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,