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

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

exclusivity.

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 said, we

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

get it.

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 don't get

it.

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.

DR. RUDORFER: Yes, thank you.

I would just like to revisit a couple of

issues that concern me at the front end of these

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

were ascertained.

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

ascertainment.

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

specific.

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. 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 the

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 optimal here.

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

suicidality.

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

effort.

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

study failed.

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 see

whether drugs work in children, and not putting

anything in seems funny, so we are reconsidering

that.

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

considerations.

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 active

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

talking about.

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 that many

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

obvious.

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 good

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

time sensitive.

What I mean by that is you only get

exclusivity if your study reports, your supplements

containing the data come in while you still have

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

exclusivity.

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, they didn't

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

possibility.

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

trials?

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

investigators.

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 into

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

have done.

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 exclusivity is

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

effective.

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 are looking

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 depression, who

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

inclusion.

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

adults.

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

of all.

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 adverse

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, and

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.

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 the

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

ask.

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 ago.

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,

though.

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 criteria

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

are withdrawn.

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.

We 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

exclusivity.

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 to, to

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 studied in

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adults.

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

being reconsidered.

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

exclusivity.

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 where it

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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 specific and

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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

this country.

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 cannot

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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

understanding.

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Can the FDA comment on any successful

programs that they can point where this has truly

worked?

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

105

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

atrial fibrillation.

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

the situation.

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 recent

106

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

other programs.

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

don't happen.

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 thalidomide

107

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 regard to

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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

of that.

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

tangible?

109

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

changed recently.

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, which as

110

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 to know

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for parents.

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 disruptive

112

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

serious worry.

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

conversation.

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. Santana said,

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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 microphone.

114

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

country.

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 percent

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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

the direction?

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

change.

I will take again other questions out of

order as long as they are directed to a

representative from ODS.

Dr. Marangell.

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

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treated.

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

drugs?

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.

117

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

percent still.

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,

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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 driving

119

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 reflect the

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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

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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 psychiatrists

122

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

prescriptions.

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 very much

123

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 your question?

124

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 specified a

125

very clear research strategy for looking for

adverse events that might be related to

suicidality.

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

suicidality.

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 that, it

126

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 dictionaries

127

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

been captured.

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

comment?

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 represents

128

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

whatever reason.

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

129

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

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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

forward.

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,

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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

this.

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

microphone closer.

DR. POSNER: I said we are very committed

to addressing this issue in terms of suicidality

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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

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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 someone down

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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

trial.

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 your

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information. If you don't come in for two more

weeks, people forget that they were scared 10 days

ago.

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

referring to.

DR. GOODMAN: I am going to need to wrap

up the remaining questions in the next five

minutes.

Dr. Irwin.

DR. IRWIN: The question I wanted to ask

specifically was related to the one that is on the

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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

trials.

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 the course

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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

problem.

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

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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

clinical trials.

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 be

139

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.

140

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

two studies.

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

positive.

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.

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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