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.