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
2
PARTICIPANTS
Wayne Goodman, M.D., Chair
Anuja M. Patel, M.P.H., Executive
Secretary
PSYCHOPHARMACOLOGIC DRUGS ADVISORY
COMMITTEE
MEMBERS
James J. McGough, M.D.
Jean E. Bronstein, R.N.,
M.S. (Consumer Rep)
Philip
S. Wang, M.D. M.P.H., Dr. P.H.
Dilip J. Mehta, M.D.,
Ph.D., (Industry Rep)
Lauren Marangell, M.D.
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.
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.
SGE CONSULTANTS (VOTING)
Norman Fost, M.D., M.P.H.
Charles E. Irwin, Jr.,
M.D.
Lauren
K. Leslie, M.D., FAAP
Steven Ebert, Pharm. D.
James M. Perrin, M.D.
Cynthia
R. Pfeffer, M.D.
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.
SGE PATIENT REPRESENTATIVE (VOTING)
Gail W. Griffith
GUEST SPEAKERS (NON-VOTING)
Kelly Posner, Ph.D.
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PARTICIPANTS
(Continued)
GUESTS (NON-VOTING)
Samuel Maldonado, M.D.,
M.P.H.
FDA
Robert Temple, M.D.
Russell G. Katz, M.D.
PARTICIPANTS (Continued)
Thomas Laughren, M.D.
M. Dianne Murphy, M.D.
Anne Trontell, M.D., M.P.H.
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C O N T E N T S
Call to Order and Opening Remarks:
Wayne Goodman, M.D. 5
Conflict of Interest Statement
Anuja Patel 6
Opening Comments
Thomas Laughren, M.D. 9
Committee Questions and Discussion 31
Presentation
Diane Wysowski, Ph.D. 152
Committee Discussion of Questions and
Vote 163
Concluding Remarks
P. Joan Chesney, M.D. 402
Wayne Goodman, M.D. 404
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P R O C E E D I N G S
Call to Order and Opening
Remarks
DR. GOODMAN: Welcome to day two of this
joint two-day session of the
Psychopharmacologic
Drugs Advisory Committee and the
Pediatric Advisory
Committee being held on September 14,
2004, here at
the Holiday Inn in Bethesda, Maryland.
We are convened to address
recent concerns
about reports of suicidal ideas and
behavior
developing in some children and
adolescents during
treatment of depression with selective
serotonin
reuptake inhibitors and other
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.
Now, I would like to turn the
microphone
to Anuja Patel of the FDA Center for Drug
Evaluation and Research and Executive
Secretary of
this committee to read the conflict the
interest
statement into the record.
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Conflict of Interest
Statement
MS. PATEL: Good morning.
The following
announcement addresses the issue of
conflict of
interest and is 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 interest as they may apply to
the general
topics at hand.
The Food and Drug Administration
has
granted particular matter of general
applicability
waivers under 18 U.S.C. 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
7
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.
A copy of the waiver statements
may be
obtained by submitting a written request
to the
Agency's Freedom of Information Office, Room
12A-30
of the Parklawn Building.
In addition, Dr. Judith
O'Fallon and Dr.
Victor Santana have de minimis financial
interests
under 5 CFR Part 2640.202 that are
covered by
regulatory waiver under 18 U.S.C.
208(b)(2).
Because general topics impact
so many
entities, it is not practical to recite
all
potential conflicts of interest as they
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
committees, these potential conflicts are
mitigated.
8
With respect to FDA's invited
industry
representative, 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.
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: Thank you, Anuja.
We will be starting off this
morning with
a presentation from Tom Laughren who will
give us
an overview and also pose the questions,
the five
questions to this committee.
Following his presentation, I
would invite
questions. I also think it would be a good time
before we get into the meat of our
discussions to
ask representatives from the FDA
questions, to
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further interrogate some of the data that
was
presented yesterday.
Before we get into the actual
discussion
of the questions, I would like us to
think of the
questions that were carried over from
yesterday,
pose those, and then we will take a short
break,
reconvene and start the process of
discussing the
questions.
Is that clear? Okay.
Tom, are you ready?
Opening Comments
Thomas Laughren, M.D.
DR. LAUGHREN: Good morning.
I would also
like to welcome everyone back to the
meeting today.
I would like to do a couple of things in
my few
minutes here.
First of all, what I want to do
is to
briefly review what I think are some of
the key
findings from Dr. Hammad's presentation
yesterday,
so that you have these in mind as you are
considering the questions before you.
Then, I want to talk a little
bit about
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what I think the data mean and talk about
what some
of the regulatory options are as you are
considering our questions, and then I
want to go
over the questions and the topics again.
These are the 24 trials that we
are
considering. Again, 16 of them were in
major
depression, and the other 8 trials were
in several
various psychiatric disorders - OCD, GAD,
1 in SAD,
and 1 in ADHD.
Again, just for summary, I
think these are
the three contributions that the Division
made to
this effort. Again, we went to a lot of
effort to
make sure that we had complete case
finding. With
the help of Columbia, we accomplished
what I think
is a rational classification of these
events, and
we both obtained and included patient
level data in
our analysis of the suicidality data
again to try
and understand some of the differences
both between
trials, within programs and across
programs.
These are the outcomes that we
looked at
again. The focus of the analysis was on
two areas,
the suicidality event data and also on
the suicide
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item data.
For the event data, could we
have the
other slide up that we had running
yesterday? Our
primary endpoint, as you recall, was the
combination of suicidal behavior and
ideation,
Codes 1, 2, and 6, where 1 was suicide
attempt, 2
was preparatory actions, and then 6,
suicidal
ideation.
So, that was our primary
endpoint, but we
also looked at secondary endpoints, at
suicidal
behavior, in other words, Codes 1 and 2,
and then
suicidal ideation, Code 6, and then for
our
sensitivity analysis, we looked at this
larger
outcome including 1, 2, and 6, but also
adding in 3
and 10, where again, 3 is self-injurious
behavior
where the intent is not known, and 10 is
not enough
information. Again, these are the cases where
there is injury, but it is not possible
to tell
whether it's self-injury or other injury.
With regard to the suicide item
data, we
looked at two measures about worsening
suicidality
on that item or emergence, and these
again are the
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cases where the patients are normal at
baseline and
have some increase during the trial.
In terms of our analytical
plan, the major
focus was on doing risk ratio analyses,
both for
the suicidality event data and for the
item data.
In both cases, we looked at individual
trials, as
well as for the event data, we looked at
various
pools.
We looked at both by drug, we
combined all
the SSRIs, MDD trials as a group, we
looked at all
of the other indications combined as a
group and
also did one pooling which included all
24 trials.
For the item data, we looked again at
individual
trials and then a pooled analysis over
all trials.
Dr. Hammad put a lot of effort into
again
trying to explain the differences that we
were
seeing between trials within programs and
across
programs, and I just want to spend a
couple of
minutes talking about exactly what he
did.
He looked for confounding
within trials
using both the univariate approach and a
multivariate approach. There were a total of 17
13
covariates that he looked at. He was not able to
find any evidence for important
confounding in that
search.
He also did stratified analysis
to explore
for effect modification. The three variables that
he looked at were age, gender, and
history of
suicide attempt or ideation, so
basically, what he
did in each of these is to stratify on
these
variables within trials to look to see if
there was
basically an interaction.
Again, he did not find any
evidence for
that, so basically, what that means is
that on
these variables, you find the signal both
in
children and adolescents, you find it
both in males
and females, and you find it both in
those with and
without history of suicide attempt or
ideation.
Finally, he looked at 12 trial
level
covariates, again, as an attempt to try
and explain
the differences across trials using a
meta-regression approach. Again, that approach was
not able to explain the variability.
Now, I would say that one of
the problems
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in doing these kinds of explorations is
that there
is very limited power, you have a very
small number
of events. When you use an eyeball approach to the
data, you can't help but thinking that
trial
differences might have made a difference.
I just use the TADS, the fluoxetine
situation as an example. The company had three
trials.
There was no signal coming from those
three trials. If you look at the careful screening
that was done to obtain the patients for
those
samples, and the exclusions of patients
with prior
histories of treatment resistance, and so
forth,
and then you look at the TADS sample,
which is many
ways was probably more representative of
the
community of patients who actually get
treated,
there is quite a difference. Again, as you recall,
in the TADS trial, you see quite a
striking signal
for suicidality.
So, even though quantitatively,