
we had known, I believe it is possible
that maybe
my daughter and our family would not have
had to go
through the agony and heartache we went
through.
My daughter is hearing impaired
and has a
cochlear implant, and has worked hard all
her life
to overcome the stigma of being hearing
impaired
and deaf.
It has been hard but she has always had
a positive attitude. Now we are sad but also find
relief in telling her that what she went
through
371
could have been prevented if the drug
companies had
made public these adverse side
effects. Yes,
relief but, unfortunately, too late. She now has
to endure the stigma that mental illness
brings to
those who suffer it. Luckily, she has shown her
determination to overcome this, as she
did her
hearing loss. She is now a junior in college and
doing great. Her determination has brought her
through many obstacles but this was one
she should
not have had to battle.
Guidelines for the use of
antidepressants
in children should be reevaluated and
studies done
to determine which, if any, are safe for
use in
children.
Thank God, we were able to get my
daughter help before it was too
late. I am sure
there are many more children who did not
get that
help and may have succeeded in their
suicide
attempts.
Thank you.
[Applause]
DR. GOODMAN: Thank you.
Speaker 42,
please.
MR. WITZCAK: My name is Chester Witzcak.
372
I am a resident of York, Pennsylvania,
and I have
no financial relationship with the FDA,
drug
companies or any advocacy group. I am attending
this hearing at my own expense.
On August 6th, 3002 my oldest
son,
Timothy, died of a Zoloft-induced suicide
at age
37.
He died after taking the drug a total of five
weeks.
It was prescribed for insomnia.
How did this happen? Zoloft was
prescribed off-label and there was no
information
regarding Zoloft's serious side effects
with the
Zoloft samples given to him by his
physician. Why
did this happen? Soon after SSRIs were introduced
the drug companies began a campaign to
establish
that they were effective treatment for
other
diseases although there was no clinical
basis for
this, and none of the serious side
effects were
discussed or highlighted in the
literature or on
the labels.
Today these drugs are
prescribed for a
long list of ills. Physicians and patients are
using it for just about anything except
hangnails
373
despite the fact that SSRIs are only
approved to
treat a few conditions. In 1997 FDA added a major
weapon to the drug company arsenal,
direct-to-consumer advertising. FDA issued
guidelines that allowed drug companies to
air
broadcasts and print advertisements that
contained
minimal information about a drug's
possible side
effects.
The United States is the only
industrialized nation that allows
direct-to-consumer advertising to the
public.
Other countries consider the practice to
be
unethical.
How effective are these SSRI
drugs really?
At present, drug companies not only plan
and pay
for the trials of their own drugs, but
also analyze
and publish the results. This conflict of interest
has introduced a bias into the testing
since drug
companies suppress test results they
don't like
when drug companies show that the drug
isn't more
effective than a placebo, a sugar pill
or, said
another way, better than nothing. That is a very
low hurdle.
374
What is needed? We need warnings for all
patients, not just juveniles being
prescribed SSRI
drugs, informing them of the serious side
effects.
Families and spouses must be warned as
well to
allow them to be aware and to watch for
the signs
for these serious adverse reactions. We need this
now, not more studies or hearings. We need to
eliminate the direct-to-consumer
advertising. You
authorized it.
Stop it now. Eliminate the
off-label use of drugs.
If a drug is to be used for a
particular
treatment, require that it is more
effective than
existing treatments, with real clinical
tests not
based on a journal article hyped by the
drug
companies. Establish a truly independent drug
testing agency. We can't go on with the fox in the
henhouse situation we currently
employ. Without
the positive actions I have indicated the
FDA will
continue to be a co-conspirator in the
assault of
the public, with the SSRI drug-induced
violence and
suicide.
Thank you.
[Applause]
375
DR. GOODMAN: Thank you.
Is speaker 43
present?
If speaker 43 is not present, then
speaker 44.
MS. PARKER: My name is Nancy Parker, and
I am a mother of a 12 year-old
African-American
girl, Rebecca, whom I adopted at the age
of three
weeks.
I am also a member of NAMI, NYC Metro.
First of all, I want to say my
heart goes
out to everyone here who has lost a loved
one, but
I am here to tell a very different
story. My
daughter has suffered from severe mental
illness
for the past seven years. Her present diagnosis is
depression with psychosis NOS. She is presently on
a regimen of 800 mg of Seroquel, a
milligram of
Haldol and 225 mg of Wellbutrin.
At the age of five and a half,
Rebecca had
her first episode. I was cleaning up a glass that
had suddenly broken when she ran in,
appearing to
be in something of a trance, picked up
what I
assumed was a small piece of glass and
swallowed
it--her first attempt at trying to hurt
herself.
She was then in therapy and had her first
376
hospitalization where she was given a
diagnosis of
bipolar disorder.
So, a little girl comes home on
depakote
and after a week she has another episode,
and when
I think she may be gaining control she
comes up
behind me and clocks me over the head
with a big
toy hair dryer. We both wound up in the ER and
when the doctor asked her, "why did
you hit your
mom over the head?" she replied
flatly, "because I
had to." At this point her doctors concurred it is
very likely that Rebecca is not bipolar.
Now there
is no diagnosis so the doctors tell me if
she acts
up just give her Benadryl.
She left the hospital and was
seeing a
therapist regularly, and in September of
1999 she
began hearing voices. At this point, her therapist
and psychiatrist put her on the first of
many
antipsychotics, Risperdal. While this was going on
her behavior became very
self-injurious. One
impulse was she would walk out in front
of cars.
When I told her she could get killed, she
answered,
"maybe I wanted to." She would bang her head on
377
the wall and tell me how she wanted to
die and be
with her grandma in heaven.
For Rebecca, the time between
ages 5-12
meant five hospitalizations and one year
in
residence. She has been on everything from
Risperdal, olonzapine and BuSpar. While in the
hospital, they put her on lithium and
then took her
off for three days because she became
violently
ill.
When she was in residence they started
Rebecca on a low dose of Risperdal and
Wellbutrin.
While that helped somewhat, it was not
the perfect
mix.
Finally they tried Serecol [?] with
Wellbutrin. There were some difficult times there
but they had upped the Serecol and
Wellbutrin to
her present dose.
Presently, she has been on
Wellbutrin and
does not hear any voices. She has not had any
hospitalization and is relatively happier
now and
there is no impulse to hurt herself.
I just want to say that we have
to have
clinical trials for these children. They must be
started at a low dose and if there is any
problem
378
the doctors have to be told that these
kids, if
they are not working out on these
particular drugs,
have to be taken off the drugs. Or, if it is a
cocktail, as in my daughter's case, maybe
the
cocktail has to be stopped. Finally...
DR. GOODMAN: Thank you.
Speaker 45,
please.
MR. SCHNEEBERG: Yes, my name is Richard
Schneeberg and I have a masters in
counseling.
Between 1997 and 2000 a person is given
14
different types of antidepressants on
eight
hospital stays. During one of the stays he tries
to jump out of a hospital window. After another
hospital stay he is found walking on the
railroad
tracks, and when he is brought to the
hospital he
is a catatonic zombie. He can't speak and he is in
a fetal position, rubbing his knees
together.
After another hospital stay the person
has a
delusion of murder. After yet another hospital
stay this very same person makes a threat
to burn
down a hotel. He is brought to a hospital and
starts having hallucinations after being
medicated
379
again.
The common thread in all of
these bizarre
actions, including suicide, is that none
of them
ever occurred before this person was given
antidepressants. The focus of this conference is
on children, however, the person who I
refer to is
not a child. It was me, a man, then in his late
40s.
England has banned all
antidepressants for
kids except Prozac. Let's have an American
revolution and ban antidepressants for
everyone and
prevent many suicides.
All of the above is documented
in my
autobiography, "Legally
Drugged," being produced
and published soon, and will be produced
as a
motion picture.
Excerpts from the hospital reports will
be in the
book, where the psychiatrists themselves
state they
were worsening my condition. Counseling only, no
drugs.
Antidepressants, weapons of mass
destruction.
[Applause]
380
DR. GOODMAN: Thank you.
Speaker 46,
please.
DR. RISINGER: I am David Risinger and
this is my wife, Sarah. I have no financial ties.
Next slide. This is my 15 year-old son,
Josh.
Next five slides. All these pictures were
taken about a year ago before Josh
started
antidepressants.
Next slide. See that smile? Suicidal?
No way!
Next slide. Not that he didn't have
problems.
He had been seeing a psychologist who
thought an antidepressant might help.
Next slide. This is Josh before Zoloft.
He was popular, athletic, had a girl
friend, was
making plans. He had hope and enjoyed life.
Next slide. Twelve tablets later he was
gone.
Next slide. Three times in those 12 days
I talked to his doctors to tell them that
he wasn't
doing well; to tell them that he couldn't
sleep at
381
all; that he seemed agitated. He cried out to us
that this medicine was making him
worse. I was
told, "give it time; these take a
couple of weeks
to work." Twelve days.
None of us recognized the
danger he was in because none of us had
adequately
been warned.
Next slide. The first I ever heard of
this controversy was this article that
ran shortly
after Josh's funeral.
Next slide. There is certainly no mention
of it in any of the product literature.
Next slide. The reason I come to you
today is to caution don't rely only on
the clinical
trials data to base your recommendations.
Next slide. I would like to give an
example from my practice, and that is
x-ray
contrast media.
Next slide. Doctors and patients are
warned of the risks of these drugs.
Next slide. Specialized training and
preparation are required to use these
drugs.
Next slide. And many lives have been
382
saved to reactions that never happened in
any of
the clinical trials, reactions that most
of my
younger colleagues have never seen and
would never
believe until they saw their first case,
and by
then it would be too late.
Next slide. But I know this happens. I
have seen it.
Next slide. I know this happens too. I
have seen it, and I am here to tell you.
Next slide. Don't rely only on the
clinical trial data. I think what you are looking
for maybe too rare to find there.
Next slide. But just because it is rare
doesn't mean it isn't important. There are
millions of people on these drugs. Thousands of
lives literally are at risk. What do we do? I
would like to give an example from my
practice. To
interpret mammograms, every three years I
have to
get 15 hours of CME. Why can't we do something
like this with these drugs? Every prescriber
should be required to periodically pass a
mandatory
certification in psychopharmacology. Surely this
383
committee would find this tool useful for
keeping
clinicians up to date, and the time is
long overdue
for effective warnings on the drug label,
in the
package insert, and in all
advertisements. This
can't wait any longer or it will be too
late.
Next three slides. For Josh and many
others it is already too late. Thank you.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 47, please.
DR. HEALY: Ladies and gentlemen, I am
here and have paid all my own costs to be
here.
This meeting you are having is more than
about a
crisis about one drug-induced side
effect; this is
a crisis for evidence-based medicine that
has
enabled the FDA and the companies to
state openly
and repeatedly that there is no credible
evidence
that there is a link between SSRIs and
suicide when
this is scientifically quite wrong.
There have been 677 trials
involving
SSRIs, and having helped review all of
these, I can
let you know that roughly only 1/4
suicidal acts
384
that have happened in these trials have
been
reported in the scientific articles that
have come
out of those trials. Nevertheless, when you
combine all of the trials year on year, as
of 1988,
the odds ratio that SSRIs are associated
with
suicide over placebo over double the rate
is there
from '88 onwards, and for each year
onwards. The
odds ratio without risk of getting well
in these
drugs is actually much less. It is only half of
the odds ratio of picking up a suicide.
The original Paxil suicide
figures that
SmithKline submitted to the FDA, in '89,
showed an
eight times greater risk of suicide on
Paxil for
adults than for the same suicidal acts on placebo.
Telling SmithKline that FDA believed
concerns about
suicidality were a public relations
first, Martin
Brecker, of FDA, invited them to resubmit
their
figures.
SmithKline did so and in the process
re-coded as placebo suicides and suicidal
acts acts
that had not happened on placebo. They were only
doing what Lilly and Pfizer had also
done.
In contrast, FDA, when faced
with
385
debatable evidence that the SSRIs worked,
had a
completely different approach. Such as the volume
of negative studies that people within
the FDA
suggested to Bob Temple that the label
for these
drugs should include some indication of
how many
negative studies there were. Martin Brecker, in
the case of Zoloft, where two of the tree
trials
back then when the drug came to FDA first
were
actually negative, and still are
negative, said he
would be embarrassed to be associated
with this
portfolio. FDA, Dr. Temple, chose not to write
into the labeling the number of negative
studies
there had been. In the light of what has
happened
with Elliott Spitzer, who characterized
such
behavior as close to fraud, it may be
time to
revisit this choice.
Having said this, I think FDA
made the
right choice to approve Zoloft and other
SSRIs.
But there is a sauce for the goose and a
sauce for
the gander issue here. The best estimate we have
of suicide on these drugs is 2.4 times
greater. In
the Paxil OCD trials the best estimate we
have...
386
[Applause]
DR. GOODMAN: Thank you very much. Is
speaker 48 here? You are speaker 49?
MS. WAINSCOTT: Yes. I
am chair of the
National Mental Health Association. I am an unpaid
volunteer and I am family member.
Depression itself creates a
significant
risk for suicide and we have known for a
long time
that as a person emerges from the black
hole that
is severe depression, there is a risk
that they
will marshall the strength to act on the
suicidal
thoughts that often accompany this
illness. I saw
this happen two times to my mother as she
bravely
struggled with depression for almost half
a century
without the benefit of today's treatment
advances.
Today, because the topic of
suicide is
uncomfortable for many, because insurance
plans
limit visits and often flatly deny
psychotherapy,
because practitioners are very time
pressed and
sometimes they are wrong, kids are often
not
adequately monitored after they receive
medication,
and parents often are not told what to
look for to
387
protect their children. There are heart-breaking
stories of the consequences.
But I came to tell you a
success story.
As a young child Jessica was sunny and
cheerful,
loving, affectionate. Then, as she turned 11 it
was clear that something was very
wrong. She was
suddenly crabby, difficult to get along
with. She
became moody and withdrawn. Jessica's father
approached her directly, "you have
to tell us
what's the matter." She replied, "I have been
telling you." "No," he said, "you have just
been
going away." After a long silence Jessica said, "I
don't know, Dad. It just seems like I'm mad all
the time." As the words tumbled out and she
described her pain he realized she needed
professional help.
She was diagnosed with
depression and
together she, her family, their
pediatrician and a
consulting psychiatrist developed a comprehensive
treatment plan that included SSRI
medication with
close monitoring.
I am happy to tell you, and I
want to show
388
you a picture, that my granddaughter is
doing
extremely well. She is the tall one. She is an
outgoing, happy 15 year-old, engaged in
her family,
successful at school. She has a lively group of
friends and is displaying a real talent
for art.
She sticks to her treatment regime and
she still
takes medication.
As I prepared this testimony I
talked with
Jessie about it. She told me, "Babi, tell them not
to do anything that will make people
afraid to go
for
help. Life is so much better with
treatment."
I asked her how it is better and she
said, "I'm
just able to be myself. There are no invisible
strings pulling me down."
So, I ask you for Jessica and
for the
millions of kids like her who do and will
struggle
with depression balance the risk of
medication with
the risks of untreated depression. Help tear down
the barriers to treatment. Don't erect new ones.
Address the issues in the broadest
possible
context.
Be mindful of the many children like
Jessie who benefit from these medications
and the
389
hundreds of thousands who need treatment
and get
nothing.
The written testimony of the
National
Mental Health Association, which you
have, makes
specific recommendations. We support the call for
closer monitoring of...
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 51, please come to the podium.
MS. GRUDER: My name is Deborah Gruder.
My husband, Scott, was never diagnosed,
ever, with
depression but on March 30th, the morning
of March
30th, after being on Paxil for 13
days--13 days
only--he went to Walmart at 7:16 a.m. and
bought a
shotgun and returned to his office and
locked the
door and shot himself.
Neither he nor I had any idea
that there
was any need to beware. We were never told we
should beware. We knew people who had been on
Paxil or other SSRIs and we had seen many
of them
benefit, and we had seen the numerous
television
commercials that showed people that were
in very
390
desperate psychological trouble, after
taking
SSRIs, all of a sudden they were dancing
through
fields of flowers; they were laughing;
they were
happy.
This is what we knew. We didn't
know there
was anything to be concerned about. Not once--not
once did we ever see in any of these
commercials--we never-ever saw a
follow-up of
anyone stepping off of a bridge into the
icy waters
of a river to their death. We never saw a woman
lock herself behind her bathroom doors
and slice
herself up with scissors. We never saw anyone take
a gun and go behind closed doors and
shoot
themself.
My husband and I did not once
hear about
the subpopulation of people, which
evidently he
belonged to, that had a very adverse
reaction to
Paxil and other SSRIs. Early this year I
understand, and for the past 10-15 years
you have
been aware that there is a problem with
SSRIs.
Shame on you! Shame on you for being aware when
you should be protecting us, the people,
all these
people sitting behind me! My story is not unlike
391
theirs.
You should be protecting us.
Where were
you?
Where have you been? Why haven't
you done
anything about this? This is just a small
percentage of people that have had a
loved one die
violently because you have not done your
job...
[Applause]
DR. GOODMAN: Thank you.
Speaker 52,
please.
MS. GUARDINO: My name is Mary Guardino
and I am the founder and executive
director of
Freedom from Fear, a national mental
illness
advocacy organization, and someone who
suffers from
anxiety and depression.
I want to thank the committee
and all
those who have participated in the
process of
gathering and sharing information related
to this
very important issue. As a mother and mental
health advocate for the past 20 years,
nothing has
been more important to me than the health
and
safety of our children.
My own depression and anxiety
began when I
was very young. Most tragically, it was not until
392
I was 40 years old that I received a
proper
diagnosis and successful treatment. I was one of
the lucky folks back in 1982 because my
treatment
combined medication and cognitive
behavior therapy.
That treatment brought me from the
darkness of
despair into the sunshine of hope. I have never
forgotten those dark, long, painful
days. They
continue to motivate me in my work as an
advocate
for those struggling with mental
illnesses and the
family and friends who love and care for
them.
When my own children showed
signs of
anxiety and depression, fortunately, I
was better
prepared to find the treatment they
needed. I
truly believe that my daughter would not
have been
able to complete law school nor my son
complete a
masters in psychological counseling if it
were not
for the early intervention and successful
treatments of their illnesses.
What also is important is that
their
positive experience with treatment has
taught them
to trust the mental health network and to
utilize
it with confidence when it is
needed. Their proper
393
treatment has increased their resilience
and
empowered them to help others.
In closing, I want to remind
the committee
to never lose sight of the goal all of us
here so
passionately strive for, that is, to
improve the
mental health status of all our
citizens. To
achieve that, we must encourage people in
need of
help to seek treatment and provide
consumers and
providers with access to the latest
scientifically
valid data and information on the best
treatment
options.
If we fail in either of these endeavors,
we will not be achieving the goal we all
aspire to.
Thank you.
DR. GOODMAN: Thank you.
Speaker 53,
please.
MS. WILLIAMS: I am here representing
Jacob Williams who died of Prozac-induced
suicide,
December 5th of 2000. I was here last February.
Therefore, I will give a brief synopsis
of my
previous statement and add a few
additional
comments that I feel are pertinent.
My son, Jacob Williams, was
born on
394
October 15th, 1986. On October 11th of 2000,
Jacob's pediatrician prescribed him
Prozac. It was
to be increased to 20 mg if there were no
side
effects.
The doctor did not describe to us what
side effects we were to look for. I assumed the
prescription insert would indicate all
side effects
related to this drug. I was wrong.
My husband
asked the doctor if Jacob's problem could
be
hormonal, and did Jacob have to be put on
medication. The doctor replied that this
medication would help him because it is
the most
commonly prescribed drug for teenagers to
help them
with their needs.
On November 6th, 2000 Jacob was
back in
the doctor's office for a follow-up
visit. At this
time his dose was increased to 20
mg. This was
Jacob's last visit to the doctor. Shortly after
this visit I began to notice an
aggressive behavior
in Jacob which had not been there
before. He also
showed a verbal aggression and short
temper that
had not been present before. When questioned about
this behavior he stated, "I don't
know what's
395
making me do this." On December 5th of 2000 I
found Jacob hanging from the rafter in
our attic.
During the time Jacob was on
Prozac, he
went to a psychologist on several
occasions. The
psychologist asked Jacob on these
occasions whether
he thought about suicide. He responded that he
would never do such a think because it
was against
his religion. My sole purpose in being here today
is to, hopefully, prevent other parents
from having
to go through the pain and anguish our
family has
gone through. Had I known suicide was a possible
side effect to this medication I never
would have
allowed my son to take it.
I appreciate the action that
has been
taken since the last hearing. However, I am
concerned that many are still saying
Prozac is a
safe SSRI. It is not safe. Since my last
appearance before you I have heard
statements from
others who survived their encounters with
SSRIs,
specifically Prozac. My son cannot speak for
himself since he did not survive, and it
is my
responsibility as his mother to speak for
him. It
396
is my firm belief that his death was a
Prozac-induced suicide.
In conclusion, Jacob trusted
me. I
trusted the doctor and the doctor trusted
the FDA
to make sure the drugs that are approved
are safe
and have proper warning labels. I plead with you
to live up to the trust our society has
placed in
you.
Thank you.
[Applause]
DR. GOODMAN: Thank you very much. Is
speaker 54 here? If not, speaker 55, please come
forward.
MS. YORKE: Good afternoon. My name is
Laurie Yorke and I am here on my own
accord.
Seven months ago I stood in my living room
and watched my 16 year-old son slash his
wrists in
a full-blown Paxil-induced rage,
screaming, "I was
born to die." I am one of the lucky ones. My son
is alive.
The process of weaning and
withdrawal
began without the help of my son's
prescribing
psychiatrist. He had refused to take my son back
397
as a patient after the suicide
attempt. It was an
Internet message for the Paxil survivors
that
walked me through the withdrawal
process. With
each lowered dose, my son experienced the
anger,
aggression, brain zaps, visual
disturbances and
insomnia.
His withdrawal symptoms followed
stunningly similar patterns that others
have
experienced. He took his last dose of Paxil at the
end of April.
Prior to my son being
prescribed Paxil for
a single panic attack I did the research
on this
drug.
As a nurse of 20 years, I am probably in the
minority because I do read drug
inserts. I do read
the PDR.
I do ask questions. When I
questioned
his psychiatrist about the use of an SSRI
in a
child his age, I was reassured by this
adolescent
psychiatrist that he has never had a
problem with
it before.
Paxil turned my child, in a
period of 13
months, from an A/B student, social,
outgoing
personality like you would not believe
into an
angry, death-obsessed, anti-social
recluse. My
398
son, now off Paxil, is once again happy,
outgoing,
socially active. What he must now deal with is the
lack of concentration still existing
after the
Paxil withdrawal. I shudder to think of what the
long-term ramifications of Paxil use will
be in his
case.
The FDA's lack of action on the
evidence
presented years ago caused my son to
become a
victim of Paxil. The FDA chose not to act on
information you received that documented
these
reactions in clinical trials. GlaxoSmithKline
chose to hide clinical trial data to
protect
profits instead or protecting our
children.
GlaxoSmithKline said on "World News
Tonight" that
they gave the information to those who
needed to
know.
I am responsible for my child. I
spend 24
hours a day with him. I needed to know. I was not
told.
Delaying banning of SSRIs for
children
means more children will die and the
violent
behavior will continue. You have failed to protect
our children from a bad drug. I was under the
399
impression that FDA approval meant that
drugs
actually went through a rigorous
investigation
prior to their being approved for
safety. I know
that the FDA approval now means
nothing. Drug
companies are allowed to pick and choose
the
clinical trials that they like. You rubber-stamp
the approval and allow the children of
the United
States to become the guinea pigs. I believe the
FDA has forgotten the Hippocratic oath,
the basic
that we all must adhere to, first do no
harm.
[Applause]
DR. GOODMAN: Thank you very much.
Speaker 56, please.
MR. FRITZ: I told the story of my 15
year-old daughter, Stephanie, last
February 2nd.
She was on Zoloft and hung herself on
November
11th.
DR. GOODMAN: Can you start over and bring
the microphone closer?
MR. FRITZ: Sure.
I told the story of my
15 year-old daughter, Stephanie, on
February 2nd
here.
She was on Zoloft and hung herself on
400
November 11th. I attended the congressional
hearing last Thursday at which Dr.
Woodcock
testified that the FDA had clinical
information
that showed that these antidepressants
were not
effective in treating children; that they
caused an
increase in suicidal thoughts. Some of these
trials are years old so the FDA has had
knowledge
and decided not to share this information
with
parents so that they could make informed
decisions
on how to care for their children.
Dr. Woodcock said there is
something in
the law that kept the FDA from putting
the
information out. She couldn't cite the law. I
guess it never occurred to her to ask
Congress to
change the law so that this information
could get
out.
Maybe the FDA was too stupid to ask them to
change the law but I don't think so. The FDA made
a conscious decision to hide this
information from
the public because they say there is no
other
treatment available, even though they
knew the
drugs weren't effective and kids would be
put at
higher risk for suicide.
401
Doctors are charged with first
doing no
harm, just like Laurie said. But you, Drs. Temple,
Laughren, Katz and Woodcock, have abused
the public
trust.
You have greatly misused the power of your
positions by keeping the information from
the
public while protecting the drug
companies'
profits.
I am asking that four of you
resign as
soon as the congressional investigation
is over so
that we can get people to work at the FDA
that will
work to protect our children and not the
drug
companies and their profits. You say that
depression is the cause of suicides that
occur with
children on these drugs. Well, you have known all
along, because of off-labeling, that kids
have been
prescribed these drugs for illnesses
other than
depression and still have completed
suicide or they
have attempted suicide, and you can't
explain away
these events on depression.
Those that have survived these
drugs talk
of violent thoughts and actions that went
away and
haven't come back since being off the
drugs. You
402
say the jury is still out on these
drugs. But it
isn't out on you people. You need to go. We need
to get people who will fulfill their duty
and
protect the people, not the drug
companies. And,
these drugs need to go. Until the drug companies
can show that they work they shouldn't be
prescribed to children.
The FDA should demand that the
drug
companies open up their files, not just
the
clinical data, on these drugs so we can
see what
they thought and what they are saying
about these
drugs--if they haven't shredded them,
that is. If
they have nothing to hide, they should do
it right
away but I don't think they will. They have known
all along that these drugs don't work and
were
potentially dangerous to children who
took them.
Dr. Cleary, from Pfizer,
testified at the
congressional hearing on Thursday as
well. She
testified in front of Congress that she
wanted to
be open and let people know what was
going on.
Well, I call on them to open up their
files now so
we know what is going on.
403
[Applause]
DR. GOODMAN: Thank you.
Speaker 57,
please.
DR. VARON:
I am a full-time child and
adolescent psychiatrist. I would like to thank the
North Baltimore Center, which is a
community-based
health center treating the children of
Baltimore
City.
I would like to thank them for allowing me
to come down today. Although they didn't provide
financial support, they forfeited a day
of billable
services to allow me to speak to you
today.
Each day I realize that some of
my
patients may one day die from the
depression I seek
to treat.
Antidepressants in children and
adolescents do work. In many cases I have seen
depression improved with the use of
antidepressant
medication. In cases where medication has been
helpful, the child has been involved in a
multi-disciplinary approach where
individual
therapy, family therapy, including parent
management training, has been utilized;
the patient
had access to partial and/or inpatient
404
hospitalization when needed; and
educational
intervention was available when
appropriate. As
well, medications were helpful only if
the right
diagnosis was made. For instance, if we were
really treating bipolar disorder as
opposed to a
depression the antidepressants, in fact,
were not
helpful.
Also, they were helpful if comorbidities
were also treated.
Second, discrimination in
obtaining mental
health care can compromise the patient's
ability to
be monitored appropriately for the
dangerous side
effects that we are talking about. And, shortages
of child and adolescent psychiatrists can
also
exacerbate this issue as these are the
physicians
most fully trained in prescribing these
medications.
Would a potential life-saving
cancer drug
with the risk of, say, aplastic anemia be
taken off
the market because of poor access to
proper
physician monitoring, or due to denial of
an
important hospital admission due to
insurance
purposes?
405
Third, I believe that there is
a
subpopulation of children that require
lower
starting doses, almost homeopathic doses
as it
were, and a longer titration periods of
SSRI
dosages.
As such, these individuals may actually
be more sensitive to the activation or
disinhibition that we are talking about
on the
SSRIs.
Thus, if they are started on the higher
doses, they may be more subject to the
events that
we are talking about today. Thus, I would like to
suggest that any future research take
this
subpopulation in mind.
Fourth, in my practice over the
last ten
years I have seen one case of an
antidepressant
causing suicidal ideation, as reported by
the mom,
prior to the child actually coming to
me. In that
case, no act, fortunately, was involved
but the
child still needed to be put on an
antidepressant
medication and subsequently did well.
I would like to talk about a
female who
was successfully treated. She had recurrent
depression for many years on many
medications. She
406
subsequently, over the last six months,
has
resolved on a combination of high-dose
Zoloft,
Risperdal and Wellbutrin and she is
currently
living without depression...
DR. GOODMAN: Thank you.
Speaker 58,
please.
MS. ZITO: My name is Julie Zito. I am
Associate Professor of Pharmacy and
Psychiatry at
the University of Maryland, in
Baltimore. I am a
pharmacoepidemiologist and I have been
studying the
use of psychotropics in children for the
past 12
years.
I am here, despite the late hour and our
exhaustion, to really ask the panel to
consider
seriously a specific scientific model in
addressing
the need for additional research on the
benefits
and risks of SSRIs in treating youth. Namely, I
ask you to recommend conducting a very
large cohort
study on a systematic sample of youths in
treatment, and to follow them for a
period of at
least a year. This non-clinical trial longitudinal
approach can address many of the
currently
407
unanswered questions that you are here to
consider.
The sample should include
youths from both
primary care and psychiatry. Data suggest there
are about two million children a year
getting an
SSRI prescription so there shouldn't be
too much
trouble in identifying 100,000 7-17
year-olds who
can be systematically assessed on
outcomes at
periodic times across a year.
A cohort study would allow us
to document
outcomes in four treatment groups, those
who get
better and stop meds., those who get
better and
continue meds., those that stop treatment
because
of
a lack of improvement, and those that stop
because of adverse events. Of course, in the case
of the last example, those rare serious
events can
be fully described.
The rationale is simple. A signal of 1.78
from retrospective trial data is really too weak to
be definitive. Randomized trials are typically too
small to address rare events. And, finally,
depression is, indeed, too serious a
condition to
unwittingly deprive those use who would
benefit
408
from treatment simply because of lack of
data that
can distinguish between the SSRI at risk
youth from
the SSRI improvers.
Federal sponsorship is
necessary to assure
that the design and assessment of such a
study
would be adequate to address the clinical
public
health questions that we are really after
at this
point.
We do need collaboration among the numerous
disciplines that are involved around this
question.
We need the participation and support of
youths and
their families, and we need support from
the
treatment settings in which they receive
care,
particularly large HMOs and large mental
health
clinic settings.
There is no existing data
source now that
is adequate to address the SSRI safety
and even the
community effectiveness questions that
you are here
to discuss. Sadly, it is the suffering of young
people...
[Applause]
DR. GOODMAN: Thank you very much. Is
speaker 59 here? If not, will speaker 60 step
409
forward?
DR. ROBB: I am Dr. Adelaide Robb and,
while I am the psychiatric liaison to the
American
Academy of Pediatrics Committee on Drugs,
I am here
speaking today as a child psychiatrist,
practicing
at
Children's National Medical Center in
Washington, D.C.
I wanted to give you a bit of a
different
perspective, that of somebody who takes
care of
kids who are sick every day with
depression and
their suffering. I first became aware of
adolescent depression and suicide when I
was 16 and
a classmate called me at two o'clock in
the
morning, saying he wanted to kill
himself. I spent
the next two hours talking on the phone,
trying to
think of good reasons to stay alive, and
the next
two weeks combing the obituaries in the
"Buffalo
Evening News" seeing if anybody
under the age of 20
had died.
I never found out who that classmate was
but it made me think a lot more about
what I was
going to do when I went to medical
school, and I
went off and did training in psychiatry.
410
I then went on to a fellowship
at the
National Institute of Mental Health where
I took
care of a lot of families with bipolar
and major
depression. Many of them were bringing in their
kids who were five and six years old and
suffering
from depression, and none of the doctors
in
Washington, D.C. wanted to treat
depression in a
five year-old because it was dangerous,
and scary,
and what kind of five year-old gets
depressed?
So, I ended up going back to do
additional
training in child psychiatry and for the last ten
years as a Board certified child psychiatrist I
have admitted 3000 patients to our
inpatient unit
at Children's, and 2000 of those kids
were
suffering from a mood disorder, and from
those
2000, about 70 percent had major
depression and
went on antidepressants. While we have lost
several patients from our unit to things
like
cancer and AIDS and other illnesses that
can cause
death in the under 18 year-olds, we have
not had a
single suicide out of those 3000 kids
admitted. I
want you to remember that.
411
I have also treated outpatients
with major
depression and have had about 500 kids
that I have
taken care of in the last ten years who
have gone
on antidepressants. Again, none of them has died.
A hundred have tone to college; two have
gone to
law school and two to medical
school. I don't
think any of that would have been
possible for them
if they hadn't gotten treatment which
consisted of
careful monitoring, medicine when
necessary, and
therapy and education about side
effects. I tell
parents I want them to call me if they
have any
questions. I tell them these medicines, especially
in the beginning, may lead to suicide and
if they
have any questions--none is too silly--I
will
answer email; I will answer a phone
call. I am
there to help the kids.
But I am a child psychiatrist
and we spend
more time with our patients and we want
to help
them.
In addition, I have actually been a PI in
ten of the trials that you guys are
talking about.
We have had 63 patients randomized in
those trials.
We have not had a single suicide in those
trials
412
either, nor have we had increase in
suicidal
ideation...
DR. GOODMAN: Thank you very much.
Speaker 61, please.
DR. REBARBER: Hello.
My name is Dr.
Steve Rebarber and I am an outpatient
child and
adolescent psychiatrist. I have been working in
Bethesda, Maryland since I completed my
child
psychiatry training in D.C. Children's
Hospital in
1991.
I appreciate the opportunity to
come
before the committee to briefly share my
experience
concerning the safety and efficacy of
SSRI usage in
children with depression, and urge the
committee to
allow sufficient time for reliable
research to be
done on this crucial matter before taking
any
dramatic steps, such as prohibiting their
usage.
In my practice I have had broad
experience
in working with families whose children
have tried
SSRIs.
SSRIs are neither the panacea, as some
proponents suggest, nor are they the
scourge that
some opponents claim. I have seen some children
413
who have become agitated with SSRIs, some
rare
instances where perhaps they have become
suicidal,
but I have also seen many children with
beneficial
and sometimes life-saving reactions in
responses to
SSRIs.
I have no doubt that if SSRI
usage is
prohibited before reliable scientific
evidence
demonstrates that they are dangerous that
many,
many children will suffer devastating
untreated
depression, and many of them are likely
to go on to
substance abuse or suicide.
I realize that the committee
has heard
dramatic examples by caring and sometimes
devastated families; that SSRIs have had
terrible
effects on their children. In some cases the
families may be correct in blaming the
medication.
In some cases, it seems to me, given the
complexity
of children's lives, the families may be
wrong.
You may be hearing from far fewer of the
far
greater number of families for whom SSRI
treatment
has been beneficial. I can imagine the pressure
that the committee may be feeling hearing
these
414
stories because at times I also find
myself hearing
the plea of parents, urging me to do
something,
anything, and sometimes the most
difficult part of
my
work is to tell parents that I don't yet have
enough information on which to act and
that the
best thing to do is to gather more
information
before acting.
I urge the committee to act,
not in the
heat of the moment, but only after you
have the
sound scientific information necessary
for making
good decisions. Thank you.
DR. GOODMAN: Thank you very much.
Speaker 62, please.
DR. KRATOCHVIL: Good afternoon. My name
is Chris Kratochvil and I am a child and
adolescent
psychiatrist, from the University of
Nebraska
Medical Center, in Omaha, Nebraska. I receive
support from pharmaceutical companies but
no
support for this testimony.
Thank you for providing me with
this
opportunity to talk to the committee
today. I come
to you today as a clinician that treats
children
415
and
adolescents with major depression and a
clinical researcher who studies the
treatment of
pediatric depression. I am the principal
investigator of the Nebraska side of the
TADS
study, which you heard Dr. March talk
about earlier
today.
In my role as a clinician I
work closely
with the children and adolescents
suffering from
depression, as well as their
families. These
youngsters experience significant
distress and
impairment as a result of the depression
that
impacts their daily life at home, school
and with
their friends. Sadly, as you have also heard,
depression can all too often lead to
suicide.
In the context of a careful
clinical
evaluation and close monitoring, I have
seen many
youths make significant gains in their
battle with
depression when antidepressants are
included as a
part of a comprehensive treatment
plan. As a
clinician, I see antidepressants playing
a critical
role in helping many of these young
people.
That being said, I do agree
with the
416
current warnings in place on the use of
antidepressants. Close monitoring is good medicine
and includes educating and including the
families
in the monitoring. In my role as a clinical
researcher in the TADS study, I have had
the
opportunity to systematically study the
safety and
effectiveness of two specific treatments
for
adolescent depression. The results of the study,
as you heard, have shown a significant
importance
in depression in adolescents treated with
fluoxetine combined with cognitive
behavioral
therapy.
But these findings are just the
beginning.
What about other
pharmacotherapies, other
psychotherapies and other age
groups? How do we
select the best treatment for a specific
child who
comes to us with a unique story and a
unique set of
problems?
Significant research remains to be done
to help guide us in our efforts to help
these young
persons and their families.
My recommendations to the
committee at
this time: Warnings for careful and systematic
417
follow-up when antidepressants are used,
particularly during the initiation,
titration and
discontinuation. Additionally, further studies on
the safety, effectiveness and role of all
antidepressants that are used in the
pediatric
population need to occur. Thank you for your time.
DR. GOODMAN: Thank you.
Is speaker 63
here?
Speaker 64?
MR. SWAN: My name is Eric Swan and I lost
my brother-in-law, Tim Witsack, to SSRI
suicide.
His story is told on the website we have
created
for him at woodymatters.com. I urge each and every
one of you to go there and study his
story.
Albert Einstein said it best
when he
defined insanity, it is doing the same
thing over
and over and expecting a different
result. I am
here to simply ask that you include
adults in
safety action you recommend or take. I believe
that if the patterns taken in the past
are repeated
we will be having a similar hearing
sooner than
later on adults on these same
issues. I believe
that no one here truly knows that the
side effects
418
of SSRIs are any less dangerous to a 19
year-old
than an adolescent. Adults matter too.
Every person sitting in this
room can do
something to help fix this tragedy. Members of the
develop committee, please hear the
stories of adult
victims of SSRI-induced suicide and
include adults
in your recommendations to FDA. Please also focus
on patients given antidepressants
off-label who are
not depressed who went on to commit
suicide out of
character.
Employees of the FDA--Dr.
Temple, Katz,
Laughren, I assume that since FDA
included adults
in the March warnings that you are also
looking at
the original safety and efficacy studies
for adults
from the late '80s and early '90s. If you truly
are part of the jury that is still out,
please
decide sooner than later. Lives are in the
balance.
And, please investigate from other angles
as well.
We have some ideas on this and will
follow-up with you.
To the pharmaceutical industry
here, your
industry is important. With that, however, comes
419
an awesome responsibility to your fellow
Americans
who take these drugs. The very minute a safety
issue is discovered it should be disclosed
and
openly worked out. There is no excuse to ever put
one penny of profit over the life of a
child,
husband, wife, mother, father, brother,
sister or
friend.
Please disclose all you know on this
matter so a solution can be found.
To the media here, thank you
for bringing
the stories into the spotlight. Please continue to
write and tell the stories that need to
be told.
On August 6th, 2003 I walked
into a
nightmare when we found my brother-in-law
hanging,
at age 37. Tim Witsack lived his life by the gauge
of doing the right thing. If we all apply that
same standard to the work before us today
we have a
chance to end the patterns of the past
and save
lives.
As an aside, Dr. Laughren, I
heard you
mention earlier that you have not seen
the same
indications in adults. Please use Woody's story
and the adult stories behind me as your
indication.
420
Thank you all for your time.
[Applause]
DR. GOODMAN: Thank you.
Speaker 65,
please.
MS. WEATHERS: My name is Patricia
Weathers.
I am a New York mother and president and
co-founder of ablechild.org, a national
grassroots
parent organization representing over 900
members,
such as Mrs. Vicky Dunkle whose 10
year-old
daughter died in her mother's arms as a
direct
result of the antidepressant prescribed
her.
I am one of the lucky
ones. My child is
still alive. My own story has been featured on
"Good Morning, America,"
"The Today Show," A&E
investigative reports and "The New
York Times,"
just to name a few. I have testified before state
legislatures and twice before
Congress. My
activism began after my son's school
coerced me to
place him on Ritalin, a drug that caused
him to
become extremely withdrawn. The school
psychologist and psychiatrist then
diagnosed him
with social anxiety disorder and
recommended Paxil
421
as a, quote, wonder drug for kids.
On Paxil, he began hearing
voices in his
head, drew violent pictures and even
attacked me.
I could no longer recognize my own
son. He pleaded
with me at one point, "Mom, make it
stop." I
finally realized that it was the Paxil that
put him
in a drug-induced psychosis so,
naturally, I
removed him from the drug. I was then charged with
medical neglect when there was no proof
that
anything was medically wrong with
him. I soon
discovered social anxiety disorder, like
bipolar
disorder and attention deficit disorder,
are not
medical conditions. Parents are told that their
child has a chemical imbalance or a
neurobiological
illness.
We risked our child's life based on this
fundamental lie.
I now know this is not true
but, more
importantly, so do you. The FDA is well aware that
there are no x-rays, biopsies, blood
tests or brain
scans that verify these mental disorders
as a
disease or illness. My point is simple. The FDA
should not be condoning or approving
these drugs
422
without evidence of disease, illness or
physical
abnormality that would justify risking
our
children's lives with a harmful and
potentially
lethal drug.
We are gathered here today,
discussing
warning labels on antidepressant
drugs. Why? The
FDA had enough evidence 14 years ago to
issue these
warning labels on these drugs and you
know this.
Now the FDA must do more. The FDA's own mission
statement says that it is responsible for
helping
the public get accurate science-based
information.
It is failing. The FDA is risking our children's
lives based on nothing more than junk
science. The
FDA is responsible for protecting the
public
health, not vested interests. I remind you that
children's lives are in your hands and I
call...
[Applause]
DR. GOODMAN: Thank you.
Speaker 66,
please.
MS. STEUBING: We are Celeste and Dan
Steubing.
This is our daughter, Ann. On
June 8th,
2003, our 18 year-old son, Matthew,
graduated from
423
high school with his whole life ahead of
him. Six
weeks later Matthew jumped to his death
from the
Cooper River Bridge in Charleston, South
Carolina.
He had been taking the antidepressant
Lexapro for
less than ten weeks. Matthew was the youngest of
our six children. He was a happy and healthy child
with no prior history of depression. Matt was a
normal teenage boy. He loved sports, loud music,
pretty girls, cool cars and
Seinfeld. He loved his
family.
Matthew had plans for
college. He had
plans to join the Air Force ROTC
program. He did
not plan to die. Matthew was experiencing some
difficult life lessons. He began to withdraw from
his friends and his normal
activities. He lost
interest in school, work, his plans for
college,
even basketball, the thing he loved
most. We
sought the help of a counselor who
recommended a
combination of therapy and medication as
the best
way to help Matthew's chemical
imbalance. A family
practice doctor prescribed Lexapro. Prior to
taking the medication, Matthew was
depressed; he
424
was not suicidal. After beginning the Lexapro
things changed. In Matt's words, "it just got
worse."
He became more withdrawn. He had trouble
sleeping.
He was anxious and restless as though he
couldn't stand to be in his own
skin. He had
tremors in his hands and complained
several times
that he felt like his heart was beating
too fast.
He said things like, "I feel like
I'm here but I'm
not here," and "it feels like
my head is
disconnected from my body." As for side effects,
we were told there could be things like
dizziness,
nausea and insomnia. Never did
the doctor discuss
the possibility that this drug could
worsen my
son's depression or cause a condition
called
akathisia, a condition we now recognize
as being
present in Matthew.
As parents, we have a right to make an
informed decision regarding our child's
care. That
right was taken from us when you elected
to turn a
blind eye to the evidence that had been
mounting
against these drugs for years. Had we known the
425
truth about the potential dangers of this
medication we would have been better
armed to
protect our son. Matthew would be alive today.
I said before that we lost our son. What
I truly believe is that our son was
murdered by
Forest Laboratories and the FDA has his
blood on
its hands. How many more children have to die?
How many more families have to be torn
apart before
you do the job you were charged to
do? When you
err on the side of caution, it must be in
favor of
the innocent victims who put their faith,
their
trust and their lives in your hands. We demand
full disclosure. You owe us...
[Applause]
DR. GOODMAN: Thank you very much. Is
speaker 67 here? If not, speaker 68, Dr. Mann?
DR. MANN: My name is John Mann. I am
president of the American Foundation of
Suicide
Prevention, which represents families who
are
survivors of suicide, and supports
research into
the prevention and causes of
suicide. I am also a
psychiatrist at Columbia University.
426
First slide, please. I would like to make
several points. I know that some people have
blamed the treatment and other people
have blamed
the condition for a series of tragic
suicides that
we have heard about today. The point I would like
to make is that depression is a real
lethal
condition. You may not be able to take an x-ray
but it is definitely killing a lot of
people.
Principally, it is untreated depression
that is the
major cause of suicide in the United
States in both
adults and children.
Next slide. When you do psychological
autopsies and talk to the families who
have lost
their loved ones, it is clear that the
principal
problem in these suicides is not that
they have
been taking antidepressants that have
killed them.
The principal problem is that they have
been taking
nothing.
Most of them have taken no
antidepressants and a small minority have
taken low
doses of antidepressants, and very few
have had
adequate treatment.
Next slide, please. Do antidepressants
427
work in children? What is of interest is that
fluoxetine, where three studies have
shown
efficacy, those three studies were not
conducted by
the pharmaceutical industry; they were
conducted by
academics. That probably suggests something about
design and who should be doing the
studies.
Next slide, please. Non-SSRIs, however,
pretty unanimously do not seem to be
effective.
Next slide. Now, what is remarkable is
that those individuals in the United States
that
live in particular areas where the
highest
prescription rates exist for SSRIs, in
those
demographic groups that have received the
highest
prescription rates of antidepressants, in
particular SSRIs, have had the biggest
fall in
suicide in the United States. This applies to both
adults and children and it is true around
the
world.
Next slide. The suicide rate rose 31
percent in the United States up to 1986
or prior to
SSRIs.
Since 1987 there has been a steady fall in
the suicide rate. Why?
428
Next slide. The women, for example, who
have received roughly twice the
prescription rate
of men, have had about double the drop in
suicide
rates.
Next slide. Those areas of the United
States that have the highest prescription
rates of
SSRIs, both in adults and children, have
had the
biggest falls in suicide rates.
Next slide. In fact, if you calculate,
for every 10 percent increase in
prescription
rates, there are approximately almost a
1000
decreases in suicide...
DR. GOODMAN: Thank you.
Speaker 69,
please.
DR. BRAIN: I am Lawrence Brain, child
psychiatrist practicing in Bethesda,
Maryland and
president of the Child and Adolescent
Psychiatric
Society of Greater Washington.
Until two years ago and for
over 20 years
I treated seriously ill children in
psychiatric
hospitals, and for most of that time was
medical
director of these large programs. Therefore, I
429
have been involved in the treatment of
thousands of
significantly ill child patients and have
had an
opportunity to observe the effectiveness
of the
SSRI antidepressant group.
I wish the committee to focus
on another
clinical element. Until approximately ten years
ago seriously depressed children were
admitted to
psychiatric hospitals for assessment and
treatment.
Initially this required a comprehensive
evaluation
and the development of an extensive
treatment plan.
I believe it is essential that in
evaluating the
effectiveness and safety of the SSRI
group it is
imperative that this be placed within the
context
of an adequate and comprehensive
treatment plan.
In the past, after evaluation,
depressed
children were prescribed antidepressant
medications, frequently of the SSRI
group.
However, they remained hospitalized in a
safe
therapeutic environment where, in
addition to
medication, they received numerous
psychotherapeutic services during which
we had an
opportunity to observe the impact of the
medication
430
so that if activation and escalation of
suicidal
ideation or impulsive and potentially
dangerous
behavior occurred, this was able to be
contained.
As it is known that this
activation
typically occurs within the first three
weeks of
treatment, the patients remained in the
facility
until we observed a therapeutic response
and a
pattern of safe behavior. Patients were then
discharged to day treatment where intensive
daily
treatment was provided until safe
discharge to
outpatient care was achieved.
This process changed with the
intrusion of
managed care, such that now significantly
depressed
children are not hospitalized unless
there is an
absolute assessment of being a danger to
themselves
or others. Currently, it is typical for
hospitalization to be brief; assessment
to be
superficial and if medication prescribed,
the
patient is discharged within 3-5
days. Managed
care reviewers have focused on the
utterance of
suicidal thoughts as the only determinant
of
potential dangerousness.
431
As a clinician, I have argued
vociferously
on many occasions that, if not present,
this does
not represent real change and that
potential danger
exists.
Given the known duration before clinical
effectiveness can occur, it is evident
the current
policies are exposing children
unnecessarily to the
vicissitudes of their illness. It is my experience
that these medications are safe and
effective
provided they are used within the context
of a
comprehensive treatment plan, and I urge
this
committee to look beyond the limitations
of brief
studies, to provide guidance and
direction as to
the totality of care as outlined in the
practice
parameters developed by the American
Academy of
Child and Adolescent Psychiatry.
While it is the responsibility
of the
treating psychiatrist to ensure as much
as
possible...
DR. GOODMAN: Thank you.
Speaker 70,
please.
MR. SHAPIRO: My name is Mark Shapiro. I
am here from Duke University. I have no financial
432
association with any drug makers.
First of all, I know you are
tired so I
would like to thank you for listening to
me and
thank you for your thoughtful
deliberations on this
difficult topic. I am speaking here as a member of
the public. However, I am the manager of child and
adolescent psychopharmacology
trials. I am also a
past sufferer from major depression.
In my early 20s I sought
treatment for
depression and, like many sufferers, it
was not
until I was suicidal that I even
recognized the
need for treatment. In my case, paroxetine and
frequent session with a psychiatrist
saved my life.
Although I was skeptical of psychiatry
before that
experience, therapy helped me to
understand and
overcome my illness. However, without
antidepressant medication I could not
have made it
to this session and might not be standing
before
you today.
I would like to comment on the
DNDP and
ODS
analyses and to commend those involved for
their efforts to address the current
issue in a
433
fair and scientific manner. However, it should be
noted that the potential pitfalls of
meta-analysis
are well documented and grow as the
heterogeneity
of the included studies grows. As Dr. Dubitsky
noted, these analyses include nine drugs
plus an
extended release formulation, five
distinct
psychiatric disorders, varied treatment
durations
and both in- and outpatient
settings. In other
words, meta-analysis in this case may be
better for
generating a hypothesis for a randomized,
controlled trial than actually making a
policy
decision.
Although there may be a weak signal, the
results are not conclusive either for the
individual drugs or in aggregate.
Why might this be? I believe that the
regulatory climate in which they were
conducted
creates a situation that may have
affected the
trial teams and sites. This stems from the fact
that many of the trials were aimed at
gaining
six-month exclusivity. From a financial
perspective, the six-month marketing
exclusivity is
frequently worth a great deal more than a
pediatric
434
label change, particularly in cases where
a drug is
already being used off-label. When planning a
trial companies may, therefore, view
labeling
changes of secondary importance.
In my own experience, study
sponsors have
often set unrealistically aggressive time
lines for
these projects. Such pressures can lead to
questionable or at least expeditious
choices
regarding trial design and implementation
and
subject recruitment. This may result in an
elevated placebo response, reduced trial
power and
distorted safety profile.
In contrast, the publicly
funded TADS
study offers meaningful and clinically
useful
information about how best to treat
adolescent
depression. However, to address the risk/benefit
ratio of antidepressants and detect rare
but,
nonetheless, significant adverse effects
such as
increased suicidality, a large randomized
and well
designed study is required. Faced with similar
challenges, other areas of medicine have
successfully adopted practical clinical
trials.
435
The Child and Adolescent Psychiatry
Trials Network
is an NIMH-funded initiative that has
recruited
more than 200 child psychiatrists who are
willing
to conduct this research in a real-world
setting in
an attempt...
DR. GOODMAN: Thank you.
Speaker 71, and
then our last speaker will be number 73,
so three
more speakers.
MS. MILLING-DOWNING: On January 10th,
2004 our beautiful little girl, Candice,
died by
hanging four days after ingesting 100 mg
of Zoloft.
She was 12 years old. The autopsy report indicated
that Zoloft was present in her
system. We had no
warning that this would happen. This was not a
child who had ever been depressed or had
suicidal
ideation.
She was a happy little girl and a friend
to everyone.
She had been prescribed Zoloft
for
generalized anxiety disorder, by a
qualified child
psychiatrist, which manifested in school
anxiety.
We were monitoring her diet, encouraging
her
physical activates and had testing
accommodations
436
put in place at school. She had the full support
of a loving, caring, functional family
and a
nurturing school environment. Her death not only
affected us but rocked our community.
How could this have happened to
such a
happy and loving child? When Candice died her
school was closed for the day of her
memorial
service, a service that had to be held in
the
school gym in order to seat the thousand
or so
people who attended. How ironic, Dr. Laughren,
that your family attended Candice's
memorial
service.
Our daughters had been in class together
since kindergarten. How devastating to us that
your daughter will graduate from the
school that
they both attended for the past eight
years and
that Candice will never have the
opportunity to do
so.
Bishop Chain wrote to me
following
Candice's service which he helped
officiate. He
referred to Candice as a spiritually
gifted child.
How fitting that he officiated at
President
Reagan's memorial service on June 11th,
what would
437
have been Candice's 13th birthday.
Candice's death was entirely
avoidable,
had we been given appropriate warnings
and
implications of the possible effects of
Zoloft. It
should have been our choice to make and
not yours.
We are not comforted by the insensitive
comments of
a corrupt and uncaring FDA or
pharmaceutical
benefactors such as Pfizer who sit in
their ivory
towers, passing judgments on the lives
and deaths
of so many innocent children. The blood of these
children is on your hands. To continue to blame
the victim rather than the drug is
wrong. To make
such blatant statements that depressed
children run
the risk of becoming suicidal does not fit
the
profile of our little girl.
We attended the public hearings
held in
February three weeks after Candice
died. We had a
very hard time learning about the
specifics of this
meeting as none of our calls to the FDA
were ever
returned.
Imagine our shock as we sat and listened
to person after person describing their
personal
pain and suffering at losing a child like
us. How
438
could we not have known? These warnings were not
an isolated case. We were never told of any danger
associated. I voiced concern and was told that
there was no problem.
After the hearings I again
tried to
contact the FDA and again no one returned
my phone
calls.
I wrote a formal letter complaining about
Pfizer and was told it would be forwarded
for a
reply.
It is six months later and I am still
waiting for my reply.
I want to know why. Why you have done
these things to us, and why...
[Applause]
DR. GOODMAN: Thank you.
Speaker 72.
DR. KAHN: My name is Dr. Peter Kahn. I
am a Board certified child and adolescent
psychiatrist, in practice for 25
years. I am one
of the medical directors of the Shepherd
Pratt
Health System.
DR. GOODMAN: Please bring the microphone
closer.
DR. KAHN: Okay.
Do you want me to start
439
again?
I am one of the medical directors of the
Shepherd Pratt Health System. I am also on the
clinical staff at the University of
Maryland School
of Medicine. Our experience at Shepherd Pratt in
prescribing antidepressants to treat
children and
adolescents with major depressive
disorders has
been overall positive, particularly when
combined
with psychotherapy. Too often our young patients
keep suicidal ideation and harmful
behavior secret
from their parents and, thus, parents may
be
unaware of how negatively severe
depression
influences their child's thinking and
behavior.
When prescribing medication, it
is good
practice to carefully evaluate patients
for
comorbid conditions that might negatively
influence
their response to antidepressants, and to
probe for
history of suicidal and homicidal
ideation and
history of harm.
Informed consent includes both
risk/benefits of antidepressant use and
the
risk/benefits of not prescribing
antidepressants.
As one college age patient said to me last
week in
440
thinking back about her adolescence,
"without my
antidepressants I would have been
dead."
Psychiatrists have known for years that
during the
initial phase of treatment the risk of
suicide may
increase.
Thus, it is good practice to carefully
educate patients and their parents,
provide 24/7
emergency phone coverage and assess
outpatients at
least weekly during the first weeks of
antidepressant treatment, following dose
changes
and during discontinuation.
As all patients do not respond
to a single
antidepressant, it may be necessary to
switch an
antidepressant ineffective in one individual
to
another, hopefully, more effectiveness
medication.
To make these decisions we need unbiased
data.
I am aware that my experiences
in
prescribing these medications, while
positive, are
retrospective and anecdotal. Clearly, we need more
unbiased clinical research not just on
antidepressants but on all medications
for
children.
Towards that end, I support the
establishment of a mandatory clinical
registry for
441
all clinical trials. In the meantime, this process
has finally gotten the appropriate
attention of
physicians patients and their families.
The FDA's warning must be
clear.
Judicious monitoring is necessary. I believe that
it is imperative that physicians be
properly
educated and then have the option to
prescribe
antidepressants for the child and
adolescent
patients.
Thank you.
DR. GOODMAN: Our final speaker
for this
evening?
MS. MCGINN: Good afternoon. My name is
Eileen McGinn. I have a master of public health
degree and I have several members of my
family who
have schizophrenia, bipolar disorder,
alcoholism.
The current process for the
approval of
drugs for the American market is
scientifically
flawed.
Science requires reliability and validity.
The trials for many psychotropic drugs
are not
reliable nor are they valid. Reliability in
science requires that research be
independently
replicated in different labs by different
442
researchers. In the case of drug trials, the same
firm producing the drugs conducts all the
trials.
This is an inevitable source of bias and
a breach
of the scientific method.
In terms of validity, there are
several
problems.
First and most important, the samples
are not representative. People in a research study
are supposed to represent the general
population
with the illness. Most trials systematically
exclude many people, especially those
with severe
illness.
The group study does not represent the
population with the illness so we cannot
generalize
the results.
Second, often the outcome
measures are not
clinical measures. There is no blood test or brain
scan to mark the presence of psychiatric
illness so
researchers use rating scales, similar to
questionnaires, to measure the severity
of
symptoms.
On a scale of 1-20 clinicians may agree
that a score under 7 demonstrates
wellness, while a
score over 7 shows that the person is
ill. It
would seem logical to use the cut score
of 7 to
443
sort out the responders from the non-responders.
This simple, direct method is not
used. Instead,
researchers use a mathematical formula
based on a
percent decrease in scores. A person may decrease
from 20 to 10 but at 10 he is still quite
ill. In
children the percent decrease is often
20-30
percent, not 50 percent.
The dropout rates for some
trials approach
50 percent, a dropout rate that biases
the results
and calls into question any conclusions
of the
trial.
The information from the dropouts, like
adverse events or non-response, is rarely
analyzed
or reported. Scientific methods exist to deal with
the dropout data but they are rarely
reported in
the trial results.
Trials are short and
small. Small size
means that less common adverse events are
not
captured.
Short duration means that delayed
harmful events are not known by the end
of the
trial.
Fifth, trials are not valid
because the
double-blind...
444
Summary by the Committee
Chair
DR. GOODMAN: Thanks to you and to
everybody else who has taken out the time
and
poured our their hearts today. It has been a long
day.
I appreciate your attentiveness and your
patience.
I, for one, feel exhausted not only
because of the late hour but because of
some of the
heart-rending stories that I have heard
today.
On your agenda, the next item
is for me to
take a stab at a summary of what we heard
today.
We could take a break before that. I will leave it
up tot he committee. My preference would be just
to go into it so that we can leave,
hopefully, by
6:15 as originally planned.
What I would like to do then,
as I see no
objection, is to summarize some of what
we heard
today, touching on some of the salient
points. I
don't mean this to be a comprehensive
summary by
any means.
First let me begin with where
we stood
going into this meeting. We learned at our last
meeting that there was a suicidality
signal in
445
several of the studies that were
submitted in
pediatric depression, meaning that there
was more
suicidal behavior or ideation reported in
the drug
versus the placebo group--not the
expected finding.
It is opposite, in fact, to what you
would expect
since suicidality is one of the symptoms
of the
underlying condition. In fact, the only drug for
which there was no suicidality signal at
all were
the trials submitted for fluoxetine.
Coupled with this, we learned
that three
out of the 15 studies in pediatric major
depression
were positive so that the majority of the
studies
were either failed or negative. So, in addition to
adverse effects that were of concern, we
had
question about the overall benefit of
this class of
agents, raising then naturally questions
about
benefit/risk ratio.
Finally, we heard public
testimonies last
time as well, and many of those, like the
ones we
heard today, were passionate and
plausible. When I
listened to them last time, as I did
today, I was
looking for a pattern. Certainly they don't
446
necessarily fit into a pattern but
several of the
cases--I didn't exactly count but quite a
few of
the cases seemed to suggest that suicides
or the
suicidal behavior that was reported by
the public
testimony occurred relatively early after
the
initiation of medication.
That observation I think
resonated, at
least with my own clinical experience and
that of
many other clinicians, as something that
we have
known for a long time, both in children
and adults,
that there are some patients who are
susceptible to
a behavioral toxicity. We know for sure that
patients with bipolar diathesis seem to
be
particularly prone to developing a
syndrome that
may represent induction of mania after
the exposure
to antidepressants. We also know from child
psychiatrists that they are particularly
alert,
even before the warnings were
issued--they have
been alert all along as part of their
training that
there are some patients, some kids who
are
exquisitely sensitive to these
medications and then
they adjust the dose, the titration and
the
447
observation accordingly.
There is also an impression,
despite the
lack of efficacy in most of these trials
that were
submitted--a strong conventional wisdom
among
clinicians that there are many children
out there
who have benefited from the use of
antidepressant
medications. However, the data supporting that
observation is rather elusive.
We also heard from John Mann
today during
the public testimony that untreated
depression is
the major cause of suicide in youth.
Now, based upon what we heard
last time,
we did not conclude that there was
sufficient
evidence to articulate a direct link
between
administration of the antidepressants and
the
suicidal behavior. However, I think we heard
enough to suggest that there was a
potential risk;
that we needed to do something quickly to
mitigate
that risk. I think what we gravitated to was a
hypothesis that many of these cases, from
what we
heard both in the public testimony as
well as what
we saw in the clinical trials, can be
attributed to
448
behavioral toxicity, particularly
something that
occurs early in treatment and
perhaps--and this is
only perhaps, it is a hypothesis--if one
is more
vigilant, if the prescriber, and the
family members
and the patients are more vigilant about
monitoring
for side effects such as activation,
things that
have been referred to as akathisia and
insomnia,
that those symptoms or signs may
represent a
precursor to the symptom we most fear,
that of
suicide intent.
We reconvened this time with
the intention
of going back to the data after a
reclassification
of the events and also the opportunity to
look at
any additional data that emerged in the
interim.
So, reviewing what we heard today, first
we heard
from Dr. Laughren who brought us up to
speed and
reviewed some of the history of the
clinical
trials, the FDA steps that have been
taken, and he
also reminded us of something that I wish
to
revisit tomorrow.
So, in part I am giving the
summary as
kind of a demarcation between today and
tomorrow,
449
and also to try to set the stage for some
of our
discussions. I reminded us that a number of these
studies were conducted under the
conditions in
which the sponsor could be granted six
months
exclusivity if they submitted a trial in
pediatric
depression. I think this was certainly
well-meaning.
There had been an outcry
previously that
these drugs were being looked at
off-label but
there weren't sufficient studies. But the question
that I think is on all our minds is whether
this
well-meaning action could have led to
some
unintended consequences. Although we haven't
exactly articulated what those might be,
that is
certainly what comes to my mind--could the
sponsors
have used marginal estimates of
power? If their
goal was to have a positive study, not
just a trial
submitted but a positive outcome, would
they have
set the sample size higher? Would we have had a
different outcome? I will turn to the
statisticians tomorrow perhaps to say
whether there
is any evidence of that. There is though, from
450
what I can tell, a powerful effect size
so I am not
sure that that is the case. Nevertheless, I think
we should talk about that more tomorrow.
One of the other speakers also
mentioned
the possibility that there might have
been some
incentives or encouragement towards rapid
enrollment, and could some of that
process to speed
it up since the companies were going to
receive
six-month exclusivity--could that have
led to some
contamination in the data set? That is all
speculation but I think we should turn to a
discussion of those possibilities
tomorrow.
Dr. Wysowski then turned to
other sources
of data that might have bearing on our
discussions,
including ecological studies, and
mentioned work,
published by Dr. Schaefer at Columbia,
showing an
inverse relationship between the use of
antidepressants and the decrease of
suicide in our
youth, and pointed out that correlation
does not
equal causality and that there were other
factors,
intervening variables that could explain
that
pattern over time. Dr. Schaefer did have an
451
opportunity to rebut during the open
presentations
later.
What was also presented were
some
patient-level controlled observational
studies,
including a study by Jick that was
published in
JAMA.
This was a study that compared several
different antidepressants to each other
with
respect to suicide risk. It was pointed out that
our ability to infer the suicide risk
contributed
by the drugs is limited since there was
no
unexposed group as one of the controls.
Interestingly, however, what was
found
significant was a relationship between
time of
onset of medication and reports of
suicidal
behavior, such that the patients who had
started
antidepressant medication in the past nine
days
showed a significantly higher rate of
suicidal
behavior than those who had been on
antidepressants
for six months or more. That finding certainly did
fit with one of the hypotheses that I
think has
been on our minds and that led to some of
the
warnings in the interim, that the adverse
effects
452
could be something that will occur early
in the
course of treatment.
Dr. March then presented results from the
TADS study. This is in contrast to the other
studies we have looked at, sponsored by
NIMH. It
was a trial that had four arms that
included
cognitive behavioral therapy. Our focus on this
study though was not on the cognitive
behavioral
therapy so the most germane component of
that study
is the comparison between fluoxetine and
placebo.
Furthermore, those are the two studies
that were
conducted in a double-blind fashion.
What we learned is that on
several but not
all measures fluoxetine was superior to
placebo.
As I understand it from the presentation
and
reading the article, talking about
benefit,
fluoxetine was not significantly superior
to
placebo on changes in mean scores on the
Children's
Depression Rating Scale, although it
nearly met
statistical significance. With regard to
suicidality, reported rates of suicidal
ideation
decreased in all the treatment groups.
453
Dr. Dubitsky gave us a summary
of the data
and a handout that I think will be
extremely useful
tomorrow as a reference, and reminded us
that only
three of the 15 studies in major
depression were
positive.
Dr. Posner, from Columbia, then
reviewed
the methodology and how it was
implemented to
reclassify the data from the clinical
trials. The
presentation struck me as being very
rigorous and
comprehensive, and it was validated by
Dr. Iyasu,
from the FDA who looked at a sample using
the same
strategy that was used by Columbia and
came out
with very good agreement between their
results and
the reclassification as ascertained by
the Columbia
group.
Then we moved into what I would
see as the
cornerstone of the data that was
presented today,
the new data that we had been
anticipating and that
I think we will continue to examine
tomorrow. Dr.
Hammad presented the reanalysis that was
conducted
by the FDA based upon the
reclassification of
suicidality. I will not, in the interest of time,
454
attempt to review all the findings, but
suffice it
to say it is my impression at this
juncture that
that reanalysis reinforced the existence
of
association between drug and suicidality.
He also introduced another
metric to us,
that of risk difference, something that I
think
helps translate the risk into something
we can
understand more at the patient level, and
said that
overall the risk difference was computed
to be 2.3
percent, meaning that two to three out of
100
patients might incur an increase in
suicidality
during exposure to one of these
antidepressants.
There was also a time-to-event
analysis
that I would like to revisit
tomorrow. My
understanding was that Dr. Hammad did not
find any
evidence for relationship between time of
exposure
to drug and suicidality. This is certainly
disappointing to me. It certainly deviates from my
working hypothesis but I think I would
like to
understand it a little better. I know there was a
statistical discussion around the table
but I had a
little trouble following it so I hope
that tomorrow
455
maybe we can revisit it so I can at least
convince
myself that there was no evidence base
for earlier,
rather than later, suicidality.
The reason that is important,
of course,
in my mind, in addition to a failing
hypothesis
that matches your own clinical
experience, is that
it does give you hope that by merely--not
merely
but by introducing increased vigilance
about the
early phases of treatment one can abort
of prevent
suicidality if, in fact, the risk is
evenly spread
over the course of treatment, or the
strategy that
we have adopted is going to be less
effective.
Dr. Mosholder then compared the
analysis
he conducted with the subsequent analysis
based on
the reclassification of the data. Although there
were some individual differences, for the
most part
the findings were in the same range.
Also, a metric that he came up
with that I
thought was helpful is in giving some
sense of the
magnitude of the suicidality signal. As he said,
there would be one suicide event every 12
patient-years of drug exposure.
456
During the presentations by
industry, one
of the presenters argued not to consider
the
medications as a class. That is one of the
questions before us tomorrow. He pointed out that
we need to attend to the differences in
their
pharmacodynamic as well as their
pharmacokinetic
properties.
Another presenter pointed out
the
limitations of the data based upon the
clinical
trials with regard to understanding the
risk of
suicidality, indicating that these
studies were not
designed to test the suicidality. So, this is a
post hoc analysis, and I think we did our
best with
the existing data set but there are
certainly
limitations based upon how those studies
were
designed and the instruments that were
used. There
is also no direct drug-drug comparison.
In the public hearing we once
again heard
passionate and moving testimony, and many
cases
that, again, seem quite plausible to me
that in
some way implicated a role of
antidepressants in
suicide.
It was pointed out by other speakers, as
457
well as myself earlier today, that in the
process
we cannot forget about all the other
individuals
that we think are out there with
depression who
have been protected against suicide
because of
their treatment.
What didn't we learn
today? We didn't
learn much about the long-term efficacy
of the
antidepressant medications. I think most of the
conventional wisdom and clinical lore
about their
effectiveness is not so much based upon
the results
of an acute trial but the impression of
what
happens over a longer period of
time. The
available data presented here or that I
have looked
through do not give us an answer to this
very
important question. There is an overall dearth of
prospective data on the question of
efficacy of
antidepressants in the pediatric
population.
We also don't have enough
information to
know whether some of the events that we
might
classify as a result of behavioral
toxicity
represent an interaction with an
underlying
vulnerability of that individual. What comes to
458
mind in particular is an individual that
might be
bipolar or have a bipolar diathesis. Or, maybe
there are other factors that are patient
specific,
even the way they metabolize the drug,
that may
make them more vulnerable to that
behavioral
toxicity.
So, I think the work is cut out
for us
tomorrow.
What I would ask you to do this evening
in preparation for tomorrow is review the
questions
that the FDA has asked us to
address. Some of
those will come to a vote. I don't think we have
decided which ones yet but I think some
of them
will come to a vote, and certainly most
will
involve considerable discussion.
One of the decisions I think we are
going
to make is in answering the over-arching
question,
have we done enough yet. Has it been enough to
issue warnings to make everyone more
vigilant about
possible adverse effects that could lead
to suicide
or suicidality?
Is there anything anybody from
the
committee would like to add at this
point?
459
DR. FOST: Just one comment that I would
like to have on the record for today's
meeting.
Many of the families who spoke in their
grief and
anger, understandably, felt a need to
find blame or
cause of the tragedies that have befallen
them, and
Bob
Temple, Tom Laughren and others were sometimes
identified by name and, by implication,
others in
the FDA.
I think it needs to be said
that these are
all people who work very hard, with great
integrity, to try to find out what the
right thing
to do is.
I have no ties, by the way, to any
companies involved in any of these
issues. Bob
Temple, in particular, is I think one of
the most
important public servants we have had in
this
country in the last 25 years. I would guess
conservatively that he has saved tens of
thousands
of lives, probably hundreds of thousands,
by
setting very high standards for the
agency to
ensure that drugs that are dangerous do
not get
into the marketplace. So, the notion that he would
be soft on dangerous drugs is just not
plausible.
460
So, I understand the grief and the anger
and the
need to place blame, but I think these
are not the
people to assign it to.
DR. GOODMAN: Thank you.
Anyone else that
would like to comment before I give you a
few
ground rules?
[No response]
So, before adjourning, I will
ask the
members of the committee to take the
materials with
them, including the statements received
from the
public.
Wear your name tags tomorrow. I
guess
that has been added because some of you
haven't
been doing that. We ask all the FDA presenters to
be prepared with their backup slides--I
am sure
they will be--for tomorrow's
discussion. Once
again, I wish to remind the committee to
refrain
from speaking to each other about the
meeting. If
I see you together, I assume you are
talking about
sports or the weather.
I wish to inform the public
that they can
submit their written statements to the
FDA through
Dockets Management. The fliers on the information
461
desk outside the ballroom will explain
the
procedure.
Finally, to remind the
committee and the
public that the meeting is scheduled to begin
promptly at 8:00 a.m. tomorrow. We plan to end at
5:00 p.m. but may or may not end
early. Thank you
very much for your attention.
[Whereupon, at 6:10 p.m. the
proceedings
were adjourned, to be resumed at 8:00
a.m., on
Tuesday, September 14, 2004.]
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