**WRITTEN TESTIMONY**

**OF**

**PFIZER INC**

**Submitted to the**

**House Committee on Energy and Commerce**

**Subcommittee on Oversight and Investigations**

**Regarding**

**Zoloft Studies in the Pediatric Population**

**Cathryn M. Clary M.D.**

**Vice President, U.S. Medical**

**Neuroscience and Customer and Market Development**

**Pfizer Global Pharmaceuticals**

**Pfizer Inc**

**235 E 42nd Street**

**New York NY 10017**

**Summary of the Major Points of the Written Testimony of Pfizer Inc**

**Depression among children and teenagers is a serious medical condition
with significant public health implications.**

-   Suicidal thinking and behavior often accompany major depression,
    particularly in the young, who are ill equipped to manage the
    illness.

```{=html}
<!-- -->
```
-   Suicide is the third leading cause of death among children and
    teenagers ages 10-19, and when it occurs, it is often due to
    untreated depression.

**Pfizer has conducted a clinical program with Zoloft in the pediatric
population.**

-   In 1997, FDA approved Zoloft for the treatment of
    Obsessive-Compulsive Disorder in the pediatric population. Although
    Zoloft was not approved for the treatment of major depression in
    this population, Pfizer's studies yielded important information that
    was added to the Zoloft label.

-   There were no patients who committed suicide in the Zoloft pediatric
    studies.

-   The number of suicide-related events in the Zoloft pediatric studies
    is small, and, because none of these numbers are statistically
    significant, no conclusion can be drawn that treatment with Zoloft
    in these studies is associated with an increased risk of suicidal
    behaviors.

**Pfizer has disclosed the results of the Zoloft pediatric studies.**

-   Seven of the nine completed Zoloft pediatric studies have been
    published in peer reviewed journals and one has been submitted to a
    peer-reviewed journal for publication. A manuscript is currently
    being completed for the ninth study that also will be submitted to a
    peer review journal. Prior to publication, the results of these
    studies have been presented in posters and abstracts at scientific
    meetings. Pfizer has also shared information about the Zoloft
    pediatric program with doctors and the public in the form of
    "Medical Information" letters.

-   The Zoloft pediatric studies have led to a series of important
    changes in the Zoloft label, informing doctors about the valuable
    information learned from those studies.

-   Pfizer is committed to communicating the results of all Phase 3 and
    4 controlled clinical trials of marketed products, regardless of
    outcome. Pfizer is participating in a PhRMA initiative to develop a
    clinical trial results database to contain summaries of studies that
    fall within the scope of the PhRMA Principles on the Conduct of
    Clinical Studies and the Communication of Clinical Study Results.

**Table of Contents**

Summary of the Written Testimony i

A Introduction [1](#introduction)

A.1 The History of Zoloft Approvals in the United States
[1](#the-history-of-zoloft-approvals-in-the-united-states)

A.2 Prevalence, Symptoms and Impact of Major Depressive Disorder in the
Pediatric Population
[3](#prevalence-symptoms-and-impact-of-major-depressive-disorder-in-the-pediatric-population)

A.3 Treatment Options for Major Depressive Disorder in the Pediatric
Population
[6](#treatment-options-for-major-depressive-disorder-in-the-pediatric-population)

B Pfizer's Zoloft Pediatric Program
[9](#pfizers-zoloft-pediatric-program)

B.1 Introduction [9](#introduction-1)

B.2 Studies Conducted by Pfizer [10](#studies-conducted-by-pfizer)

B.3 Design and Conduct of the Zoloft Pediatric Depression Program
[12](#design-and-conduct-of-the-zoloft-pediatric-depression-program)

B.3.1 Study Design Issues [12](#study-design-issues)

B.3.2 Results [15](#results)

C Pfizer's Disclosure of the Zoloft Pediatric Studies
[20](#pfizers-disclosure-of-the-zoloft-pediatric-studies)

C.1 Pfizer's Publication of Zoloft Pediatric Data at Scientific Meetings
and in Peer-Reviewed Journals
[21](#pfizers-publication-of-zoloft-pediatric-data-at-scientific-meetings-and-in-peer-reviewed-journals)

C.2 Dissemination of Information by Medical Information Letters
[24](#dissemination-of-information-by-medical-information-letters)

C.3 Changes to Zoloft Labeling [25](#changes-to-zoloft-labeling)

D Conclusions [28](#conclusions)

Table 1. Summary of Pediatric Studies Conducted with Zoloft
[10](#__RefHeading___Toc81788011)

Table 2. Efficacy Outcome for Primary Endpoint in Zoloft Pediatric MDD
Studies [15](#__RefHeading___Toc81788012)

Table 3. Incidence of suicide attempts in placebo-controlled studies of
Zoloft in children and adolescents [19](#__RefHeading___Toc81788013)

Table 4. Incidence of suicidal ideation in placebo-controlled studies of
Zoloft in children and adolescents [19](#__RefHeading___Toc81788014)

Table 5. Incidence of suicide attempts and suicidal ideation in
placebo-controlled studies of Zoloft in children and adolescents
[19](#__RefHeading___Toc81788015)

Table 6. Zoloft Pediatric Studies: Selected Abstracts, Posters, and
Publications [22](#__RefHeading___Toc81788016)

# Introduction

This written testimony is submitted in support of the oral testimony to
be provided by Cathryn M. Clary, M.D., Vice President, U.S. Medical,
Neuroscience and Customer and Market Development, Pfizer Inc, before the
United States House of Representatives, Committee on Energy and
Commerce, Subcommittee on Oversight and Investigations, Hearing on
Publication and Disclosure Issues in Antidepressant Pediatric Clinical
Trials on September 9, 2004. This document summarizes the completed
clinical trials that Pfizer has conducted in the pediatric population
with Pfizer's selective serotonin reuptake inhibitor (SSRI) medicine,
Zoloft® (sertraline HCl), with particular emphasis on Pfizer's public
disclosure of these studies in publications and presentations at
scientific meetings, medical information letters, and the addition of
information to the Zoloft label (package insert)[^1].

## The History of Zoloft Approvals in the United States

The clinical development program for Zoloft began in the early 1980s,
and Pfizer received its first approval for Zoloft from the U.S. Food and
Drug Administration (FDA) in 1991 for the treatment of Major Depressive
Disorder (MDD) in the adult population. Since 1991, Pfizer has received
five additional approvals for Zoloft for the treatment of other mood and
anxiety disorders, which are chronic and often debilitating psychiatric
illnesses.

For each of the approved indications in adults---Major Depressive
Disorder (MDD), Obsessive-Compulsive Disorder (OCD), Panic Disorder,
Posttraumatic Stress Disorder (PTSD), Premenstrual Dysphoric Disorder
(PMDD), and Social Anxiety Disorder (SAD)---Pfizer submitted to the FDA
two or more double-blind studies in patients with the indicated illness
that demonstrated that Zoloft was more effective than placebo. Because
Zoloft had been approved for adult OCD, only a single positive
placebo-controlled trial was required by and submitted to FDA for the
pediatric OCD labeling. OCD is the only approved use for Zoloft in the
pediatric population.

The following diagram illustrates the chronology of adult approvals for
Zoloft, as well as the addition of pediatric information to the Zoloft
label.

![](media/image1.wmf){width="5.992361111111111in"
height="3.654166666666667in"}

## Prevalence, Symptoms and Impact of Major Depressive Disorder in the Pediatric Population

Major depressive disorder is a significant public health issue for
American children and teenagers. The annual prevalence of depression is
estimated to be 2--3% in children aged 8--12 years and 4--8% in those
aged 11 ½ to 18 years[^2], as compared with a rate of 6.6% in adults
aged 18 and older[^3]. It is estimated that one in five adolescents has
had an episode of MDD by the age of 18Error: Reference source not found.
Studies have demonstrated that each successive generation since 1940 is
at higher risk for MDD and that the disorder is being experienced
earlier in life than it had been previouslyError: Reference source not
found~.~

The Diagnostic and Statistical Manual of Mental Disorders version IV
with revisions (DSM)[^4] is used to diagnose depression. As the Manual
states, "Major Depressive Disorder may begin at any age." The diagnostic
criteria for a Major Depressive Episode are five or more of the
following symptoms during the same two-week period:

> -- Depressed or irritable mood
>
> -- Lack of interest or pleasure in activities
>
> -- Sleep disturbance
>
> -- Appetite/weight changes
>
> -- Concentration and attention difficulties
>
> -- Fatigue or loss of energy
>
> -- Psychomotor agitation or retardation
>
> -- Cognitive changes: worthlessness, excessive guilt, hopelessness
>
> -- Recurrent thoughts of death, suicidal ideation without a specific
> plan, or a suicide attempt or a specific plan for committing suicide

The criteria used to diagnose children and adolescents are similar to
those used to diagnose adults, with the exceptions that DSM notes that
children and adolescents may exhibit an irritable mood, rather than a
depressed mood, and that a child's failure to make expected weight gains
should be considered. In all age groups, suicidal thinking or behavior
is one of the diagnostic criteria.

Depression in children is a devastating disease. Children and teenagers
who suffer from MDD frequently experience thoughts of guilt, shame, and
self-criticism that may leave them feeling worthless, helpless, and
hopeless. As described in the Surgeon General's Report on Mental
Health[^5]: "Depressed children are sad, they lose interest in
activities that used to please them, and they criticize themselves and
feel that others criticize them. They feel unloved, pessimistic, or even
hopeless about the future; they think that life is not worth living, and
thoughts of suicide may be present. . . .. Associated anxiety symptoms,
such as fears of separation or reluctance to meet people, and somatic
symptoms, such as general aches and pains, stomachaches, and headaches,
are more common in depressed children and adolescents than in adults
with depression." Children with MDD frequently experience functional
impairment such as a drop in school performance, family
tension/problems, and conflicts with friends. They are also at risk for
other psychiatric disorders, substance abuse, anxiety disorders, and
disruptive behavior disordersError: Reference source not found. In
addition, follow-up studies have found that 20% to 40% of teenagers with
MDD will go on to develop bipolar I disorder (a disorder which is
characterized by episodes of depression alternating with another
clinical state called mania) within a period of 5 years after the onset
of depression[^6].

Exacerbating the distressing nature of MDD is the risk of suicidal
behavior that often accompanies the disease, particularly in the young,
who are ill equipped to manage the illness. Suicide is the third leading
cause of death among young people aged 10‑19 years and the incidence of
suicide attempts peaks during the mid-adolescent years[^7]. An ongoing
surveillance of health-risk behaviors in young people reported in 2003
that among high school students nationwide in the preceding year, 28.6%
had felt so sad and hopeless that they stopped doing some of their usual
activities; 16.9% had seriously considered, and 16.5% had made a plan to
attempt, suicide; and 8.5% had actually attempted suicide, 2.9% to the
extent that they needed medical attention[^8].

The evidence is strong that over 90% of children and adolescents who
commit suicide have a mental disorder[^9]. As then-Surgeon General David
Satcher noted in his Report on Mental Health in 1999, "Children, and
particularly adolescents, who suffer from depression are at much greater
risk of committing suicide than are children without depression"Error:
Reference source not found. Approximately half of all teenagers with MDD
attempt suicide at some time during their lives, and among children with
MDD there is a 4- to 5-fold higher lifetime risk of suicide attempt,
compared with healthy children without depression[^10] [^11] [^12]. At
the beginning of a study in outpatient youths with MDD, 66% of patients
acknowledged a history of suicidal ideation, and 9% had already made at
least one suicide attempt. The rate of suicide attempts in this study
reached 24% by age 17[^13]. Because mood disorders such as depression
substantially increase the risk of suicide, suicidal behavior is a
matter of serious concern for clinicians who deal with the mental health
problems of children and adolescents. Given this background, it can be
difficult to disentangle the causal factors for a suicide attempt when a
child is being treated for MDD, regardless of the type of treatment.

Studies in children and teenagers have shown that a typical episode of
MDD lasts 2‑9 months, although episodes may last much longer. Even after
remission, which is defined as the complete absence of symptoms, *i.e*.,
recovery from the episode of depression, there is a high probability
that the disease will return: up to 40% within 2 years and 70% by 5
yearsError: Reference source not found. These rates are similar to the
rates of recurrence that have been reported for adults[^14].

## Treatment Options for Major Depressive Disorder in the Pediatric Population

The options for the treatment of MDD in children and adolescents have
historically been limited. Prior to the advent of the SSRIs, tricyclic
antidepressants (TCAs) were the most commonly used medications for MDD
treatment. Although TCAs were associated with some improvement in small
open studies in children, more rigorous controlled studies failed to
demonstrate that TCAs were more effective than placebo. TCAs also pose
certain safety risks in children, specifically, cardiac arrhythmias and
a potential lethality in overdoseError: Reference source not found. The
high degree of acceptance of SSRIs for the treatment of adult MDD,
together with their low incidence of side effects, easy once-a-day
administration, and safety when taken in overdose made it natural that
physicians, faced with the need to treat patients suffering from MDD,
would prescribe these in younger patients, even though most of these
products had not been approved by FDA in that population. Fluoxetine
(Prozac®), approved in January 2003,[^15] is the only SSRI that has been
approved by FDA for the treatment of pediatric MDD.

Psychotherapy, also used in the treatment of MDD, may take the form of
individual, group, or family therapy; cognitive behavioral therapy; or
interpersonal-, problem-solving-, or play therapy. There are, however,
few controlled studies with psychotherapy. In small studies,
cognitive-behavioral therapy has been shown to have some benefit in
treating depression, but this treatment by itself does not appear to be
as effective for episodes of depression with more severe symptomsError:
Reference source not found~.~

The American Academy of Child and Adolescent Psychiatry currently
recommends psychotherapy, SSRI treatment, or both combined, for
first-line acute treatment of MDD in children and adolescentsError:
Reference source not found.

A recently published study[^16] of adolescents with major depression
showed that of the treatments studied, the combination of fluoxetine and
cognitive behavioral therapy was the most effective treatment, and that
therapy alone was not more effective than placebo, while fluoxetine
alone was also effective, though less so than combination treatment.

Despite reports that antidepressants are being widely prescribed for
America's youth, prescription data show that only 4% of antidepressant
prescriptions are for the treatment of individuals younger than 18 years
old[^17]. It is interesting to note that concurrently with the
introduction and usage of SSRIs, which is associated with higher
diagnosis and treatment rates of depression, there has been a reduction
in suicide rates among both the adult and pediatric populations.
Epidemiological studies in both adults[^18] and adolescents[^19]
addressed rates of suicide since the introduction of SSRIs. Each of
these studies demonstrated that as the rate of SSRI usage increased, the
rate of completed suicides decreased. The adolescent study, which
entailed the assessment of a large managed-care database over the last
decade, showed that as the use of antidepressants has increased, there
has been an overall decrease in the suicide rate. These data can also be
expressed as a risk reduction for adolescent suicide of 0.23/100,000
population per year with only a 1% increase in antidepressant
usageError: Reference source not found~.~

# Pfizer's Zoloft Pediatric Program

## Introduction

Clinical trials may be conducted as 'open-label' studies, in which there
is no comparison group and patients and investigators know that all the
patients are receiving the drug under study, or as 'double-blind'
studies, in which patients are randomly assigned to receive study drug
or placebo (an inert sugar pill made to look exactly like the study
drug), with the treatment assignment unknown to everyone until the study
is completed. The presence of a placebo comparison group and the
anonymity of the treatment assignment, to both patients and
investigators, lend an additional level of rigor to the data from these
studies.

Mental illnesses pose a unique challenge to researchers as they try to
document the severity of the symptoms and the degree of change in these
symptoms over time. In contrast to infections or physiological illness,
mental illnesses, such as depression, do not have a simple laboratory
test or physician finding that can accurately measure and quantify the
changes in the illness. Instead, researchers must rely on responses to
specific questions and on observations. The organization of this
information into standard rating scales that are validated as meaningful
and sensitive to treatment effects over time is the standard in the
field of psychopharmacology research.

Because the responses to such questions are inherently subjective (based
on the patient\'s own feelings, thoughts, and willingness and ability to
describe those feelings and thoughts accurately), psychiatric rating
scales may show more differences between subjects and different
investigators than tests used to measure other illnesses. In addition,
patients with disorders such as depression can often get better due to
their hopefulness about treatment, their faith in the doctor or research
institution, or just the passage of time. When this occurs in patients
who are randomized to placebo in a clinical trial, then the improvement
is called a \"placebo response.\" The distinction between a placebo
response and a real treatment effect presents an additional challenge in
clinical research.

## Studies Conducted by Pfizer 

Pfizer began a pediatric program for Zoloft in 1991 with studies in
obsessive-compulsive disorder (OCD). Since then, Pfizer has completed
nine studies and has two studies still in progress in the pediatric
population (ages 6-18 years), demonstrating its commitment to
understanding the safety, efficacy and tolerability profile of Zoloft in
this population. Table 1 lists all 11 studies conducted or being
conducted by Pfizer in the pediatric population. Six of these studies
are open-label and five of these studies are double-blind.

[]{#__RefHeading___Toc81788011 .anchor}Table 1. Summary of Pediatric
Studies Conducted with Zoloft

+--------------+--------------------+----------+-------+------+-----+
| **Study**    | **Study Design**   | **Indi   | **Age | *    |     |
|              |                    | cation** | Ra    | *No. |     |
| **(          |                    |          | nge** | Of   |     |
| Objective)** |                    |          |       | Pa   |     |
|              |                    |          |       | tien |     |
|              |                    |          |       | ts** |     |
+==============+====================+==========+=======+======+=====+
|              |                    |          |       | **   | **  |
|              |                    |          |       | Zolo | Pla |
|              |                    |          |       | ft** | ceb |
|              |                    |          |       |      | o** |
+--------------+--------------------+----------+-------+------+-----+
| **Early Open |                    |          |       |      |     |
| Label        |                    |          |       |      |     |
| Studies**    |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **9          | Open Label,        | OCD/MDD  | 6-17  | n=61 | n/a |
| 0CK21-0525** | 6-week,\           |          | yrs   |      |     |
|              | fixed--dose        |          |       |      |     |
| (Pharm       | (200mg)            |          |       |      |     |
| acokinetics\ |                    |          |       |      |     |
| and          |                    |          |       |      |     |
| t            |                    |          |       |      |     |
| olerability) |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **9          | Open Label, 24-    | OCD/MDD  | 6-18  | n=43 | n/a |
| 1CK21-0550** | week,\             |          | yrs   |      |     |
|              | flexible--dose\*   |          |       |      |     |
| (extension\* | (50-200mg)         |          |       |      |     |
| of 0525 to   |                    |          |       |      |     |
| collect      |                    |          |       |      |     |
| safety data) |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **Studies in |                    |          |       |      |     |
| Obsessiv     |                    |          |       |      |     |
| e-Compulsive |                    |          |       |      |     |
| Disorder**   |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **9          | Double Blind, 12-  | OCD      | 6-17  | n=92 | n   |
| 0CE21-0498** | week,\             |          | yrs   |      | =95 |
|              | flexible--dose     |          |       |      |     |
| (Efficacy    | (50-200mg)         |          |       |      |     |
| and Safety)  |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **9          | Open Label, 52-    | OCD      | 6-17  | n    | n/a |
| 1CE21-0536** | week,\             |          | yrs   | =137 |     |
|              | flexible--dose     |          |       |      |     |
| (extension   | (50-200mg)         |          |       |      |     |
| of R-0498 to |                    |          |       |      |     |
| collect      |                    |          |       |      |     |
| long-term    |                    |          |       |      |     |
| data)        |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **Studies in |                    |          |       |      |     |
| Depression** |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **R-0246**   | Open Label, 22-    | MDD      | 13-18 | n=53 | n/a |
|              | week,\             |          | yrs   |      |     |
| (Pilot study | flexible--dose     |          |       |      |     |
| for          | (50-200mg)         |          |       |      |     |
| efficacy,    |                    |          |       |      |     |
| Safety and   |                    |          |       |      |     |
| Tolerability |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **STL-       | Open Label, 24-    | MDD/D    | 11-18 | n=27 | n/a |
| CDN-94-002** | week,\             | ysthymia | yrs   |      |     |
|              | flexible--dose     |          |       |      |     |
| (Safety and  | (50-200mg)         |          |       |      |     |
| T            |                    |          |       |      |     |
| olerability) |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **A0501001** | Double Blind, 10-  | MDD      | 6-17  | n=97 | n   |
|              | week,\             |          | yrs   |      | =91 |
| (Efficacy    | flexible --dose    |          |       |      |     |
| and Safety)  | (50-200mg)         |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **A0501017** | Double Blind,      | MDD      | 6-17  | n=92 | n   |
|              | 10-wk,\            |          | yrs   |      | =96 |
| (Efficacy    | flexible--dose     |          |       |      |     |
| and Safety)  | (50-200mg)         |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **A0501015** | Open Label, 24-    | MDD      | 6-17  | n    | n/a |
|              | week,\             |          | yrs   | =226 |     |
| (extension   | flexible--dose     |          |       |      |     |
| of A0501001  | (50-200mg)         |          |       |      |     |
| and A0501017 |                    |          |       |      |     |
| to collect   |                    |          |       |      |     |
| long-term    |                    |          |       |      |     |
| data)        |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **Ongoing    |                    |          |       |      |     |
| Studies**    |                    |          |       |      |     |
+--------------+--------------------+----------+-------+------+-----+
| **A0501061** | Double Blind, 10-  | PTSD     | 6-17  | 160  |     |
|              | week,\             |          | yrs   | p    |     |
| (Efficacy    | flexible\--dose    |          |       | roje |     |
| and Safety)  | (50-200mg)         |          |       | cted |     |
|              |                    |          |       |      |     |
|              |                    |          |       | 73   |     |
|              |                    |          |       | enro |     |
|              |                    |          |       | lled |     |
|              |                    |          |       | (Aug |     |
|              |                    |          |       | 2    |     |
|              |                    |          |       | 004) |     |
+--------------+--------------------+----------+-------+------+-----+
| *            | Double Blind,      | OCD      | 6-17  | 324  |     |
| *A0501033 ** | 9-month,\          |          | yrs   | p    |     |
|              | flexible\--dose    |          |       | roje |     |
| (Efficacy    | (50-200mg)         |          |       | cted |     |
| and Safety)  |                    |          |       |      |     |
|              |                    |          |       | 25   |     |
|              |                    |          |       | enro |     |
|              |                    |          |       | lled |     |
|              |                    |          |       | (Aug |     |
|              |                    |          |       | 2    |     |
|              |                    |          |       | 004) |     |
+--------------+--------------------+----------+-------+------+-----+

MDD: Major Depressive Disorder; OCD: Obsessive-Compulsive Disorder;
PTSD: Posttraumatic Stress Disorder\
\* extension studies are continuations of initial studies under a new
protocol to allow collection of additional, long-term data; patients who
complete the initial study have the option of continuing in the
extension\
\* flexible dose: dosage individualized based on patient response

The early studies, 90CK21-0525 and its extension, 91CK21-0550, were
open-label studies conducted to collect preliminary safety and
tolerability data and to understand whether Zoloft dosing in young
people was similar to adults.

Study 90CE21-0498 and its extension, 91CE21-0536, were the basis of
Zoloft's approval for treatment of children and adolescents with OCD.
Pfizer also conducted two early pediatric depression studies. Study
R-0246 was an open-label study in 53 adolescents with MDD conducted to
fulfill Pfizer's post-approval commitment to FDA following the 1991
approval of Zoloft for MDD in adults. Study STL-CDN-94-002 was a small
(27-patient) open-label study conducted by Pfizer Canada to evaluate the
safety and tolerability of Zoloft in the treatment of adolescents.

The placebo-controlled studies, A0501001 and A0501017, form the core of
Pfizer's program to understand the effectiveness of Zoloft in the
treatment of pediatric depression and are described in further detail in
the following section. Their open-label extension, Study A0501015,
gathered additional information about long-term treatment.

Because of the current interest in clinical studies of SSRIs in
pediatric patients with MDD, this document will describe in some detail
Pfizer's studies of Zoloft in this population. However, in the following
Section C, we discuss the dissemination of the clinical trial results of
all of the studies in the Zoloft pediatric program.

## Design and Conduct of the Zoloft Pediatric Depression Program

In April 1999, the FDA issued a Written Request[^20] for Pfizer to
conduct pediatric depression studies with Zoloft. The FDA required that
Pfizer conduct two trials, each enrolling equal numbers of children and
adolescents, and using the Children's Depression Rating Scale-Revised to
measure efficacy. Pfizer was required to submit the data from these
studies within three years of FDA's Written Request, and did so.

### Study Design Issues

To comply with the requirements of the Written Request, Pfizer conducted
two identical, double-blind, flexible-dose, multicenter studies of
Zoloft in children and adolescents with MDD. Study A0501001 was
conducted from December 1999 to May 2001, and Study A0501017 was
conducted from February 2000 to March 2001. Patients were required to
have a current episode of MDD. As is typical in such depression studies,
patients who had previously attempted suicide or who posed a serious
suicidal or homicidal risk were excluded from the studies. In both
studies an equal number of children and adolescents received Zoloft and
placebo.

The Children's Depression Rating Scale-Revised (CDRS-R) was agreed upon
with FDA as the primary outcome measure in the study, *i.e*., the way to
measure depressive symptoms. At the time Pfizer began these studies, the
CDRS-R was emerging in the psychiatric field as the gold-standard
depression rating scale for the pediatric population, although it had
only been validated in children, not adolescents. It had also not
previously been used in any multicenter study. With this scale, both the
children and their parents are asked to rate the severity of the
depressive symptoms being experienced by the child. The clinical
investigator then combines the patient and the parent scores to derive a
composite score for the patient. A higher score represents more severe
symptoms; a decrease in score indicates improvement. It is a somewhat
difficult scale to utilize, and there can be variability in ratings from
investigator to investigator. To ensure greater consistency in the use
of the CDRS-R, all investigators performing the CDRS-R evaluations were
required to participate in a training session at the startup of the
study, and to demonstrate proficiency in using this scale.

An important element in the design of any clinical trial is the
estimation of the number of patients to be included. Statisticians
determine this number by looking at the data from previous similar
trials to obtain information regarding the extent to which differences
between treatment groups represent a true effect of treatment or might
be due to random variability between patients. The larger the number of
patients, the greater the confidence that an effect observed in a study
accurately reflects the true effect. However, in a homogeneous group it
can be expected that a smaller sample will be representative, whereas,
if the whole group is diverse and has greater variability, a larger
sample is required in order to see an effect, if one is there.

Pfizer determined the number of patients needed for its two pediatric
MDD studies by examining data from a small (96 patients) *single center*
study of fluoxetine (Prozac®) in children and adolescents with MDD, the
only published placebo-controlled study of an SSRI utilizing the CDRS-R
at the time[^21]. Based on these data, Pfizer estimated that 160
subjects would be required to provide reasonable confidence that an
observed effect would represent a true situation.

At the time Pfizer was designing its two multicenter studies, there had
been no published *multicenter* trial that had used the CDRS-R to
demonstrate efficacy, and hence no data to provide information regarding
any additional variability, between subjects and between sites, that
might be expected in a larger, multicenter trial. To address the concern
that the random variability in such a study might be greater than in a
small well-controlled single-site study, the two studies were designed
to be identical in order to allow a combined analysis. Indeed, before
the studies were completed, and before the blind was broken (before
investigators or Pfizer researchers knew what treatment anyone was
taking) Pfizer decided to pool the two studies, in order to have
sufficient power to show a difference, if one existed.

### Results

[Efficacy]{.underline}

Table 2 shows the results from the two MDD studies for the primary
measurement of efficacy (reduction in CDRS-R score from the start of the
study). In each study, the improvement in the Zoloft group was greater
than in the placebo group, but the difference was not statistically
significant (statistical significance in these studies required a
p-value less than 0.05), except for a greater proportion of responders
on Zoloft in Study A0501017. However, when the two studies were pooled,
thus providing an adequate sample size to test if there were true
differences, the treatment effect of Zoloft compared to placebo,
although modest in size, was shown to be statistically significant.

[]{#__RefHeading___Toc81788012 .anchor}Table 2. Efficacy Outcome for
Primary Endpoint in Zoloft Pediatric MDD Studies

  ------------------------------------------ ------------ ------------- -------------
                                             **Zoloft**   **Placebo**   **P-value**

  **Study A0501001** N=                      93           88            

  CDRS-R: Total Score, Baseline **→**        64.2→38.1    63.8→41.9     0.08\^
  Endpoint                                                              

  CDRS-R: Responders\* %                     62.4%        56.8%         0.46

                                                                        

  **Study A0501017** N=                      92           91            

  CDRS-R: Total Score, Baseline **→**        64.4→36.1    65.4→39.3     0.17
  Endpoint                                                              

  CDRS-R: Responders\* %                     75.0%        60.4%         0.03

                                                                        

  **Combined Data: (A0501001 + A0501017)**   185          179           
  N=                                                                    

  CDRS-R: Total Score, Baseline **→**        64.3→37.1    64.6→40.6     0.03
  Endpoint                                                              

  CDRS-R: Responders\* %                     68.7%        58.7%         0.05
  ------------------------------------------ ------------ ------------- -------------

\* Responders were individuals who had a 40% decrease in the adjusted
CDRS-R total score from baseline to endpoint.\
\^ P \<0.05 indicates statistical significance

Although the difference between Zoloft and placebo was not statistically
significant in the two individual studies, this does not mean that
Zoloft did not bring about an improvement in depressive symptoms. In
fact, on average, CDRS-R scores were almost halved, and approximately
two thirds of the patients responded to treatment with Zoloft, a rate
similar to that seen in adults. However, the patients receiving placebo
*also* showed a substantial improvement from baseline. This is known as
the 'placebo effect,' and its occurrence is not unusual in clinical
studies of depression. In these studies the placebo effect was so high
that in the individual, uncombined studies there was not a statistically
significant difference between the effect seen with Zoloft and that seen
with placebo.

Research suggests that two psychological variables significantly
increase the placebo effect: high suggestibility, and high
expectancy[^22] [^23] [^24]. Children are known to be more suggestible
than adults, and the younger the children, the more suggestible they
tend to be. Children also show higher expectancy effects, i.e., a
treatment effect produced from the belief or expectation that the doctor
and the treatment will help them, compared to adults, especially when
treated in the novel setting of a treatment research office, often in an
academic center. In addition, the time that their parents or caregivers
take in bringing them to the office and speaking with the clinical staff
about their disorder can, in itself, be therapeutic. It is worth noting
that when the combined data from the Studies A0501001 and A0501017 were
analyzed separately for children (6-12 years) and adolescents (13-17
years), the children's group had a higher placebo response than the
adolescent group. In fact, the adolescents treated with Zoloft had a
statistically significant greater improvement in CDRS-R scores than
placebo-treated adolescents[^25]. In contrast, in the children's group,
although the Zoloft-treated patients also had greater improvement than
the placebo-treated patients, the higher placebo effect resulted in the
difference not meeting statistical significance.

[Safety]{.underline}

In the Zoloft pediatric depression program, as well as in the other
pediatric studies, safety data, including time and severity of adverse
events, vital signs, laboratory test values, electrocardiograms, and
other events occurring during the trial were systematically collected
and analyzed. This information was submitted to FDA as part of the
clinical study reports and a summary of this information was also
disclosed in the clinical trial publications. In addition, the safety of
pharmaceutical drug products, such as Zoloft, is evaluated through an
ongoing analysis of Pfizer's spontaneous adverse event report database.

We have not included general safety data about Zoloft in this Testimony,
although Pfizer is willing to provide such information to the Committee.
Instead, because of current discussion and debate surrounding the issue,
we are focusing our comments about Zoloft safety on the issue of
suicide-related behaviors from the pediatric controlled trials. This
issue will also be discussed at a joint meeting of the FDA Pediatric
Advisory Committee and the Psychopharmacologic Drugs Advisory Committee
scheduled to take place on September 13 and 14, 2004.

[Suicide-Related Behaviors in the Controlled Pediatric
Studies]{.underline}

There were no suicides in these studies, nor were there suicides in any
of Pfizer's other pediatric trials with Zoloft. In addition, a
comprehensive evaluation conducted by Pfizer of the Zoloft
placebo-controlled trials shows that the risk of suicide-related
behavior in children and adolescents treated with Zoloft in clinical
trials of MDD is no greater than that with placebo.

In the MDD program, in Study A0501001, one patient in the Zoloft-treated
group was classified by the investigator as having made a suicide
attempt. In Study A0501017, two patients in the Zoloft-treated group and
two patients in the placebo-treated group made a suicide attempt. One
patient in the placebo-treated group attempted suicide twice. Three
cases of suicidal thinking (also called \"ideation\") were reported in
MDD study A0501001, and one in the OCD program (90CE21-0498), none of
which were deemed by the investigator to be related to the study drug.
The following tables summarize the incidence of suicide attempts and
suicide ideation in the placebo-controlled Zoloft pediatric trials.

[]{#__RefHeading___Toc81788013 .anchor}Table 3. Incidence of suicide
attempts in placebo-controlled studies of Zoloft in children and
adolescents

+------------------+-----------+-------------+------------+----------+
| []{.mark}        | *         |             | *          |          |
|                  | *Zoloft** |             | *Placebo** |          |
+------------------+-----------+-------------+------------+----------+
| **Diagnosis**    | **n/N**   | **Incidence | **n/N**    | **I      |
|                  |           | %**         |            | ncidence |
|                  |           |             |            | %**      |
|                  |           | **\[95%     |            |          |
|                  |           | CI\]**      |            | **\[95%  |
|                  |           |             |            | CI\]**   |
+------------------+-----------+-------------+------------+----------+
| MDD (A0501001)   | [1/9      | 1.0%        | 0/91       | 0.0%     |
|                  | 7]{.mark} |             |            |          |
|                  |           | \[0.03 --   |            | \[-\]    |
|                  |           | 5.61%\]     |            |          |
+------------------+-----------+-------------+------------+----------+
| MDD (A0501017)   | [2/9      | 2.2%        | 2\*/93     | 2.2%     |
|                  | 2]{.mark} |             |            |          |
|                  |           | \[0.26 --   |            | \[0.26   |
|                  |           | 7.63%\]     |            | --       |
|                  |           |             |            | 7.55%\]  |
+------------------+-----------+-------------+------------+----------+
| MDD Combined     | 3/189     | 1.6%        | 2\*/184    | 1.1%     |
|                  |           |             |            |          |
|                  |           | \[0.33 --   |            | \[0.13   |
|                  |           | 4.57%\]     |            | --       |
|                  |           |             |            | 3.87%\]  |
+------------------+-----------+-------------+------------+----------+
| OCD              | 0/ 92     | 0%          | 0/95       | 0%       |
| (90CE21-0498)    |           |             |            |          |
|                  |           | \[-\]       |            | \[-\]    |
+------------------+-----------+-------------+------------+----------+
| All Combined     | 3/281     | 1.1%        | 2/279      | 0.7%     |
|                  |           |             |            |          |
|                  |           | \[0.22 --   |            | \[0.09   |
|                  |           | 3.09%\]     |            | --       |
|                  |           |             |            | 2.57%\]  |
+------------------+-----------+-------------+------------+----------+
| Combined Ages    | 1/158     | 0.6%        | 2/151      | 1.3%     |
| 12--17           |           |             |            |          |
|                  |           | \[0.02 --   |            | \[0.16   |
|                  |           | 3.48%\]     |            | --       |
|                  |           |             |            | 4.70%\]  |
+------------------+-----------+-------------+------------+----------+
| Combined Ages    | 2/123     | 1.6%        | 0/128      | 0%       |
| 7--11            |           |             |            |          |
|                  |           | \[0.20 --   |            | \[-\]    |
|                  |           | 5.75%\]     |            |          |
+------------------+-----------+-------------+------------+----------+

\* there were 3 attempts in 2 patients

[]{#__RefHeading___Toc81788014 .anchor}Table 4. Incidence of suicidal
ideation in placebo-controlled studies of Zoloft in children and
adolescents

+------------------+-----------+-------------+------------+----------+
| []{.mark}        | *         |             | *          |          |
|                  | *Zoloft** |             | *Placebo** |          |
+------------------+-----------+-------------+------------+----------+
| **Diagnosis**    | **n/N**   | **Incidence | **n/N**    | **I      |
|                  |           | %**         |            | ncidence |
|                  |           |             |            | %**      |
|                  |           | **\[95%     |            |          |
|                  |           | CI\]**      |            | **\[95%  |
|                  |           |             |            | CI\]**   |
+------------------+-----------+-------------+------------+----------+
| MDD              | 3/189     | 1.6%        | 0/184      | 0%       |
|                  |           |             |            |          |
|                  |           | \[0.33 --   |            | \[-\]    |
|                  |           | 4.57%\]     |            |          |
+------------------+-----------+-------------+------------+----------+
| OCD              | 0/92      | 0%          | 1/95       | 1.1%     |
|                  |           |             |            |          |
|                  |           | \[-\]       |            | \[0.03   |
|                  |           |             |            | --       |
|                  |           |             |            | 5.73%\]  |
+------------------+-----------+-------------+------------+----------+
| All Combined     | 3/281     | 1.1%        | 1/279      | 0.4%     |
|                  |           |             |            |          |
|                  |           | \[0.22 --   |            | \[0.01   |
|                  |           | 3.09%\]     |            | --       |
|                  |           |             |            | 1.98%\]  |
+------------------+-----------+-------------+------------+----------+

[]{#__RefHeading___Toc81788015 .anchor}Table 5. Incidence of suicide
attempts and suicidal ideation in placebo-controlled studies of Zoloft
in children and adolescents

+------------------+-----------+-------------+------------+----------+
|                  | *         |             | *          |          |
|                  | *Zoloft** |             | *Placebo** |          |
+------------------+-----------+-------------+------------+----------+
| **Diagnosis**    | **n/N**   | **Incidence | **n/N**    | **I      |
|                  |           | %**         |            | ncidence |
|                  |           |             |            | %**      |
|                  |           | **\[95%     |            |          |
|                  |           | CI\]**      |            | **\[95%  |
|                  |           |             |            | CI\]**   |
+------------------+-----------+-------------+------------+----------+
| MDD              | 6/189     | 3.2%        | 2/184      | 1.1%     |
|                  |           |             |            |          |
|                  |           | \[1.17 --   |            | \[0.13   |
|                  |           | 6.78%\]     |            | --       |
|                  |           |             |            | 3.87%\]  |
+------------------+-----------+-------------+------------+----------+
| OCD              | 0/92      | 0%          | 1/95       | 1.1%     |
|                  |           |             |            |          |
|                  |           | \[-\]       |            | \[0.03   |
|                  |           |             |            | --       |
|                  |           |             |            | 5.73%\]  |
+------------------+-----------+-------------+------------+----------+
| All Combined     | 6/281     | 2.1%        | 3/279      | 1.1%     |
|                  |           |             |            |          |
|                  |           | \[0.79 --   |            | \[0.22   |
|                  |           | 4.59%\]     |            | --       |
|                  |           |             |            | 3.11%\]  |
+------------------+-----------+-------------+------------+----------+

In the tables above, it is clear that the number of events is very
small, and because none of these numbers are statistically significant,
no conclusion can be drawn that treatment with Zoloft in these studies
is associated with an increased risk of suicidal behaviors. These data,
which are congruent with the classification of the Zoloft cases
conducted by the Columbia University researchers, as requested by FDA,
will be discussed in more detail at the upcoming FDA Advisory Committee
meeting on September 13 and 14.

# Pfizer's Disclosure of the Zoloft Pediatric Studies 

As a research-based pharmaceutical company, Pfizer recognizes that the
availability of meaningful clinical trial results is critical to the
communication of important new information for the medical profession,
patients and the public. Pfizer is committed to the timely communication
of meaningful results of Pfizer sponsored hypothesis-testing clinical
trials (essentially all Phase 3 and 4 trials), regardless of outcome,
for Pfizer's marketed prescription medicines. In short, Pfizer is
dedicated to making public the results of all clinical trials that have
the potential to improve patient care. Pfizer's practices conform to the
PhRMA Principles on the Conduct of Clinical Studies and Communication of
Clinical Trial Results and are also codified in Pfizer's Policy on
Public Disclosure of Clinical Trial Results which is available on
Pfizer's website[^26]
(<http://www.pfizer.com/are/about_public/mn_about_ethical_trials.html>).

Pfizer continues to examine ways to improve accessibility to meaningful
clinical trial information. To that end, Pfizer is actively
participating in and supports a recent PhRMA initiative to develop a
centralized database to provide access to clinical trial results on
studies that fall within the scope of the PhRMA Principles. Pfizer
believes that the development of a single database containing summaries
of studies sponsored by all participating PhRMA member companies will
facilitate healthcare providers' accessibility to clinical trial results
and positively impact patient care.

Important safety and efficacy information generated from clinical trials
can be publicized and disseminated in a number of ways:

-   Through abstracts, posters and presentations at scientific meetings,

-   Through publication in peer-reviewed journals,

-   Through inclusion in "Medical Information" letters, and

-   Through filing to regulatory authorities and subsequent inclusion in
    the product label.

Most frequently, clinical data from studies are presented first as
abstracts and posters at scientific meetings. This is useful since it is
relatively rapid, provides opportunity for questions and discussion and,
because scientific meetings may be attended by many thousands of
individuals, has the potential to reach a large audience. The more
rigorous system of publication in a peer-reviewed journal may take
longer due to the time involved in peer review and journal publication
dates, but benefits from the thoughtful scrutiny of subject-matter
experts. These peer reviewers are appointed by the journal and, working
independently and anonymously, may suggest additions or deletions, as
well as challenge analyses and suggest new ones, as pre-requisites for
publication.

## Pfizer's Publication of Zoloft Pediatric Data at Scientific Meetings and in Peer-Reviewed Journals

Information obtained from the Zoloft pediatric program has been made
public in numerous ways. Seven of the nine completed studies have been
published in respected journals, and one has been submitted for
publication to the Journal of Child and Adolescent Psychopharmacology,
where it has recently undergone peer review. Some of the Zoloft
pediatric trials have provided data for multiple publications. For
example, large placebo-controlled studies like A0501001 and A0501017
with extensions (like A0501015, in which some patients were followed for
up to 34 weeks) are rich in data and have provided the opportunity to
understand the results better through subset analyses. The data from
Studies A0501001 and A0501017 have been used to revise and validate
efficacy scales (CDRS-R and PQ-LES-Q) for use in adolescent populations
and provided technical advances in this field of research[^27].

Table 6 lists the nine completed studies and a selection of the posters
and publications they have generated. In addition, a comprehensive
review of Zoloft safety data, including the individual efficacy results
of the two pediatric depression studies, was presented at a special
invited session during the annual meeting of the American Academy of
Child and Adolescent Psychopharmacology in October, 2003.

[]{#__RefHeading___Toc81788016 .anchor}Table 6. Zoloft Pediatric
Studies: Selected Abstracts, Posters, and Publications

+-----------+-----------------------------+---------------------------+
| Study \#  | Abstract/Poster             | Publication               |
|           |                             |                           |
| I         |                             |                           |
| ndication |                             |                           |
+===========+=============================+===========================+
| **90CK    | Alderman J et al.           | Alderman J et al.         |
| 21-0525** | Sertraline treatment in     | Sertraline treatment of   |
|           | children and adolescents:   | children and adolescents  |
| MDD/OCD   | tolerability, efficacy, and | with obsessive-compulsive |
|           | pharmacokinetics. APA, 1996 | disorder or depression:   |
| 6 weeks,\ | (poster); also Eur          | pharmacokinetics,         |
| Open      | Neuropsychopharmacol 6      | tolerability, and         |
| Label     | (suppl 3) June 1996         | efficacy. **J Am Acad     |
|           | (abstract)                  | Child Adolesc             |
|           |                             | Psychiatry** 1998; 37     |
|           |                             | (4): 386-394              |
+-----------+-----------------------------+---------------------------+
| **91CK    |                             | Manuscript being prepared |
| 21-0550** |                             | for submission            |
|           |                             |                           |
| MDD/OCD   |                             |                           |
|           |                             |                           |
| 24        |                             |                           |
| weeks,\   |                             |                           |
| Open      |                             |                           |
| Label,    |                             |                           |
| con       |                             |                           |
| tinuation |                             |                           |
| of        |                             |                           |
| 90        |                             |                           |
| CK21-0525 |                             |                           |
+-----------+-----------------------------+---------------------------+
| **90-CE   | Wolkow R et al. Sertraline  | March J et al. Sertraline |
| 21-0498** | in pediatric OCD: a         | in children and           |
|           | multicenter controlled      | adolescents with          |
| OCD       | trial; World Congress of    | Obsessive-Compulsive      |
|           | Biological Psychiatry, June | Disorder. **JAMA** 1998;  |
| 12        | 1997 (poster)\              | 280 (20): 1752-1756       |
| weeks,\   | \                           |                           |
| Double    | Wolkow et al. A             | Wilens TE et al. Absence  |
| Blind     | placebo-controlled trial of | of cardiovascular adverse |
|           | sertraline for pediatric    | effects of sertraline in  |
|           | OCD; APA, 1997 (abstract)   | children and adolescents. |
|           |                             | **J Am Acad Child Adolesc |
|           |                             | Psychiatry** 1999; 38     |
|           |                             | (5): 573-577              |
+-----------+-----------------------------+---------------------------+
| **91CE    | Wagner KD. Safety and       | Cook E et al. Long-term   |
| 21-0536** | efficacy of sertraline in   | sertraline treatment of   |
|           | long-term pediatric OCD     | children and adolescents  |
| OCD       | treatment: a multicenter    | with obsessive-compulsive |
|           | study; NCDEU 1999 (poster)  | disorder. **J Am Acad     |
| 52 weeks, |                             | Child Adolesc             |
|           | Cook E et al.               | Psychiatry** 2001; 40     |
| Open      | Obsessive-compulsive        | (10): 1175-1181           |
| Label,    | disorder: Long-Term         |                           |
|           | Sertraline in Children and  | Wagner KD et al.          |
| con       | Adolescents, AACAP, 1999    | Remission status after    |
| tinuation | (poster)                    | long-term sertraline      |
| of        |                             | treatment of pediatric    |
|           | Wagner KD et al. Long-term  | obsessive-compulsive      |
| 90-       | sertraline treatment for    | disorder. **J Child       |
| CE21-0498 | pediatric OCD: remission    | Adolesc Psychopharmacol** |
|           | rates and functional        | 2003; 13 (Suppl 1):       |
|           | status; APA 2002 (poster)   | S53-60                    |
+-----------+-----------------------------+---------------------------+
| *         | Presented at AACAP, 1997    | Ambrosini P et al.        |
| *R-0246** | (poster)                    | Multicenter open-label    |
|           |                             | sertraline study in       |
| MDD       |                             | adolescent outpatients    |
|           |                             | with major depression.    |
| 22 weeks, |                             | **J Am Acad Child Adolesc |
|           |                             | Psychiatry** 1999; 38     |
| Open      |                             | (5): 566-572              |
| Label     |                             |                           |
+-----------+-----------------------------+---------------------------+
| **STL-CD  | Simeon JG et al. Sertraline | Nixon MK et al.           |
| N-94-00** | in adolescent depression    | Sertraline effects in     |
|           | and dysthymia: a 6-month    | adolescent major          |
| MDD/      | open trial. APA 1998        | depression and dysthymia: |
| Dysthymia | (poster)                    | a six-month open trial.   |
|           |                             | **J Child Adolesc         |
| 24 weeks, |                             | Psychopharmacol** 2001;   |
|           |                             | 11 (2): 131-142           |
| Open      |                             |                           |
| Label     |                             |                           |
+-----------+-----------------------------+---------------------------+
| **A       | Donnelly C et al. Efficacy  | Wagner KD et al. Efficacy |
| 0501001** | and safety of sertraline in | of sertraline in the      |
| and       | the treatment of pediatric  | treatment of children and |
| **A       | major depressive disorder;  | adolescents with major    |
| 0501017** | ACNP 2001 (poster)          | depressive disorder: two  |
|           |                             | randomized controlled     |
| MDD       | Wagner KD et al. Efficacy   | trials. **JAMA** 2003;    |
|           | and safety of sertraline in | 290 (8):1033-1041 and     |
| 10 weeks, | the treatment of pediatric  | reply in **JAMA** 2004;   |
|           | major depressive disorder;  | 291 (13): 1561-2          |
| Double    | APA 2002 (poster); ECNP     |                           |
| Blind     | 2002 (poster)               | Donnelly C et al. A       |
|           |                             | comparison of the         |
|           | Endicott J et al.           | response to sertraline in |
|           | Reliability and validity of | children and adolescents  |
|           | the CDRS -- Revised in      | with major depressive     |
|           | children and adolescents    | disorder **(**submitted   |
|           | treated with sertraline;    | to **J Am Acad Child      |
|           | NCDEU 2002 (poster)         | Adolesc Psychiatry)**     |
|           |                             | []{.mark}                 |
|           | Donnelly C et al. A         |                           |
|           | comparison of the response  | Endicott J et al: The     |
|           | to sertraline in children   | Pediatric Quality of Life |
|           | and adolescents with major  | Enjoyment and             |
|           | depressive disorder; NCDEU  | Satisfaction              |
|           | 2003, AACAP 2003 (poster)   | Questionnaire (PQ-LES-Q): |
|           |                             | Reliability and Validity  |
|           | Wagner KD et al. Efficacy   | **(**submitted to **J Am  |
|           | of sertraline in anxious    | Acad Child Adolesc        |
|           | subgroup in youth with      | Psychiatry**, April       |
|           | major depression; APA 2004, | 2004**)**                 |
|           | NCDEU 2004 and CINP 2004    |                           |
|           | (poster)                    |                           |
+-----------+-----------------------------+---------------------------+
| **A       | Rynn MA et al. ACNP 2002    | Rynn, M **(**submitted to |
| 0501015** | (poster)                    | **J Child Adolesc         |
|           |                             | Psychopharmacol)**        |
| MDD       | Rynn MA et al. Long-term    |                           |
|           | safety and tolerability of  |                           |
| 24 weeks, | sertraline in children and  |                           |
|           | adolescents with major      |                           |
| Open      | depression; APA 2003, ECNP  |                           |
| Label,    | 2003, ACNP 2003 (poster)    |                           |
|           |                             |                           |
| con       |                             |                           |
| tinuation |                             |                           |
| of 1001   |                             |                           |
| and 1017  |                             |                           |
+-----------+-----------------------------+---------------------------+

JAMA: Journal of the American Medical Association

AACAP: American Academy of Child and Adolescent Psychopharmacology

APA: American Psychiatric Association

NCDEU: New Clinical Drug Evaluation Unit Meeting --sponsored by National
Institute of Mental Health

ACNP: American College of Neuropsychopharmacology;

ECNP: European College of Neuropsychopharmacology

CINP: Collegium Internationale Neuro-Psychopharmacologicum

The only study that Pfizer has not published, although the data from the
study have been submitted to FDA, is open-label extension study
91CK21-0550. Because this was a small, open-label study---32 patients
with depression, 10 patients with OCD, and one patient with OCD and
depression---and its results were consistent with known data about
Zoloft in this population, Pfizer did not seek to have it published.
However, given the current interest in SSRI data in the pediatric
population, Pfizer is preparing a manuscript of this study for
submission and publication. Since this was also an extension study, all
of these 43 patients had participated in the parent study (90CK21-0525)
that was published by the Pfizer researchers who conducted the
study[^28].

## Dissemination of Information by Medical Information Letters

Medical Information letters are another means by which pharmaceutical
companies provide important information about their products to
interested healthcare practitioners and the public. These letters
generally respond to unsolicited inquiries about a particular drug from
health care professionals, patients or others. Healthcare professionals
employed by the pharmaceutical company prepare these letters after an
extensive review of the particular topic to be addressed.

There are two letters in the Pfizer Medical Information database that
are related to the Zoloft pediatric program. One letter reviews data
related to the two Zoloft pediatric depression trials, as well as
related published data. It should be noted that in this letter, Pfizer
clearly states that Zoloft is not approved by the FDA for the treatment
of MDD or dysthymic disorder in pediatric patients and that Pfizer does
not recommend the use of Zoloft for these conditions. The second letter
provides all available information on suicide-related adverse events in
children and adolescents from Pfizer's pediatric program for Zoloft, as
well as from independently conducted (non-Pfizer) studies. In this
letter, Pfizer also provides a review of the case reports in the
scientific literature as well as position statements concerning the
topic of suicidal behavior in children and adolescents with major
depression.

## Changes to Zoloft Labeling

In today's demanding and complex healthcare system, doctors lack the
time, and often the capacity, to review, analyze and evaluate the
enormous quantity of clinical data that is generated for the enormous
number of drug products that are on the U.S. market, as well as the many
others that are in clinical development. Because of this, the FDA, by
virtue of its statutory authority, conducts comprehensive reviews of the
data related to each drug to make determinations about its overall
Risk/Benefit profile and approvability. The FDA objectively evaluates
the wealth of data that are gathered in the preclinical and clinical
development programs of a new drug, as well as the ongoing clinical
research that expands knowledge of approved medications. The output of
its review is the product label, which, through its consistent
presentation of data, allows doctors to objectively compare drugs in a
therapeutic class and make the best decisions for their patients. The
product label is arguably the most important vehicle for the
dissemination of information about drug safety and efficacy.

The nine completed Zoloft pediatric studies have all been submitted to
the FDA. Together with the extensive written reports and complete
analyses for each study, the FDA also receives all the efficacy and
safety data collected in these trials, allowing its medical and
statistical reviewers to conduct additional analyses and checks. In
addition, the FDA routinely receives safety data in the form of Annual
Reports. These mandated reports require a drug sponsor to summarize, for
each drug in development or already on the market, the safety
information from trials in progress or completed in the previous year,
including tabular summaries of adverse events, information about
patients who dropped out of a study for adverse events, and any new
information that is learned relating to a drug's actions. These studies
have led to a series of important changes in the Zoloft Package Insert
(PI) and have consequently informed doctors about valuable information
learned from those studies.

In October 1997, on the basis of data from Studies 90CK21-0525 and
90CE21-0498, Zoloft was approved for the treatment of pediatric OCD.
Text added to the label informed doctors about how the blood levels
observed in children and adolescents compared with those in adults,
described the conduct of the double-blind clinical trial, the magnitude
of the improvement observed, noted adverse events that had been
recorded, and gave specific dosing recommendations for children and
adolescents. In October 2001, additional text was added to the label
that described the one-year continuation study in pediatric OCD (Study
91CE21-0536) providing information on the long-term safety of Zoloft in
pediatric use. Since the study supporting this label change was open
label, no long-term efficacy information was added.

In September 2003, the Zoloft label was again modified to add safety
information gained from the pediatric MDD trials, Studies A0501001 and
A0501017 and the long-term extension, Study A0501015. Specifically, the
added text advised doctors that weight loss had been observed in the
first ten weeks of treatment, although with longer treatment weight gain
was again as expected. Regular monitoring of weight and growth in
children treated with Zoloft was recommended. An indication for the use
of Zoloft in pediatric MDD was denied since Pfizer had not fulfilled the
requirement for two positive trials (individually the two studies were
not each positive, and the pooled efficacy analysis, albeit positive,
constituted just a single trial). The FDA chose not to describe the
studies in the label, stating in their letter to Pfizer that: "*Given
the fact that negative trials are frequently seen, even for
antidepressant drugs that we know are effective, we do not feel that it
would be useful to describe these negative trials in labeling, since
this may be misinterpreted as evidence that Zoloft does not work in this
population. Rather, we feel that the existing language, suggesting
simply that efficacy has not been established in this population, is
still most appropriate*"[^29].

In August 2004, the Warnings section of the Zoloft label was amended to
advise doctors that adult and pediatric patients with MDD could
experience a worsening of their illness that might include thoughts of
suicide. The Warning further advised that patients should be carefully
monitored, especially when starting treatment with an antidepressant or
changing dose levels. The label also advised that caregivers should be
told to be watchful for changes in symptoms and notify healthcare
providers if they notice a change in symptoms.

In summary, there have been four additions to the Zoloft label relating
to pediatric use:

(1) the original pediatric use for OCD on 10/10/97

(2) the pediatric OCD long-term safety inclusion on 10/12/01

(3) safety information inserted as a result of the pediatric MDD trials
    on 9/16/03

(4) Warning to monitor for suicidality on 8/19/04

These four important label changes to the Zoloft label served to provide
new information about Zoloft to healthcare professionals and in
particular to those responsible for prescribing Zoloft.

# Conclusions

Pfizer has conducted a rigorous pediatric program for Zoloft, consisting
of nine completed studies and two studies still in progress. In 1997,
FDA approved Zoloft for the treatment of Obsessive-Compulsive Disorder
in the pediatric population. Although Zoloft was not approved for the
treatment of major depression in this population, Pfizer's studies
yielded important information that was added to the Zoloft label.

There were no patients who committed suicide in the Zoloft pediatric
studies.

The number of suicide-related events in the Zoloft pediatric studies is
small, and, because none of these numbers are statistically significant,
no conclusion can be drawn that treatment with Zoloft in these studies
is associated with an increased risk of suicidal behaviors.

Pfizer submitted all of the completed studies to the FDA, resulting in
several important changes to the Zoloft label, providing doctors with
important safety and efficacy information from those studies.

Moreover, Pfizer sought a wider dissemination of the safety and efficacy
results of its pediatric program through its publication of study
results. The results of eight of Pfizer's pediatric studies have been
shared with the medical and scientific community in the form of
abstracts, posters, and presentations at scientific meetings as well as
publication in respected peer-reviewed journals. Publications based on
the databases generated in the Zoloft pediatric trials have not only
served to disclose the findings from the studies, but have also
contributed to the understanding and evaluation of devastating
psychiatric illnesses in a vulnerable patient population.

[^1]: This document does not address studies conducted as Independent
    Research Grants by researchers outside of Pfizer and funded or
    otherwise supported by Pfizer or studies that were neither supported
    nor sponsored by Pfizer.

[^2]: American Academy of Child and Adolescent Psychiatry (1998),
    Practice Parameters for the Assessment and Treatment of Children and
    Adolescents with Depressive Disorders. *J Amer Acad Child Adolesc
    Psychiatry* 37 (10 suppl).

[^3]: Kessler RC et al. The epidemiology of Major Depressive Disorder;
    results from the National Comorbidity Survey Replication (NCS-R)
    *JAMA* 2003; 289: 1395-1305.

[^4]: Diagnostic and Statistical Manual of Mental Disorders version IV
    with revisions (DSM-IV TR) p353-354.

[^5]: Mental Health: A Report of the Surgeon General, published 1999,
    (David Satcher, Surgeon General). p150-152.

[^6]: Birmaher B; Ryan ND, Williamson DE, etal. Childhood and Adolescent
    Depression: A Review of the Past 10 Years. Part I, *J Amer Acad
    Child Adolesc Psychiatry* 1996 35(11):1427-1439.

[^7]: Centers for Disease Control and Prevention. Web-based Injury
    Statistics Query and Reporting System (WISQARS) \[Online\]. (2003).
    National Center for Injury Prevention and Control, Centers for
    Disease Control and Prevention (producer). Available from: URL:
    www.cdc.gov/ncipc/wisqars. 30 Aug 2004.

[^8]: Youth Risk Behavior Surveillance System -- United States, 2003;
    Volume 53/SS-2.

[^9]: Mental Health: A Report of the Surgeon General, published 1999
    (David Satcher, Surgeon General). p150-152.

[^10]: Rao U, Weissman MM, Martin JA and Hammond RW (1993) Childhood
    depression and risk of suicide: a preliminary report of a
    longitudinal study. *J Am Acad Child Adolesc Psychiatry* 32:21-27.

[^11]: Weissman MM, Wolk S, Goldstein RB *et al* (1999a). Depressed
    adolescents grown up. JAMA 281:1701-1713.

[^12]: Weissman MM, Wolk S, Wickramaratne P *et al* (1999b). Children
    with prepubertal-onset major depressive disorder and anxiety grown
    up. *Arch Gen Psychiatry* 56:794-801.

[^13]: Kovacs M, Goldston D, and Gatsonis C (1993). Suicidal behaviors
    and childhood-onset depressive disorders: A longitudinal
    investigation. *J. Am. Acad. Child & Adol. Psychiatry* 32(1):8-20.

[^14]: Birmaher B; Ryan ND, Williamson DE, et al. Childhood and
    Adolescent Depression: A Review of the Past 10 Years. Part I, *J
    Amer Acad Child Adolesc Psychiatry* 1996 35(11):1427-1439.

[^15]: <http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01187.html> \[FDA
    Talk Paper announcing approval of Prozac for MDD\].

[^16]: Treatment for Adolescents with Depression Study (TADS) team
    (2004). Fluoxetine, Cognitive Behavioral Therapy, and their
    combination for adolescents with depression. *JAMA* 292:807-820.

[^17]: Scott-Levin MAT, May 2004.

[^18]: Hall WD, Mant A, Mitchell PB et al (2003). Association between
    antidepressant prescribing and suicide in Australia, 1991-2000:
    trend analysis. *BMJ* 326:1008-1012.

[^19]: Olfson M, Shaffer D, Marcus SC et al (2003). Relationship between
    antidepressant medication treatment and suicide in adolescents.
    *Arch. Gen. Psychiatry* 60:978-982.

[^20]: In 1997, Congress passed the Food and Drug Administration
    Modernization Act (FDAMA), intending in part to ensure that
    medicines that could benefit children were properly evaluated in the
    pediatric population. It allowed the FDA to issue Written Requests
    to manufacturers of these medicines to conduct the relevant trials
    within a specified time. Clinical trials in children are more
    difficult to conduct than trials in adult populations. To provide
    incentive for manufacturers to conduct such trials and to balance
    their cost, sponsors could be eligible for a 6-month patent
    extension upon submission of the complete package of required data
    to the FDA.

[^21]: Emslie GJ, Rush AJ, Weinberg WA *et al* (1997). A double-blind,
    randomized, placebo controlled trial of fluoxetine in children and
    adolescents with depression. *Arch. Gen. Psychiatry* 54:1031-1037.

[^22]: De Pascalis V, Chiaradia C, Carotenuto E. The contribution of
    suggestibility and expectation to placebo analgesia phenomenon in an
    experimental setting. *Pain* 2002;96:393-402.

[^23]: Leigh R, MacQueen G, Tougas G, Hargreave FE, Bienenstock J.
    Change in forced expiratory volume in 1 second after sham
    bronchoconstrictor in suggestible but not suggestion-resistant
    asthmatic subjects: a pilot study. *Psychosom Med* 2003;65:791-795.

[^24]: Vase L, Robinson ME, Verne GN, Price DD. The contributions of
    suggestion, desire, and expectation to placebo effects in irritable
    bowel syndrome patients. An empirical investigation. *Pain*
    2003;105:17-25.

[^25]: Donnelly C et al. A comparison of the response to sertraline in
    children and adolescents with major depressive disorder; NCDEU 2003
    (poster) and Donnelly C et al. A comparison of the response to
    sertraline in children and adolescents with major depressive
    disorder (submitted to *J Am Acad Child Adolesc Psychiatry*).

[^26]: Publication of findings from Zoloft pediatric studies predates
    the formulation of the current disclosure policy, but is concordant
    with all the principles embraced in the policy.

[^27]: See Endicott J et al. Reliability and validity of the CDRS --
    Revised in children and adolescents treated with sertraline; NCDEU
    2002 (poster) and Endicott J et al: The Pediatric Quality of Life
    Enjoyment and Satisfaction Questionnaire (PQ-LES-Q): Reliability and
    Validity (submitted to *J Am Acad Child Adolesc Psychiatry*, April
    2004**).**

[^28]: Alderman J et al. Sertraline treatment of children and
    adolescents with obsessive-compulsive disorder or depression:
    pharmacokinetics, tolerability, and efficacy. *J Am Acad Child
    Adoles. Psychiatry* 1998; 37 (4): 386-394.

[^29]: Correspondence from FDA to Pfizer, September 30, 2002.