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

Monday, September 13, 2004

8:00 a.m.

Holiday Inn Bethsda

8120 Wisconsin Avenue

Bethesda, Maryland

PARTICIPANTS

PSYCHOPHARMACOLOGIC DRUGS ADVISORY

COMMITTEE MEMBERS:

Wayne K. Goodman, M.D., Chair

Jean E. Bronstein, R.N., M.S.

(Consumer Representative)

James J. McGough, M.D.

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

Lauren Marangell, M.D.

Dilip J. Mehta, M.D., Ph.D.

(Industry Representative)

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., Chair

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.

CONSULTANTS AND GUESTS (Voting):

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

Charles E. Irwin, Mr., M.D.

Laurel K. Leslie, M.D., F.A.A.P.

Steven Ebert, Pharm.D. (Consumer Representative)

James M. Perrin, M.D.

Cynthia R. Pfeffer, M.D.

Gail W. Griffith

(Patient Representative, Voting)

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.

PARTICIPANTS (Continued)

GUEST SPEAKERS AND GUESTS (Non-Voting):

Kelly Posner, Ph.D.

John March, M.D., M.P.H.

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

(Industry Representative

Barbara Stanley, Ph.D.

Madelyn Gould, Ph.D., M.P.H.

FDA PARTICIPANTS:

Robert Temple, M.D.

Russell G. Katz, M.D.

Thomas Laughren, M.D.

M. Dianne Murphy, M.D.

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

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

C O N T E N T S

Call to Order and Opening Remarks,

Wayne Goodman, M.D. 6

Introduction of Committee 9

Conflict of Interest Statement,

Anuja Patel, M.P.H. 20

Overview of Issues:

Dianne Murphy, M.D., Director, Office of

Pediatric Therapeutics,

Office of the Commissioner 25

Russell Katz, M.D., Director, Division of

Neuropharmacological Drug Products,

DNDP, CDER 34

Regulatory History and Background,

Thomas Laughren, M.D., Team Leader, DNDP, CDER 46

Recent Observational Studies of Antidepressants

and Suicidal Behavior,

Diane Wysowski, Ph.D., Division of Drug Risk

Evaluation, Office of Drug Safety, CDER 62

Brief Report on TADS Trial,

John March, M.D., M.P.H., Duke University 74

Committe Discussion on TADS Trial 93

Characteristics of Pediatric Antidepressant Trials,

Greg Dubitsky, M.D., Medical Officer,

DNDP, CDER 107

Classification of Suicidality Events,

Kelly Posner, Ph.D., Columbia University 117

OCTAP Appraisal of Columbia Classification

Methodology,

Solomon Iyasu, M.D., M.P.H., Team Leader,

Office of Counter-Terrorism and Pediatric

Drug Development 140

C O N T E N T S (Continued)

Results of the Analysis of Suicidality in Pediatric

Trials of Newer Antidepressants,

Tarek Hammad, M.D., Ph.D., M.Sc., M.S., Senior

Medical Reviewer, DNDP, CDER 152

Comparison Between Original ODS and DNDP Analyses

of Pediatric Suicidality Data Sets,

Andrew Mosholder, M.D., M.P.H., Division of

Drug Risk Evaluation, ODS, CDER 200

Citalopram and Escitalopram Product Safety Data,

Jeffrey Jonas, M.D., Forest Laboratories, Inc. 219

Sertraline Use in Pediatric Population: A

Risk/Benefit Discussion,

Steven J. Romano, M.D., Pfizer, Inc. 232

Wyeth Pharmaceuticals, Joseph S. Camardo, M.D. 247

Open Public Hearing 255

Summary by the Committee Chair 444

P R O C E E D I N G S

Call to Order and Opening Remarks

DR. GOODMAN: I wish to welcome you to

this two-day joint session of the

Psychopharmacologic Drugs Advisory Committee and

the Pediatric Advisory Committee, being held on

September 13th and 14th here, at the Holiday Inn in

Bethesda, Maryland.

I am Wayne Goodman, Professor of

Psychiatry at the University of Florida, today

wearing my hat as chair of the advisory committee.

As you settle in, please take this opportunity to

put into silent mode your cell phones and any other

devices that emit sounds in the audible range of

human beings.

Some of you may be surprised not to see

Matt Rudorfer in this seat but we arm-wrestled for

the position and he won.

[Laughter]

In all seriousness, his term has ended but

we are fortunate to see him return as a voting

consultant to the committee.

I have some official language to read to

you. All committee members and consultants have

been provided with copies of the background

materials, from both the sponsors and the FDA, and

with copies of letters from the public that we

received by the August 23rd deadline. The

background materials have been posted on the FDA

website. Copies of all these materials are

available for viewing at the FDA desk outside this

room.

We have a very large table, a full house

and important topic today so I would like to start

with a few rules of order. Please speak directly

into the mike when called on. We will be keeping

track of individuals at the table who wish to speak

and we will call upon them in order.

FDA relies on the advisory committee to

provide the best possible scientific advice

available to assist us in the discussion of complex

topics. We understand that issues raised during

the meeting may well lead to conversations over

breaks or during lunch. However, one of the

benefits of an advisory committee meeting is that

the discussions take place in an open and public

forum. To that end, we request that members of the

committee not engage in off-record conversations on

today's topic during the breaks and lunch.

Whenever there is an important topic to be

discussed there are a variety of opinions. One of

our goals today and tomorrow is for the meeting to

be conducted in a fair and open way where every

participant is listened to carefully and treated

with dignity, courtesy and respect. Anyone whose

behavior is disruptive to the meeting will be asked

to leave. We are confident that everyone here is

sensitive to these issues so understand that these

comments are as a gentle reminder.

We look forward to a productive and

interesting meeting. This is an unusual meeting in

that we have two advisory committees represented

here, Psychopharmacological Drugs Advisory

Committee, chaired by myself, and the Pediatric

Advisory Committee, chaired by Joan Chesney, to my

left. We will now go around the table and have the

committee introduce themselves, starting on my

right. Please indicate your expertise and

affiliation. We will start in that corner, over

there.

Introductions

DR. TEMPLE: Bob Temple. I am the Office

Director, ODE I.

DR. KATZ: Russ Katz, Division Director,

Division of Neuropharmacological Drug Products,

FDA.

DR. LAUGHREN: Tom Laughren, phychopharm.

team leader, in the Neuropharmacological Division.

DR. MURPHY: Dianne Murphy, Office

Director, Office of Pediatric Therapeutics.

DR. TRONTELL: Anne Trontell, Deputy

Director, Office of Drug Safety.

DR. FANT: I am Michael Fant, University

of Texas Health Science Center in Houston. My

expertise is neonatology and biochemistry.

DR. PFEFFER: Cynthia Pfeffer. I am a

child psychiatrist at Weill Medical College of

Cornell University, and I have expertise in

depression suicidal behavior in children and

adolescents.

DR. FOST: Norm Fost, University of

Wisconsin, Professor of Pediatrics, Director of the

Bioethics Program and Chair of the IRB.

DR. ORTIZ: Irene Ortiz, University of New

Mexico, Albuquerque VA. My expertise is in

depression in the elderly.

DR. MALONE: Richard Malone, Drexel

University College of Medicine, and my area is

child psychiatry.

DR. NELSON: Robert Nelson, Children's

Hospital of Philadelphia and the University of

Pennsylvania. My expertise is in pediatric

critical care medicine and ethics.

DR. PERRIN: Jim Perrin, Professor of

Pediatrics, Harvard Medical School and Head of the

Division of General Pediatrics at the Mass. General

Hospital. I have shortened my expertise as being

in general pediatrics.

DR. GRADY-WELIKY: Tana Grady-Weliky,

Associate Professor of Psychiatry at the University

of Rochester School of Medicine and Dentistry. My

expertise is in mood disorders and women across the

reproductive life cycle and medical education.

DR. EBERT: Steven Ebert, Department of

Pharmacy of Meriter Hospital and School of

Pharmacy, University of Wisconsin, Madison.

DR. GIBBONS: Robert Gibbons, Professor of

Statistics and Professor of Psychiatry and Director

of the Center for Health Statistics at the

University of Illinois, Chicago. I only do math!

DR. PINE: Danny Pine, child and

adolescent psychiatrist, National Institute of

Mental Health intramural research program. I am a

clinical child psychiatrist.

MS. BRONSTEIN: Jean Bronstein,

psychiatric nurse, Stanford University Hospital,

the consumer representative.

DR. RUDORFER: Matthew Rudorfer, National

Institute of Mental Health. My areas of expertise

are mood disorders and psychopharmacology.

MS. PATEL: Anuja Patel, Advisors and

Consultants Staff, Executive Secretary for the

Psychopharmacologic Drugs Advisory Committee.

DR. CHESNEY: Joan Chesney, the University

of Tennessee, in Memphis, and Professor of

Pediatrics, and my specialty is infectious

diseases.

DR. MCGOUGH: Jim McGough, Professor of

Psychiatry, UCLA. My area is child and adolescent

psychopharmacology.

MS. GRIFFITH: My name is Gail Griffith

and I serve as the patient rep. on this committee,

and I would just like to take this opportunity to

say why I am here. First, I am not a medical

professional; I am a consumer. I have suffered

from major depression since I was a teen. Second,

I have a son who suffers from major depression and

three years ago, at age 17, after he was diagnosed

and placed on a regimen of antidepressants he

attempted suicide by overdosing intentionally on

all his medications. He nearly died. So, I know

this illness. I know what it does to adolescents.

For the record, I would simply like to

state that I have no professional ties to any

advocacy group or any patient constituency. I also

wish to affirm that I have no ties to any

pharmaceutical company, nor do I hold any

investments in pharmaceutical manufacturers. My

sole responsibility is to ensure that the interests

of concerned parents and families are represented

at this meeting.

DR. MARANGELL: Lauren Marangell, Baylor

College of Medicine. I specialize in adult

interventions in mood disorders, both unipolar and

bipolar.

DR. ROBINSON: I am Delbert Robinson. I

am from the Albert Einstein College of Medicine, in

New York, and I specialize in psychotic disorders

and anxiety disorders.

DR. LESLIE: Laurel Leslie. I am a

behavioral developmental pediatrician at Children's

Hospital, San Diego and my area of expertise is in

children's mental health services research.

DR. IRWIN: Charles Irwin. I am a

professor of pediatrics at the University of

California, San Francisco. I am in charge of the

Division of Adolescent Medicine at the University,

which is a multi-disciplinary program that cares

for adolescents and trains large numbers of

individuals caring for teenagers, and my research

is in the area of risk-taking during adolescence.

MS. DOKKEN: I am Deborah Dokken. I

reside in the Washington, D.C. Metro area. I do

not have a specific institutional affiliation, and

I have for several years been involved in parent

and family advocacy and health care.

DR. NEWMAN: I am Thomas Newman. I am a

professor of epidemiology and biostatistics in

pediatrics at the University of California, San

Francisco, and a general pediatrician.

DR. WELLS: I am Barbara Wells. I am a

professor and Dean of the School of Pharmacy at the

University of Mississippi. My expertise is in

psychiatric pharmacotherapy.

DR. POLLOCK: I am Bruce Pollock. I am a

professor of psychiatry, pharmacology and

pharmaceutical sciences at the University of

Pittsburgh. I head the Division of Geriatric

Psychiatry at the university.

DR. O'FALLON: Judith O'Fallon, Emeritus

Professor of Biostatistics from the Mayo Clinic,

with 30 years of experience particularly in cancer

clinical trials but clinical trials methods.

DR. SANTANA: Good morning. I am Victor

Santana. I am a pediatric hematologist/oncologist

at St. Jude's Children's Research Hospital in

Memphis, Tennessee.

DR. WANG: I am Philip Wang, Harvard

Medical School. I am a psychiatrist and

epidemiologist and those are my areas of expertise.

DR. GORMAN: Richard Gorman, a practicing

pediatrician for 20 years in the Baltimore suburbs,

Chair of the American Academy's Committee on Drugs,

and representing the American Academy of Pediatrics

at this table.

DR. MALDONADO: Sam Maldonado. I work at

pediatric drug development at Johnson & Johnson. I

am one of the industry representatives to this

committee.

DR. MEHTA: Dilip Mehta, retired industry

executive and industry representative on the

Psychopharmacologic Drugs Advisory Committee.

DR. GOODMAN: Thank you, all, for being

with us these two days. Our session today is the

second of two planned advisory committee meetings,

convened to address recent concerns about reports

of suicidal ideation and behavior developing in

some children and adolescents during treatment of

depression with a selective serotonin reuptake

inhibitor, an SSRI, or other newer generation

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.

I would like to thank the many groups,

individuals and families that submitted written

statements in advance of the meeting, many of which

were quite informative as well as moving. A major

portion of today's meeting will be devoted to a

four-hour open public hearing during which dozens

of people from around, and even beyond, the country

will have the opportunity to present their own

personal or professional experiences and ideas

about the relative risks and benefits of

antidepressant medication in children and

adolescents. Although the necessary consideration

of the clock will permit only a short time at the

microphone for each speaker, I can assure you that

the committee welcomes and values input from all

viewpoints and feels it is essential to our work

that all voices be heard.

The committee's task is more difficult

than usual. Our review is not confined to whether

one agent is safe and effective based upon the

corresponding clinical trials submitted to the FDA.

We are faced, instead, with assessing efficacy and

safety for nine drugs that represent more than one

chemical class of antidepressants, all of which are

already available on the market.

Although the cornerstone of the data under

examination is derived from randomized clinical

trials submitted to the FDA this time, following a

reclassification of the adverse events, we find

ourselves turning to information from a wide

variety of sources, in particular to inform

ourselves about the drugs' possible benefits in

this population. However, once we open our minds

to consideration of data originating outside

randomized clinical trials we rest upon a slippery

slope in which variations in interpretation are

introduced according to the weighting each member

places on the merits of the source.

For me, the difficulty in assessing the

balance between benefit and risk is multiplied by

the nature of the adverse events under scrutiny.

Psychiatrists grapple, for the most part, with

illnesses that produce significant morbidity and

more rarely mortality except from suicide. Nothing

in my experience is more tragic than the loss of a

child to suicide. To think that I might prescribe

an agent that contributed to that outcome is

unbearable. Equally unbearable is to think that I

did not do enough to prevent it. This is the

essence of the dilemma before us.

We may not have all the data we would

like, especially to assess long-term benefit. We

can make recommendations about what research should

be conducted, but we will be faced at the

conclusion of business tomorrow to make

recommendations based upon what we know at this

cross-section in time. In deliberating on the

safety of antidepressant treatment in children, let

us not forget the toxicity of the underlying

disease. Major depression remains an

under-diagnosed, under-studied and under-treated

serious disorder among many thousands of our

nation's youth, leading to considerable suffering,

disability and heartbreak in many families.

I believe that all of us in this room

share the desire to alleviate the suffering from

this disorder through the successful use of

interventions that are made available to all those

who need them. Despite the daunting task before

us, I remain hopeful that with a fair and

open-minded review of the evidence this advisory

committee will constructively address the issues

and ensure that interventions for this serious

disorder meet high standards for both effectiveness

and safety.

Now I will ask Anuja Patel, executive

secretary for the advisory committee, to review

some of the ground rules for this committee and the

public hearing.

Conflict of Interest Statement

MS. PATEL: Good morning. Before I

continue, I would like to notify you of a

correction on the roster attached to the agenda.

The following consultants, Dr. Robert Gibbons, Dr.

Matthew Rudorfer, Dr. Richard Malone, Dr. Tana

Grady-Weliky and Dr. Irene Ortiz will be added to

the roster. Amended copies of the roster will be

available later this morning at the information

desk outside this ballroom.

As you know, we have a very full open

public hearing today, and in the interest of both

fairness and efficiency we are running it by some

strict rules. To make transitions between speakers

more efficient, all speakers will be using the

microphone and podium in front of the audience.

Each speaker has been given their number in the

order of presentations and when the person ahead of

you is speaking, we ask that you move to the nearby

next speaker chair. Individual presenters and

families have been allotted three minutes for their

presentations. The one consolidated presentation

has been given five minutes. We will be using a

timer and speakers who run over their time will

find that the microphone is no longer working. We

apologize for the need for the strict rules, but we

wanted to be fair and to give as many people as

possible an opportunity to participate.

The public may submit comments after this

meeting directly to the FDA's Division of Dockets

Management. Instructions for submitting electronic

and written statements are available at the

registration desk outside this room. The docket

will remain open until July 29, 2005. Thank you

for your cooperation.

I would like to read the meeting statement

into the record now. 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 interests as they may apply to the

general topics at hand. The Food and Drug

Administration has granted particular matters of

general applicability waivers under 18 USC

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 Infection Office, Room 12A-30

of the Parklawn Building.

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

Victor Santana have financial interest under 5 CFR,

Part II, Sec. 40.202 that are covered by a

regulatory waiver under 18 USC 208(b)(2).

Because general topics impact so many

entities, it is not practical to recite all

potential conflicts of interest as they may 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 committee, these

potential conflicts are mitigated.

With respect to FDA's invited industry

representatives, 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: We will now proceed with a

series of formal presentations that will bring us

to 11:45 a.m. and then a 15-minute discussion

before lunch. In the interest of time, I would

like to ask my fellow committee members to restrict

their questions after each presentation to issues

of clarification only. There will be time, 15

minutes, for some discussion between 11:45 and

12:00 and tomorrow there will be a great deal of

time for discussion and consideration of the

questions before us. So, please, if you have

questions about clarification, you can ask them

after each presentation but restrict it to those

kinds of issues.

With that, I would like to introduce Dr.

Dianne Murphy, of the FDA, who will be followed by

Dr. Russell Katz, also of the FDA.

Overview of Issues

DR. MURPHY: Good morning and welcome to

this very important discussion. Before we begin

today's important deliberations, I would ask us to

step back and see the broader context in which this

meeting is occurring. I am going to spend a few

minutes trying to describe that for you.

There are four points I hope you take from

this short presentation. One is that the majority

of medicines given to children in this country are

prescribed off-label and have not been studied in

all the pediatric populations in which they are

used.

Second, because of new legislation and

regulations since 1998, FDA has seen an increase in

products that are used in children being studied in

children.

Third, for the first 100 products,

involving over 200 studies conducted as a result of

the new legislation, FDA has found that

approximately one-fourth of the time there was a

need to change the dose, a new pediatric-specific

adverse event was described or the product was not

found to be efficacious despite the fact that it

was efficacious in adults.

Fourth, part of the reason we are here

today is because we are finally studying the

therapies that are being given to children.

Children deserve the same level of evidence that is

required for adults to determine that their use by

them is safe, effective and properly dosed. They

are a heterogeneous group who undergo rapid

metabolic, hormonal, physiologic, development and

growth changes in comparison to us, adults, who are

rather static and tend only to deteriorate.

Over the last two decades FDA has actively

supported, along with the American Academy of

Pediatrics and many other groups, the efforts to

encourage development of information and

appropriate use of therapies in the pediatric

population.

Very quickly, and this is important to

understand, again, the context in which some of

this information has been brought to you, in the

last decade we have made tremendous progress. In

1994 the agency published an approach that it hoped

would help foster and encourage development of

therapies that we be used in children. Congress

passed legislation in 1997 which is referred to as

the exclusivity or the incentive to develop studies

on products that are being used in children.

In 1998 the FDA published the Pediatric

Rule, which was an effort to say that if a sponsor

is going to develop a product in adults and that

same disease occurs in children, or condition, that

product in most circumstances and certain

conditions would be required to be studied.

We are going to go more into the 2001

adoption by FDA of Subpart D, Pediatric Ethics

Regulations, and I wanted to bring up the Best

Pharmaceuticals for Children Act, which you will

hear referred to as BPCA, because it renewed the

congressional legislation of '97 and is important

in that, again, it is the renewal of the incentive

to study products that are being used in children.

Another congressional legislative

activity, the Pediatric Research Equity Act, in

essence confirmed FDA's authority to require

studies in children in certain circumstances.

In the last decade, particularly really

since 1997, the FDA has issued over 290 written

requests to sponsors asking them to study products

in children because these products are being used

in children. We have had submitted to us over 110

products, involving over 220 studies in children,

and have now more than 76 new labels that have new

pediatric information from these studies.

The major depressive disorders were

included in the written requests that were issued,

and written requests were issued for the products

you see listed here, Prozac, Zoloft, Remeron, Paxil

Effexor, Celexa and Serzone. Those studies were

all conducted under this program or in response to

this program.

This is a list of some of the programs and

activities that are in place at FDA to help ensure

the quality and ethical conduct of studies and the

approach to pediatrics. This is really focusing

mostly on the drugs component of this. But there

is, at the Commissioner's level, an Office of

Pediatric Therapeutics. This was enacted by the

Best Pharmaceuticals for Children Act in 2002 and

first staff were hired last year. We now have in

place an ethicist whose focus is pediatric ethics.

You will hear a little bit more about the Pediatric

Advisory Committee and Subpart D referrals in a

minute. You just heard about the exclusivity

process which has been important in making sure

that trials do get conducted. I will spend a few

moments at the end talking about disclosure

requirements that are unique to pediatric studies

that are conducted under exclusivity.

This is another meeting, actually in a

long series of meetings that have occurred to

ensure the scientific and ethical quality of

activities involving studies that are being

conducted in children. Since 1999, the Pediatric

Advisory Subcommittee has had, including today's

meeting, over ten meetings that have addressed over

ten scientific issues, three ethical issues and, in

addition, starting last year, began having specific

safety reviews of products that have been approved,

again under the exclusivity provisions, so that all

adverse events that occurred in the year after

product was granted exclusivity were reviewed.

Again, this is just to inform you of the ongoing

pediatric activities that are occurring at the FDA,

some of them.

The new advisory committee, I should say

full Pediatric Advisory Committee is meeting for

the first time today. It was chartered this year

and is mandated to include patient and family

organizations, and its mandated responsibilities

include safety, labeling disputes and Subpart D

referrals and general pediatric issues.

The first Subpart D ethics panel met this

past Friday and will report to this committee on

Wednesday. I will tell you a little bit more about

that.

It is important to understand that Subpart

D, which is part of the Common Rule, was those

extra protections for children applied to only

federally funded activities until recently. In

2000, the Children's Health Act required FDA

regulated products to be in compliance with

additional protections for children that are

embodied in the Subpart D of the Common Rule.

Subpart D is fundamentally a referral

process. There is much more to it but it is a

process for IRBs when they are unsure they can

approve or under which regulation they should

approve a study involving children. The Pediatric

Ethics Subcommittee reports to the Pediatric

Advisory Committee and this is a public process.

The disclosure of the studies that are

conducted in children is distinct for studies that

are conducted in children under the exclusivity

provisions of BPCA. I mention this because it is

unusual in the FDA if a product is not approved

that those studies would be disclosed. However, we

now have, again under BPCA, a requirement that

within 180 days of submission of a pediatric study

a public summary of the medical and clinical

pharmacology reviews will be posted. There are now

41 pediatric summaries posted at this website.

Basically, you can go to the FDA page and get there

by going to the Center for Drugs or pediatric

summary\summary review.

The summaries of Effexor, Paxil, Serzone,

Celexa, Zoloft and Remeron are available on the

pediatric summary review site. As you know, and

will hear, Prozac is the only antidepressant that

is approved for use in children, and it is posted

up on FDA's site for approved applications. That

URL is provided for you here and in your handouts.

The new pediatric data has taught us that

our knowledge of pediatric therapeutics is in its

infancy; that we must study children if we are to

understand pediatric-specific adverse events and

reactions or if a product is going to work in

children. The pharmacokinetics in children has

proven to be more variable than anticipated. The

submitted studies that we are receiving are

teaching us that we need to know more about

pediatric endpoints, pediatric trial designs and

how to conduct these trials, and that we will need

to change some of our trials as we move forward.

Ethical issues require reassessment from a

pediatric perspective. Therefore, at this point no

longer shall each child be an experiment of one in

which not much knowledge is gained.

As we move forward, it will require our

careful attention if we are to discover why

children are behaving differently. If children are

to be appropriately treated, we will need to know

more than how to correct those things or describe

adverse events. We are going to need answers to

such fundamental questions as to why children react

differently, what are the metabolic, physiologic

events that are occurring that necessitate

different dosing, or why is there a therapy that

works in adults and does not work in children. Our

public policy must be more knowledge to replace our

ignorance. Thank you, and we look forward to your

discussion.

DR. MARANGELL: Dr. Murphy, a quick

question, when the FDA requests a study can you

specify methodology and assessments that you would

like to see included?

DR. MURPHY: When FDA requests a study we

do put in that written request the trial design,

the number of patients, the adverse events--you

know, under exclusivity all of that does go into

the written request.

DR. GOODMAN: Thank you, Dr. Murphy. Now

Dr. Katz?

Overview of Issues

DR. KATZ: Thank you, Dr. Goodman, and

good morning. I would like to welcome you to this

joint meeting of the Psychopharmacologic Drugs

Advisory Committee and the Pediatric Advisory

Committee.

As you know, we are here to present to you

and to ask for your guidance in interpreting the

results of our analyses of the relationship between

antidepressant drug use and suicidal behavior in

controlled trials in pediatric patients. This

meeting is in follow-up to the meeting of these two

committees held in February of this year. At that

meeting, as you recall, we presented to you and

obtained your endorsement of our plans to perform

these analyses.

At this point I would like to very briefly

recap how we arrived to this point. As you know,

we first became aware of a possible relationship

between antidepressant drug use and suicidal

behavior in pediatric patients in May of 2003 when,

in response to our request for further

clarification of their data, GlaxoSmithKline, the

manufacturer of Paxil, submitted data to us that

suggested such a link for that drug. As a result

of this submission, the agency issued a public

statement recommending that this drug not be used

in pediatric patients with depression, and

independently we asked all other manufacturers of

antidepressant drugs to resubmit the relevant data

from controlled studies with their drugs in

pediatric patients.

Based on our review of this data, we

issued a statement informing prescribers that there

was a potential relationship between all of these

drugs and suicidal behavior, and that these drugs

should be used with caution in these patients.

However, at that time we also noticed that

the data submitted to us from the various companies

was not reported to us in a form that would permit

definitive analyses. Specifically, each company

classified various behaviors as being

suicide-related adverse events in their own

idiosyncratic manner. This led to questions about

whether or not these events were, in fact,

suicide-related and, in addition, prevented

meaningful comparisons between drugs in this class.

For this reason, we decided that an

independent assessment of these possible events by

experts in suicidology would be the most

appropriate way to definitively answer the question

of whether or not any, all or none of these drugs

increased the risk of suicidal behavior in

pediatric patients. Let me just add that by

definitive analyses I mean analyses that make the

best possible use of the available data.

It was at this time that we brought the

issue before you. At that meeting we presented you

with our plans to submit blinded narrative

descriptions of possible suicide-related events to

a group of independent experts, to be coordinated

by Columbia University, whose task it would be to

classify these events as being suicide-related or

not. Although no formal vote was taken, this

committee fully endorsed this effort and agreed

that the data in hand at that time did not permit

definitive analyses to be done.

The committee also recommended, based in

part on the data in hand but also, I believe

importantly, on the basis of testimony from members

of the public who had suffered the tragedy of loved

ones who had committed suicide while taking these

drugs, that the agency should ask sponsors of these

products to warn prescribers that patients being

treated with these drugs, especially at the

beginning of treatment, should be closely watched

for the emergence of signs and symptoms that might

suggest a worsening in their clinical state.

Since that February meeting a number of

important things have happened. Based on your

advice, the agency drafted, and all of the sponsors

of these drugs have adopted, language in product

labeling warning about the possibility of

significant behavioral changes at the outset of

treatment with these drugs in both pediatric and

adult patients, and the prescribing community and

the public have been informed of these changes.

Critically, this warning made clear that

the possibility of worsening and a possible

increased risk of suicidal behavior at the outset

of treatment could not necessarily be attributed to

the drugs because the data did not permit such a

definitive conclusion. Nonetheless, it was

considered appropriate and prudent to inform

prescribers and patients and their families that

changes in behavior could occur with the onset of

treatment.

Also, the Columbia group has completed

their task of reclassifying the potential cases of

suicidal behavior and, importantly, we have

completed our reanalyses of these data. As

promised at our February meeting, we are now ready

to present to you the results of these analyses.

At this point I would just like to give

you a brief overview of the agenda for today's and

tomorrow's session. First Dr. Tom Laughren, of the

Neuropharmacology Division, will provide you with a

more detailed account of the regulatory history and

events that have brought us here this morning. He

will be followed by Dr. Diane Wysowski, of the

agency's Office of Drug Safety, who will briefly

present the results of some recently published

epidemiologic studies relevant to this question.

We have provided the committees with copies of

these published materials. Although, of course, we

consider our reanalyses of the controlled data to

be the primary source of data on which your

discussions and recommendations will be based, we

thought it important to present at least briefly

the available relevant epidemiologic data.

Next, Dr. John March, of Duke University,

will present a brief report of the Treatment for

Adolescent Depression Study, or TADS trial, a

recently completed trial that evaluated the effects

of fluoxetine in adolescents with depression. As

you know, fluoxetine is the only drug approved in

the United States for the treatment of depression

in pediatric patients and, as you will see, these

data make an important contribution to our overall

assessment of the problem before us.

Dr. Greg Dubitsky, again of the

Neuropharmacology Division, will then present an

overview of the design of the pediatric trials from

which the data for our analyses were derived. This

exploration is important because similarities and

differences in design elements among these trials

can have important implications for whether or not

these data can be examined as a whole, or whether

they must be considered separately.

Then, Dr. Kelly Posner, of Columbia

University and the primary person responsible for

coordinating the blinded reclassification effort,

will present to you the methodology her group used

to produce what we now consider to be the

definitive data on which we have based our

reanalyses.

Because the reclassification of these

clinical events was the critical activity on which

all subsequent analyses and decisions will have

been based, and because by its nature it involved

subjective assessments of the primary data, we felt

strongly that it was appropriate to ensure that the

methodology used by the Columbia group could

reliably and reproducibly yield similar results

when applied by an independent group. For this

reason, agency scientists performed such an

independent reclassification of a percentage of

these cases, utilizing the Columbia classification

schema, and Dr. Solomon Iyasu, of the agency's

pediatric group, will present the results of this

independent audit of the Columbia process.

At that point, Dr. Tarek Hammad, of the

neuropharmacology group, will then present the most

critical results of his extensive reanalyses of the

data as reclassified by the group of outside

experts. These analyses look at the data for

individual drugs, as well as across all drugs, and

will provide the data on which the committee

subsequent discussions will be based.

Finally, the last formal agency

presentation will be given by Dr. Andrew Mosholder,

of the Office of Drug Safety. Dr. Mosholder's name

is undoubtedly familiar to you. Dr. Mosholder was

the agency reviewer who had, prior to the February

advisory committee meeting, performed analyses on

the cases as submitted, that is, the

non-reclassified cases, and had concluded that

these drugs did, in fact, increase the risk of

suicide-related behaviors in this population. As

you know, Dr. Mosholder did not present his

conclusions at the February meeting, although the

data on which his analyses were based were

presented and we noted at that time that some in

the agency had already reached a definitive

conclusion on this question.

There has been since that meeting

considerable public discussion and controversy

related to the fact that Dr. Mosholder was not

given the opportunity to present his conclusions at

that meeting. The reasons for our decision at that

time were straightforward. As I have discussed

today and as we have discussed publicly on numerous

occasions, we had decided that at the time of the

February meeting the data had not been submitted in

a form in which we could reliably agree that the

events described as representing suicide-related

behavior did, in fact, represent such behavior.

We, therefore, felt that conclusions reached on the

basis of analyses that relied on these descriptions

could no, in turn, be considered completely

reliable.

We felt, and still feel, that presenting

conclusions based on potentially unreliable

analyses could have led to errors in either

direction, that is, resulted in a conclusion that

the drugs were dangerous when they really were not,

or resulted in a conclusion that the drugs were

safe when they were not. A mistake of either kind

could have, in our view, disastrous consequences.

For this reason it was, and remains, our view that

these decisions must be based on the most reliable

analyses possible. Now that the definitive

analyses have been done, however, Dr. Mosholder

will present his own analyses and conclusions, with

particular attention to a comparison between his

results and Dr. Hammad's.

Following lunch we will hear brief

comments from several of the pharmaceutical

companies who have antidepressant drug products on

the market, and the day will end with the open

public hearing. A total of 73 members of the

public have signed up to make statements. As you

have heard and as in the February meeting, we will

again need to limit the statements from the public,

this time to three minutes per individual. We

recognize that this is not much time and we

apologize for the limit but it would be impossible

for all those who wish to make statements to do so

without imposing this limitation. We appreciate

your understanding on this point and, as you have

heard, anyone who wishes may submit written

testimony to the docket.

Tomorrow the committee will discuss the

data you will have heard. We, of course, look

forward to this discussion and in particular to

your answers to the questions we have brought to

you and which we have provided in your background

packages. We are, in brief, interested in your

views on our approach to the reclassification

effort and, critically, whether you believe that

the analyses establish that one or more of the

drugs studied increases the risk of suicidality in

pediatric patients. Importantly, if you do

conclude that there is a signal for suicidality,

whether for one or more of these drugs, we need to

know what additional regulatory action, if any, you

believe should be taken.

The results of our reanalyses are complex

and their interpretation is not immediately

obvious. They raise difficult questions, not only

about the fundamental meaning of the results of the

analyses for each drug, but also about the

comparability of the various treatments and,

therefore, whether it is appropriate to consider

the drugs as a class for which any conclusion

reached should globally apply or whether the drugs

must be considered individually. Further, the

question of any further regulatory action is also a

thorny one and must take into account the

consideration of the lack of available

effectiveness data for all of the drugs, except

fluoxetine, although the absence of this

effectiveness data is not easily interpreted

either.

Because of the complex nature of the

evidence and because of the extraordinary

importance for the public health of the decisions

that we need to make, we are turning to you, the

experts, for guidance on these matters. We thank

you in advance for your efforts.

DR. GOODMAN: Thank you, Dr. Katz. I

would like to invite Dr. Tom Laughren to come to

the podium.

Regulatory History and Background

DR. LAUGHREN: Thank you, and I would also

like to welcome everyone to the meeting today. I

am going to begin by briefly giving an overview of

events leading up to today's meeting. I am then

going to talk about the key elements in the

division's exploration and analysis of the

pediatrics suicidality data. I will then spend a

little time talking about our March 22nd public

health advisory and the subsequent labeling changes

that have now been implemented. Then I am going to

spend a little time talking about the effectiveness

data. I did this at the last meeting; I will do

this again because I think it is important to have

these data in mind since they are an important part

of the context of this discussion about pediatric

suicidality. Then I am going to quickly go over

the questions and the issues for which we are going

to be seeking feedback tomorrow. I think it is

important that you have these questions in mind as

you hear the talks this morning.

This slide lists a number of the people at

FDA who have been involved in looking at these

data. As you can see, these people come from

various sections of the agency. It is a long list,

and really the point of this slide is that we take

this matter very seriously and we have invested a

lot of effort into trying to understand these data.

You heard earlier about the two laws,

FDAMA and BPCA, that give FDA authority to grant

additional market exclusivity for companies which

do pediatric studies. The point of this slide is

that most of the data that we are dealing with this

morning come from these types of studies, in other

words, studies that were done to obtain additional

marketing exclusivity. However, we have also

included in our analysis data from a ninth

antidepressant drug, Wellbutrin, that was not

studied for exclusivity. That was one study in

ADHD. We are also including in our analysis data

from the TADS trial that you will hear about in

more detail later in the morning from John March,

from Duke.

As Dr. Katz pointed out, this issue first

came to our attention based on a review of the

Paxil supplement. In that review, the reviewer

noticed that events suggestive of possible

suicidality were subsumed, along with other

behavioral events, under the preferred term

"emotional lability." This led FDA to issue a

request to the sponsor, GSK, to explain this coding

practice. Ultimately, that resulted in a report to

FDA, in May of last year, on pediatric suicidality

with Paxil. As Dr. Katz pointed out, that report

did suggest a signal of increased suicidality in

association with drug use, particularly in one of

three depression trials in that program.

What I am going to do in this slide is

very quickly run through subsequent events that led

us up to the February advisory committee meeting.

So, in June of last year we issued a public

statement cautioning about the use of Paxil in

pediatric patients with depression. In July we

issued requests to sponsors of eight other

antidepressant products to ask them to give us the

same kind of summary data that GSK had provided for

Paxil.

In September of last year we held an

internal regulatory briefing at FDA. The purpose

of this was to brief upper management about this

signal. The two points that I took away from that

meeting from the standpoint of the division's work

were, number one, there was general agreement that

it would be important to try and classify these

events since many of them were not clearly related

to suicidality and we felt it would be very

important to do a rational classification.

Secondly, there was sentiment that we ought to try

and obtain patient-level data information, beyond

the summary information, in order to try and

explain differences among trials and between

programs.

In September and October we began to get

responses to our July requests. Also, in October

we issued requests to sponsors for the

patient-level data sets that I mentioned earlier.

Also in October, we decided to go outside of FDA to

get a classification of these cases accomplished.

Then, again as Dr. Katz mentioned, in October we

issued a second public health advisory, this time

extending the cautionary language to all current

generation antidepressants. Finally, in November

and December, having looked at the responses to the

July request for summary data, it occurred to us

that we may not have obtained all of the relevant

events and so we sent additional requests to have a

broader search for events that we would then try

and get classified.

That brings us up to the February advisory

committee that we held. At that meeting you

advised us to basically continue with our analysis

of the data but, in the meantime, to go ahead and

make some labeling changes. In March of this year

we issued a public health advisory announcing the

changes that we had requested. In the meantime,

the classification of the cases was ongoing by the

Columbia group. Those were completed in June of

this year. Then, in August of this year we

completed our analysis of the pediatric suicidality

data.

In this slide what I am doing is basically

summarizing what I think is the major contribution

of the division to this effort. Again, we went to

a lot of effort to try to ensure completeness of

case findings, that we had a complete set of events

to have classified. We then worked with Columbia

University to have these events classified.

As an aside, I would like to mention that

this effort, conducted by Kelly Posner and her

group at Columbia and the very exceptional group of

outside experts that they assembled to do this,

represents a very substantial effort that has not

only helped us to understand these data but I think

will have implications for the field in terms of

developing a standard approach to classifying these

kinds of data, and also will lead to guidance

document that, hopefully, will improve

ascertainment for suicidality, which was a very

significant problem in these trials.

Finally, the third effort that we were

involved in was, again, in obtaining the

patient-level data sets that allowed us to try and

explore for confounding and effect modification, in

essence, to try to explain some of the striking

differences we were seeing in the signal across

trials within programs and across programs.

As mentioned, at the February advisory

committee you advised us to go ahead and strengthen

labeling, in particular for monitoring for

suicidality, while we were completing our analysis.

We did this and we announced the request that we

were making in a March 22nd public health advisory.

The changes in labeling that we requested

have now all been implemented for the ten drugs of

interest. I would add here that our plan is to

extend the standard language to all

antidepressants, not just the current generation

and, in fact, that has already been done for some

of these drugs. We are waiting to do it for the

others until we work out the final standard

language, which will be based on advice we get from

you at this meeting.

What I want to do in this slide is to very

quickly go over the labeling changes that have been

implemented now. This slide focuses on the advice

for clinicians who are using antidepressants for

treating any condition really, whether in adult of

pediatric patients. So, the advice is as follows,

first of all, we are asking clinicians to closely

observe patients who are being treated with

antidepressants for clinical worsening and for the

emergence of suicidality, especially at the

beginning of therapy but also at times of dose

change.

Secondly, we are asking clinicians to

consider changing the therapeutic regimen in

patients whose depression is either persistently

worse or whose emergent suicidality is severe,

abrupt in onset, or was not part of the patient's

presenting symptoms.

Finally, we are also asking clinicians to

observe for the emergence of other symptoms as

well, for example, anxiety, agitation, panic

attacks, insomnia, irritability, hostility,

impulsivity, and so forth. The idea here is that

there is a belief, not really solidly empirically

established but a belief that many of these events

may represent precursors to emerging suicidality.

So, we are also asking clinicians to be alert to

these symptoms.

This slide focuses on advice for families

and caregivers that also is included in labeling.

We are asking those folks to also be alert to the

emergence of these same symptoms and to report

those symptoms to healthcare providers if they

emerge.

Now I want to turn to briefly describing

the efficacy data for the 15 short-term trials that

we looked at in our review of these pediatric

supplements. I am going to be focusing on primary

outcomes in those trials. I also want to spend a

little time talking about the difficulty in

interpreting negative findings in this setting and

again I want to note that although I am not going

to be talking about the TADS efficacy data, you

will be hearing about the TADS efficacy data from

John March a little bit later in the morning.

This is kind of a busy slide but basically

each row in this table represents a different

trial. Again, there was a total of 15 trials.

This is color-coded so you can separate the

different programs. There were seven programs.

Paroxetine had three trials. The rest all had two

trials. The column to look at is the far column

where I have summarized the results on the primary

endpoint.

Basically I have characterized the results

as follows: Where the p value on drug versus

placebo on the primary endpoint was less than 0.05,

I am calling it positive. As you can see, that

applies to the two fluoxetine trials and one of the

citalopram trials. If the p value fell between

0.05 and 0.1 I am characterizing it as a trend.

That applies to one of the sertraline trials and

one of the nefazodone trials. If the p value was

greater than 0.1 on that primary endpoint I am

characterizing it as negative. That applies to all

the remaining trials. So, basically what you have

here is three out of 15 trials meeting FDA's

standard for being positive.

The other point I want to make on this

slide is that this represents FDA's view and I

think it is a reasonable standard, however, it is

not the only standard. To illustrate that, I want

to talk about two published papers, one for study

329, the paroxetine trial, a paper that was

published by Keller in 2001. That paper

characterized that trial as a positive study, the

argument being that although it failed on the

primary endpoint it succeeded on all the secondary

endpoints. So, the authors of that paper

considered it a positive trial and many in the

community also considered that a positive study.

Secondly, there was a paper published on

the two sertraline trials by Wagner et al., in

2003, that was based on a pooling of the two

trials. Individually those trials did not make it

but if you pooled them you got a significant p

value. Again, many in the community view that as

evidence of effectiveness of sertraline in

pediatric depression. This does not meet FDA's

standard but the point is that different folks have

different views of the same data.

Now I want to talk a little bit about the

problem of interpreting negative findings in this

setting. First I want to turn to adult depression

trials for drugs that we believe work. Llooking at

trials that on face should work, about half the

time those trials fail. If that failure rate can be

extrapolated to the pediatric population, the

expectation in two study programs and most of these

programs were two study programs--the expectation

is that three out of four times you would fail to

get two positive studies. So, perhaps it shouldn't

have come as such a surprise that many of these

programs failed. On the other hand, the fact that

the overall success rate, again according to FDA's

standard, is only 20 percent success is clearly a

concern.

Other factors to think about in looking at

negative trials in this setting is, first of all,

the history of antidepressant trials in pediatric

depression. If you go back to the tricyclic era,

there were 12 trials comparing tricyclics with

placebo in this population. All of them failed.

There are many interpretations of that. One, of

course, is that these drugs simply don't work in

that population.

Another might be that there is even

greater heterogeneity in this population of

patients captured under the diagnostic criteria for

major depression than we see in adults. That would

work against getting positive trials.

Another factor to think about is the

somewhat unusual regulatory context in which these

studies were done. Ordinarily, when companies do

studies they only benefit if they get a positive

trial. In this setting they would win in terms of

getting exclusivity whether the trial succeeded or

failed. I don't know whether or not that was a

factor in the conduct of these trials but it is

another thing to think about.

Finally, at the time that we issued

written requests for these programs we were not

routinely asking for phase 2 dose-finding studies

as we are now. That, again, maybe a factor. It is

possible that the dose was not right in some of

these trials.

In any case, the bottom line in terms of

efficacy is that I think there are plausible

reasons for failure to find efficacy other than the

obvious one that maybe the drugs don't work. On

the other hand, a very important point I believe is

that even though most of these programs have failed

to meet FDA's standard for approval, this is not

the same thing as saying that we have proof that

the drugs have no benefit. The drugs may have

benefit that has simply not yet been demonstrated.

On the other hand, the failure to demonstrate

benefit clearly is a concern, especially when we

have a risk, as we have now seen, of emerging

suicidality. So, the burden is clearly on those

who believe that these drugs do have benefit to

show that benefit. Tomorrow I am going to talk a

little bit about some possible designs for looking

at longer-term benefits with these drugs.

Now what I would like to do is quickly

move through the questions that we are going to be

asking you to discuss and comment on tomorrow.

Again, we think it is important that you have these

in mind as you hear the presentations this morning.

First of all, we are going to ask you to

comment on our approach to classifying the possible

cases of suicidality and our subsequent analyses of

the resulting data for the now 24 trials--again,

the additional trial is the TADS trial.

The question then would be do 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 that risk apply? In other

words, is this a class effect of all

antidepressants? Does it apply to certain

subclasses within this broader class or only to

specific drugs?

If you believe there is a class risk or a

risk that applies only to certain drugs, how should

this information be reflected in the labeling for

each of these products? What, if any, additional

regulatory actions do you think we need to take?

Finally, again we would like you to

consider what additional research might be needed

to further delineate the risks and the benefits of

these drugs in patients with pediatric depression?

Thank you very much.

DR. GOODMAN: Thank you, Tom. I imagine

people have questions but I want to try to catch up

this morning to make sure that we have time for all

the presentations. So, I will ask you to hold your

questions and I would like to invite the next

speaker, Dr. Diane Wysowski, who will be looking at

data from different sources other than clinical

trials.

Recent Observational Studies of Antidepressants

and Suicidal Behavior

DR. WYSOWSKI: Good morning. In this

presentation I will be reviewing recent studies of

antidepressants and suicidal behavior and briefly

discuss their methods, results and limitations.

I reviewed two types of studies,

ecological and patient-level controlled,

observational studies. Ecological studies show

increasing antidepressant use and simultaneous

decreasing suicide rates. However, such

correlations do not necessarily imply causality.

Findings of ecological studies can be merely

coincidental. Numerous factors such as changes in

risk factors, social and economic changes, more

available counseling, changes in gun access and

choice of a less lethal means of suicide in

children and adolescents may coincide with

decreases in the suicide rate in children and

adolescents.

Ecological studies don't show which factor

or factors are responsible for an observed trend.

Furthermore, an increased relative risk of suicide

with antidepressants in children and adolescents

may coexist with a decreased suicide rate. To

better examine causality, we turned to

patient-level controlled studies, such as

observational studies, in clinical trials.

For the rest of this presentation I will

be focusing on two patient-level controlled,

observational studies. The first is the Jick study

that was published this July in The Journal of the

American Medical Association. It is a matched case

control design based on patient prescriptions and

diagnoses obtained from the United Kingdom's GPRD,

the General Practice Research Database, for the

period 1993-1999. The GPRD is a database of

medical records from general practitioners of more

than three million patients in the United Kingdom.

For this study subjects were 10 through 69

years of age. Exposures studied were the most

widely used antidepressants in the U.K.,

amitriptyline, fluoxetine, paroxetine and

dothiepin. Dothiepin was chosen as the reference

category. From data on these antidepressants

users, the investigators identified 555 cases of

nonfatal suicidal behavior, defined as ideation or

attempts. They identified 17 cases of suicide.

From the base group of antidepressant users, the

investigators matched the cases with more than 2000

controls who did not develop suicidal behavior.

The researchers then compared the suicidal cases to

the non-suicidal controls for initiation of each

antidepressant.

Controlling for age, sex, calendar time

and time from first antidepressant prescription to

onset of suicidal behavior, the range of relative

risk for nonfatal suicidal behavior was 0.83 to

1.29 for the antidepressants compared to dothiepin.

None of these risks were statistically significant.

Paroxetine, with a relative risk of 1.29 and a 95

percent confidence interval of 0.97 to 1.7, had

borderline statistical significance.

Similar results were obtained for those

10-19 years old. No statistically significant

association was found between each antidepressant

and completed suicide. No statistically

significant association was found between stopping

an antidepressant and nonfatal suicidal behavior.

The relative risk for nonfatal suicidal

behavior and suicide were highest for patients

first prescribed an antidepressant within 1-9 days,

versus 90 days or more, before the suicidal

behavior of the case in the same time period for

the control. For nonfatal suicidal behavior the

relative risk for antidepressant use within 1-9

days was 4, with a 95 percent confidence interval

of 2.89 to 5.74. For suicide the relative risk for

antidepressant use within 1-9 days was 38, with a

wide confidence interval of 6.2 to 231.

Reviewing the limitations of this study,

the results are only as good as the GPRD data.

There are concerns about possible missing data,

possible incomplete ascertainment and

misclassification of patients, and possible

uncontrolled biases among the antidepressant drugs,

such as selection by severity of depression. There

were no interviews of cases and controls so

medication compliance is not systematically known.

There was no unexposed group, and the

antidepressant risks are only in reference to the

dothiepin group.

FDA asked Dr. Jick and colleagues to

reanalyze their results with amitriptyline as the

reference category. They kindly responded to our

request, and asked that their interpretation of the

results be presented verbatim to the committee. If

the committee wishes to see these supplemental

analyses I will be glad to present them in the

question and answer period.

Other limitations of the study include the

fact that suicidal ideation is a more subjective,

softer diagnosis than suicide attempts and the

risks were not examined separately. This was a

study of mostly adults and there is limited

information on children and adolescents.

Finally, the investigators excluded

patients with a history of 11 other

neuropsychiatric diagnoses, calling into question

the representativeness of the patients compared

with those in clinical practice.

Another patient-level controlled study

examined the relationship between antidepressants

and the risk of suicide attempt by adolescents with

major depressive disorder diagnoses. The study was

done by investigators at the University of Colorado

School of Pharmacy and Medicine. Robert Valuck was

the principal investigator. It was presented as a

poster at the International Society of

Pharmacoeconomics and Outcomes Research meeting,

this past May.

It is a retrospective cohort study of paid

medical claims data from the PharmMetrics

Integrated Outcomes Database of 70 managed health

plans for the period 1995 through March, 2003.

Paid claims data include health care provided in

which costs are incurred, such as for

prescriptions, doctor visits, emergency room visits

and hospitalizations.

The investigators identified about 16,000

adolescents aged 12-18 with the first major

depressive disorder diagnosis. They classified

patients into cohorts by antidepressant

prescription, those who received none over the

entire follow-up period, which was the reference

group, and those who received SSRIs, tricyclic

antidepressants or other antidepressants within 30

days of diagnosis. They followed the cohorts for

at least 6 months.

The researchers used a Cox proportional

hazards regression analysis to control for some 14

covariates and to examine the multivariate

relationship between antidepressant use and time to

suicide attempt. The majority of patients, 78

percent, had no antidepressant filled in the 6

months after diagnosis; 15 percent had SSRIs filled

within 30 days of diagnosis. And, 209, 1.3

percent, of the 16,000 patients made at least one

suicide attempt in the follow-up period.

The investigators concluded that

antidepressant treatment with any class of drugs

did not increase the risk of suicide attempt.

Antidepressant use for less than 6 months, compared

with use for 6 months or more, was associated with

a statistically significant 3-fold increased risk

of suicide attempt. Females, those who received

psychotherapy within 90 days of major depressive

diagnosis, patients with substance abuse,

schizophrenia or another mental health disorder,

patients with more chronic diseases and those in

the Midwest and West were independently at greater

risk of suicide attempt.

Dr. Valuck and co-investigators recently

expanded their study to include 24,000 eligible

patients with a new diagnosed major depressive

disorder. This expanded study is currently being

reviewed for publication. The researchers added a

propensity matching adjustment to control for

predictors of treatment and to achieve greater

balance among the antidepressant groups. The

proportion of suicide attempters, 1.4 percent, was

about the same proportion as in their smaller

study.

In this expanded study the hazards ratio

for SSRIs compared to no treatment was 1.58, not

statistically significant. The hazards ratio for

tricyclics was not estimable due to small numbers

and it was 1 for the other antidepressant category.

The hazards ratio for multiple antidepressants was

1.43, also not statistically significant. The risk

of suicide attempt declined with longer use of an

antidepressant. Compared with patients having less

than 8 weeks of use, those with equal to or greater

than 6 months of use had a statistically

significant decline in the risk of suicide attempt.

Concerning the limitations, the results

are only as good as these paid claims data. There

are concerns about possible missing data, possible

incomplete ascertainment and misclassification of

patients, and possible uncontrolled selection

biases by antidepressant group. There were no

interviews of patients so we don't have

systematically collected information on medication

compliance. There are no data on the outcomes of

the attempts. We don't know how many of the

attempters died, and there is no information on

suicides. Also, there is no information on

individual antidepressants. There were differences

in study results between the poster and the

expanded study, although this is probably due to

the larger size of the expanded study.

In conclusion, although most of the

results for the individual antidepressants or

classes of antidepressants were not statistically

significantly associated with suicidal behavior, I

do not believe that the Jick and Valuck studies

completely rule out a possible increased risk of

suicidal behavior with antidepressant use. The

studies reviewed were in agreement in showing that

the risk of suicidal events occurred statistically

significantly closer to diagnosis and onset of

antidepressant treatment. The studies did not

provide data about the characteristics of patients

who did not respond to antidepressants or whose

illness worsened with them. The studies had actual

or potential methodological limitations.

I conclude that more definitive studies,

perhaps large randomized, controlled trials of

sufficient length, are needed concerning the risk

of suicidal behavior and suicide as related to

antidepressant use in children and adolescents.

With so much at stake, children and adolescents,

their parents and physicians and society in general

deserve to know which therapies and which

individuals work best for treatment of depression.

Thank you.

DR. GOODMAN: Thank you very much, Diane.

My preference would be that you present those

additional Jick data tomorrow. I don't think we

have time for it today. Would that be an agreement

by the committee as well? So, I think we are in

accord on that, if you could prepare to present

that data tomorrow to us. There is one question,

yes, we will allow that.

DR. PINE: I am wondering if you could

clarify in the Valuck 24,000 patient study, if you

looked at the association in the less than 8-week

treatment versus no treatment group. Did that

confidence interval exclude 1? I mean, I saw that

you gave less than 8 weeks versus prolonged

treatment but I didn't see an odds ratio for less

than 8 weeks versus no treatment.

DR. WYSOWSKI: I don't think that I have

those data. I don't think that they did that

analysis. Their results are still being considered

for publication and we just got an abstract. You

saw the poster in your package. Then, when they

did the expanded analysis they only gave us an

abstract of the results. So, we don't have a lot

of detail on the expanded study.

DR. GOODMAN: Dr. Fost, you had a question

also?

DR. FOST: One of the theories of why

suicide behavior might be increased shortly after

prescribing is that the patients are at the worst

then and that is why they are started on

prescriptions. If that were true, one might expect

to see increased suicidal behavior in the week or

two before prescribing. Do either of these studies

allow for that analysis?

DR. WYSOWSKI: I believe the Jick study

did look at that. Actually, no--no, I don't see

any information on that; it is just after.

DR. FOST: And the data set doesn't allow

itself for that reanalysis?

DR. WYSOWSKI: Well, it may. I don't know

whether either investigator has information on

that.

DR. GOODMAN: I think that was an

excellent question. Now I would like to invite Dr.

John March, from Duke University, to present

results from the TADS trial.

Brief Report on TADS Trial

DR. MARCH: Thanks, it is a pleasure to be

here and I would like to begin the presentation by

thanking the committee for inviting the TADS team

to present the TADS data, and also thank the FDA

for the comprehensive and thoughtful way that it is

approaching this question of enormous public health

importance.

The TADS trial, the Treatment for

Adolescents with Depression Study, is an

NIMH-funded comparative treatment trial, and I am

going to present efficacy and safety data from the

stage-1 outcomes that were published in The Journal

of American Medical Association several weeks ago.

We have a detailed safety paper in preparation. We

have a methods paper which has been published and a

baseline paper which looks at the sample

composition in press, and those of you who are

interested in the TADS trial are referred to these

papers for further information.

As I mentioned, this is a study funded by

the NIMH, coordinated by the Department of

Psychiatry at Duke University and the Duke Clinical

Research Institute, the DCRI. It has had the

benefit of oversight and consultation from numerous

consultants, a scientific advisory board. The

NIMH, DSMB participants included 12 sites from

around the United States. Lilly provided

fluoxetine under an independent educational grant

to Duke University, had no input into the design of

the study, the conduct of the study, the analysis

of the data or the preparation of the manuscript.

My sense is that the major credit for this work, as

for all of the research on which we base

evidence-based practice, goes to the children and

families who are willing to participate in

research. Without their participation, we would

have no evidence at all.

The overall objective of the TADS trial

was to examine the effectiveness of medication and

cognitive behavioral psychotherapy alone and in

combination for the acute and long-term treatment

for adolescents with DSM-IV diagnosis of major

depression. The design of the trial was a

balanced, randomized, controlled study that was

masked by use of independent evaluators; four

groups, placebo, cognitive behavioral

psychotherapy, fluoxetine and their combination,

and the study involved 36 weeks of treatment, of

which I am going to present the stage-1 data for

the first 12 weeks of treatment. We also have a

year of naturalistic follow-up and we have recently

been funded to follow these youngsters out into

young adulthood. That data will not be discussed

today.

Now, it is important, in understanding the

generalizability of the data, to know a little bit

about the sample composition. The inclusion

criteria included outpatients, both boys and girls

age 12-17, with a DSM-IV diagnosis of major

depressive disorder and an IQ greater than or equal

to 80. Youngsters with severe conduct disorder or

substance abuse, other than nicotine, pervasive

developmental disorders, thought disorder, bipolar

disorder, or history of suicidality or homicidality

were excluded from the trial.

Because suicidality is the question at

issue today, I thought it important to say a little

bit more about these exclusion criteria, kids were

excluded if they had a hospitalization within the

previous 3 months or if they were considered to be

high risk, which meant a suicidal event of some

sort within the past 6 months, the presence of

active intent or plan, or if they had suicidal

ideation in the context of a family which was so

disorganized that we felt that even with the

intensive monitoring in the TADS trial framework

that it would not be reasonable to enter them into

a randomized, controlled research study.

This was a moderate to moderately severely

ill population. We had 439 kids, as you can see,

randomized equally into the 4 groups. The total

sample on the Children's Depression Rating Scale

had a CDRS scale score of 60. That, again, is a

mean score of moderate to moderately severely

depressed, with a range from mild to severe

depression. The T score for that mean score is 75.

That means that these kids were more than 2

standard deviations out from normal with respect to

severity of depression. The sample was multiply

comorbid, as is characteristic of patients in the

clinical samples. This was the first major

depressive episode for about 90 percent of the

sample. Ten percent of the sample had had more

than one depressive episode. The mean duration of

major depression was 42 weeks. Again, over 50

percent of the sample was comorbid for another

mental disorder, both internalizing and

externalizing disorders; 14 percent of the sample

had ADHD and half of those kids were on concurrent

psychostimulant treatment.

So, unlike the industry-funded trials, the

TADS sample is largely representative of patients

who are treated in clinical practice with major

depressive disorder. As you might expect, given

the severity of illness and the pattern of

comorbidity, these youngsters suffered significant

functional impairment. This is the children's CGAS

rating and you can see that the mean CGAS score was

between 40-50, so significant functional impairment

associated with mental illness in this patient

population.

What did we learn in the trial? This is a

take-home efficacy message. Four groups, again,

began at a CDRS raw score of 60. These are random

regression analyses looking at the adjusted or

predicted means at baseline, week 6 and week 12 of

treatment. Actually, all 4 treatments showed

significant improvement, a characteristic of major

depression. The placebo group and the cognitive

behavioral psychotherapy group were superimposed,

one on top of the other. There is no additional

benefit from receiving cognitive behavioral

psychotherapy, either in the slope term or at the

end point, over receiving placebo. There was

significant benefit from fluoxetine alone, and the

largest effect was associated with the combination

condition. The combination condition beat the CBT

condition and the placebo condition on all 4

efficacy measures. Fluoxetine beat these CBT on

all 4 measures and placebo and placebo on 3 of the

4 measures.

If we look at the impact of treatment

using effect size calculations, the mean of the

control condition minus the mean of the placebo

condition, divided by the pooled standard

deviation, the effect size for the combination was

close to 1. This is a very large effect. For

fluoxetine it was around 0.6, a moderate to large

effect. For CBT there was no difference between

CBT and placebo, effect size calculated relative to

placebo.

If we look at response rates, defined as a

clinical global importance measure rated by the

independent evaluator of much improved or very much

improved, 71 percent of the combination kids

improved; 61 percent of the fluoxetine-treated

patients improved; 43 percent of the cognitive

behavioral psychotherapy treated patients and 35

percent of the placebo-treated patients improved.

Combination statistically was no different than

fluoxetine. CBT was no different than placebo.

The two drug-containing conditions were superior to

the two non-drug-containing conditions on responder

analysis.

If we look at the effect size calculated

as a derivative of the odds ratio of improvement

for the active treatments relative to placebo for

the responder analyses, the results parallel the

analyses on a scale or outcome variable, the

Children's Depression Rating Scale. The effect

size for combination was 0.8, almost 0.6 for

fluoxetine, and about 0.2 for cognitive behavioral

psychotherapy. So, again, clear superiority for

the drug-containing conditions, with the largest

effect reserved for the combination of medication

management and CBT.

Now, of interest here are the safety

outcomes from the TADS trial. Although we spent an

enormous amount of time and energy on measuring

adverse events, particularly measuring the impact

of the treatments on the potential for harm, I

think it is important to point out that the study

did not have safety as a primary outcome. With 439

subjects randomized to 4 conditions, it is easy to

see that for these outcomes the study is clearly

under-powered.

It is I think important to separate

ideation from behavior. Despite the exclusion, we

had significant suicidal ideation in the TADS

sample. This is looking at the Reynolds Adolescent

Depression Scale, item 14, and 7.5 percent of the

sample exhibited a score of 4 or above which is the

threshold for clinical investigation on the RADS.

CDRS item 6, serious suicidal ideation, the kind of

suicidal ideation that leads you to consider

hospitalization, 2 percent of the sample met CDRS

item 13 criteria for severe suicidal ideation. On

the suicidal ideation questionnaire 2 measures, the

SIQ flag which is to prompt clinical investigation,

or elevated scores on any one of the items on the

SIQ that would also prompt suicidal ideation, 29

percent and 10 percent of the sample respectively

on these measures exhibited clinically significant

suicidality. So, although suicidality was an

exclusion criterion, there was plenty of suicidal

ideation exhibited in the TADS sample at baseline.

Now, as expected, suicidal ideation

occurred across all 4 groups taken in the

aggregate. One sees here, looking at the CDRS item

13 score, in this case greater than 1, or SIQ

score, SIQ flag greater than 31, significant

suicidal ideation at baseline. It came down at

week 6 and was significantly reduced overall at

week 12. This is the aggregated data across all 4

treatment groups.

Random regression analyses looking at

between group differences on the SIQ, although it

looks like these groups might be different at

baseline, in fact there were no statistically

significant differences on the SIQ in all 4

treatments.

One sees a different result than we found

in the pattern for depression. This is placebo;

this is fluoxetine; this is CBT and this is

combination. The take-home messages here are

three. First, as we saw in the previous slide,

suicidal ideation improves with treatment

irrespective of which treatment one gets. Second,

fluoxetine and placebo are indistinguishable with

respect to suicidal ideation, either with respect

to the slope or at entry, indicating that

fluoxetine, at least on average, is not provoking

suicidal ideation. Finally, the only treatment

which separated from placebo with respect to

reducing suicidal ideation was the combination of

fluoxetine and CBT. So, here the combination

offers a significant advantage over medication

monotherapy.

Moving on to behavior, using a

comprehensive adverse event monitoring procedure,

we looked at the incidence of three kinds of

harm-related adverse events. Harm-related events,

the broadest category, were defined as harm to

self. This could involve no suicidal ideation,

ideation or attempt. Or, harm to others which

required aggressive ideation or actual behavior

involving harming another person or physical

property. These events are subsumed one within the

next. So, a suicide-related event, which is a

subset of harm-related events, involves harm to

self, either ideation or attempt. Then we had

suicide attempts themselves. What differentiates

harm-related events from suicide-related events is

primarily one subject with aggression and 7

subjects, I believe, who exhibited self-injury

without ideation, primarily cutting.

These are the actual rates of harm-related

and suicide-related events divided by treatment

group. One sees that there is a larger number of

harm-related events and suicide-related events in

fluoxetine-treated kids relative to placebo-treated

kids. The combination group is intermediate

between harm-related and suicide-related events,

intermediate between fluoxetine and placebo. The

cognitive behavioral psychotherapy group was

roughly comparable to the placebo group.

If you look at children who received drug,

that is, combining the fluoxetine and the

combination groups and comparing them to the

placebo group, 10 percent, 22 of those

fluoxetine-treated kids exhibited a harm-related

event; 7 percent exhibited a suicide-related event;

and the rates of these events overall were quite

low, 7.5 percent of 439 kids, or 33 kids had a

harm-related event, 24 of 439 kids, or 5.5 percent

exhibited a suicide-related event.

I think it is very important as we move

through this discussion to understand that the base

rates of these events are extremely low relative to

the rates that we see for benefit.

If we look at the odds ratios calculated

from the actual rate data, the relative risk is 1.5

for combination, 2 for fluoxetine, less than 1 for

CBT. Those is calculated relative to placebo. For

the collapsed category of fluoxetine and

combination the relative risk is slightly greater

than 2. This is the only statistically significant

relative risk in which the confidence interval

crosses 1. That is largely because these events

are so rare so the power is quite low to identify

these events. In fact, the power for detecting a

20 percent difference is about 10 percent.

For suicide-related events there are no

statistically significant differences although, as

you can see from the graph, the odds ratios pretty

closely track the odds ratios for harm-related

events.

The take-home message from this

presentation actually is in this table--no, it is

in the next table. This is the table that looks at

the suicide attempts in the trial. We had 7 of

them out of 439 kids, or slightly less than 2

percent of the sample, Two fluoxetine-treated

kids, 4 combination-treated kids, 1 CBT and no

placebo-treated patients made a suicide attempt.

There probably is an imbalance in randomization

which may in part be responsible for this. There

were more kids with an elevated SIQ flag randomized

to the drug-containing than the non-drug-containing

conditions so it is not clear what to make of this

data.

Here I think is where the take-home

message lies relative to safety. This is looking

at the benefit/risk ratio using analyses for the

number needed to treat and number needed to harm.

What we see here is fluoxetine compared to placebo,

in the first column; combination compared to

placebo; and the collapsed category, SSRI versus no

SSRI. The absolute benefit increase is calculated

as the control, the experimental event rate minus

the control event rate. So, it is the absolute

benefit increase for receiving the treatment. The

absolute risk increase is calculated, again, as the

experimental event rate minus the control event

rate, that is, the risk increase attributable to

the treatment over the placebo condition in

absolute numbers.

The NNT and the NNH are the reciprocal of

the absolute benefit increase and the absolute risk

increase respectively, 1 over the absolute benefit

increase or 1 over the absolute risk increase.

These are defined as the number of patients for

benefit that would need to be treated to find one

patient who had benefit over the benefit occurring

from the control condition or, in the case of the

NNH, the number of patients who would need to be

treated to find one patient who would be harmed

over treatment with the control condition. So, it

is a nice metric that combines both the absolute

rate and the magnitude of the effect.

One sees clearly here that 27 percent of

patients benefit from treatment with fluoxetine,

with an NNT of 4 which is a large effect; 27

percent of patients benefit from treatment with

combination, with an NNT of 3, again a very large

effect; for SSRI versus no SSRI, combining the

categories, 31 percent of patients benefit, again

with an NNT of 3.

The absolute risk increase for a suicidal

event with respect to fluoxetine is 4.7 percent as

compared to placebo; 2 percent for combination over

placebo; and 3 percent for the combined category.

NNH is number of patients that you would need to

treat with the active treatment to find one patient

who would be harmed over the control condition of

21, 50 for the combination condition and 4 for the

collapsed categories.

From a clinical point of view, these

patients would be easy to pick out in a crowd,

easily identifiable who is getting better and who

is not getting better, active treatment versus

control. These effects are so small and so

uncommon that one could not possibly pick out

patients who would be harmed by the medication

versus patients who would commit these

suicide-related event behaviors with placebo

treatment. If you calculate the NNT to NNH ratio

looking at benefit to risk, one sees clearly here

that the benefit tilts in favor of the treatment,

and particularly the combination treatment.

So, we conclude that the combination of

fluoxetine and CBT is the most effective treatment

for adolescents with major depression. Fluoxetine

alone is effective but not as effective as the

combination of the two treatments. CBT alone is

less effective than fluoxetine and not

significantly more effective than placebo. We also

conclude that placebo is acceptable in randomized,

controlled trials of adolescent major depression

and, in fact, is essential for looking at the

adverse event outcomes, at least in this study.

Suicidality decreases substantially with treatment.

The improvement in suicidality is greatest with the

combination and least for fluoxetine alone.

Fluoxetine does not increase suicidal ideation.

Suicide-related adverse events which are uncommon

may occur more often in fluoxetine-treated

patients. CBT may protect against suicide-related

adverse events in fluoxetine-treated patients.

Taking both risk and benefit into account, the

combination of fluoxetine and CBT appears superior

as a short-term treatment for major depression in

adolescents.

Now, the most practical clinical trialist,

the kind of trial models that are used in other

areas of medicine--cardiology, oncology, infectious

disease for example, would much prefer a large

simple or practical clinical trial in 2000 subjects

to a meta-analysis of 10 under-powered subject

trials. So, it is our sense from looking at the

FDA data and also the TADS data that we have a

significant signal for drug treatment relative to

suicidality but the evidence is not conclusive. In

fact, a definitive study has not been done and we

would, as a field and as consumers of this

information, much benefit from a

placebo-controlled, practical clinical trial

comparing fluoxetine to another SSRI, perhaps

sertraline or citalopram. This trial could be run

easily on the child and adolescent psychiatry

trials network, which is a clinical trials network

that we are now putting in place to run these kinds

of trials in the pediatric population. Thank you.

DR. GOODMAN: Thank you, John. My first

question is will you be here tomorrow?

DR. MARCH: No.

DR. GOODMAN: Oh, you won't? That may

affect my subsequent questions because I am sure,

besides myself, there will be a number of questions

for you. I don't know if we have time to take them

all right now. I wonder if there is any other

option, Anuja. What time do you leave today, Dr.

March?

DR. MARCH: Noon.

Committee Discussion on TADS Trial

DR. GOODMAN: I am going to ask a

question. My understanding in looking at your

results is that on the categorical measures of

response fluoxetine is superior to placebo.

However, if you look at a comparison of the mean

scores on the CDRS fluoxetine is not superior to

placebo. Is that correct?

DR. MARCH: The slope term on the random

regression analysis for the CDRS, the p value was

0.08 for fluoxetine versus placebo. Fluoxetine was

statistically significantly different than CBT but

not placebo.

DR. GOODMAN: So, from a standpoint of

FDA, if this trial had been submitted to the FDA

and you didn't have the CBT group, it seems to me

that it might be classified as a negative study.

DR. MARCH: It would have been classified

as a negative study using the CDRS as the primary

endpoint, the slope term.

DR. GOODMAN: Do you have any comments

about the methodology or outcome measures we are

using and whether we are using the most appropriate

ones in your opinion?

DR. MARCH: Well, I think it is actually a

very important question. If you look at the

fluoxetine outcomes on the predicted endpoint, the

week 12 endpoint on the CDRS predicted by the CDRS

slope, on the clinical global improvement measure

dichotomized and on the Reynolds Adolescent

Depression Scale fluoxetine was statistically

better than placebo. It was simply a near miss on

the slope term, which probably relates to the way

the random regression analyses handle standard

errors. So, my sense of the story that the data is

telling us is that fluoxetine--and also if you look

at the effect size calculations--the story the data

is telling is that fluoxetine is an effective

treatment and it would be a mistake to consider

this a negative trial. On the other hand, the

technical definition used by the FDA would require

that the study be considered negative.

DR. GOODMAN: Dr. Perrin?

DR. PERRIN: On the other side of the

equation, you made comments that the sample was

somewhat different from some of the trials that

have been sponsored by industry. Could you be a

little bit more specific about what the differences

are, and how they might have affected the results,

and what are the implications for meta-analyses of

these studies?

DR. MARCH: I think it is a very important

question, and we have a paper that is in press in

The Journal of Child Medicine Psychiatry, the

"orange journal," which describes the TADS sample

in some detail and compares the TADS sample to

epidemiologic samples and to treatment samples,

both on the pharmacotherapy side, primarily the

industry data sets, and also the cognitive

behavioral psychotherapy trials, of which there are

13 published at this point. In general, our sample

is not substantially different from either the

epidemiologic or the treatment seeking samples,

with the caveat that we are slightly sicker and

slightly more comorbid, particularly relative to

the CBT samples.

So, given that the range of depression

goes from mild to severe and half the sample is

comorbid, there are plenty of patients in the data

set who resemble the mildly ill patient all the way

up to the severely ill, multiply comorbid patients.

So, I think the result of the TADS trial is

generalizable to the total sample.

With respect to meta-analyses, it would be

better to have a very large sample including all

these variations, but by combining the data sets

one gets a better picture, I believe, of the total

variation in the patient population than simply

using the industry data sets which tend to exclude

the more complicated and clinically ill patients.

DR. GOODMAN: Dr. Newman, did you have a

question?

DR. NEWMAN: Normally when you use a

continuous outcome you have greater power than when

you dichotomize. I assume that is why you

specified that as the endpoint at the beginning of

the trial. A reason why you might not is that the

medication helps maybe a majority but actually

harms a minority and then you could actually see

that if you dichotomize the percent to improve is

statistically significantly greater in the

fluoxetine group but the mean may not be

significantly greater because there are some people

who are harmed and they drag the mean down, whereas

they have no effect on the dichotomized variable.

Did you look to see whether there was evidence that

the variation in the standard deviation in the

effect size differed between the two groups and

might have been greater with fluoxetine?

DR. MARCH: That was actually the point

that I made, that the standard errors are larger in

the fluoxetine-treated group than in the combo or

the placebo--

DR. NEWMAN: Actually, not just the

standard errors but the standard deviation, meaning

that, in fact, there are some people who are harmed

by it and that diminishes the apparent benefit when

you average.

DR. MARCH: It would be impossible to look

at the standard errors or the standard deviation

and make a judgment about harm because there is a

fair amount of variability data point to data point

which is intrinsic to the disorder. Some patients

get better; some patients deteriorate.

We do have in the safety paper a whole set

of analyses looking at shifts, which I am not

confident enough in to have wanted to present

today. We will try to examine what percentage of

patients are getting worse with respect to ideation

and behavior, and how that relates to treatment

classification and also how it relates to other

adverse events like mania activation, anxiety

disinhibition and so on. I think the secondary

paper is going to shed a fair bit of light on these

questions.

DR. GOODMAN: Dr. Pfeffer?

DR. PFEFFER: I have two questions. One

is were there any differential dropout rates in the

samples? This also relates to the question of

compliance in the different treatments. My last

question is these were intent-to-treat analyses?

DR MARCH: All very good questions. The

analyses are all intent-to-treat. Although I

didn't present the data, if we look at observed

cases analyses, those who were still on their

assigned arm at any given assessment point or

completer analysis, the results are exactly the

same. About 10 percent of the kids in each

treatment overall dropped before the week-12 data

100

point. Another 10 percent were what we call

prematurely terminated. That is, for ethical

reasons. They received an out of protocol

treatment at some point during the first 12 weeks

of the study. There were no statistically

significant differences across treatment groups in

either the rate of dropping out or the rate of

receiving an ancillary treatment, that is, a

premature termination.

You will see this afternoon when FDA

presents its analysis of the TADS data that the

odds ratios for being harmed by receiving

fluoxetine are greater than we presented, or I

presented this morning on behalf of the TADS team.

That is because the FDA data set excluded those

kids who were prematurely terminated and received

another treatment. That actually represented two

kids in the placebo group and that, in turn,

inflated the odds ratios in the FDA results versus

the TADS results. So, there is some method

variance in there which accounts for the

differences between the two findings.

101

DR. GOODMAN: Dr. Gorman?

DR. GORMAN: Does analysis of your data

set allow interpretation of the time of onset of

treatment to behaviors that we are studying today?

DR. MARCH: That is a very good question

and, in fact, one that we will address in the

secondary paper. I can tell you that the majority

of the events occurred within the first 6 weeks but

not within the first 2 weeks. But I don't have

that data presented in slide form so I can show it

to you, but it will be in the safety paper that we

are currently preparing.

DR. GOODMAN: So you don't know what the

differential rates are between the groups at this

point, particularly between fluoxetine and placebo?

DR. MARCH: In terms of time?

DR. GOODMAN: Yes, in terms of the early

events.

DR. MARCH: My general impression, looking

at the data, is that the fluoxetine events occurred

early and the placebo events occurred later, which

is kind of what you would expect given what we know

102

about the compounds. But I wouldn't want to cite

chapter and verse or have you base your decisions

based on that because we haven't completed the

final analyses of the data.

DR. GOODMAN: Dr. Rudorfer, you will be

the penultimate questioner.

DR. RUDORFER: If I can go back to the

characteristics of the patients for a moment, we

will be looking at a number of studies that were

submitted to the FDA by various sponsors, and it

seems to me that the TADS inclusion criteria go

beyond DSM-IV in terms of length of illness and

degree of dysfunction in various spheres of life.

Could you comment on that?

DR. MARCH: Sure, it is a very good

question. That is, the exclusion criteria included

requirements that were designed to ensure a stable

baseline. So, we required at least six weeks of

mood disorder symptoms that crossed two or three

contexts--home, peers in school--which, of course,

are not required in the DSM-IV criteria. This was

done in part to minimize the chance of a placebo

103

response and to ensure that we had a sick patient

population that would be both ethical to randomize

and would offer some opportunity for the

combination treatment to separate from the two

monotherapy conditions.

I think we actually designed a very good

experiment, and looking at a 35 percent placebo

response rate did exactly what we had intended to

do. But in that sense, this population is sicker

perhaps than what is seen in the industry data sets

and certainly sicker than what is seen in the CBT

data sets on average.

DR. GOODMAN: I will permit two final

questions and that is it, one from Dr. Pine and

then Dr. Fant.

DR. PINE: I want to return to the first

question from Dr. Goodman as far as how this study

would be evaluated from an FDA perspective. My

sense from reading the paper is that there were two

primary outcome measures and three analyses, and

two of the three were positive so that the CGI

analysis done categorically was positive, the CDRS

104

analysis done categorically was positive, and it

was only the third analysis, the CDRS continuous

measure, that was not positive.

So, my take on that from an FDA standpoint

of, you know, do the primary outcome measures make

it or not is that it would be closer to positive

than negative. Do I have that right?

DR. MARCH: You have it partially right.

There is a CDRS slope analysis, and whether that is

positive or negative depends on whether you treat

the intercept term as random. I mean, there is a

fair amount of method variance on a subtle level

that can tilt these things one way or the other

when it is a near miss. There is a CDRS endpoint

analysis based on the predicted or marginal mean.

There is a categorical analysis, logistic

regression, and there is a self-report scale which

was included, the Reynolds Adolescent Depression

Scale, which was included because the CBT

literature relies heavily on patient self-report.

Three of those four measures, all but the CDRS

slope analysis, were positive for the

105

fluoxetine-placebo comparison. The CDRS slope

analysis, again, was a p value of 0.08, a near

miss.

So, I think the take-home message is

actually in the effect sizes, not in whether you

are looking at p values or not. Clearly,

combination and fluoxetine have larger effect

sizes, meaningful effect sizes relative to placebo

as contrasted to CBT.

DR. FANT: For the sake of the study I

know it was necessary to exclude certain patients

to optimize the conditions for the study, but I

think in real-world practice a lot of the patients

who were excluded would be patients who would be

prescribed medication under various conditions. Is

there any reason, from your standpoint or

perspective, to think that that population of

patients may be at a different risk for fulfilling

suicidal attempts, ideation, and carrying it

through to the ultimate result, or may be affected

differently by the medication than patients that

are not excluded from the study?

106

DR. MARCH: That is a very good question.

That is, is there some issue to believe that there

would be a differential treatment response in

patients who would be excluded, particularly

excluded for harm to self or others, as compared to

the TADS sample of patients? I don't know of any a

priori reason to believe that there would be a

differential treatment effect relative to the TADS

sample. I do think it is quite clear from the

treatment and epidemiologic literature that they

would be at higher risk for adverse harm-related

outcomes but whether they would be more at risk

than, say, the TADS sample patient I don't think we

know. My guess as a clinician is probably not.

We are actually doing an NIMH-funded study

called the Treatment of Adolescent Suicide

Attempter Study, in which we are comparing a

medication algorithm to cognitive behavioral

psychotherapy to the combination--no untreated

control condition obviously in this sample--to try

to understand something about treatment for this

particular patient population precisely because

107

they have been excluded from these other trials,

and we need additional data on their care. So,

that trial is now under way and should be completed

in the next couple of years.

DR. GOODMAN: Thank you very much, John.

The final question that I will take the chairman's

privilege to ask is do you have data that you

haven't presented yet on long-term outcome based on

this trial?

DR. MARCH: The final subjects in the

trial are out in a naturalistic follow-up window so

that 36-week data is in the can, but that data set

has not been cleaned and locked yet. We expect it

will be cleaned and locked and ready for analysis

in the spring, and we hope to have that data in

press by this time next year.

DR. GOODMAN: Thank you very much, John.

DR. MARCH: Thank you.

DR. GOODMAN: I would like to ask our next

speaker to come forward, Dr. Greg Dubitsky.

Characteristics of Pediatric Antidepressant Trials

DR. DUBITSKY: Good morning. You just

108

heard about the TADS trial from Dr. March. I would

like to now go on and briefly summarize the other

studies that were included in the FDA's primary

analysis of suicidality.

I do want to emphasize that my review and

this presentation are really descriptive only. I

am not going to touch on efficacy outcomes or

safety outcomes. The discussion of the risk of

suicidality in these trials with be presented later

this morning by Dr. Hammad.

The study pool, again excluding the TADS

study, consisted of 23 placebo-controlled studies

which were conducted between 1984 and 2001. Each

study was done with one of nine different

antidepressant drugs and studied patients with one

of five different diagnostic indications; major

depression, obsessive compulsive disorder,

generalized anxiety disorder, social anxiety

disorder or attention deficit disorder.

These studies all had some features in

common. They were all randomized, double-blind,

placebo-controlled. They utilized a parallel group

109

design and a flexible dosing regimen.

I did prepare a handout to go with this

talk which should be in your packets, at least for

the advisory committee members. It consists of two

tables which summarize some of the design

characteristics of these 23 studies. Table 1 has

some basic study information, to include the

diagnostic indication, the age range that was

studied, number of patients by treatment group, the

duration of double-blind treatment, and the dose

range that was used in the particular study.

I would like to point out though that I

don't intend for everybody to read this and

memorize it; this is really for reference for later

this morning when you hear about the analysis of

these trials.

The second table in the handout includes

some information on screening and exclusionary

criteria. Some of the studies used very extensive

diagnostic screening. I have indicated those in

the table. I have also indicated information on

whether there was a placebo lead-in, and also

110

whether certain exclusionary criteria were employed

in the various studies to include whether people

were excluded who had a history of treatment

resistance, current suicide risk, history of a

suicide attempt, bipolar disorder, or family

history of bipolar disorder.

My review of these studies did include a

number of other variables. I have listed in these

two tables the most relevant ones but in my review

that is on the Internet I do describe some other

characteristics which you might be interested in,

such as the location and number of sites, whether

stratified randomization by age group was utilized

and other exclusionary criteria such as homicidal

risk or the presence of psychotic symptoms.

There were a few notable differences

between these studies that I would like to point

out. One study with Prozac, HCCJ, was a very small

study. It was the smallest of the 23 studies, with

only about 40 patients and it was terminated early.

Only one of the 23 studies included an

active control arm. That was study 329 with Paxil

111

in major depressive disorder. That included an

imipramine control arm. The others only had a

placebo control.

Two of the studies did include inpatients

as well as outpatients, the Celexa study, 94404,

and Wellbutrin, 75.

Last, I did want to point out that three

of the studies did use a rather extensive

diagnostic screening of the patients, much more so

than the other studies, Prozac studies X065 and

HCJE, and Paxil study 329. Those three studies

were done in major depressive disorder.

One other difference involves the

treatment options after patients completed the

acute phase of double-blind treatment. This was

quite variable across the trials. In eight studies

there was a taper of acute treatment before

discontinuation. Seven other trials just abruptly

discontinued treatment, and there was no provision

for continued treatment. Five trials did allow for

continuation of open-label treatment, and in three

trials patients could continue double-blind

112

treatment.

However, this was also very variable

within trials. For instance, in Paxil 329

responders could continue double-blind treatment

but non-responders were tapered off treatment.

This variability in the follow-up treatment

following the acute phase made it very difficult to

do any analysis of suicidality-related events post

double-blind treatment.

I would like to point out that none of

these studies was specifically designed to assess

suicidality. Suicide attempts and ideation were

detected only through routine safety monitoring,

that is, through treatment emergent adverse events

and through suicide-related items on various

depression scales, such as the HAM-D and the CDRS.

One problem with this is that often descriptions of

possibly suicide-related events were rather vague

or incomplete and often made it difficult to reach

a classification.

I have no specific conclusions since this

is really a descriptive review and overview of the

113

studies. I think one of the important questions

that arises from this information though is whether

any of these differences in design characteristics

could contribute to any observed differences in

suicidality risk that we observed across these

studies. That is a question that will be addressed

later this morning by my colleague, Dr. Hammad.

So, that is all I have.

DR. GOODMAN: Thank you for being concise

and providing us with an outstanding handout for

our reference. We have one question. Dr.

Rudorfer?

DR. RUDORFER: Thank you. Could you

clarify, of the 23 trials how many were submitted

in response to the pediatric exclusivity rule?

DR. DUBITSKY: I don't have the exact

number. I believe most of them were but some of

them were submitted well before pediatric

exclusivity took place or came into effect. I

don't have the exact number off the top of my head.

DR. GOODMAN: Dr. O'Fallon?

DR. O'FALLON: Asking the question in a

114

somewhat different way, the data that you have for

this reanalysis, does any of that data come from

outside, beyond the data that was submitted to the

FDA? That is, were you able to go in and obtain

data from studies that were never submitted to the

FDA for approval or whatever?

DR. DUBITSKY: Well, to my knowledge,

there was one study that had not been submitted as

part of an efficacy supplement or an approval

package. The other ones, I believe, were. Dr.

Hammad actually requested data sets for all these

studies. Correct me if I am wrong, but I believe

we had relatively complete data sets to allow

reasonable analysis for all these studies.

DR. O'FALLON: But I am asking whether

there are, as some are claiming, studies that were

done but were never submitted to the FDA. Are

there any of those data here, if they exist?

DR. DUBITSKY: There are some studies that

are not included in this analysis, but those are

mainly open-label continuation studies of the acute

studies. Also, there were a number of pediatric

115

pharmacokinetic studies but I think for obvious

reasons we didn't include those in the analysis.

But, to my knowledge, I think we have everything.

DR. GOODMAN: Dr. Laughren, do you also

want to respond to the question?

DR. LAUGHREN: I think I can respond to

that. The vast majority of these programs were

submitted under pediatric exclusivity so the

companies were required to submit every scrap of

data they had as part of those supplements. The

only trial here that was not submitted as part of

an application, in terms of a company trial, was

the ADHD study for Wellbutrin. The other study

that we have included safety data for is the TADS

trial and, of course, that was also independent.

But those are the only two trials of the 24 that we

looked at that were not submitted as part of an

application.

DR. GOODMAN: Dr. Marangell?

DR. MARANGELL: How many of the studies

excluded family history of bipolar disorder?

DR. DUBITSKY: Let's see, actually I think

116

I have that in table 2. I don't know the number

off the top of my head. It looks like about ten of

the studies excluded a family history of bipolar

disorder.

DR. MARANGELL: Thank you.

DR. GOODMAN: Dr. Perrin?

DR. PERRIN: You are saying basically that

the extensive diagnostic screening occurred only in

three studies, I believe. Is that right?

DR. DUBITSKY: I am sorry?

DR. PERRIN: The extensive diagnostic

screening occurred only I think in three

studies--one of the points that you made. Does

that give us some information about the potential

diagnostic heterogeneity and also raise questions

about whether entrance into these studies of

children, ages 7-17, might not have had MDD in the

MDD studies? My last related question is, since I

am not a psychiatrist at all, what do we know about

the ability to distinguish bipolar disorder from

MDD in the 7-17 year-olds?

DR. DUBITSKY: Well, it is true that in

117

looking across all 23 studies, those three studies

did stand out as far as using more extensive

diagnostic criteria. I believe that it certainly

is possible that we might have more confidence that

those patients did actually have the diagnosis

under consideration. Whether that is actually true

or not, I don't know and I don't know any good way

of figuring that out.

I am not a child psychiatrist so I can't

answer your last question about the ability to

diagnose. I understand it is very tricky though.

DR. GOODMAN: Thank you again. I would

like to ask Dr. Kelly Posner to come up to the

podium to present. Dr. Posner is from Columbia

University and she will be talking to us about the

reclassification of the clinical trials data

according to suicidality.

Classification of Suicidality Events

DR. POSNER: I would like to start by

introducing my expert work group from Columbia that

included myself, Dr. Maria Oquendo, Dr. Barbara

Stanley and Dr. Madelyn Gould. Dr. Stanley and Dr.

118

Gould are here with me today. Our statistical

consultant was Mark Davies.

Why was reclassification needed? The

problem is that the field is challenged by a lack

of well-defined terminology and common language to

refer to suicidal behavior, and this was reflected

in the lack of standardized language used in the 25

trials in question. That is why there was

difficulty in interpreting the meaning of all of

these reported adverse events that occurred in

these trials. So, AEs that should have been called

suicidal may have been missed and there may have

been AEs that were inappropriately classified as

suicidal.

Here are some illustrative examples of the

difficulties in adverse event labeling in the

field. I want to make sure to note that these

labels have nothing to do with the labels the

sponsor gave these events, but just original

investigators at the site. Again, they are extreme

examples just to reflect the problem.

You see the first one, it says patient

119

attempted to hang himself with a rope after a

dispute with his father. Investigator did not

consider this event to be a suicide attempt but

called it a personality disorder in this 10

year-old patient.

The second one is one we have all heard a

lot about. The patient is reported to have engaged

in an episode of auto-mutilation where she slapped

herself in the face, called a suicide event. Then,

the patient took 11 tablets impulsively then went

to school--called a medication error.

So, how do we address this problem? Well,

a common set of guidelines needed to be applied and

we needed to look at the data consistently across

trials using research-supported definitions and

concepts that had reliability and validity. We

also needed to broaden the range of adverse events

that we were looking at. This was for two reasons.

The first one is to avoid bias in readings. We

wouldn't have wanted the expert raters only to have

had what the sponsors had identified as possibly

suicidal. Also, to identify suicidal events that

120

may have been missed.

So, what was included in this broadened

range of events? Of course, the events originally

identified by the sponsors as possibly suicide

related, all accidental injuries which included

accidental overdoses, and serious adverse events

which includes life-threatening events and all

hospitalizations.

Why did we need experts in suicide? Well,

you all heard about the limited information

provided in the narratives, particularly frequent

lack of stated suicidal intent. So, only experts

in suicide would have allowed for inference based

on details of behaviors and related clinical

information.

This is the list of our very distinguished

international panel of experts. I will just read

their names very quickly, Drs. Bautrais, Brent,

Brown, Van Herringen, King, Mazark, O'Carroll,

Rudd, Spirido and Miller.

So, what was the Columbia classification?

I want to move to this slide because it goes

121

through the definitions which I will just go

through briefly. Suicide attempt, of course, which

is defined as a self-injurious behavior associated

with some intent to die. Intent can be stated or

inferred by the rater. It is important to know

that no injury is needed.

Then there was preparatory actions towards

imminent suicidal behavior. So, the person takes

steps to injure himself but is stopped by self or

other, anything beyond the threshold of a

verbalization but not quite making it to a suicide

attempt.

Then we had self-injury behavior, intent

unknown. These are cases where we know there was

some self-injury but we don't know what the intent

was. So, the associated intent to die is unclear

and cannot be inferred.

Self-injurious behavior with no suicidal

intent is the next category. That is where, again,

we know there was deliberate self-harm but there

was no intent to die so behavior is intended to

affect other things. This is what we think of

122

self-mutilation typically.

Suicidal ideation was the next relevant

category, which can be passive or active thoughts,

passive thoughts of wanting to be dead or active

thoughts about killing oneself.

Then we had all the other categories.

That is essentially one rating, anything other than

deliberate self-harm or something suicidal. That

could include accidents, psychiatric events or

medical events.

Finally, we had not enough information,

which meant that there was insufficient information

for a rater to be able to say whether or not there

was some deliberate self-harm or something

suicidal.

The scheme is laid out conceptually here

for you. I think it helps make a little more sense

of it. The blue boxes refer to what you will hear

later as the FDA's primary outcome. These are

ratings that are considered definitively suicidal,

suicidal behavior and suicidal ideation. You see

codes 1, 2 and 6. Suicide attempt, preparatory

123

actions and ideation. The next are non-suicidal

events, all the other events and the self-injurious

behavior without suicidal intent, and then

indeterminants. The green boxes are what will be

referred to as the sensitivity analysis, things

that could have been suicidal but there is no way

to know.

So, what was done? The classification

methodology involved, of course, choosing the

expert panel who had expertise in adolescent

suicide and suicide assessment, based on reputation

and publications. They had no involvement in

industry youth depression trials in question, and

no expert rater was employed by Columbia

University.

We had a training teleconference to review

classification parameters, then training

reliability exercise to ensure appropriate

application of classifications. All case

narratives were blinded to any potentially biasing

information, and I will review that in a minute.

There was random distribution of 427 events to 9

124

expert raters. Each case was independently rated

by 3 raters. Each rater received approximately 125

events to rate, and any group of 3 raters shared

only 5 cases. All ratings were reviewed for

quality assurance and identification of

non-agreement cases. Consensus teleconferences

were held for any disagreement cases, and there was

double data entry for quality assurance.

Now, what was the consensus process I

referred to? If ratings did not have unanimous

agreement, then a consensus discussion was held.

Each case was discussed by the three raters

involved only. Discussion of each case was led by

an expert other than those originally assigned the

case. The goal of the discussion was to reach 100

percent agreement. If 100 percent agreement could

not be reached, the case then became indeterminate.

Sometimes the original majority opinion did not

always end up as the final consensed

classification. In other words, if there was a

minority rating, sometimes that ended up being the

final outcome.

125

Now, what was rated? Blinding of event

narratives to avoid bias included--we received the

narratives from the FDA blind to all potential drug

identifying information. This included drug name,

company sponsor name, patient identification

numbers, whether they were on an active or placebo

arm, and any and all medication names and types

because there could be associated treatments that

might bias somebody or tip them off as to what drug

was being talked about and, of course, primary

diagnosis. We also did some additional blinding of

potentially biasing information which included the

original label of the event given by the

investigator or sponsor and serious or non-serious

labels.

Rating guidelines--how was the

classification scheme applied? We wanted the

experts to apply concepts using their clinical

expertise and judgment; to use their experience to

integrate clinical information and infer when

appropriate. We wanted them to have a reasonable

certainty in order to commit to a rating, and

126

rating was based on what was probable, not what was

possible.

The guidelines for intent inference

involved inferring if something was clinically

impressive, and I am going to give you an example

of that in a moment, or using two smaller pieces of

clinical information. The clinical information

that could inform inference of intent included

clinical circumstances. That could be method used,

number of pills; past history of suicide attempt;

past history of self-injurious behavior or

self-mutilation; and family history of suicide or

suicide attempts.

Now, here is a case example of inferred

intent, what we call clinically impressive

circumstances. This is the first time you are

actually seeing one of these real narratives. In

this case clinical impressiveness actually

overruled stated intent, so you see the subject

attempted suicide by immolation. Her siblings

doused the flames immediately. She was left with

minor burns on her abdomen and on her left

127

shoulder. The subject admitted she was angry with

her parents for going away and leaving her alone at

home because she was fearful. The subject admitted

that she had acted impulsively and had not intended

to kill herself.

Here are more examples. This is another

example actually of clinically impressive

circumstances which was ultimately called a suicide

attempt. It is also important to know that we had

no idea what the sponsor ratings were but both

these cases were consistent with what the sponsor

had said as well.

This case involved a 16 year-old who

claimed to have ingested 100 tablets of study med

after a fight with her mother. The patient

informed her mother. The mother brought her to the

ER. The patient reported feeling shaky. Emergency

room physician said she was slightly tachycardic

with a pulse of 100. The tox. screen was negative

but the patient did have some illness and she

stayed in the ER until she was asymptomatic, and

then was later admitted to the psych. unit.

128

Another example of a suicide attempt, a

patient age 17 took an overdose of 20 tablets. In

the father's opinion the overdose was 5 tablets.

The patient didn't have any symptoms of an

overdose, not even nausea, but it was classified as

a suicide attempt, of course.

More overdose examples. You see in this

first example there were 113 tablets and it

exemplifies how medication types were blinded so

you see all the different numbers there. Then, the

next one is patient aged 15, impulsively slit her

wrist following an altercation with her mother.

Finally, age 17, attempted suicide by taking 8

tablets after a fight with her father, whom she

considered harsh and rejecting.

Now, these are examples of self-injurious

behavior, intent unknown. So, this is where we did

some harm but we just don't know why. A patient

aged 10 had superficial scratches, left arm,

scratched herself with scissors. That was all the

information that was there essentially.

Patient, aged 14, ingested or simulated

129

ingestion of 2-3 cigarettes. The patient was

reported as feeling tired and playing a theatrical

role. Subject, aged 9, reported he had ingested 4

of his brother's tablets on a dare. Finally,

patient, aged 10, swallowed a small amount of

after-shave lotion while angry. It is hard to know

what to make of those without information.

Examples of preparatory actions, age 16,

tried to hand herself and was prevented from doing

so by her family. The next case, age 18, a voice

commanded him to jump from the roof. Although he

went up, he did not jump. Next one, age 10, held a

kitchen knife to her neck while alone but did not

cut herself. Event was not witnessed. Finally, a

patient, age 18, was noted to be hostile, hopeless

and helpless and had written suicide notes. As I

said, anything beyond a verbalization was

considered a preparatory action, including writing

a suicide note.

These are good examples of self-injurious

behavior, no suicidal intent. In the first case

the patient stated there was increased family

130

tension. She made superficial cuts on her wrist

with an Exacto knife. The patient and mother

reported the cuts weren't deep and they looked like

cat scratches. Patient adamantly denied any

suicidal gestures or intent. She stated she only

wanted a release and that cutting and hitting her

legs offers her a release.

The second case, denied suicidal thoughts.

The first time she cut herself was age 16. She

stated she did it for attention. Today her cutting

was more spontaneous. She reported that cutting

gives her a good weird feeling.

So, what were the results? This slide

just refers to what we are talking to in our

results, or referring to, and there were 427 events

but some patients had more than one event so we

ultimately, in the reliability data, used 378

cases. We employed the same severity hierarchy

that the FDA used. So, we just took the most

severe event for cases that had multiple events.

Expert rater consensus--only two of 427

cases had no agreement among the three raters. So,

131

each rater had a different rating in only two

cases. Fifty-nine cases had agreement among two of

three raters, and those had to go to

teleconference. There were no cases in which

consensus was not able to be reached during the

teleconference and they, of course, had that

option.

Now, discordant cases between the sponsor

and Columbia classifications, there were 40 out of

the 427 cases in which the sponsor and the Columbia

classification differed. Twenty-six new cases were

identified that had not been identified by the

sponsor as possibly suicide-related. There were

two new cases of self-injurious behavior without

suicidal intent that had been labeled something

other than deliberate self-harm, and 12 cases were

originally called possibly suicidal and were

changed to something other than possibly suicidal.

Here it breaks it down for you further.

Of the 26 new possibly suicide-related events, one

was a suicide attempt; one was a preparatory act;

13 were ideation events; four were intent unknown

132

acts; and seven were not enough information to say

whether there was deliberate self-harm.

Here is an example of one of the newly

identified suicidal events. This is a preparatory

act. The patient, age 11, held a knife to his

wrist and threatened to harm himself. The patient

was hospitalized with an acute exacerbation of

major depressive disorder. The reason we have this

is because, as I mentioned before, every

hospitalization is a serious adverse event so that

is why this preparatory act was caught.

The events that were changed from suicidal

to something other included two changed to

psychiatric; one changed to an accident; and nine

changed to self-injurious behavior with no suicidal

intent. Again, our famous example, a patient

reported to have engaged in an episode of

auto-mutilation where she slapped herself in the

face. The event resolved the same day without any

intervention.

These are actually the kappa, the

agreement between the sponsor and Columbia. So,

133

Columbia's classification of possibly

suicide-related and the sponsor's classification of

possibly suicide-related, the kappa was 0.77. You

see in the 2 X 2 table that the numbers correspond

to the numbers that I just went through with you.

Now, if you want to look somewhat more

specifically or at least what we think is more

specific, we did a comparison of what Columbia said

was definitively suicidal and what the sponsor said

was possibly suicidal, and the kappa was 0.69.

Here are the reliability results of the

ratings with the nine expert raters. The median

ICC was 0.86 and what the FDA will refer to as the

primary outcome variables, you can see the numbers

here, suicide attempts is 0.81; preparatory

actions, 0.89; suicidal ideation, 0.97.

Where do we go from here? We need to

improve our adverse event reporting for

suicide-related events by developing consistent

terminology; developing guidelines for

classification of suicidality so that adequate

information is provided by the clinician;

134

utilization of research assessment tools, what

questions to ask, how to ask, and what measures aid

this; finally, hopefully, that will lead to

improved, more valid identification and

documentation of suicidality.

DR. GOODMAN: Thank you very much. Dr.

Chesney?

DR. CHESNEY: Thank you. This is a little

bit of thinking outside the box, but we heard at

the February meeting a number of examples of

homicidal behavior. I wonder if, in your

speciality, homicidal behavior is ever identified

as being self-injurious primarily to affect

circumstance or to affect an internal state.

DR. POSNER: No, that did not represent

any of those self-injurious, no suicidal intent

ratings. So, the classifications that you are

referring to, internal state and circumstance, are

not synonymous at all with the cases that had

homicidal ideation or any kind of aggressive

behavior. It doesn't mean that it couldn't be

looked at in another analysis but it wasn't

135

represented in these cases.

DR. CHESNEY: I guess my more general

question, I just wonder in the bigger question,

homicidal behavior outcome is bound to be bad and

self-injurious, and if it is just another factor

that we should consider in this whole picture.

Thank you.

DR. GOODMAN: Dr. Robinson?

DR. ROBINSON: Do you know how many of the

events led to hospitalization and how it breaks

down in terms of your classification?

DR. POSNER: Dr. Laughren, do you know?

DR. LAUGHREN: I don't have that figure

off the top of my head. There were a substantial

number of events leading to hospitalization, I

believe somewhere in the ballpark of maybe 40

percent. I don't have the exact number. It was a

common outcome.

DR. POSNER: It is important to know that

we were very narrowly just looking at obtaining the

most appropriate label for the particular event in

question, and we didn't have any of the surrounding

136

information or follow-up information in this

particular piece of the project.

DR. GOODMAN: Dr. Wang?

DR. WANG: I have a question. Do you know

how many of the sponsors originally submitted

reports that were categorized as serious? The

reason I am asking is to get a sense of how many

cases may not have been originally reported. I

know you had these serious cases sent to you for

adjudication, just to check in case there were

cases that were being missed in what the sponsors

were reporting, but did you look as to how many

cases were not considered serious by the sponsor,

jut to give us a sense of how many may be sort of

out there in the non-serious pool?

DR. POSNER: Again, we were blinded to

sponsors' classifications throughout the entire

process. I don't know if somebody from the FDA can

answer that question for you.

DR. LAUGHREN: Again just a ballpark

figure, I think it is probably somewhere in the

vicinity of maybe 65-70 percent. But you have to

137

understand that a designation of serious is a

judgment that is made by the sponsor fairly

subjectively. I mean, there are criteria for

regulatory serious. It is fatal, life-threatening,

seriously disabling, leading to inpatient

hospitalization. But even though, you know, that

on face appears to be fairly definitive, sponsors

in many cases, in my view, made the judgment that

if it was considered to be suicide-related it was,

by definition, serious.

So, if you look at many of the narratives

that were classified as serious, I think no

reasonable person looking at those would consider

that, in a common sense notion, as a serious event.

But the point is that that designation--how that

judgment was made varied from sponsor to sponsor.

So, you know, some of them classified many more of

the events as serious than other sponsors. But the

answer to the question is that overall roughly

two-thirds of these events that were included in

the analysis were designated as regulatory serious.

DR. GOODMAN: Ms. Griffith?

138

MS. GRIFFITH: I have a question about

cutting specifically. It seems to me that most of

the examples of cutting fall into self-injurious

behavior, intent unknown or self-injurious behavior

with no intent. I am just curious as to are you

confident that the reporting that you received and

reviewed actually got to whether or not there was

intent or no intent, and how subjective is the

reporting likely to be?

DR. POSNER: Again, as you can see,

cutting is a method that is used both in suicidal

behavior and self-injurious behavior without

suicidal intent. If you remember the conceptual

scheme, there was the category self-injurious

behavior, intent unknown, because cutting can be

used both ways. I forget the exact number but

there were 20-something cases in which they cut but

we don't know if it was suicidal or not. That is

why we had to come up with a category just to

categorize and deal with that issue. The FDA will

point out that the included that in the sensitivity

analysis so just in case all of those were

139

suicide-related events, they have those numbers.

DR. LAUGHREN: If the question you are

asking were the narratives lacking in detail, they

absolutely were. These were not by any sense

complete descriptions. Ideally, many more

questions would have been asked when these events

occurred to help flesh them out. That is why it

was necessary to use inference as one approach to

try and get at intent because intent was not

included for the vast majority of these.

DR. POSNER: Which is why only experts in

the field could have been able to infer from the

surrounding information. The narratives were

limited with respect to suicidal intent often but