1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

JOINT MEETING OF THE

CDER PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

AND THE

FDA PEDIATRIC ADVISORY COMMITTEE

Tuesday, September 14, 2004

7:56 a.m.

Holiday Inn Bethesda

8120 Wisconsin Avenue

Bethesda, Maryland

PARTICIPANTS

Wayne Goodman, M.D., Chair

Anuja M. Patel, M.P.H., Executive Secretary

PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

MEMBERS

James J. McGough, M.D.

Jean E. Bronstein, R.N., M.S. (Consumer Rep)

Philip S. Wang, M.D. M.P.H., Dr. P.H.

Dilip J. Mehta, M.D., Ph.D., (Industry Rep)

Lauren Marangell, M.D.

Delbert G. Robinson, M.D.

Daniel S. Pine, M.D.

Barbara G. Wells, Pharm. D.

Bruce G. Pollock, M.D., Ph.D.

PEDIATRIC ADVISORY COMMITTEE MEMBERS

P. Joan Chesney, M.D.

Deborah L. Dokken, M.P.A.

Michael E. Fant, M.D., Ph.D.

Richard L. Gorman, M.D.

Robert M. Nelson, M.D., Ph.D.

Thomas B. Newman, M.D., M.P.H.

Judith R. O'Fallon, Ph.D.

Victor M. Santana, M.D.

SGE CONSULTANTS (VOTING)

Norman Fost, M.D., M.P.H.

Charles E. Irwin, Jr., M.D.

Lauren K. Leslie, M.D., FAAP

Steven Ebert, Pharm. D.

James M. Perrin, M.D.

Cynthia R. Pfeffer, M.D.

Robert D. Gibbons, Ph.D.

Tana A. Grady-Weliky, M.D.

Richard P. Malone, M.D.

Irene E. Ortiz, M.D.

Matthew V. Rudorfer, M.D.

SGE PATIENT REPRESENTATIVE (VOTING)

Gail W. Griffith

GUEST SPEAKERS (NON-VOTING)

Kelly Posner, Ph.D.

PARTICIPANTS (Continued)

GUESTS (NON-VOTING)

Samuel Maldonado, M.D., M.P.H.

FDA

Robert Temple, M.D.

Russell G. Katz, M.D.

PARTICIPANTS (Continued)

Thomas Laughren, M.D.

M. Dianne Murphy, M.D.

Anne Trontell, M.D., M.P.H.

C O N T E N T S

Call to Order and Opening Remarks:

Wayne Goodman, M.D. 5

Conflict of Interest Statement

Anuja Patel 6

Opening Comments

Thomas Laughren, M.D. 9

Committee Questions and Discussion 31

Presentation

Diane Wysowski, Ph.D. 152

Committee Discussion of Questions and Vote 163

Concluding Remarks

P. Joan Chesney, M.D. 402

Wayne Goodman, M.D. 404

P R O C E E D I N G S

Call to Order and Opening Remarks

DR. GOODMAN: Welcome to day two of this

joint two-day session of the Psychopharmacologic

Drugs Advisory Committee and the Pediatric Advisory

Committee being held on September 14, 2004, here at

the Holiday Inn in Bethesda, Maryland.

We are convened to address recent concerns

about reports of suicidal ideas and behavior

developing in some children and adolescents during

treatment of depression with selective serotonin

reuptake inhibitors and other antidepressants.

Our goal is to gather information from a

variety of sources and perspectives to help us

understand this complex situation and ultimately,

to offer the best possible recommendations to the

FDA.

Now, I would like to turn the microphone

to Anuja Patel of the FDA Center for Drug

Evaluation and Research and Executive Secretary of

this committee to read the conflict the interest

statement into the record.

Conflict of Interest Statement

MS. PATEL: Good morning. The following

announcement addresses the issue of conflict of

interest and is made a part of the record to

preclude even the appearance of such at this

meeting.

The topics to be discussed today are

issues of broad applicability. Unlike issues

before a committee in which a particular company's

product is discussed, issues of broader

applicability involve many industrial sponsors and

products.

All Special Government Employees and

invited guests have been screened for their

financial interest as they may apply to the general

topics at hand.

The Food and Drug Administration has

granted particular matter of general applicability

waivers under 18 U.S.C. 208(b)(3) to the following

Special Government Employees which permits them to

participate fully in today's discussion and vote:

Jean Bronstein, Dr. Joan Chesney, Dr. Wayne

Goodman, Dr. Lauren Marangell, Dr. James McGough,

Dr. James Perrin, Dr. Bruce Pollock. In addition,

Dr. Philip Wang has been granted a limited waiver

that permits him to participate in the committee's

discussions. He is, however, excluded from voting.

A copy of the waiver statements may be

obtained by submitting a written request to the

Agency's Freedom of Information Office, Room 12A-30

of the Parklawn Building.

In addition, Dr. Judith O'Fallon and Dr.

Victor Santana have de minimis financial interests

under 5 CFR Part 2640.202 that are covered by

regulatory waiver under 18 U.S.C. 208(b)(2).

Because general topics impact so many

entities, it is not practical to recite all

potential conflicts of interest as they apply to

each member, consultant, and guest speaker.

FDA acknowledges that there may be

potential conflicts of interest, but because of the

general nature of the discussion before the

committees, these potential conflicts are

mitigated.

With respect to FDA's invited industry

representative, we would like to disclose that Dr.

Dilip Mehta and Dr. Samuel Maldonado are

participating in this meeting as industry

representatives acting on behalf of regulated

industry. Dr. Mehta is retired from Pfizer and Dr.

Maldonado is employed by Johnson & Johnson.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firm whose product they may wish to comment

upon.

Thank you.

DR. GOODMAN: Thank you, Anuja.

We will be starting off this morning with

a presentation from Tom Laughren who will give us

an overview and also pose the questions, the five

questions to this committee.

Following his presentation, I would invite

questions. I also think it would be a good time

before we get into the meat of our discussions to

ask representatives from the FDA questions, to

further interrogate some of the data that was

presented yesterday.

Before we get into the actual discussion

of the questions, I would like us to think of the

questions that were carried over from yesterday,

pose those, and then we will take a short break,

reconvene and start the process of discussing the

questions.

Is that clear? Okay.

Tom, are you ready?

Opening Comments

Thomas Laughren, M.D.

DR. LAUGHREN: Good morning. I would also

like to welcome everyone back to the meeting today.

I would like to do a couple of things in my few

minutes here.

First of all, what I want to do is to

briefly review what I think are some of the key

findings from Dr. Hammad's presentation yesterday,

so that you have these in mind as you are

considering the questions before you.

Then, I want to talk a little bit about

what I think the data mean and talk about what some

of the regulatory options are as you are

considering our questions, and then I want to go

over the questions and the topics again.

These are the 24 trials that we are

considering. Again, 16 of them were in major

depression, and the other 8 trials were in several

various psychiatric disorders - OCD, GAD, 1 in SAD,

and 1 in ADHD.

Again, just for summary, I think these are

the three contributions that the Division made to

this effort. Again, we went to a lot of effort to

make sure that we had complete case finding. With

the help of Columbia, we accomplished what I think

is a rational classification of these events, and

we both obtained and included patient level data in

our analysis of the suicidality data again to try

and understand some of the differences both between

trials, within programs and across programs.

These are the outcomes that we looked at

again. The focus of the analysis was on two areas,

the suicidality event data and also on the suicide

item data.

For the event data, could we have the

other slide up that we had running yesterday? Our

primary endpoint, as you recall, was the

combination of suicidal behavior and ideation,

Codes 1, 2, and 6, where 1 was suicide attempt, 2

was preparatory actions, and then 6, suicidal

ideation.

So, that was our primary endpoint, but we

also looked at secondary endpoints, at suicidal

behavior, in other words, Codes 1 and 2, and then

suicidal ideation, Code 6, and then for our

sensitivity analysis, we looked at this larger

outcome including 1, 2, and 6, but also adding in 3

and 10, where again, 3 is self-injurious behavior

where the intent is not known, and 10 is not enough

information. Again, these are the cases where

there is injury, but it is not possible to tell

whether it's self-injury or other injury.

With regard to the suicide item data, we

looked at two measures about worsening suicidality

on that item or emergence, and these again are the

cases where the patients are normal at baseline and

have some increase during the trial.

In terms of our analytical plan, the major

focus was on doing risk ratio analyses, both for

the suicidality event data and for the item data.

In both cases, we looked at individual trials, as

well as for the event data, we looked at various

pools.

We looked at both by drug, we combined all

the SSRIs, MDD trials as a group, we looked at all

of the other indications combined as a group and

also did one pooling which included all 24 trials.

For the item data, we looked again at individual

trials and then a pooled analysis over all trials.

Dr. Hammad put a lot of effort into again

trying to explain the differences that we were

seeing between trials within programs and across

programs, and I just want to spend a couple of

minutes talking about exactly what he did.

He looked for confounding within trials

using both the univariate approach and a

multivariate approach. There were a total of 17

covariates that he looked at. He was not able to

find any evidence for important confounding in that

search.

He also did stratified analysis to explore

for effect modification. The three variables that

he looked at were age, gender, and history of

suicide attempt or ideation, so basically, what he

did in each of these is to stratify on these

variables within trials to look to see if there was

basically an interaction.

Again, he did not find any evidence for

that, so basically, what that means is that on

these variables, you find the signal both in

children and adolescents, you find it both in males

and females, and you find it both in those with and

without history of suicide attempt or ideation.

Finally, he looked at 12 trial level

covariates, again, as an attempt to try and explain

the differences across trials using a

meta-regression approach. Again, that approach was

not able to explain the variability.

Now, I would say that one of the problems

in doing these kinds of explorations is that there

is very limited power, you have a very small number

of events. When you use an eyeball approach to the

data, you can't help but thinking that trial

differences might have made a difference.

I just use the TADS, the fluoxetine

situation as an example. The company had three

trials. There was no signal coming from those

three trials. If you look at the careful screening

that was done to obtain the patients for those

samples, and the exclusions of patients with prior

histories of treatment resistance, and so forth,

and then you look at the TADS sample, which is many

ways was probably more representative of the

community of patients who actually get treated,

there is quite a difference. Again, as you recall,

in the TADS trial, you see quite a striking signal

for suicidality.

So, even though quantitatively, 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

difference.

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,

and 6.

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 is a

statistically significant finding. So, this is the

pooled data.

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

suicidal ideation.

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 from if

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

from ideation.

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

ideation.

For Effexor, there is a signal coming from

both, but it is clearly coming more from ideation.

Here, the confidence interval is almost

significant.

For Remeron, it is all coming from

ideation, and from Zoloft, there is nothing

happening for behavior, it is all coming from

ideation.

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

coming from.

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

drug.

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

significant finding.

The signal appears to be coming mostly

from major depression, although perhaps not

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

trial.

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, that 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

percent.

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 who are

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, and I

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

event.

Now, that language as it currently is

written suggests that causality has not been

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

language.

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

packaging.

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 topics.

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

specific drugs?

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 in

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

outcome.

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 with that.

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 distinguishing

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 setting

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

difficult environment.

I hope that as we discuss these issues and

make a decision, that we not make it impossible for

them to practice medicine.

Thank you.

DR. GOODMAN: Thank you, Tom, for a cogent

and clear presentation.

I would like to ask committee members if

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

in children?

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 is getting

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

those.

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

question.

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 suicides

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

question.

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

regulatory action?

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 what would

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

long-term data.

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

talked about.

So, there is a mechanism to require

studies.

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 monitoring

system that might give us a better handle on how

many of these events are actually happening in

regular treatment?

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

to talk.

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 patients, we

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

at all-use.

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

reporting.

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

effective.

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 effective drugs

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

discussion.

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

effectiveness.

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

trials.

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.

Thank you.

DR. GOODMAN: Thanks for that statements,

Dianne. I just want to make sure I understand it

completely.

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 that

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

drugs.

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 respond?

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 adults, and

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

available?

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

not.

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, for the

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

that.

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 antidepressants

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,

as well?

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

about that?

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 whatever

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 be

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, that are

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

the treatment.

In the randomized withdrawal setting, the

success rate for drugs that are known to work is

nearly 100 percent. Very few of those trials ever

fail.

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

new drugs.

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 studies. They

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 inform

adequate trial design in this population, in this

setting.

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, but these

were some of the very earliest ones that were

issued.

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

relationship.

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 question for

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

getting to.

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, black boxes,

revised label warning, but is this a potential

option?

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

that training.

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

about it.

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 what some

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

interventions.

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

consider that.

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

are allowed.

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 condition of

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

used.

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 persuade

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 asthma study

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

occurred.

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 have,

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 to be

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

now.

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

been established.

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