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
FDA PEDIATRIC ADVISORY COMMITTEE
Wayne Goodman, M.D., Chair
Anuja M. Patel, M.P.H., Executive Secretary
PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE
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.
Samuel Maldonado, M.D., M.P.H.
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.
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
Thomas Laughren, M.D. 9
Committee Questions and Discussion 31
Diane Wysowski, Ph.D. 152
Committee Discussion of Questions and Vote 163
P. Joan Chesney, M.D. 402
Wayne Goodman, M.D. 404
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
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.
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
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
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.
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
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
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
further interrogate some of the data that was
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
Is that clear? Okay.
Tom, are you ready?
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
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
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
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
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
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
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
covariates that he looked at. He was not able to
find any evidence for important confounding in that
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
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
So, even though quantitatively, we weren't
able to tease that out and to explain the
differences using various quantitative approaches,
it is hard to think that that may not
have made a
In my next three slides, I am going to
present very briefly some of the data.
What this slide is, is presenting the risk
ratios for various poolings. So, in this column,
you have the risk ratios on our primary endpoint,
which was suicidality ideation or behavior, 1, 2,
In the second column, you have this
expanded sensitivity analysis, 1, 2, 6, plus adding
3 and 10. The first row is all trials, so this is
a pooling across all 24 trials. In the second row,
you have the pooling of the 11 trials with SSRIs
and major depression.
Now, there are two things I want you to
notice about this slide. First of all, in every
case, the risk ratios are around 2. They range
from 1.7 to 2.2, but they are sort of in the
vicinity of 2.
Secondly, if you look at the confidence
intervals on these risk ratios, in every case, it
does not include 1, so in that sense, it
statistically significant finding. So, this is the
What I have given you in this slide are a
different set of poolings. Here, what I am doing
is pooling the individual depression trials in the
7 programs that looked at depression, and these are
the 7 programs listed here. Every row is a
separate depression program.
What I have given you here, first of all,
is the outcome on our primary endpoint a
combination of 1, 2, and 6. I have also given you,
in the second column, the outcome on suicidal
behavior, and in the third column, the outcome on
There are a couple of things I want you to
notice about this slide. First of all, in every
instance where we have events, and we had no events
for Serzone, but in the other 6 instances where you
have events, the risk ratio is always greater than
Now, I want to turn to trying to tease
apart where that overall effect is coming
you break it apart by behavior and ideation. Dr.
Hammad made this point yesterday, in three cases it
appears as if the overall effect is coming from
behavior, in three cases it looks like it is coming
So, if you look at Celexa, here is the
risk ratio for behavior, 2.23. There is nothing
happening for ideation.
If you look at Paxil, again, it looks like
it is coming mostly from behavior.
If you look at Prozac, it looks like it is
probably coming more from behavior than from
For Effexor, there is a signal coming from
both, but it is clearly coming more from ideation.
Here, the confidence interval is almost
For Remeron, it is all coming from
ideation, and from Zoloft, there is nothing
happening for behavior, it is all coming from
I am not sure what this
means. As Dr.
Hammad pointed out, this may simply be a small
numbers problem, but we are not seeing a consistent
finding in terms of where the overall effect is
Finally, what I have given you in this
slide is the data from the individual other 8
trials in non-MDD indications. As you get into
these trials, the number of events you are dealing
with is very small, and just to illustrate that, I
have put the actual number of events in this slide.
So, in each of these parentheses, the
first one is the number of events for drug, and the
second one is for placebo. So, you can see the
small number of events that we are dealing with.
If you recall from the previous slide, for
Effexor, we were seeing quite a strong signal for
major depression. These are two GAD studies.
There is nothing at all happening here.
For Luvox, again, Luvox was only studied
in OCD, there was no depression trial. Just one
study in depression, only two events. They were
both happening in the drug group.
For the two non-MDD Paxil studies, one in
social anxiety, one in OCD, again, small numbers of
events, but in both cases, they were happening in
the drug group.
The same for the Prozac OCD, just one
event, but it happened in the drug group.
No events for Wellbutrin.
For Zoloft, this is the only case where
the one event is happening in placebo, and not in
It is hard to know what to make of all of
this, although the one thing that you can't help
noticing is that even though there are a small
number of events, where events occurred, they most
happen on the drug side.
Just to summarize these data, again, if
you look at various pooled analyses, the risk
ratios hover around 2. They range from 1.7 to 2.2.
In all cases for those poolings, it appears to be a
The signal appears to be coming mostly
from major depression, although perhaps
exclusively. Despite those findings, there still
are these inconsistencies in this risk, both across
trials, within programs and across programs.
On the other hand, my view is--and there
isn't necessarily one consistent view coming out of
FDA on this--but my view is that this is a
reasonably consistent signal for risk. You are
seeing it in seven of nine programs. We don't see
any events in Wellbutrin. On the other hand,
Wellbutrin was only studied in ADHD, just one
There is no signal coming from Serzone,
which was studied in major depression. I am not
sure if that means that Serzone is free of risk or
it simply may mean that the events, the
ascertainment in those programs was not good enough
to pick them up. I don't know the answer.
One other point that Dr. Hammad made
yesterday, that I want to return to, is a way of
thinking about this risk is in terms of risk
difference, and if you look over all these trials
and estimate what the risk difference is,
the difference in the risk between drug and
placebo, so you are subtracting the placebo risk
from the drug risk, it is in the range of 2 to 3
What that means is that again, out of 100
patients treated--this is short term now,
short-term treatment--you can expect 2 or 3 out of
that 100 will have some excess of suicidality above
and beyond what would be in the background that is
due to drug.
As a clinician, what you have to do is to
balance that risk against the perceived benefit.
The problem here, of course, is that we only have,
at least from FDA's standpoint, a demonstration of
benefit for Prozac, but if you take the TADS trial
as an example of benefit, there, you can look at
the benefit difference, and the benefit difference
in the TADS trial, difference between drug and
placebo in percent of responders, using that as the
measure of benefit, it is about 25 percent.
Again, you can interpret that in the same
way, so that if you look at 100 patients
treated with fluoxetine, you can expect that about
25 out of 100 will have that benefit if you are
looking at response as the benefit.
So, you balance that against the risk,
which again in that trial, the risk actually was
greater than the 2 percent, it was probably more on
the order of 7 percent, but you balance that risk
against the benefit. That is the kind of calculus
that a clinician has to do.
Finally, as was pointed out, there were no
completed suicides in any of these trials.
Again, we did not see the same signal in
looking at the item data. One exploration we tried
to do to see if that could be explained by patients
dropping out, and unfortunately, that was not an
explanation. The analysis of completers did not
show really any difference from the analysis of the
patients who dropped out.
So, how should these findings be
interpreted? I think that this is an indication
that there may be some increased risk for
suicidality during short-term treatment,
think this is probably a class effect. Again, you
are not seeing it in every drug that we looked at,
Serzone and Wellbutrin being the two exceptions,
but I think there is enough here to suggest that
this is probably a class effect.
The signal appears to be most compelling
in major depression. It may not be limited to that
population, but again we are left with this very
unusual variation in the signal across trials,
within programs and across programs that we have
not been able really to explain.
What I want to do next is to talk about
what some of the regulatory options are, and I
first want to talk about possible labeling changes.
As you recall, we already made a fairly
major change to labeling back in March, and all of
those changes have now been implemented. There is
a fairly prominent warning statement that directs
the attention of prescribers to this possible
Now, that language as it currently is
written suggests that causality has not
established. One thing that might be done to
modify that, if there is agreement on this, we
could say that causality has now been established
for this risk in pediatric patients.
In addition to that, we could go beyond
that and provide specific suicidality findings in
the labels for different products. We could also
provide more specific information about the
efficacy findings for specific products in that
There are other things to talk about in
terms of that warning statement including things
like bolding language or putting black boxes.
These are all options that are on the table.
The other option that you need to think
about, and you heard many yesterday in the open
session ask us to do this, you can think about
contraindications. The one thing I want to point
out is that in this country, for our label, a
contraindication means never. It means that that
drug will never be used in treating these patients,
it is not an option.
The other thing I want to point out is
that the term "contraindication" has different
meanings in different regulatory settings. In some
settings, it does not mean never. If you read the
fine print in the UK, for example, there is a
suggestion that specialists may still use that
drug. So, you need to keep that in mind that in
this country, a contraindication means that that
drug is never an option.
In addition to labeling changes, there are
some other obvious actions that we can and almost
certainly will take. Our plan at present is to
write a medication guide. This is basically
labeling which ideally would be attached to the
medication when it is prescribed in unit of use
In addition to that, we will undoubtedly
have another public health advisory when we decide
on what needs to be done, and we will try and
communicate these findings to our partners.
Now, what I would like to do again is to
quickly go through the questions and the
The first topic is again we would like to have your
comments on our approach to classifying these cases
and to our analysis of the data.
One of the questions for which we really
need to have you vote on is do you feel that 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 this increased risk
apply, in other words, is this a class effect for
all antidepressants, does it apply to certain
subclasses within this broader class, or to
If this is a class risk or if it applies
to certain drugs, how should this information be
reflected in the labeling for each of these
products, and what, if any, additional regulatory
actions should the agency take?
Finally, there is this question about what
additional research is needed to further delineate
the risks and the benefits of these drugs
pediatric patients with psychiatric illness.
At our last meeting, I suggested one type
of study that you might think about, and I am going
to make that suggestion again, because we think
that this is one study that might get at one of the
deficiencies here, and that is, not only do we not
have enough information about short-term benefit,
we also have little information about longer term
benefit or risk.
One way of getting at longer term benefit
is the randomized withdrawal study. Basically, the
way the study works is that patients who are
responders or appear to be responding to treating,
at some point in the course of treatment, are
randomized to either continue on drug or randomized
to placebo, and one looks at time to relapse as the
Now, I know there are concerns about that
design. You know, one concern is the ethical issue
of taking patients off a medication when they
appear to be responding. I agree that is a concern,
but I think there is a way of dealing
The usual randomized withdrawal trial is
done after too short a period of time on treatment.
I mean typically, they are done now after 12 weeks
or so of treatment. That is too soon. No
clinician would take a patient off of one of these
medications at that point in time.
On the other hand, at some point in the
course of treatment, whether it is six months or
nine months or a year, it seems to me that it is a
reasonable question. At some point, you reach
equipoise where the clinician has to ask the
question, well, is this long enough, you know, is
there any benefit in continuing the treatment
beyond this point in time.
Now, that is a much harder study to do, to
keep patients on treatment for nine months or a
year before you randomize them, but that would be a
way of answering that important question of whether
or not there is continuing benefit beyond that
point in time.
The other concern that has been raised
about these trials is the issue of
between withdrawal symptoms and relapse. Again, I
agree that this is a reasonable concern, but I
think there is also a way of addressing that.
In clinical practice these days, these
drugs are tapered. One doesn't stop them cold
turkey. I think that could also be part of that
design, and that could address that issue. So,
that is one thing to think about.
Before I end, I want to leave you with two
thoughts. We clearly have an obligation at FDA to
inform clinicians and patients about the risks that
are associated with these drugs, and we take this
obligation very seriously.
Along those lines, I just want to point
out that our current regulations do not require the
same level of certainty with regard to safety in
terms of causality as is required for efficacy. In
other words, we can issue warning statements with
somewhat lesser certainty about causality than is
required to support a claim.
Secondly, as I have pointed out several
times, the lack of efficacy data in this
for most of these drugs needs to be part of this
discussion. On the other hand, and I am not making
your job easy, please bear in mind that depression,
whether in adults or children, is a very serious
illness that is associated with morbidity and
mortality quite apart from whatever role
antidepressants might have.
As was pointed out yesterday, this is the
major cause of death in this population, the
depression itself, so please bear that in mind.
I have very profound respect and gratitude
for the clinicians who are out there on the front
lines still willing to take care of these patients
despite what has become a very controversial and
I hope that as we discuss these issues and
make a decision, that we not make it impossible for
them to practice medicine.
DR. GOODMAN: Thank you, Tom, for a cogent
and clear presentation.
I would like to ask committee
they have any questions of Tom.
Committee Questions and Discussion
DR. FOST: This is for Tom or anyone else
who has a handle on the numbers. I know there is
no precise answer to it, but it would be helpful to
me to just hear you or someone else, maybe Dr.
Shaffer, if he is still here and is allowed to
talk, this question.
Suppose there were no SSRIs, suppose they
were contraindicated, that is, prohibited,
approximately, let me just ask the question about
suicides, about completed suicides, and I
understand there is no suicides in the FDA data,
but based on everything that we know,
approximately, would there be more suicides, fewer
suicides, or the same amount if there were no SSRIs
DR. TEMPLE: There is not going to be any
way to answer that, in part because you can't do
rigorous studies of the kind that would answer
that. No one is going to let you not treat, not
institutionalize, et cetera, someone who
worse and worse, and it would require long-term
studies presumably against no treatment, and it is
not easy to figure out how anybody is going to do
So, you are left with the kind of data
that people have pointed out is always uncertain,
the data on suicide rates and whether they are
going up or down, so it is very hard to answer that
There were no completed suicides in the
pediatric data, so that doesn't give you a clue.
You can form your own judgment about whether
increased suicidal behavior or thinking is going to
lead to suicides in a certain fraction of cases.
It is hard to imagine that it couldn't, but you
don't know what that ratio is.
The success rate of suicidal attempts is
relatively low. I gather it is higher in males
than females, but I don't think there is going to
be ways to put numbers on that.
You have to form your judgment about
whether you think the overall decline in
has got something to do with therapy or has
something to do with other aspects of life in the
United States, and nobody can give you a firm
answer to that, as Dr. Wysowski said and as others
have said. So, it is very hard to answer that
Certainly, some of the people who spoke
yesterday, some of the treating physicians were
quite sure that they were helping people with the
drugs, and you heard families who said that their
relatives were made much worse by the drugs.
Putting numbers on that, though, isn't feasible
based on the data we have.
DR. FOST: A related question. To those,
Dr. Shaffer and others who note a decline in
suicides in the United States, in parallel with the
increased use of SSRIs, and let's just say which
should be an increase in suicidality, suicidal
ideation due to SSRI, what is the hypothesis there,
that there is fewer suicides, but more suicidal
ideation? That is what the data seemed to suggest,
and I am confused by that.
DR. TEMPLE: Can I make another comment?
The studies you are looking at are all the
short-term studies. As Tom was pointing out, we
have none of the long term sort of relapse
prevention data. It seems entirely possible that a
drug could be causing early suicidality, but once
you are over that period, it prevents relapse,
which could have an impact.
You know, there is just literally no way
to sort that out with present data. I mean it has
never been my thought that any benefit these drugs
have consists entirely of their treatment of the
acute episode, because in adults anyway, we have
lots of data showing that the likelihood and timing
of relapse is affected by continued therapy.
As Tom said, most of those studies go
earlier than you would like to do in a pediatric
population, because they consistently show that
quite reliably. Maybe that is where their
importance is, it is very hard to know.
DR. GOODMAN: Dr. Pine is next.
DR. PINE: I have a question about some of
the regulatory options. In thinking both about a
number of the comments that were made yesterday, as
well as your comments at the end about how
difficult the decision that we will have today,
related at least in part to the dearth of data that
we really need.
Are there any options from a
pharmacovigilance standpoint as far as regulatory
actions that might increase the degree to which we
are focusing over the next time period on the
emergence of these events or bring, you know, new
data over the next months to years based on a
DR. KATZ: There is the mechanism of Phase
IV requirements that say we can impose requirements
on sponsors to do various studies in Phase IV and
postmarketing environment. The question would be
what those studies would look like. I think that
is the question.
There are other obviously entities, the
NIMH and others who were set up obviously to do
large trials, and again the question is
those trials look like. You could do I suppose
large long-term, and again, you have heard, I
think, a lot of people say that there is a need for
I suppose you could do long-term
comparative trials, you can't do long-term
placebo-controlled trials, so other than the sort
of randomized withdrawal design I think that Tom
So, there is a mechanism to require
DR. PINE: I guess I am not so much asking
about studies, and this maybe is a bit of an unfair
analogy, but in New York, for example, as well as
other states, whenever you write a prescription for
a psychostimulant, there are a whole host of
procedures that kind of go with that, that are
designed to allow monitoring of the use of
psychostimulants and the associated effects.
Is there any--again, I realize I am
thinking a little bit out of the box--is there any
form of, I don't know, computer based or
system that might give us a better handle on how
many of these events are actually happening in
DR. TEMPLE: ODS should comment on that,
but it is worth just looking at, say, the study Dr.
Jick tried to do. There isn't any no-treatment
group in that. He is just comparing the risk with
one group of drugs with another, and you can
definitely do studies like that, but if you tried
to compare treated people with untreated people,
there will always be the concern of whether the
groups are fundamentally different, a very
difficult problem because people are treated.
There might be environments in which
treatment is not so common, where there is less
likelihood to treat. Maybe in those environments,
you could do something like that, but Anne wanted
DR. TRONTELL: Just to expand briefly, you
are talking about using observational data as Dr.
Temple pointed out, where you don't have a control
group, and although you might register
have seen even in clinical trials that we have been
discussing this past day, that the issue of
ascertainment of these events is very complicated
when you actually have a clinical trial mechanism
in place to capture those events.
The other challenge that you face with
observational data, because people don't receive
the drugs randomly, there is a phenomenon called
"confounding by indication," in fact, some of your
sicker patients you might presume are the ones who
are getting the medication.
We try and control for that, but it is
very complex. I think the better option is to
think of some systematic way, and then you are in
the realm of studies, as Dr. Katz was saying.
DR. MURPHY: I just wanted to follow up on
one last thing. Because we already know that using
the system we have now for follow-up
post-exclusivity because it is already mandated
that we do one-year reporting once these products,
whether they are approved or not, so we are looking
We do look at that and we report that, and
we know that that is not going to inform us, you
know, to answer the questions we need to answer,
because of all the things that will impact that
DR. GOODMAN: Dr. Temple.
DR. TEMPLE: I just wanted to mention one
related, but not quite on-point matter. We talked
yesterday about concern that the studies that had
been done to gain exclusivity might have been not
as good as we would like.
We weren't particularly talking about the
design of the studies, which we think is okay, but
let's say the approach to them. Maybe there was
too much of a rush, and so on. If we were to put
out a written request now, it would be one that
required a third arm to the study, namely, a Prozac
arm, because we know that Prozac can be shown to be
So, the study wouldn't count unless it had
been able to show that it had what we call "assay
sensitivity," the ability to tell
from ineffective drugs. We couldn't do that before
because there wasn't anything at the time we wrote
those requests that was known to be showable in
children, but now there is. There is three studies
that all seem to show something.
So, we should have much better information
about what the pediatric population does in future
requests. That doesn't help the present
DR. MURPHY: I wanted to address that
issue again, too, because I think I want the
committee to be very clear on the fact that the
Agency tells the company very clearly the type of
studies that need to be done.
We do give them, you know, a broader
picture of the number of patients. We tell them
what we know will be the minimum, and, in general,
I think Tom would agree that most of these studies
have come in with the numbers in each arm that we
have seen in other studies where they have shown
So, the point here being that
we do have
control over the types of trials that are done, the
number of patients, and the monitoring. However,
because there is a template up on your web that
basically tells you what we ask for in depression
When you look at what the safety is, as
has been pointed out many times, these trials were
not set up to answer that question. So, I think it
is those kinds of issues that we would like to hear
more about today. As Dr. Temple said, it is how
better to do these trials in the future.
DR. GOODMAN: Thanks for that statements,
Dianne. I just want to make sure I understand it
I think what you are saying, that if the
conditions had been different at the time, that is,
that the drug company was required to show, not
only have a study, but a study that was positive.
Then, the design would not have been any different,
the sample size would not have been any different
under those circumstances than the ones
existed at the time.
DR. MURPHY: I think what we are saying,
that for the trials that we designed, they were the
same for the one that did show some effect, which
is Prozac, as those that did not, and that what we
don't know is if a company is putting a trial
together, and let's say we said that they had to
have 300 patients to get their exclusivity, but for
other reasons they really wanted this product
approved, and they felt the enrollment was not
going the way that they needed, would there be some
other push within that company to then go out and
get more patients, so that their enrollment would
be better versus an exclusivity where all they had
to do was meet that criteria.
I am making that number up. I think the
issues that people were trying to get at is that is
there a difference that affects behavior when you
just know you have to do certain things versus you
have another goal, which may be approval.
DR. GOODMAN: Dr. Temple.
DR. TEMPLE: The requirement for a third
arm in evidence of assay sensitivity leaves it up
to the company to decide how they are going to do a
successful study. They can look at the available
data on Prozac and say, oh, here is the number I
need, here is the kind of patients I need. That
succeeded in those three trials.
They would then know that the trial would
have to be one that can show the difference between
Prozac and placebo. That doesn't mean their drug
has to show a difference between drug and placebo.
That would be determined by the results,
and there is no obligation that the drug be
successful, but we would at least know we had a
study that was capable of detecting effective drugs
and distinguishing effective drugs from ineffective
That would then become a requirement for
meeting the terms of the written request because
they would have to show that they had an adequate
study. Before there was an effective drug, there
was no way to do that. You couldn't tell whether
the study was a good study or not.
DR. GOODMAN: Dr. Marangell.
DR. MARANGELL: If I could go back and
address the question of what would the hypothesis
be for long term, certainly, in the absence of
data, there is some degree of speculation. I do
have a question directly to the FDA. Is it okay if
I think the number one hypothesis would be
in the short run when you have depressed patients
who are not yet stabilized, you may see an
increased risk, and you do see certainly in this
population an increased risk of suicidality.
I imagine that what we would see with
longer term data is a substantial decrease in
suicidality over time, and that is what we are
inferring from the cohort and the epidemiologic
data. I think that clinically makes sense, as well
as mechanistically makes sense.
The question for the FDA, can you give us
a sense, I mean do we feel confident that we
actually have all the available studies now in both
children, adolescents, as well as in
what is the FDA policy on requiring review of those
studies including negative studies, when do they
come to you and when do they become publicly
DR. TEMPLE: Well, let me start, others
can comment. When you submit to us an application
to change the labeling, to add a claim, say, for
pediatric use, you are clearly obliged under the
law to provide every study, successful ones,
unsuccessful ones, things that were interrupted,
and so on.
As far as we know, we are getting all
those studies. Of course, if there were something
that were done that we didn't know about, well,
then, we wouldn't know about it, but as far as we
know, we are getting them all.
So, most of the pediatric submissions to
us were associated with labeling requests or
something like that, so as far as we know, we have
all those data.
Dianne can tell you what is required under
the best BPCA, and I think there, too,
they have to
provide them. We have no rule that affects whether
people have to publish results. Congress is
considering that, so are the journals and everybody
is talking about that.
Under BPCA, however, when we grant
exclusivity, we provide summarized results, and we
have done that for the drugs where the written
requests were written after the BPCA, and we have
gone back and asked the companies for permission to
summarize our analyses for all of the others where
it wasn't totally clear whether we could do it or
So, the summarized result, that is not the
same as a complete study report, the summarized
results are now available publicly on all of those.
I am sure between PhRMA's commitment to provide a
registry between the journals insistence that they
will get a registry, between congressional
interest, I am quite confident that there will be a
change in the way things get published.
DR. MURPHY: The only thing that I could
add to that is that for the committee,
routine practice within FDA, if a company submits
an application, we review it, the studies are
negative, there is no public acknowledgment of that
unless the company for some reason wants to make
that knowledge public. We are not allowed to
comment on that.
Now, under BPCA, it said, it has a
disclosure section that says you, FDA, will
publish, as Dr. Temple is referring to, the
summaries, the medical and pharmacology summaries
up on the web--make them public, and actually, we
have chosen to do that on the web--and we have done
One of the issues that has happened is
that between the enactment of the new legislation
and the old legislation, legally, things were
considered issues under the old legislation, so
even though the studies came in, we had to reissue
all those written requests to be able to say they
now were subject to this new mandate.
So, what again Dr. Temple was telling you
is that unfortunately, many of the
came in, in that period when we had not yet issued
that letter, but despite that, we have asked the
sponsors to allow us to put those summaries up, and
they have given permission to do so.
That is why yesterday we said up on the
web now are the summaries. Again, this is not the
data. There is variations in, you know, some
medical officers will put in more information than
others in how much data is in these summaries, but
they are up now, publicly available.
DR. MARANGELL: Is that true for adults,
DR. MURPHY: No, adults are still under
the same standard. In other words, if the study is
negative, we don't talk about it.
DR. MARANGELL: So, as an example, if an
antidepressant manufacturer did a study in a new
indication for a drug that is currently available,
found increased risks of suicidality, no one would
be under any obligation to make that public?
DR. MURPHY: That is a different issue.
DR. MARANGELL: But that is the question.
DR. MURPHY: The issue is safety, and the
Agency always has the ability to make public safety
issues that arise.
Bob, do you want to say anything else
DR. TEMPLE: We consider, for example, if
someone with an antidepressant comes in for, I
don't know, obsessive compulsive disease, and we
don't buy it, we do not make those data available,
they are considered confidential commercial
information. Obviously, a lot of the people, a lot
of the public doesn't like that approach. We think
that is what we are required to do. I can't
comment on that, I am not the lawyer here.
However, companies have a separate
obligation for drugs that are marketed to report
serious and unexpected, and any serious adverse
reactions to us, and to do so promptly. A finding
of increased suicidality where that was not known,
clearly meets that test, and they would be obliged
to report it to us. If we then thought that was
true, we would add it to the label or do
we are supposed to do.
So, safety data meets a different
standard. A new carcinogenicity study or
something, those do have to be reported to us.
Other studies have to be reported in the
annual report, but they are not necessarily
reported in detail, and not that much is
necessarily made of them, and they do not
necessarily become public.
DR. GOODMAN: Dr. Pollock.
DR. POLLOCK: Yes, the serious safety
issue would have to be reported while the trial is
ongoing to you, right?
DR. TEMPLE: Well, if it arises from a
trial, it has to be. Actually, the requirements
for reporting serious unexpected events in a trial
are more or less identical to the requirements
before a drug is marketed. They have to be
reported to us within 7 or 15 days.
A finding from an epidemiologic study,
there is some judgment involved in whether that
represents the kind of thing that has to
reported promptly, but they basically do.
DR. KATZ: There is also some judgment
involved in whether or not an event is considered
to be unexpected. So, for example, suicide in a
study of patients who are at risk anyway might not
be reported to us in real-time, because it might be
considered to be expected, the blind is still
intact, you don't know if it's drug or placebo if
it is in the context of a controlled trial.
Afterwards, though, when the trial is done
and analyzed, and it turns out that there is an
increased incidence on drug compared to placebo,
that is something we would find out about.
DR. GOODMAN: Go ahead, Dr. Pollock.
DR. POLLOCK: I actually wanted to explore
your thinking a little bit about the recommendation
for a maintenance trial. I guess there are a
couple of things. One is if there is this acute
toxicity that we are concerned about, clearly, it
doesn't address that because you are dealing with
the children or the adolescents who have actually
responded, and then are withdrawn.
But I wondered if there was implicit in
your request for that, a concern that still that
the shorter half-life SSRIs seem to be, maybe not
statistically, but certainly qualitatively more at
risk in causing this phenomenon.
I was taking that as implicit perhaps in
your suggestion, maybe I am over-interpreting it,
but is there a belief that somehow--I mean it just
seems more than coincidence that signals seem a
little bit higher.
I know it has now emerged with Prozac, but
certainly, Effexor, venlafaxine stands out at one
end, then followed by paroxetine, and if there was
kind of an implicit question that you were asking,
assuming that people are still using after we are
finished, you know, those medications, that you can
require that those manufacturers actually conduct a
serious maintenance trial as part of you were
saying your Phase IV regulatory requirement.
DR. LAUGHREN: We certainly, you know,
until we saw the TADS data, were entertaining the
notion that discontinuation might be one
explanation for the bigger signal, the apparent
signal that we are seeing with Paxil and Effexor.
The TADS finding certainly challenges that
notion as a unitary explanation, since that is the
single trial among the 24 that, by itself, has a
statistically significant finding for that signal.
That doesn't mean that the other explanation isn't
possible. I mean this could be a much more complex
situation than one might seem at first glance.
But a maintenance trial is not going to
answer all those questions. I mean a maintenance
trial is only going to answer the question of
longer term benefit, but the reality is that many
clinicians, despite these concerns, are probably
going to continue to use these drugs, and we have a
dearth of information about what the longer term
benefits are. The maintenance trial is one way, I
think, of getting at that.
Now, there is this issue of how to
interpret emerging symptoms in that setting, you
know, when you take patients off the drug. Of
course, the drugs like Paxil and Effexor,
known to have a stronger signal for
discontinuation, obviously are a challenge in doing
that kind of trial, but I think that one could, as
one does in clinical practice, taper those patients
to try and address that, and then look for what
would be considered for relapse.
DR. GOODMAN: Dr. Temple.
DR. TEMPLE: There is another reason to do
randomized withdrawal studies. As everybody knows,
in adults, the failure rate for conventional
clinical trials of the acute episode is about 50
percent. That is, half the trials can't tell drug
from placebo, and that is true even when you
include a third arm of a drug that is known to
work. That appears to be the nature of the beast.
Nobody really has a good explanation
because if they did, they would fix it, but we at
least think it has something to do with the
environment and the discussions that go on even
informally, even if it is not planned as part of
In the randomized withdrawal
success rate for drugs that are known to work is
nearly 100 percent. Very few of those trials ever
There are at least two reasons. One, only
people who seem to be doing well are in the trial,
so they are enriched with a responder population.
You can make of that what you will.
The other possibility, though, is that the
environmental things that help people get better
aren't really there, they are just out living in
the community, there is nothing nurturing about it.
They are just back in their usual environment.
So, one of the attractiveness of these is
to find out whether the drugs actually provide some
benefit, even in people who seem to be doing well
on them, which seems an important question here. I
mean, as Tom has pointed out repeatedly, the
failure of most of the drugs to show effectiveness
doesn't mean they don't work. On the other hand,
we don't have evidence that they do work, and that
is not irrelevant either.
A good way to show that, if they do, is
the randomized withdrawal study. At least that has
been the history in adults, so there is a lot of
attractiveness to it.
DR. GOODMAN: Dr. Chesney.
DR. CHESNEY: Thank you. I have two
questions. The first one is for Dr.
Murphy and Dr. Temple, and the second for Dr.
Laughren. The first question addresses the
exclusivity issue. I feel like in this case, we
bypass the Phase I/Phase II stages that we would
normally go through with new drugs, so we never did
do the pharmacokinetic/pharmacodynamic dose finding
in children that we would have done had these been
I wondered, I probably should know this,
but could either of you explain, when we offer
exclusivity with a new drug, if it is a new drug to
children, do we require those studies, or do we
not? I am sure it is not that straightforward.
DR. MURPHY: We did required
pharmacokinetic studies. Actually, on the
template, we outline three types of
have to do two randomized, double-blind,
placebo-controlled, acute treatment trials with
recommendation at six to eight weeks for safety and
efficacy. They also are to do a pharmacokinetic
study to provide information pertinent to dosing of
study drug, and they are to do a safety study.
So, all of those were asked for. Now, if
you are asking do we go back and demand redoing
dose finding again in these, no, they were not
worded that way. It was said that the PK study
could be a traditional PK or, alternatively, a pop
PK, and actually, I don't think that the study had
any other information that would have, in essence,
told the company that they needed to redo the dose
finding, if that answers your question.
DR. CHESNEY: So, do we have dose
information on all of these drugs? Do we know what
the usual ranges are, and what excessive ranges
are, all those things?
DR. GOODMAN: Go ahead, Dr. Katz.
DR. KATZ: I think Tom mentioned this in
one of his slides yesterday. The written requests
that we issue now are very different from the
written requests we issued that probably generated
most of the trials that we are talking about here
yesterday and today.
As Dianne pointed out, for example, in
pharmacokinetics, we gave sponsors the opportunity
to generate the kinetics in kids based on so-called
population pharmacokinetic analyses, which is to
say from data generated in the controlled trials.
So, it was sort of after the fact. It was
just what is the kinetics of the doses you happen
to give in the trials.
In the earlier written requests, it was
sort of the pediatric drug development was sort of
tacked onto the adults, in other words, when the
trials were designed even, the treatment effect
size, for example, was used to calculate sample
size was taken from the treatment effect size seen
in adults. We had no information, even preliminary
information in kids.
So, we didn't have a lot of preliminary
information in those days that could
adequate trial design in this population, in this
Nowadays, we ask for different things. We
ask for formal PK, so we can learn before the
definitive trial design, what the kinetics are,
what doses give rise to what plasma levels. We ask
for dose finding studies, so we can determine
before we design the definitive trials what the
tolerated dose range is.
So, the written requests are much
different now than they were at the time that the
requests are generated, these data were written.
DR. MURPHY: Just to reinforce that is
that these were some of the earliest written
requests that went out, so they really, as has been
stated, and I think we tried to say this earlier
on, we are learning.
I mean because of the lack of prior
research and some fundamental scientific questions
haven't been answered, we are learning from the
trials that we have now about how to do a better
job on designing some of these trials,
were some of the very earliest ones that were
DR. CHESNEY: Dr. Temple, did you want to
comment on that?
DR. TEMPLE: Well, I just wanted to say
there isn't any pharmacodynamic measure to allow
you to do what is called PK/PD other than
effectiveness itself. In a lot of cardiovascular
settings, there is at least something you think
relates to the desired effects, so you can do
relatively short-term studies and get a PK/PD
Here, your only way to do it is to insist
that every drug, every study be a dose response
study, which is of considerable difficulty. We
have trouble getting really good data even in
adults actually given the sample sizes involved,
but there isn't any measure yet. Maybe one of
these days there will be an MRI measurement or
something, but not yet.
DR. CHESNEY: Well, I don't want to
overstay my welcome, and I do have a
Dr. Laughren, but one does wonder about some of
these children who didn't even express ideation and
just suddenly, very early on, if they didn't have
excessive levels. I guess that is one issue I was
Dr. Laughren, I wanted to come back to the
point Dr. Pine was making. I thought Dr.
Reisinger's point in the open session yesterday was
a very interesting one, which is that you would
have to undergo some kind of computer-based
learning program or some kind of program that
authorized you to prescribe psychoactive drugs.
Certainly, we have to do computer-based
CBLs for all kinds of things in our hospitals and
in other areas nowadays. That had a real
attraction to me, and I guess the question is what
kind of authority does the FDA have in an area like
that, can you say that anybody that prescribes
SSRIs must do a computer-based learning program on
line, or is that something that the professional
societies take on?
You offered several options,
revised label warning, but is this a potential
DR. TEMPLE: We can certainly recommend
things like that. Every labeling for a cancer drug
says that this should only be used by people who
are trained in oncology. That comes with no
enforcement on our part except that people may be
anxious about the consequences if they don't have
A labeling recommendation is certainly a
possibility. A step further to limit the drugs to
people who have been given that way, those are very
iffy questions, and it is not clear whether we can,
in fact, do that. There would have to be a debate
There are some examples of fairly
interventionist activities. As you all know, you
can't get clozapine unless you have a white blood
count, so no blood, no drug.
There are not a whole lot of other
examples like that, but there are other cases where
patients must be given a form that lists
of the adverse effects might be, and things like
that. You have to weigh the risk you are concerned
about with the burdensomeness to the community and
to the medical profession of those kinds of
Putting something in labeling about what
you should know doesn't carry those kinds of
concerns, so if something sensible, suggesting that
people ought to be trained in a certain way seemed
like a reasonable thing, we could certainly
DR. TRONTELL: I would just like to add on
to Dr. Temple's comments, because the FDA regulates
drugs, but doesn't regulate the practice of
medicine, and we walk a fine line in terms of
dealing with some drug products where we may feel,
as with clozapine, that only very tight controls on
prescribing and dispensing and use of the product
There are a very small handful of drugs,
they tend to be the exception rather than the rule,
where training has been required as a
approval. One product in particular is the drug
product dofetilide, where, in fact, training is
required for pharmacists or clinicians. There is a
highly structured way in which that product can be
Again, those have tended to be reserved
for situations where we feel the drug cannot be
safely used without that very high level of
precaution. It is extremely difficult to put those
in place for products that have already been
marketed and used by professionals.
DR. CHESNEY: The public sees your role I
think in a much broader perspective, as we heard
yesterday, and I think that is something that is
useful to clarify as to where your limits are. You
mentioned there is a fine line, and I think that is
what we are all looking for, is where does your
authority end and that of prescribing physicians
begin, I guess in a sense.
DR. TRONTELL: I don't think we yet have
an answer. I think we always have the authority of
our agency and hopefully, our ability to
individuals, but I think that the actual legal
authority to do some of these is a matter of debate
within and outside of the agency.
DR. GOODMAN: Dr. Nelson.
DR. NELSON: I would like to return to the
topic of the incentives on the part of industry to
perform well-conducted trials.
There has been a lot of discussion about
the evolution of the written request and about the
improvement with three-arm studies and changes in
the ability to request that, but my understanding,
I am interested to know if this is accurate, is
that there is still two potential linkages that
don't exist that might decrease the incentive to do
a well-conducted study, and that is, absent safety
concerns, there is no tie to putting any efficacy
information in labeling, so that they receive
exclusivity if a labeling change occurs.
Second, is that there is no link of
exclusivity to a well-conducted study unless that
has changed with written request, since I read them
on the current web site, there is one
where there was members of the drug group that had
no drug level, members of the placebo group that
had measurable drug levels, and the FDA concluded
that the data was uninterpretable, but
nevertheless, exclusivity was granted.
I am wondering, is that a problem with the
written request that is now fixed, or is there
other solutions that would need to be put into
place, such as legislation, to address those two,
what I perceive as gaps.
DR. MURPHY: I think there was significant
discussion about how exclusivity should work,
should it be only if the product is approved. I
was not privy to those discussions, but I know they
The reason for why it was put in place the
way it is, I can't give you, Dr. Nelson, but I can
tell you that one of the explanations I have heard
is that there was such little data, and FDA was
given the authority to define the trials, so again,
as you have heard, we would like to improve, and we
know we have to learn from what trials we
that by providing FDA the authority to define the
trials, that they hope that the trials would be,
you know, of the best that they could be, and that,
therefore, we would learn from the trials even they
were failed, because that is important information,
failing is important.
So, I guess what you would say, you are
asking if, and that is in a number of our labels,
and that is a whole other discussion, but in
situations, you know, we know that is the only
study we are going to get and this is it, failing
is put, that they failed to show effectiveness has
been put in the label in a number of situations,
and certain dosing or safety information.
As I said, about a fourth of the time, we
are describing, even irrespective of whether the
study is positive or negative, we are finding
safety signals, you know, important dosing
information, and we are able to put that
information in a label.
The intent is that the information that is
obtained, whether the product is proven
effective or not is important, and that safety
information, et cetera, would be obtained.
So, that is the best explanation I can
give you as to why it is set up the way it is right
DR. NELSON: I understand, but let me
focus my question, I guess. Right now the efficacy
or lack of efficacy data is not in the existing
labeling that we are discussing, so, for example,
just to pick one, paroxetine, there is five
studies, and the pediatric use just says it has not
Although that is a true statement, it is a
bit misleading because many people interpret that
to mean the studies hadn't been done.
The other question is you could ask them
to do a three-arm active control study, but if they
do it badly, do they still get the money? Even if
they have done it, if they do it badly, do they
still get the money?
DR. GOODMAN: Dr. Temple wants to respond.
DR. TEMPLE: If the written request says
you need to do a three-arm study and need to show
that the trial has assay sensitivity, that is, the
ability to distinguish active drugs from inactive
drugs, and the Prozac arm doesn't beat placebo,
then, they would have failed to meet the
requirement of the written request.
We couldn't do that before, as I said,
because we didn't have a known active control, so
we wouldn't have known what to say. So, in that
case, the incentive to do a proper study becomes
quite clear. If they don't do a proper study, and
succeed in showing that, they would not get
In other cases, we have insisted that the
variance be such that for, say, a blood pressure
drug, an effect size of 3 or 4 millimeters of
mercury could be detected, so if the whole thing is
done sloppily and they could not have detected such
a thing, then, they would not get exclusivity.
Some of the other things, however, that
you mentioned, don't have an obvious remedy. I
mean I guess following the example you
could say, oh, by the way, people should have blood
levels showing that they took the drug. Well, we
hadn't been smart enough to think of that, and
maybe that is something we should be adding, that
is, some kind of compliance check.
That, I don't think has been part of
written requests to date. That doesn't mean it
couldn't be. The test that Congress imposed is
that if you comply with the terms of the written
request, you get exclusivity. That means if we
weren't smart enough to ask a question, that is not
considered their fault, and they are supposed to
DR. MURPHY: And we have denied
exclusivity where we thought the trials were done
sloppily, and actually, sometimes when the sponsor
said, well, we know you asked for this, but we
didn't think it was correct to keep going, so we
didn't do this for some reason, and we said, no,
you should have come in and talked to us about why
you weren't going to do it, you didn't do it, we
told you, you need to do it, sorry, you
So, what I guess we are trying to say is
if it's really sloppy, and they don't do what we
tell them, we deny them exclusivity. The problem I
think we are dealing with here is that we all are
learning how to better do the trials, and your
other question about whether that should go in the
label, the negative information should go in the
label, is a whole other discussion.
DR. GOODMAN: I have a list of seven other
committee members who wish to speak. After we give
them that opportunity, I am going to ask Dr.
Wysowski to come up to the podium. We had asked
her to follow up on something from yesterday. Is
there somebody else that has a burning--we have one
more and that is it--two more, that's it.
Dr. Irwin. His question has been
answered. Thank you.
DR. RUDORFER: Yes, thank you.
I would just like to revisit a couple of
issues that concern me at the front end
studies, and I recognize everyone from the FDA is
pointing out that this is a learning process, on
the other hand, we are faced with the dilemma of
having these particular trials to deal with.
The dosing question that was just
discussed brings to mind a concern I have related
to how the suicidal events we have been looking at
As I understand it, for the most part,
these were from adverse events questionnaires and
surveys. Is that correct? I mean there was no
particular suicidal scale?
DR. LAUGHREN: Well, all of these trials
included standard depression rating instruments
like HAM-D or CDRS, and so forth, and there is a
suicide item in each of those instruments, and that
is part of what we analyzed.
But the problem is we don't really know
how those were applied. My guess is that most of
the event data we are dealing with were spontaneous
report or general questioning rather than specific
That is really one of the areas that we
are trying to explore with Columbia to try and work
on a more specific instrument for improving
ascertainment for suicidality, but no, in these
trials, I don't think ascertainment was very
DR. RUDORFER: My question, as we deal
with these data, would be this. I appreciate the
very dedicated and elegant work that both the FDA
and Columbia have applied to these findings. The
question I have relates to the issue of the active
drug versus placebo groups.
Since it sounds as if much of the data
were spontaneous reports or I assume perhaps
discussion between the raters and subjects, or the
investigators and the subjects, I am wondering if
part of this is not dependent on the assumption
that the blind was kept intact throughout the
studies, and I wonder if we have any measure of
that or any sort of quality control on that issue.
DR. LAUGHREN: No, we have no idea of
That is typically not something that is
really ascertained. It is the assumption, but how
would you check on that?
DR. RUDORFER: In some studies, patients
and raters are asked at some point. I mean here, I
am just wondering if, in fact, if a patient
volunteered that, for instance, they were
experiencing some side effects, they come in, the
rater asks how are you doing this week, and their
first comment relates to GI distress or something
that sounds like a side effect, if they simply
don't get more attention, in other words, maybe
there is more discussion, maybe there are more
questions asked as opposed to a patient that comes
in and say, gee, I am feeling pretty good, I don't
seem to have any side effects.
Again, that would not obviate the fact
that if we find signals, then, the signals are
present. I guess I am just concerned about the
active drug versus placebo difference.
DR. GOODMAN: Let me interject. I don't
think I am as concerned about the unblinding, but
your question raises at least in my mind
possibility that in the data, is it possible that
we would see other somatic symptoms, more side
effects reported in those patients, who also
reported suicidality than in the opposing group,
was there any attempt in the data to look at
whether there were any other--was any other
increase of adverse experience outside the target
symptoms of suicidality in those patients who
reported suicidality, the reason being that if
there was, that would suggest it was part of a
larger behavioral syndrome that was being induced
by the medication.
DR. LAUGHREN: Our analyses had to be
limited by what we had in our database, and we had
to design this database late last summer. We
didn't anticipate all of these questions. As it
was, the database we had was a very time-consuming
process to put together. It took a number of
months to get it.
They are all good questions, but we don't
have all those answers, but I agree that
ascertainment for suicidality was not
DR. GOODMAN: But the question is at this
point, could you go back to that same data and look
to see if there is a higher rate of other adverse
experiences reported in those patients who were
also identified as experiencing or exhibiting
DR. LAUGHREN: Not without designing
another database and going back to the companies
and waiting for a number of months, and I am not
confident enough in the quality of the data we have
here that that would justify that additional
I mean again, these are all good
questions, but we are faced with making a decision
at this point in time with what we have, and we are
asking the committee's advice on what you think we
can do now based on what we have done.
DR. GOODMAN: No, I agree with that, I
understand that, but we were also asked what other
advice we would give in terms of future research or
studies or data that we would like to see.
DR. TEMPLE: Tom, we did look at the
association with certain kinds of things, the
activation syndrome, things like that, right?
DR. LAUGHREN: We included in our database
two other symptoms, hostility and agitation based
on the preferred terms that the companies used, and
again, we haven't looked, I suspect that there is
variability across different companies in what
actually got subsumed under those two things.
There are the only two other events, and
we don't even have the timing for that. All we
have is an indication of whether or not, at some
point during treatment, a patient experienced
agitation or hostility. We don't have all the
other somatic kinds of things that you are alluding
to. That would mean going back and trying to
create another database.
DR. GOODMAN: Dr. Temple.
DR. TEMPLE: Let me just mention one other
thing that has come up briefly and that Dianne
touched on, and that is inclusion of negative
results in labeling.
As Tom has explained at the previous
meeting and now, as a general policy, we don't
usually put in labeling the fact that a study
hasn't worked, because we don't think that proves
that it doesn't work. It just means that that
But we are actively thinking about that
policy for the pediatric part, because the whole
point of doing the studies was the possibility that
adults and children are different, otherwise, you
wouldn't even think about doing that whole program.
All I can say is we are actively thinking about it.
It is not an easy to thing to do, however,
because what you would want to say could depend on
how good you thought the study was, and then there
is the conundrum of what do you do if there is one
study that says yes and one study that says no.
That is virtually somebody a claim, which we really
wouldn't want to do if it wasn't merited.
So, I am not going to suggest that this is
easy, but we are reconsidering this whole thing,
because the whole point of the Best Pharmaceuticals
for Children Act is to find the data and
whether drugs work in children, and not putting
anything in seems funny, so we are reconsidering
DR. GOODMAN: Dr. Perrin.
DR. PERRIN: Part of my question Dr.
Chesney eloquently asked before, but I wonder if we
can get access to the wording that you used for
cancer drugs as perhaps a guide to us for our
My other quick question, I think back to
one of the FDA group is am I hearing you right that
if you have a drug that has been shown to be
efficacious in a particular indication, that all
trials requested in the future require an arm that
includes that drug?
DR. TEMPLE: I am not ready to say that
one would always do that, there are other ways to
try to assure quality, but in this setting, it is
reasonable to assert that we need to know whether
your trial was an adequate test of whether this
drug worked, and the only way we know to be sure
that it is an adequate test is to have an
control, and to have that active control be
distinguishable from placebo. Then, you know this
is a trial capable of showing things.
We have determined that our future written
requests will include a requirement for a three-arm
trial, because that's the only way we know to be
sure that the trial is a trial that is capable of
showing what the answer is, and we want to be sure
we get the answer.
This comes up in written requests all the
time, how much assurance do you have to have and
how do you gain that assurance that the trial is a
useful trial, and the reason it comes up is the one
that everyone has alluded to, we don't think people
are deliberately trying to mess things up, but the
incentives to do a really good trial are greater
when you have to win.
DR. PERRIN: I am a little confused. As a
clinician, you know, typically, if I am looking at
a new medication, I want to know that it is better
than current therapy. I mean all of us are really
interested in that.
There are a number of pediatric drug
trials, not in the area of antidepressants that I
am aware of, where new drugs come on the market,
approved by the FDA, where there are only
drug/placebo trials, and not trials comparing the
new drug with currently approved FDA medications.
That is where I am confused.
DR. TEMPLE: Good question. There are two
possible uses for having an active control. One is
where you want to compare the two therapies. Now,
to do that, you would need a very, very large
study, because you would be interested in even
modest differences. That is not what we are
We are talking about the use of the third
arm to show something about trial quality.
Actually, a third arm is extremely common in
depression trials now, because if the trial fails
to show that your drug is better than placebo,
there are two possibilities.
One is that your drug is no good, and the
other is that the study was no good, and
it is very
important to somebody developing a drug to know
which of those two things it is.
If the trial shows that Prozac, say,
works, and your drug doesn't, you get rid of the
drug. If the trials shows that neither Prozac nor
your drug works, you do another study. So, it is
extremely important. But the two purposes of the
trials are quite different.
To actually do a comparison and try to
detect a small difference, you would need very,
very large groups. That is an unusual thing for
people to do, and usually, the drugs can't be
distinguished. It is very hard to do that.
DR. GOODMAN: Dr. Temple, I heard you say
before, if I heard correctly, that incentives are
different when you need to win. Were you referring
to the conditions of the six-month exclusivity
arrangement, and if you were, if the incentives
were different at that time, would you predict any
difference in the design of those trials or the
conduct of those trials?
The reason, let me say, I think
of us keep harping on this point, is not so much
because we think that the suicidality data would
have turned out differently. I think it is the
absence of a benefit, the absence of efficacy that
at least I am concerned about, because that is
mostly what we have in assessing benefit or those
trials, and we only have 3 out of 15 that are
positive, so if there was something about the
conditions in which those studies were designed or
conducted that might have negatively impacted the
outcome, I would like to know it.
DR. TEMPLE: Well, Russ and Tom need to
respond, but we haven't seen anything in the design
of those trials as written in protocols that makes
them look any worse than any other trials. They
seem to have reasonable size, so there is nothing
But, you know, this is an issue that comes
up when you do so-called "non-inferiority" trials.
The incentive, you know, the point of such trials
show no difference between treatments, and as I
have written repeatedly, that is not a
incentive to give people.
It doesn't stimulate the kind of optimal
behavior that you want, which is stimulated by the
need to try to show a difference between
treatments, and that is a problem here if you don't
need to win, to gain exclusivity, and I don't
disagree with the idea that you shouldn't need to
win, the point is to get the data. That is why the
BPCA was done that way.
On the other hand, you do want a good
trial, and one way to guarantee that the trial is a
good trial, however the drug comes out, is to be
sure that it is capable of showing something we
need to be true, namely, that Prozac seems to work.
DR. KATZ: Can I just add? One thing you
need to remember about studies done in response to
written requests is that they are very time
sensitive, or at least it's possible that they are
What I mean by that is you only get
exclusivity if your study reports, your supplements
containing the data come in while you
some residual patent life left or exclusivity left.
So, they have to be done within a particular time
frame. In fact, the letters that we send, the
written requests include a date by which the
studies have to be submitted.
So, in some cases, there is at least
potentially motivation to do studies rapidly, so
that they are done and study reports are written,
and the supplement, which includes these data, are
submitted in time, so that they can still get their
So, one at least potential question that
has been raised is enrollment so rapid or does it
need to be so rapid into these trials that maybe
not all the patients are adequately diagnosed, and
maybe they have something other than depression.
It is very, very difficult for us, if not
impossible for us, to be able to independently
corroborate diagnoses in something, in conditions
like these, so we, of course, take it on faith that
they got the right patients, but maybe, for
example, because of time constraints,
get the right patients, and that might contribute
to a negative finding even if the drugs were
effective in a true population. So, that is one
DR. GOODMAN: I think that is a fair
answer. Anybody that wanted to comment
specifically on that? Dr. Marangell.
DR. MARANGELL: Are you aware, is there a
greater proportion of non-academic sites in these
DR. MURPHY: I don't know that we have
looked at that. I mean I know that there are
definitely, in some of these studies, very, you
know, academic sites that have been involved in
numerous or actually well-known to us
I do want to make one thing again. One
thing that every division within FDA is told, when
writing their written requests, they are asked a
number of questions - what is the public health
benefit, what are the trials to get to that public
health benefit, and you are not to take
consideration--and most of the time they don't even
know because you would have to go into a lot of
patent law--they don't know or are told to not pay
any attention to when the patents expire or the
exclusivity marking would go out, they must look at
it only from what are the trials that they need to
Now, what is being told to you, though, is
that--and we have written requests where the
companies come back and say, well, that is not
going to help us, because you put a date on here
that it was due by 2007, and our patent expires in
2005, and we have said, you know, we are sorry, we
need these kind of trials.
Now, would, in that situation, a company
try to compress by getting more sites or, you know,
whatever, would they try to do that trial in a
different way? Yes, possibly.
I mean that is what we are trying to
explain the balance between the way the process is
set up, it is not to be driven by the time when the
patents are expiring, the marketing
expiring, the divisions are to determine what the
studies are that are needed to the best of their
knowledge at that time. They are to design those
studies to answer those questions.
Do we try to be reasonable and say, gee,
we would like a 10-year follow-up study, but we
don't ask that for other--you know, we have to be
reasonable within the realm of what we would
normally ask for, for an approval product.
Again, though, maybe we can be--we say we
have to get this information because children grow
and will go through a period where that might be
DR. GOODMAN: Thank you, Dianne.
DR. MURPHY: So, you have to ask for
additional information, you might not, for adults.
I am trying to explain the process.
DR. GOODMAN: I will accept some questions
out of order if they are on this specific topic.
Dr. Rudorfer, I think you had one.
DR. RUDORFER: I just wanted to follow up
on Dr. Katz's comment about whether we
at the right patients, which was an issue we
discussed some yesterday.
Just one point that I want to follow up
on. It is clear that in young people who present
with major depression, there is a disproportionate
number who go on to develop bipolar disorder, and I
think one concern that we expressed yesterday was
that the trials are very inconsistent in that
especially in terms of accounting for family
history, it sounded as if in some trials, a subject
could literally be brought to the clinic by a
parent who has bipolar disorder, and yet the child
could be included in the trial.
I realize this question might be, as we
said, a little out of the box. I would think that
if there is any way to encourage the companies to
actually try to find some of these thousands of
young people and see what has happened to them in
the 5 or 10 years since they were in the study, it
could be tremendously informative simply in seeing
whose longitudinal course has played out as what we
recognized in young adults as major
developed bipolar disorder, who developed some
other disorder, and go back and re-look at, for
instance, those who after the fact are confirmed to
have the diagnosis that we thought they did on
DR. GOODMAN: Dr. Pfeffer.
DR. PFEFFER: Yes, I want to I guess
continue on what Dr. Rudorfer is saying, because I
think diagnosis is critical, and I think we can
learn something about this that we have learned a
little bit about depression in other realms, too,
namely, that children are, in fact, different than
So, what appears to be adult depression
and what appears to be childhood depression may, in
fact, be quite different, so that perhaps a lack of
efficacy in most of the studies tells us something
about the nature of the developmental course, first
I agree with what you are saying about the
potential for bipolar. That is one issue that is
crucial, I think, in terms of maybe the
response that children are having, but also if we
think of the number who had some suicidal thinking,
that also might be a subgroup of the children who
are in these studies also.
The other part that I want to mention is
that when I gave that talk last meeting, I talked
about the complexities about what looks like
depression in children, and not only course and
family history, but life event circumstances, and
that has not been looked at.
So, for example, children who might have
been having immediate family turmoil and looked
depressed, that is an issue that might have led to
some resistance in response, for example.
The other point I would like to make is
that we hear from some of our childhood
psychiatrist colleagues yesterday who advocate to
not ban use of these drugs, because they do see
efficacy, and it may very well be that in their
practice, with very careful assessment, careful
diagnosis, they are selecting the subgroup of
youngsters who potentially could respond,
respond very, very well.
So, I think the question of diagnosis is
crucial, which means that in terms of the study
design, in a way, who has the most reliability to
make a diagnosis, and what kinds of questions
really are being asked and what data is being
collected that might help us even look at
predictability of response, and I don't think we
have that, such as life events, such as family
history, such as perhaps other issues that we would
need to come up with and understand.
DR. GOODMAN: Thank you.
DR. GORMAN: A lot of us keep saying that
children are different, and I don't think it should
come to us, then, as a surprise that children may
respond differently to medicines than adults do.
I think I would be more concerned about
the efficacy of these trials if they were all
unidirectional in the sense if they had all failed
or they had all succeeded. I have heard nothing
from the FDA to this point that says that
playing field has been tilted in any way since one
of these drugs in this class, which may not
actually be a class, but it seems like it might be
a class, actually works for children in the bar
that the FDA sets up.
So, I am now going to address my single
question to the rushing hypothesis. After Monday
Night Football last night, I like the rushing
hypothesis. There is one small question I have to
Prozac was the first mover in this field,
therefore, I assumed it came to market first, and
probably then had the least time before its patent
extension. Is that a safe statement?
So, it came to market first. Did it have
the smallest amount of time? It was the first to
go off patent, yes or no?
DR. TEMPLE: I believe it was the first
one to go off patent by a little bit. It is off
patent now, and only, I don't know, are any of the
others off patent? So, we know it was the first
off patent, which happened sort of a year
DR. GORMAN: So, that would run
counterintuitive to the rushing hypothesis, because
Prozac had to get there first, and therefore, seems
to have had the least time and would be the most
likely to be rushed to get labeling.
DR. TEMPLE: Some of the trials were done
before this program even started, I think, and they
were done a long time ago.
DR. LAUGHREN: One of the trials was done
by Emslie several years before, and the company
obtained the data and submitted those data as part
of that supplement. It was done in the early '90s,
DR. KATZ: Right. The studies that we
asked for in the written requests don't necessarily
have to be done or initiated after the written
request is written.
If they have a study that is very old, but
that meets the criteria that we put into the
written request, they can use that, so they don't
have to be done specifically in response to the
written request, they have to meet the
that we lay out, and it can have been submitted to
us either before the written request.
But they could have done a study many,
many years in advance before we even contemplated
written requests. If they met the criteria, they
can submit it in response.
DR. TEMPLE: But, also, remember it's a
hypothesis. We don't know why those trials fail.
It could be that children really don't respond. I
mean we don't know the actual answer.
DR. GORMAN: Well, I would love to be in
the position where I can say something nice about
the pharmaceutical industry, because it sometimes
seems to happen so rarely, but if Lilly did the
trials before there was the potential for financial
gain, because all they were doing was looking for
labeling in children without the congressionally
mandated reward for that particular behavior, and
therefore had these studies in place, maybe the
rushing hypothesis fails, but there is another
hypothesis that could be generated from that.
DR. LAUGHREN: Again, in fairness, the
Emslie trial was funded by NIMH. This was not
sponsored by Lilly. They went back and obtained
the data, and they did subsequently an independent
trial that also succeeded.
DR. GOODMAN: Dr. Newman.
DR. NEWMAN: I think Dr. Temple did a good
job of explaining why, if you have an active
treatment arm, the trial is likely to be of higher
quality when asked to demonstrate that difference.
I wonder if another approach to motivating
high quality studies would be to require that in
order to get the exclusivity, that the trial be
written up in a way that passes some sort of peer
review and be published.
That way, even published on FDA web site,
that way, if the trial is sloppy and finds the drug
doesn't work, those results would not be buried,
they would become public and that I think would
provide some motivation to do a good job.
I am a little troubled. I wrote down a
quote from Dr. Murphy. It said, "If a study is
negative, we don't talk about
it." I think if
that's the case, then, there is a lot less
motivation to do a really good job on the study.
Why not require the studies be published, be
written in a way that it is of sufficient quality
that they can be interpreted, and then maybe the
quality would improve.
DR. MURPHY: But for peds now, we do.
That is the difference. That statement was for
adults. For pediatric studies, well, I should say
it is for pediatric studies that aren't done under
exclusivity, but for pediatric studies done in
response to these written requests, we now are
mandated to make them public whether they are
approved, they are not approved, or even if they
DR. TEMPLE: But you are also talking
about a level of detail in the presentation
sufficient for people to really get into was it a
high quality study, and things like that.
DR. NEWMAN: Why not?
DR. TEMPLE: it is a fairly good question.
don't believe we have authority to insist that
things be published. We get full details, we get
all the data.
DR. NEWMAN: But you could peer review,
you could peer review them. You could send them
out and say is this something that is publishable,
and have people at FDA, who I am sure are very good
at that, say no, this gets an F, you know, this is
not good enough, send it back, or you don't get the
DR. TEMPLE: Well, our reviews, when we
approve something, you get on our web site the
contents of our reviews, so you get to see what we
thought of all of the studies. If we do not
approve, however, we don't believe we have
authority to make those data public, so you don't
get to see our reviews. That is our legal
interpretation of what confidential commercial
information is, and I can't rebut it or comment on
it. It's a legal determination.
DR. GOODMAN: Dr. McGough.
DR. McGOUGH: Just on that point, does the
FDA now have the authority, if you wanted
put negative studies in the pediatric label, do you
have the authority or does Congress have to do
something for you to get the authority?
DR. TEMPLE: We have authority. What I
was saying before is--and we are, as I said,
considering whether in the pediatric case, we
should do that. In other cases, we would, too, if
we thought it was important to point out the
negativity, and the negativity was a true bill.
It is just the fact that if one study
fails, doesn't necessarily say that something
doesn't work, so we have been somewhat reluctant to
just do that until it was convincing.
But as Dianne said, we are actively
thinking about amending that policy for the
pediatric setting where the whole point of getting
the studies done was to see how the drugs worked in
children, for the very same things that they have
been studied for in adults.
It is a little different from novel use or
something like that. The BCPA calls for studies of
the exact same things that have been
DR. MURPHY: And we are putting negative
information in some of the labels already for other
types of products, but because of the complexities
that you have heard, it has been the policy for
antidepressants for children not to do that at this
point, but I think, as has been mentioned, it is
So, we have, and I have got all the labels
here that we have done, we are putting that
information in some of these labels.
DR. POLLOCK: For the new approvals.
DR. MURPHY: No.
DR. TEMPLE: For where we grant
DR. MURPHY: Right. In other words, if a
product comes in and doesn't work, we have put that
information in some labels where we think it is
very clear-cut, you know, eight more studies is not
going to change this for whatever reason, and we
put that in here.
We have also put in information
hasn't worked where there are safety issues
involved, and we are not clear what those safety
issues are, but we want to tell you about them.
So, those are in the label, too, even when it
wasn't approved for that indication.
DR. GOODMAN: Dr. Santana.
DR. SANTANA: I have a comment and then a
question that really relates to a point that Dr.
Chesney made about issues regarding the boundary of
practice and FDA regulation.
My comment is that there was some comment
related to oncology and issues, how we deal with
some prescription and safety issues in oncology,
and I think we have to recognize that pediatric
oncology is unique in this country and that most of
the trials, even the exclusivity trials, of which I
have participated in some in oncology, are really
under the umbrella of research centers and academic
centers. Very little pediatric oncology is done in
the private practice.
So, by force, you are now dealing with a
group of individuals that are more
more geared up to looking at issues that
potentially could be relevant, whereas, I think in
the other pediatric arenas that we are talking
about, that doesn't occur.
So, I think it would be a misnomer to use
pediatric oncology, maybe it should be the gold
standard, but I think we need to recognize that it
is kind of unique in the way it is practiced in
Having participated in some of the
exclusivity oncology trials, I can tell you that
they are at the same caliber and at the same
rigorous structure as any of our other oncology
trials are in the cooperative group setting, et
cetera, et cetera. So, that was just a comment to
clarify the pediatric oncology issue.
I want to get back to patients and
practicing physicians, because we have been talking
a lot about study design and how to analyze data.
I want to get back to the issue of patients,
parents, and practicing physicians, and this
boundary of what the FDA can regulate and
regulate in terms of the practice of medicine.
I was struck yesterday by many of the
testimonies from parents and families, and
actually, there was even a gentleman who showed a
slide, in which his child was given the medication
as a free sample. I am not sure that all these
whistles and alarms that we put in labels are
really going to work unless somehow that practice
stops for certain medications that we think
potentially have a greater risk.
I wanted the FDA to address the issue
historically. Is there any ruling that you guys
can impose or potentially think about, about how
these medications are given without prescriptions,
that is, either free samples or in the marketing
world, so you could comment on that.
Secondly, does the FDA have any historical
data on successful programs? There was a mention
that maybe a med guide to parents and families
would be a way to address some of the safety issues
and bring people to a better level of
Can the FDA comment on any successful
programs that they can point where this has truly
DR. TEMPLE: Just on the free sample
thing, my understanding, but I don't really know,
was that a physician did use a free sample to, you
know, like start the child out. That is not
without a prescription, it may not have been well
done and may not have had adequate follow up, but I
am not sure that it is the free sample that is
involved, it is the lack of follow up that was
described that seems like the problem.
It is not easy to know how successful our
various endeavors have been, and Anne Trontell may
want to comment on that. Some of them have effects
that are not entirely what we wanted. She
mentioned the program on dofetilide.
To start, dofetilide is a drug that is
used to prevent recurrence of atrial fibrillation,
but it is a drug that causes QT prolongation and
Torsade de Pointes, and there is no doubt about it.
The recommendation in labeling,
and it is
enforced by the need to give out various
information requires that you come into a hospital
or outpatient facility for a couple of days to see
what your creatinine clearance is and to see
whether you are a person who has QT prolongation to
an excessive degree.
Then, after that you can go out and be
treated with it for long-term use in preventing
What appears to have occurred is that that
is sufficiently difficult, so that people instead
use sotalol, which doesn't have such a program, or
quinidine, neither of which are an improvement of
So, people can avoid some of these things
if they are inconsistent across the drug classes,
so you always worry about that.
There is a very rigorous requirement for
periodic measurement of liver tests with a drug
called Bosentan, which is used for pulmonary
hypertension, and although the drug was quite toxic
when it was being developed, my most
information is that we haven't had any fatal liver
outcomes, perhaps a testimony to the fact that
people are indeed following up these patients.
Of course, this is a class of patients who
are very sick and very closely watched. You don't
know if that is typical how we are going to do.
Anne, you want to comment on some of the
DR. TRONTELL: Sure. On the issue of
sampling, first of all, I think in some instances,
at the time of product approval, there have been
informal agreements, but no FDA authority to
restrict sampling exists to my knowledge, but there
may be agreement, you know, certainly, we don't
sample oncology drugs. There are things that just
On the issue of what is a successful
program, I think we struggle in the agency, because
good evaluations have not been done on a standard
basis. We have the best information for those
programs that are most restrictive, programs like
clozapine or programs like the one for
to prevent pregnancy exposures.
So, the available data to us to tell us
what works tends to be only in those extreme cases
where we have put, as Dr. Temple just described,
for Bosentan, you know, very severe restrictions.
If you are asking for specific information
about medication guides, I think we have in the
general literature evidence to suggest that good
education certainly facilitates good behaviors, but
I don't think we have any evidence yet that it
guarantees that they do take place.
So, if you had questions about the
intermediate ones, I think for the most part, we
don't have information about those specific
educational programs or the reminder ones. Not
uncommonly, education is applied in the context of
these very restrictive programs that I just
described, and again, teasing out what the
education alone does is very difficult.
DR. GOODMAN: Dr. Katz.
DR. KATZ: You are hearing the
difficulties that we think we have with
imposing various sorts of restrictions although
again, there are ways to do it although they may be
very difficult to implement.
But it occurs to me that it might be
particular difficult in this case because the use
we are contemplating in all but one case is off
label, and I don't even know what the implications
of that are. Certainly, there are legal questions
about what you can say and what you can restrict
with regard to off-label use, and I don't think
that we have thought through all the implications
DR. SANTANA: So, as a follow up to that,
since we last met in February and there was a
recommendation to do something with the label that
occurred and some warnings, has the Agency
monitored the change in practice?
I heard a number yesterday of 10 percent.
That is prescriptions, but has that been rigorously
looked at, that there was an impact of that
modification that translated to something very
DR. TRONTELL: I will ask either Michael
Evans or Judy Stafford from the Office of Drug
Safety. All we have really been able to monitor
since the last advisory committee is volume of use,
but they do have some information on how that has
DR. GOODMAN: Ms. Griffith.
MS. GRIFFITH: I would just like to pursue
this for a moment with respect to the patient and
physician relationship. When Dr. Chesney was
proposing perhaps some sort of a computerized
programming or education, or even with respect to
these med guides, when Dr. Temple suggested that
perhaps there would be, you know, a mechanism much
like you have for other drugs, that the patient and
practitioner would be signing a consent form
outlining the risks and benefits, I want to
understand the reason that you thought that that
might be too great a deterrent to pursue, simply
because from my perspective as patient rep and
parent, it seems to me that in the course of any
treatment process for any severe illness,
we all understand depression is, you are often
asked to look at the risks and to sign some
statement to the effect that you understand what
these risks are.
You even have to do that if you get a shot
of botox, not that I know, but it just strikes me
you have put the parents now in the position of
actually doing the risk-benefit analysis. That is
where we all are.
If by providing the families with the
statement that these risks are indeed serious, I
think that what we heard yesterday was how little
awareness there was on the part of the parents that
these drugs could be lethal in certain cases.
I am arguing for more information rather
than less, not more restrictions, and I agree with
the point that Dr. Santana made, that how often
does a parent either open the box and read the
information or understand it.
So, if it is very clearly stated between
the doctor and the patient or the parent, I think
it goes a long way to satisfying the need
DR. TEMPLE: There are gradations of
information, and we wrestle with how to do that
without being an attempt to be informative, but not
disruptive, so that, for example, a lot of drugs
have what are called med guides. These are patient
labelings that are actually, under the law,
supposed to be given out by the pharmacist.
My own view is that if you don't make it
part of the unit of use package, you might as well
not bother, but in any case, we know that there are
ways to get that information to patients either
through the proper functioning of the pharmacy or
by making it part of the package.
An enormous additional step, which has
been done in some cases, but, you know, thalidomide
is a level of risk that is sort of in its own
category, where there is a requirement that the
patient and physician discuss all these matters.
That is a very huge step, and what you might think
is reasonable for thalidomide, something that is
used infrequently, you might find more
than you want or more difficult than you want for
drugs that are much more widely used.
As Russ pointed out, it is particularly
tricky when the recommended use isn't even in the
label. How to write a med guide or something like
that for something you are not really recommending
and don't feel able to recommend yet, that may
sound like a bureaucratic worry, but I think it's a
You don't want to warn people and
simultaneously recommend a use that you don't think
is recommendable, and any discussion like that is
tantamount to recommending the use. So, we will
need to worry all of those things based on your
MS. GRIFFITH: Could I follow up? I
understand that and I understand that there are all
sort of issues involved, liability on the part of
the physician, but I am suggesting, from the naive
perspective of the parent, I think of depression as
every bit as serious as the use of thalidomide
posing birth defect risks or, as Dr.
you know, the cancer example. Parents need to be
informed about those risks.
I don't think that this is any different,
frankly, and if it is an extraordinary measure to
take, I think that it benefits both the
practitioner and the patient parent.
DR. TEMPLE: For oncologic drugs, the
label says you should be a properly trained
oncologist. There isn't anything in there that
says what you need to discuss. Patient med guides
for oncologic drugs is by far the exception, I
think because it is assumed that there always has
to be such a conversation in the course of therapy.
I guess what is being discussed is whether
there is a common practice of having that kind of
conversation in someone who is depressed, and
obviously, we all think that there should be such a
conversation. The question is now to induce it and
what to provide people to help them be sure they
ask the right questions.
DR. GOODMAN: We have a representative
from the Office of Drug Safety at the
Could you please state your name?
MR. EVANS: Michael Evans with the Office
of Drug Safety.
With regards to drug use, comparing the
first six months of this year to the first six
months of last year, the market rose with all ages
about 7 percent. Adolescents and children, in the
first six months of the year, still comprised
between 7 and 8 percent of that total. So, they
are still widely used in children.
DR. GOODMAN: How up to date is that data?
There must be some sort of lag time, isn't there,
between when the prescription--
MR. EVANS: It is according to IMS Health,
and this is January through June is what we looked
at. This is outpatient prescription data, which
comprises about 45 percent of all pharmacies in the
DR. GOODMAN: Let me make sure I
understand. You don't see any significant drop?
MR. EVANS: No. I believe a woman
mentioned yesterday that they saw a 10
decline. We did not see that.
DR. GOODMAN: Dr. Irwin.
DR. IRWIN: Has the rate of increase
remained the same or has it leveled off, or what is
MR. EVANS: In February, one of our
colleagues, who gave drug use for 2002, that age
group was still 7 to 8 percent of the total. It is
still the same this year, first six months.
DR. GOODMAN: So, there has been no great
I will take again other questions out of
order as long as they are directed to a
representative from ODS.
DR. MARANGELL: Actually, a comment
directed to this. I think it is really critical to
this discussion that we keep in mind that our goal
is to protect risk, but also that this is really a
devastating illness, and I am not sure that I
necessarily--I don't want to necessarily see
prescriptions drop. These people need to be
What we want to do is make sure that
people are educated of what to look for early on in
terms of risk for those people that are at risk,
children or otherwise. They are not necessarily
the same thing .
DR. GOODMAN: Other questions for our
speaker? Dr. Gorman.
DR. GORMAN: Is the data on the level of
the class or is it on the level of individual
MR. EVANS: We looked at the class as a
whole and then we looked at each individual drug in
the class. That was according to IMS Health
National Prescription Audit, and we also looked at
the National Disease and Therapeutic Index from IMS
Health, and tried to apply those percentages to
outpatient projected prescriptions.
Only the players changed in that age group
of children 1 through 17. Paroxetine was knocked
out of the top five, but sertraline still is the
market leader, followed by fluoxetine.
DR. GORMAN: So, the information, there
seems to at this point only be one drug that is
efficacious in this age range, moved it up the
ladder, but didn't make it number one?
MR. EVANS: Not necessarily. This is what
we observed when we were just looking at drug use
in prescriptions outpatient, and the National
Disease and Therapeutic Index is an office-based
survey where a drug is mentioned during that survey
and linked to a diagnosis.
DR. GOODMAN: Can you differentiate
between the prescriber classes, whether it is a
primary care physician versus psychiatrist?
MR. EVANS: We did look at specialty in
MBA-Plus. Psychiatry was still about 65 percent of
the specialty, pediatrics, somewhere between 15, 20
DR. GOODMAN: Dr. Fant.
DR. FANT: Could you comment on the
indications for the prescription, was it all
depression or other off-label--
MR. EVANS: We looked at mood disorders,
anxiety disorders, ADD, and other disorders. In
age group 12 to 17, it still appears there is not
really any change. It is still mood disorders,
which includes major depression, is still
two-thirds of the indications.
It looks like in the 1 to 11-year age
group, perhaps more shift to the ADD.
DR. GOODMAN: Dr. Pollock.
DR. POLLOCK: I heard rather consistently
yesterday a lot of concern about the
direct-to-consumer advertising and the role that
that has played in this, and it may not be the
purview of this committee, but I am asking if we
can address this aspect and how that plays with the
implications of labeling, that if we do put, as was
suggested, a specific negative label in terms of
the indications and certainly as a warning, let
alone a black box warning, that the amplitude of
these warnings are heard.
I mean it is almost a penalty then for the
intense direct-to-consumer advertising, which does
play, as I understand it, a huge role in
sales for some of these antidepressants.
I just wondered if you could give us some
indication, I mean is there a direct policy with
D.D. Mack how these various gradations get
translated into the few seconds that go on the tail
end of a commercial.
DR. TEMPLE: They are certainly supposed
to. The presence of a strong warning or box
warning should be reflected right in the major
statements that are made. The direct-to-consumer
comes in two flavors, written and TV.
In TV, you can't give as much information
easily, but it has to be available readily. You
can argue about whether people make use of that
availability. But the major statement would have
to reflect the balance between those two things.
You know, I am sure people have views
about whether that is done successfully or not. If
it is written, then, the written statements have to
show that balance. Any box warning has to be
reflected in it.
So, yes, it is supposed to
balance of information that is in the labeling, so
if the labeling changes, the direct-to-consumer
advertising should change.
DR. GOODMAN: Dr. Perrin.
DR. PERRIN: Yes. Back to the ODS person.
A number of the anecdotes yesterday suggested that
people were put on antidepressants quite off label
and probably not for major depression, but rather
for minor depression and acute depression.
You said that you have the evidence on
mood disorders that includes major depression. Can
that be disaggregated at all into other non-MDD
forms of mood disorders?
MR. EVANS: We could look at that. We
didn't, we lumped them together just for a top-line
statement at this time, because we wanted the focus
to be more on suicidality than drug use.
DR. GOODMAN: Ms. Griffith.
MS. GRIFFITH: I wanted to know, since the
data you got was January to June, and the Advisory
didn't come out until late March, is it possible to
look at the data that you got April to
June to see
if there is a decline?
MR. EVANS: We did look at it monthly in
those months, and there was not any decline. I
mean it wasn't a change.
DR. GOODMAN: Are these new prescriptions?
MR. EVANS: These were total
prescriptions, new and refill.
DR. GOODMAN: Did you separate out by new
prescriptions in terms of the monthly rate?
MR. EVANS: We can, and we did, and we did
not see much of a decline in those, as well.
DR. GOODMAN: Dr. Chesney.
DR. CHESNEY: On the surface, this looks
not bad in the sense that 65 percent are being
written by psychiatrists, but although I am not
here as a patient representative, I do have a
daughter who has been on these medications, and I
know for a fact that most often psychiatrists do
not prescribe these medications.
My image is that at the end of the day,
they take a whole packet of prescriptions--and I
will be interested to have the
respond to this--a whole packet of prescriptions
that have been written by social workers,
pharmacists, psychologists, and sign their name.
So, I think when we are talking about
educating primary care providers, looking at this,
I am reassured, but I know that this does not
represent who is actually writing the
MR. EVANS: Yes, this is a limitation of
the data, too, the data is only as good as what the
pharmacist inputs at the computer, and, you know,
if that specialty is on there, hopefully, they will
put that on there.
DR. CHESNEY: I am sure they don't, but I
think this is very important in the educational
issue, because the people who are prescribing this,
on the whole, are not child psychiatrists, and they
are family practitioners, they are ER physicians,
they are nurse practitioners, they are pharmacists.
I mean I was appalled at what happened
when we visited one of these pharmacists, but no
disrespect to pharmacists, but this is
happening out there.
DR. GOODMAN: One last question for ODS
representative from Dr. Wang.
DR. WANG: I was curious, has anyone
studied what happened after the British
contraindicated these in children, just to get a
sense of what the impact of a labeling change, such
as that, might be?
MR. EVANS: In February, they looked
through 2002, the market between 2002 and 2003
group, 15 percent with no change really in the
adolescent and children population. It was still
around 78 percent, so I don't think there was a
change much in this country.
DR. WANG: But you don't know of any data
in the British--
MR. EVANS: We didn't look at that.
DR. GOODMAN: Thank you very much. You
may step down.
We have six more presenters. I am not
taking any more, that's it.
Dr. Leslie, do you remember
DR. LESLIE: My question goes way back and
is for the FDA. I think reading through the
materials that we received from the public, two of
the major concerns about the data that was coming
in were suicidality, et cetera, being captured
under other labels, such as emotional ability, and
then also the issue about dropouts were people
dropping out of either the placebo or the drug
groups, that were having the kinds of adverse
events that were of interest to us, and then not
being counted in the data.
So, I had two questions. One was do you
feel confident that the data you have received has
addressed those two issues for the analyses that we
looked at yesterday, and the second was what steps
could you potentially take to address those
drawbacks that were raised by the public in the
written requests that proceed from here on out.
DR. LAUGHREN: I can respond to the first
part of that. In terms of the data that we
received, if you recall, we issued letters to
companies in July of last year, which
very clear research strategy for looking for
adverse events that might be related to
It included both preferred terms and
verbatim terms. All these data are electronic, so
it was a string search to look for events that
might be possibly related to suicidality. In
addition to that, we asked companies to look at all
their serious adverse event narratives, any event
that had been classified as a serious adverse
event, they would have to look at and make a
decision whether or not that might represent
Then, later in the year, we issued
additional requests to basically ask them to give
us all the serious adverse event narratives, so
that we could have Columbia themselves look at
those data, and also, all accidental injuries and
accidental overdoses to try and broaden the search,
to make sure that we could capture everything that
might be related.
Now, it is true, despite all of
is possible that certain events that didn't rise to
the level of being a series adverse event might
have been captured under some other either verbatim
term or preferred term.
The other question is whether or not the
narratives that we received fully reflected the
case report forms. The narratives are created by
the companies. To try and address that, we have
sort of a second level of this contract with
Columbia that is ongoing right now.
We have done a 20 percent sampling of the
case report forms for the narratives we have, to
have them check the narratives against the case
report forms basically to see whether or not they
fully reflected, the narratives fully reflected
what was in the case report form.
In addition to that, we have asked for the
dictionaries. The dictionaries, basically,
companies, when the code data, they subsume them
under preferred terms, and once they do that, that
creates basically, a dictionary.
So, we have asked for the
from all these sponsors. Columbia is currently
looking at those dictionaries to see if there are
any other additional adverse event terms that might
be of interest to look at, again to answer that
question whether or not all relevant events have
That is a very tedious, time-consuming
process, but it is ongoing right now.
Dropouts, Dr. Hammad addressed that
yesterday. We did look at dropouts, and as he
suggested, it is true, many patients were dropping
out for these events. In a sense, it was almost a
surrogate for that endpoint.
DR. GOODMAN: Dr. Posner, did you have a
DR. POSNER: I just wanted to say that, in
addition, because we asked for all of the
accidental injuries, and that would be the most
likely place, that all of these events involved
some type of injury or another, that you would find
events that were missed, so we can feel reasonably
confident that this body of data
everything we would want to look for, but we are
doing these additional steps, as well.
DR. GOODMAN: Dr. O'Fallon.
DR. O'FALLON: Yes, this sort of follows
up. We are back to what I am concerned about, the
people who came here, they are worried about the
side effects, the toxicity here. Right from the
beginning, when you told us back in February about
this study, I was worried about what wasn't
recorded in the drug companies' records, for
I think that is still, no matter what we
do going forward, we have got to address the issues
there. So, what I am wondering about, I would like
to propose, and you shoot at and tell me that these
things are not feasible, but it seems to me what we
really need are somehow a standardized suicide
monitoring procedure or whatever for future studies
in mental illness, any kind of a drug that is
targeted toward the mind, we should be looking for
this type of thing, the suicidality side effect.
Then, I think we are going to
have to have
some sort of standardized suicide coding. They
have done it in adverse events, not great, but it
could be done better for suicide coding because of
the work that has been done here.
I think this has been a wonderful outcome
in terms of the coding issues.
Now, here is one that is going to kill
everybody, but you can make suicidality a goal, a
primary goal in, say, mental illness or maybe
depression more specifically, where you really
think that this side effect or toxicity, this
adverse event is also a symptom of the disease.
In cancer, they have had to struggle with
the issue of distinguishing side effects from
symptoms of the disease for decades, some way of
going after that.
Just one more comment. This is a comment.
I believe that there was a 40 percent--in the stuff
I saw before I came out here--I think I saw 40
percent placebo effect in TADS, the TADS study.
If that is true, this is a major issue.
That is one of the reasons why we really
do need to
have placebo arm in these different studies,
because if 40 percent of this population will have
a beneficial effect due to sugar pills, to try to
tease out true effectiveness of these medications
given their severe side effects, it is very
important that we have a placebo arm even going
I know that you are not thinking of it,
but I think some of the people in the room are
wondering why we have to go with sugar pills.
DR. LAUGHREN: Let me comment on the last
point first. We clearly agree with you about
placebo, but it is not just the act of giving a
pill. In all of these trials, there is a lot that
happens that results in improvement.
DR. O'FALLON: Yes, I know that.
DR. LAUGHREN: There is a lot of
attention, the patients have a lot of interaction
with staff. That is really the placebo effect.
But the other point you are making, I
completely agree that ascertainment is ultimately
the issue. If you don't collect the information,
it doesn't make any difference how carefully you
search the database, if it wasn't collected, it's
not there, so ascertainment is key.
Again, that is one of the things that we
hope to get out of this effort with Columbia is a
better guidance document for future trials to make
sure that suicidality is properly ascertained, but
it is an evolving thing in the field. I mean there
is not at this point in time an optimal way of
doing that, so we hope to get an instrument that we
can apply for future trials.
Again, I agree with you that coding of
data needs to be standardized, and again that is
one of the things that we expect to come out of
DR. POSNER: Could I just add to that? We
are very committed to addressing the question that
you are referring to.
DR. GOODMAN: Would you bring the
DR. POSNER: I said we are very committed
to addressing this issue in terms of
adverse event monitoring, and Dr. Laughren
mentioned guidelines that we are going to write and
measures that we actually have developed that we
can implement in all trials, that will help us
collect the right data and then be able to use
these consistent definitions to classify events, so
we can make sense across all of these trials.
What is important to note is that we are
working on a National Institute of Mental Health
study called TASA, Treatment of Adolescent Suicide
Attempters, which is very focus on this issue of
adverse event monitoring, and it is wonderful
because it is helping us inform the process, so we
have developed very, very rigorous standards of how
we ask these questions, what measures we use, and
how to do it consistently, and that will help
inform the guidelines and the measures that
industry and everybody else can use.
So, we have made a lot of progress in
that, I think.
DR. GOODMAN: Dr. Temple.
DR. TEMPLE: I just want to follow up on
the last discussion. It seems to me there are two,
somewhat separate things, and I would be interested
in people's views.
One is to make the periodic routine
question better than it is. There is a suicide
item on the score, but that didn't show anything.
Maybe that will never show anything because when it
happens, it happens abruptly and you don't happen
to pick it up at the two-week period, but it does
seem as if a better questionnaire on that question,
done routinely, might be useful.
The second part of it is how to
characterize events, what questions to ask about
those, what to write down. Is that what you are
thinking, they are two somewhat different things?
DR. LAUGHREN: I agree, they are two
separate things. There is the suicide item that is
part of every one of these instruments and sort of
standardizing how that routine information is
elicited, but then when an event occurs, you have
to ensure that the appropriate questions are asked
to flesh out that situation, so that
the road who is looking at the data is able to make
sense of it.
DR. O'FALLON: But I would like to point
out that the monitoring procedures, especially for,
say, the first two weeks or something like this,
should include a real collaboration with the
children and their caregivers, their parents,
whoever they are living with, to be on the watch
for those and to report them immediately, and that
those things would be part of the data.
DR. LAUGHREN: Let me just respond to that
quickly. Basically, you are switching gears to a
clinical setting, I think, other than a clinical
DR. O'FALLON: You guys can write the
regulations for the clinical trial, right?
DR. LAUGHREN: Right, but obviously, the
points that you are making apply to clinical
practice, as well.
DR. O'FALLON: Yes, but they would apply I
would say in the clinical trial, because I think
that you are not possibly getting all
information. If you don't come in for two more
weeks, people forget that they were scared 10 days
DR. LAUGHREN: Absolutely, I agree.
DR. POSNER: I just wanted to add that we
are also working with the CDC just on this
question, what are the right one or two questions
that need to be asked in any trial or clinical
setting to get this information to be able to
classify it appropriately, which is exactly what we
are talking about, and it is not necessarily the
best questions on the measures that were used in
this trials, but that is exactly the pertinent
point in clinical setting or in research settings
with the increased monitoring that you are
DR. GOODMAN: I am going to need to wrap
up the remaining questions in the next five
DR. IRWIN: The question I wanted to ask
specifically was related to the one that
is on the
table right now. Yesterday, we heard from several
families and individuals about really homicidal
behavior and more violent behavior outwardly
directed, not internally directed.
Of concern to me is that the focus has
been so much on suicide, but what I wanted to know
is what kind of monitoring or what kind of tools
are in place to really measure that phenomenon in
these trials, because it seems to me that we don't
have any data that has been shown to us at least on
adverse experience or events with the clinical
DR. LAUGHREN: Our focus here clearly has
been on suicidality, and not on hostility and
violence. There was a lot less of that in these
trials than we had suicidality, and we have not
come to grips with that yet, but it is a whole
other area that needs to be fleshed out and
developed in the same way that suicidality has been
fleshed out because again we have included in our
database information on whether or not these
individual patients at some time during
of treatment were coded as having hostility or
agitation as a preferred term.
If you go back and look at what got
subsumed under that, I am sure it is going to be
quite different depending on different sponsors,
and it really requires a parallel development to
try and understand what that means.
Again, all the things we have been talking
about for suicidality apply to that domain, you
know, how do you ascertain for it, what kind of
questions do you ask to flesh it out, it is a real
DR. GOODMAN: By the way, the placebo
response rate from the TADS trial is 35 percent.
Looking at the paper again, I see 35 percent.
DR. O'FALLON: Okay.
DR. NEWMAN: Just to clarify, that is much
or very much improved in the TADS trial.
DR. GOODMAN: I don't think that one is
based on the CDRS, right, that is what you are
saying, it is based on the CGI?
DR. NEWMAN: The dichotomous outcome was
were they much or very much improved, so if you
said just improved, reasonably, it would have been
a lot more.
DR. GOODMAN: But that is the standard, I
mean it has to be much or very much improved to be
a responder. That is pretty much across all
Dr. Pine, please.
DR. PINE: I want to return to a point
that was raised by Dr. Goodman and just call the
committee's attention to a couple things that he
said and then also raised a couple other issue
relevant to the discussion about 10 or 15 minutes
ago with FDA.
That is the issue of both how perplexing,
but also how important it is to think very
carefully about the efficacy data and the
difference between the data for fluoxetine, on the
one hand, and all the other antidepressants, on the
other hand, and how do we understand that.
Number one, just to underline that I agree
that the importance of that point cannot
overstated. I guess there is a couple of issues
that were not discussed 10 or so minutes ago in
sufficient detail, and really two points to raise.
One is that I do appreciate from a
regulatory standpoint that it is very difficult to
specify exactly how one is to do an appropriate
study. We talked about a lot of the details that
we don't need to go over again except one thing was
not discussed, and that was a discussion of the
level of rigor that goes into both the training of
the investigators who are going to ascertain the
samples and document the diagnosis, on the one
hand, but then also follow the response of the
patients throughout the trial.
Then, I think the last thing to say about
that specific point is that when we look at the
data that have been published, and probably the
most extensive data are from the sertraline trial
as opposed to the TADS trial, with the sertraline
trial being a pharmaceutical-sponsored study that
appeared in JAMA, and the TADS trial being an
NIH-sponsored trial that was also
published in JAMA.
There are some fairly clear signs that the
manner in which investigators were trained, that
the criteria for enrolling patients for the process
of evaluating the response as it was manifest
throughout the trial was quite different in those
Again, when we come to the issue of how
important it is to compare the data for fluoxetine
and the data for the other agents, I think we need
to acknowledge that there are already signs in the
data that have been published in the reports that
have appeared in peer review, that the quality of
the studies appears to be different.
I think it is also important to note that
if we were to look at the efficacy data by industry
sponsor versus federally funded, there have been,
to the best that I can recall right off the top of
my head, two federally funded SSRI trials, both are
So, we are 2 out of 2 on that score,
whereas, if we look at all the others, we are
basically 1 out of 13 or 1 out of 14.
DR. GOODMAN: Those two are both in
fluoxetine, isn't that correct?
DR. PINE: That's true, so, you know, we
have a confound between federally sponsored and the
compound, but those are the data that we do have,
and I think given the issues that I just discussed,
you know, we are going to be very hard pressed to
say this is a funding or design feature issue,
which it might be, or that this is a medication
issue, which again it might be.
DR. GOODMAN: I want to make sure I am
clear on the source of the fluoxetine data for the