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**Background Package**

**from**

**Pfizer Inc**

**for**

**September 13-14, 2004**

**Psychopharmacological Drugs Advisory Committee**

**of the**

**Food and Drug Administration**

August 10, 2004

# Introduction

Major Depressive Disorder (MDD) in children and adolescents is a
critical public health issue for the youth of America. If left
untreated, MDD can result in a significant risk of suicidal behavior,
and is the third leading cause of death in the pediatric population.
Epidemiological studies strongly suggest that usage of SSRIs have
resulted in a reduction of the number of suicides in this vulnerable
patient population. Moreover, Pfizer's analysis of the
placebo-controlled Zoloft^®^ (sertraline hydrochloride) pediatric
database (281 Zoloft treated subjects and 279 placebo treated subjects)
demonstrates no association between Zoloft usage and an increased risk
of suicide and/or suicide related behavior.

# Major Depressive Disorder in Pediatric Population

## Prevalence, Symptoms and Impact

**\
**Major depressive disorder (MDD) occurs in children and adolescents as
well as adults. The annual prevalence of depression is estimated to be
2-3% in children aged 8-12 years and slightly higher (4-8%) in youth
aged 11 ½ to 18 years (AACAP, 1998) as compared with rates of 6.6% in
adults aged 18 and older (Kessler, 2003).

In order to diagnose depression, the Diagnostic and Statistical Manual
Version IV with revisions (DSM-IV TR) is used. The diagnostic criteria
are similar in children and adolescents to those utilized to diagnose
depression in adults, with the exception that DSM notes that children
and adolescents may exhibit an irritable mood rather than a depressed
mood. In all age groups, suicidal thinking or behavior can be one of the
diagnostic criteria, characterized in DSM as "abnormal morbid thoughts
of death (not just fear of dying) or suicide".

Clinical and epidemiological studies in children and adolescents have
shown that a typical episode of MDD lasts 2-9 months; with a probability
of the disease returning of 40% within 2 years and 70% by 5 years,
similar to the rates of recurrence that have been reported for adults
(Birmaher, 1996). Children and adolescents who suffer from MDD may
experience a drop in school performance, family tension/problems, and
conflicts with friends.

It is common to see coexisting psychiatric disorders in depressed youth
(40% to 90% of the time). The most frequent coexisting disorders are
dysthymic disorder (sometimes referred to as minor depression in that
these youth display a chronically depressed mood or irritability lasting
at least 1 year but do not meet criterion for major depression) and
anxiety disorders (both at 30% to 80%), disruptive behavior disorders
(10% to 80%), and abuse of alcohol or illicit substances (20% to 30%)
(AACAP, 1998).

MDD in the pediatric population is associated with significant risk of
suicidal thinking, attempts and even completed suicide. Approximately
half of 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 (Kovacs, 1993; Rao, 1993). Kovacs et al (1993) noted similar
results in a study of outpatient youths with MDD. They noted that, at
study entry, 66% of subjects 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. Important
comorbid risk factors for suicide attempts included conduct and/or
substance-abuse disorders.

## Treatment Options

The American Academy of Child and Adolescent Psychiatry recommends, for
first-line acute treatment of MDD in children and adolescents,
psychotherapy, treatment with a selective serotonin reuptake inhibitor
(SSRI), or both combined, depending on the patient, the patient's
circumstances, and the severity of disease (AACAP, 1998).

Psychotherapy may take the form of individual, group, or family therapy;
cognitive behavioral therapy, interpersonal-, problem-solving, or play
therapy. There are few placebo-controlled studies with psychotherapy.
Cognitive-behavioral therapy has been shown to work in small studies,
but does not appear to be as effective for more severe illness.
Treatment studies comparing psychotherapy, medication or their
combination are needed and are beginning to be conducted, and presented.

Prior to the widespread use of SSRIs, tricyclic antidepressants (TCAs)
were the most commonly used pharmacotherapy for MDD. Although tricyclic
antidepressants (TCAs) have been shown to effect some improvement in
small open studies in children, more rigorous placebo-controlled studies
failed to demonstrate that TCAs were more effective than placebo for the
treatment of MDD in children and adolescents. TCAs also pose certain
safety risks in children, specifically cardiac arrhythmias, and a
potential lethality in overdose. The high degree of acceptance of SSRIs
for the treatment of MDD in adults, 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
also, even if off-label. Fluoxetine is currently the only SSRI is
indicated for the treatment of depression in childhood. The Zoloft label
contains safety and efficacy information with respect to the use of
Zoloft in pediatric OCD (acute and long-term), and safety information
derived from the pediatric MDD program.

Several epidemiological studies address rates of suicide following the
introduction of SSRIs in adults (Hall *et al*, 2003 \[patients ranged in
age upward from 15 years\]; Isaacson *et al*, 2000) and adolescents
(Olfson *et al*, 2003). In each of these studies, a negative correlation
was noted between usage of SSRIs and suicide rates and the correlation
coefficients noted by Hall *et al* were quite strong (men, r=-0.91,
p\<0.01; women, r=-0.76, p\<0.05). Olfson *et al* specifically assessed
the rates of suicide in adolescents in a large managed care database and
found a risk reduction for suicide of 0.23/100,000 population per year
with a 1% increase in antidepressant usage.

# Zoloft Pediatric Utilization Data

Figure 1 below shows the chronology of Zoloft regulatory approvals in
the United States, from initial approval for adult Major Depressive
Disorder (MDD) in late 1991 and launch in 1992, through the present.

**Figure 1. Zoloft Approvals: Adult and Pediatric Indications**

Since its launch into the US marketplace in January 1992, approximately
250 million prescriptions for Zoloft have been written, accounting for
over 13 billion patient days of therapy. Approximately 465,000
prescriptions were written for Zoloft in the pediatric population in
2003, which accounted for 1.4% of total Zoloft prescriptions in 2003.

**Figure 2. Distribution of Antidepressant Use in the Pediatric Market**

#  {#section .unnumbered}

# Overview of Zoloft Placebo-controlled Studies in the Pediatric Population

Pfizer has conducted three, double-blind, placebo-controlled studies in
the pediatric population. A fourth study in the PTSD pediatric
population is currently ongoing. Table 1 provides an overview of the
placebo-controlled pediatric studies.

Table 1. Summary of Placebo-Controlled Pediatric Studies Conducted with
Zoloft

  ------------------------------------------------------------------------------------------------
  **Study**     **Study Design**        **Indication**   **No. of                        **Age
                                                         Patients**                      Range**
  ------------- ----------------------- ---------------- --------------- --------------- ---------
                                                         **Zoloft**      **Placebo**     

  **Studies in                                                                           
  Obsessive                                                                              
  Compulsive                                                                             
  Disorder                                                                               
  (OCD)**                                                                                

  R-0498        DB, 12-wk, flex-dose    OCD              N=92            n=95            6-17 yrs
                (25-200mg)                                                               

  **Studies in                                                                           
  Major                                                                                  
  Depressive                                                                             
  Disorder                                                                               
  (MDD)**                                                                                

  A0501001      DB, 10-wk, flex-dose    MDD              N=97            n=91            6-17 yrs
                (25-200mg)                                                               

  A0501017      DB, 10-wk, flex-dose    MDD              N=92            n=93            6-17 yrs
                (25-200mg)                                                               

  **Ongoing                                                                              
  Study**                                                                                

  A0501061\*    DB, 10-wk, flex-dose    PTSD             n=80            n=80            6-17 yrs
                (25-200mg)                               \[projected\]   \[projected\]   
  ------------------------------------------------------------------------------------------------

\* A total of 70 patients have been enrolled to date.

## Placebo-controlled Pediatric Studies in Obsessive Compulsive Disorder 

[Study R-0498:]{.underline} This was a double-blind study to evaluate
the safety and efficacy of Zoloft compared to placebo in children (6-12
years) and adolescents (13-17 years) with obsessive compulsive disorder
over 12 weeks of treatment. A total of 187 patients were enrolled, 92
randomized to Zoloft treatment and 95 randomized to placebo treatment.
The randomization was stratified by age so there would be an even
distribution of children and adolescents in the Zoloft and placebo
groups. The starting dose was 25 mg for children and 50 mg for
adolescents and, in the absence of dose-limiting adverse events, the
doses were increased in 25 mg increments for children and 50 mg
increments for adolescents to a maximum of 200 mg/day.

## Placebo-controlled Pediatric Studies in Major Depressive Disorder 

[Studies A0501001 and A0501017:]{.underline} In order to comply with the
requirements of a Written Request, two identical, 10-week,
flexible-dose, placebo-controlled, multicenter studies of Zoloft in
children and adolescents with MDD were conducted. Study A0501001 was
conducted from December 1999 to May 2001 and Study A0501017 was
conducted from February 2000 to March 2001.

Study A0501001 enrolled 188 patients and Study A0501017 enrolled 185
patients. Patients were required to have a current episode of MDD. As is
typical in studies assessing efficacy of MDD, subjects who previously
attempted suicide or who would pose a serious suicidal or homicidal risk
were excluded from the studies. Patients entering the trial were
evaluated for two weeks (screening period) and, if all entry criteria
were met, they were randomly assigned to receive Zoloft or matching
placebo in a double-blind manner. In both studies randomization was
stratified to ensure that an equal number of children and adolescents
were included. For the first 3 days of dosing, patients received 25
mg/day of study drug, followed by an increase to 50 mg/day, thought to
be the minimum effective dose, for the remainder of the first two weeks.
Thereafter, at the discretion of the investigator and in the absence of
any dose limiting side effects, a patient's dose could be increased by
50 mg/day every two weeks to a maximum of 200 mg/day. Doses could be
decreased by 50 mg/day every week for tolerability issues. The
Children's Depression Rating Scale-Revised (CDRS-R) was chosen as the
primary endpoint measure for depressive symptoms because it was the
emerging standard outcome measure in the field, even though there were
at the time few studies that had used it in the public record.

An important element in the design of any clinical trial is the
estimation of the number of patients to be included. As in any sampling
situation, the larger the sample the greater the confidence one can have
that an observed effect accurately reflects the true effect. In a very
uniform and homogeneous group one can expect 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 get a good
estimate of the number of patients needed, statisticians look at the
data from previous similar trials to get information regarding what
values might be due to random variability between patients and what
values represent a true effect. The sample sizes for Studies A0501001
and A0501017 were calculated based on data from a small (n=48 per
treatment group) single-center study of fluoxetine in children and
adolescents with MDD published by Dr. Graham Emslie, the only published
placebo-controlled study of an SSRI utilizing the CDRS-R at the time.
Based on the available estimates of treatment effect using the CDRS-R
scale, it was estimated that 160 subjects (80 per treatment group and
age stratum) would be required to provide 88% likelihood that an
observed effect would represent the true effect.

There was at that time no published multicenter trial that had used the
CDRS-R rating scale 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-placebo-controlled
single site study, a plan was generated to make the two studies
identical and, at a point half-way through the studies, to re-do the
sample size calculations using the real-time data from the ongoing
studies. When this predefined and protocol-specified blinded evaluation
of the variability in the individual studies was performed, it was clear
that the original sample size estimate based on the single-center
experience with the CDRS-R was a substantial underestimate for the
multicenter setting. Indeed, the variability in the studies was
approximately three-fold higher than the expected value that had been
built into the original sample size calculation. It was clear that the
two individual study datasets would need to be combined. Analyzed
together, the two studies would provide a sample size that was large
enough to ensure that the result would be true and accurate to a 90%
level of confidence. Statistical analysis plans for the double-blind
studies and a statistical analysis plan for the combined analysis of the
two studies were all finalized on May 5, 2000, well before completion of
subject enrollment for the studies. The primary analysis for all three
study reports (two individual and one combined) was the mean adjusted
change from baseline to endpoint (Last Observation Carried Forward
\[LOCF\]) for the CDRS-R total score in the intent- to- treat (ITT)
population. All analyses were conducted in accordance with the
statistical analysis plan.

# Evaluation of Suicide-Related Behavior in Placebo-controlled Zoloft Pediatric Studies

There were no completed suicides in the placebo-controlled pediatric
trials with Zoloft. 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.

## Suicide Attempts

Table 2 summarizes the incidence of suicide attempts in the
placebo-controlled Zoloft pediatric trials. In the MDD program, in Study
A0501017, two patients in the Zoloft-treated group and two patients in
the placebo-treated group were classified as having made a suicide
attempt. One patient in the placebo-treated group attempted suicide
twice. In the attempts with high lethality, one subject was taking
Zoloft (subject 5010-4022: multi-drug overdose) and two subjects were
taking placebo (subject 5062-4321: 2 attempts, attempted hanging and
drug overdose; subject 5061-4329: attempted self-immolation). There were
no suicide attempts in the OCD program.

[]{.mark}

Table 2. Incidence of suicide attempts in Zoloft placebo-controlled
pediatric studies

+---------+-------+-----------+-------+-----------+-------+-----------+
| **Diag  | **Se  |           | *     |           | **    |           |
| nosis** | rtral |           | *Plac |           | Sertr |           |
|         | ine** |           | ebo** |           | aline |           |
|         |       |           |       |           | -Plac |           |
|         |       |           |       |           | ebo** |           |
+=========+=======+===========+=======+===========+=======+===========+
|         | n / N | **        | **n / | **        | **p-  | **Dif     |
|         |       | Incidence | N**   | Incidence | value | ference** |
|         |       | %**       |       | %**       | ^2^** |           |
|         |       |           |       |           |       | **\[95%   |
|         |       | **\[95%   |       | **\[95%   |       | CI\]^3^** |
|         |       | CI\]^1^** |       | CI\]^1^** |       |           |
+---------+-------+-----------+-------+-----------+-------+-----------+
| **MDD** | 2 /   | 1.1%      | 2 /   | 1.1%      | 1.000 | -0.03%    |
|         | 189   |           | 184\* |           |       |           |
|         |       | \[0.1 --  |       | \[0.1 --  |       | \[-2.1 -- |
|         |       | 3.8%\]    |       | 3.9%\]    |       | 2.1%\]    |
+---------+-------+-----------+-------+-----------+-------+-----------+
| **OCD** | 0 /   | 0%        | 0 /   | 0%        | 1.000 | 0%        |
|         | 92    |           | 95    |           |       |           |
|         |       | \[-\]     |       | \[-\]     |       | \[0\]     |
+---------+-------+-----------+-------+-----------+-------+-----------+
| ^       |       |           |       |           |       |           |
| 1^exact |       |           |       |           |       |           |
| b       |       |           |       |           |       |           |
| inomial |       |           |       |           |       |           |
| con     |       |           |       |           |       |           |
| fidence |       |           |       |           |       |           |
| bounds. |       |           |       |           |       |           |
|         |       |           |       |           |       |           |
| ^2^F    |       |           |       |           |       |           |
| isher's |       |           |       |           |       |           |
| exact   |       |           |       |           |       |           |
| test.   |       |           |       |           |       |           |
|         |       |           |       |           |       |           |
| ^3^95%  |       |           |       |           |       |           |
| con     |       |           |       |           |       |           |
| fidence |       |           |       |           |       |           |
| in      |       |           |       |           |       |           |
| tervals |       |           |       |           |       |           |
| based   |       |           |       |           |       |           |
| on      |       |           |       |           |       |           |
| normal  |       |           |       |           |       |           |
| approx  |       |           |       |           |       |           |
| imation |       |           |       |           |       |           |
|         |       |           |       |           |       |           |
| \*there |       |           |       |           |       |           |
| were 3  |       |           |       |           |       |           |
| a       |       |           |       |           |       |           |
| ttempts |       |           |       |           |       |           |
| in 2    |       |           |       |           |       |           |
| s       |       |           |       |           |       |           |
| ubjects |       |           |       |           |       |           |
| on      |       |           |       |           |       |           |
| p       |       |           |       |           |       |           |
| lacebo, |       |           |       |           |       |           |
| when    |       |           |       |           |       |           |
| ex      |       |           |       |           |       |           |
| pressed |       |           |       |           |       |           |
| as      |       |           |       |           |       |           |
| events  |       |           |       |           |       |           |
| in      |       |           |       |           |       |           |
| cidence |       |           |       |           |       |           |
| is 1.6% |       |           |       |           |       |           |
| \[0.3   |       |           |       |           |       |           |
| --      |       |           |       |           |       |           |
| 4.7%\]  |       |           |       |           |       |           |
+---------+-------+-----------+-------+-----------+-------+-----------+

## Suicidal Ideation 

Table 3 summarizes the incidence of suicide ideation in the Zoloft
pediatric placebo-controlled trials. Three cases of suicide ideation
were reported in MDD study A0501001, and one in the OCD program, none of
which were deemed by the investigator to be related to study drug.

Table 3. Incidence of suicidal ideation in Zoloft placebo-controlled
pediatric studies

+---------+-------+-----------+-------+-----------+------+-----------+
| **Diag  | **Se  |           | *     |           | **   |           |
| nosis** | rtral |           | *Plac |           | Sert |           |
|         | ine** |           | ebo** |           | rali |           |
|         |       |           |       |           | ne-P |           |
|         |       |           |       |           | lace |           |
|         |       |           |       |           | bo** |           |
+=========+=======+===========+=======+===========+======+===========+
|         | n / N | **        | **n / | **        | **   | **Dif     |
|         |       | Incidence | N**   | Incidence | p-va | ference** |
|         |       | %**       |       | %**       | lue^ |           |
|         |       |           |       |           | 2^** | **\[95%   |
|         |       | **\[95%   |       | **\[95%   |      | CI\]^3^** |
|         |       | CI\]^1^** |       | CI\]^1^** |      |           |
+---------+-------+-----------+-------+-----------+------+-----------+
| **MDD** | 3 /   | 1.6%      | 0 /   | 0.0%      | 0.   | 1.6%      |
|         | 189   |           | 184   |           | 2481 |           |
|         |       | \[0.3 --  |       | \[--%\]   |      | \[-0.2 -- |
|         |       | 4.6%\]    |       |           |      | 3.4%\]    |
+---------+-------+-----------+-------+-----------+------+-----------+
| **OCD** | 0 /   | 0%        | 1 /   | 1.1%      | 1    | -1.1%     |
|         | 92    |           | 95    |           | .000 |           |
|         |       | \[-\]     |       | \[0.03 -- |      | \[-3.2 -- |
|         |       |           |       | 5.7%\]    |      | 1.1%\]    |
+---------+-------+-----------+-------+-----------+------+-----------+
| ^       |       |           |       |           |      |           |
| 1^exact |       |           |       |           |      |           |
| b       |       |           |       |           |      |           |
| inomial |       |           |       |           |      |           |
| con     |       |           |       |           |      |           |
| fidence |       |           |       |           |      |           |
| bounds. |       |           |       |           |      |           |
|         |       |           |       |           |      |           |
| ^2^F    |       |           |       |           |      |           |
| isher's |       |           |       |           |      |           |
| exact   |       |           |       |           |      |           |
| test.   |       |           |       |           |      |           |
|         |       |           |       |           |      |           |
| ^3^95%  |       |           |       |           |      |           |
| con     |       |           |       |           |      |           |
| fidence |       |           |       |           |      |           |
| in      |       |           |       |           |      |           |
| tervals |       |           |       |           |      |           |
| based   |       |           |       |           |      |           |
| on      |       |           |       |           |      |           |
| normal  |       |           |       |           |      |           |
| approx  |       |           |       |           |      |           |
| imation |       |           |       |           |      |           |
+---------+-------+-----------+-------+-----------+------+-----------+

## Event Classification Issues

Classification by investigators of behaviors exhibited by children and
adolescents in a clinical program is inherently subjective. This is
particularly the case with potential suicide related behaviors. As
described in the study report narratives (see section F, individual
patient narratives) some of the cases involving Zoloft-treated subjects
may have been inappropriately classified by the investigator. With
respect to suicide attempts, subject 5049-3095 made no clear attempt;
rather, the child expressed intent in the midst of an argument with his
mother two weeks after his grandmother had attempted suicide. With
respect to cases of suicidal ideation, for subject 5028-1022, the
emergency room attending physician (not the study investigator) treating
the subject saw no evidence of suicide related behavior.

# Individual Patient Narratives

+------------+---------------------------------------------------------+
| Subject ID | Narrative                                               |
|            |                                                         |
| (study)    |                                                         |
+------------+---------------------------------------------------------+
| 90N0242-19 | The subject is a 12 year old female with a principal    |
|            | diagnosis of obsessive compulsive disorder and          |
| (90        | secondary diagnoses of social anxiety disorder and      |
| CE21-0498) | attention deficit hyperactivity disorder randomized to  |
|            | double blind placebo treatment. The subject had the     |
| Placebo    | adverse event of suicidal ideation on day 12.           |
|            |                                                         |
| treatment  | At screening, the subject was administered a Hamilton   |
|            | Depression Rating Scale in order to exclude subjects    |
|            | with significant MDD. The subject's score was 7 without |
|            | any suicidal ideation. It was noted that prior to       |
|            | entering the trial the patient had not responded to     |
|            | either fluoxetine or clomipramine. Physical exam and    |
|            | labs were unremarkable except for mild thyromegaly and  |
|            | low normal T4. The subject did not receive any          |
|            | concomitant medication during the study. At screening   |
|            | baseline, the subject's CYBOCS was 26.                  |
|            |                                                         |
|            | Prior to the event, on day 8 of the study, the subject  |
|            | had a CYBOCS score of 21 and a CGI-S score of 6         |
|            | (severely ill). On day 12 of blinded treatment, the     |
|            | patient experienced 2 days of mild suicidal ideation    |
|            | which did not require any action. In the investigator's |
|            | judgement, the AE was due to the subject's frustration  |
|            | with recurrent OCD symptoms. The patient subsequently   |
|            | continued her participation until week 6 of the study.  |
|            | No clinical improvement was noted on placebo.           |
+------------+---------------------------------------------------------+
| 5026-2006  | The subject is a 12 year old male with a diagnosis of   |
|            | MDD, recurrent, with current episode that began 3       |
| (A0501001) | months prior to study entry randomized to double blind  |
|            | sertraline. The subject also has a past history of      |
|            | suicidal ideation. The subject experienced the AE of    |
|            | suicidal ideation on day 49 on a dose of sertraline     |
|            | 100mg.                                                  |
|            |                                                         |
|            | His medical history was significant for congenital      |
|            | ventricular septal defect, physical exam and lab        |
|            | evaluation was otherwise unremarkable. At baseline, the |
|            | subject's CDRS-R score was 53, with an irritability     |
|            | item score of 3 and suicidal ideation item score of 2.  |
|            | His CGI-S score was 5 (markedly ill).                   |
|            |                                                         |
|            | On day 42, the subject's CDRS-R total score was 62, and |
|            | his irritability item score was 6 and the suicidal      |
|            | ideation item score was 1. The sertraline dose was      |
|            | increased at this visit to 100mg. Over the next 8 days  |
|            | prior to the AE of suicidal ideation, he forgot to take |
|            | his medication on days 44, 47, and 49. On day 49, the   |
|            | subject experienced worsening symptoms of major         |
|            | depression and expressed suicidal ideation. Because the |
|            | subject could not contract for safety, the investigator |
|            | decided to hospitalize the subject. The subject was     |
|            | withdrawn from the study. The event was considered      |
|            | resolved on 25 July 2000, 13 days after the AE was      |
|            | reported. In the investigator's opinion, the event was  |
|            | due to the major depression.                            |
+------------+---------------------------------------------------------+
| 5027-1089  | The subject is a 10 year old female with a primary      |
|            | diagnosis of MDD, single episode of 8 months duration,  |
| (A0501001) | and secondary diagnoses of separation anxiety disorder, |
|            | GAD, and panic disorder of 2 years duration randomized  |
|            | to double blind sertraline. The subject experienced     |
|            | suicidal ideation with plan on day 35.                  |
|            |                                                         |
|            | At the time, the subject was taking 100 mg of           |
|            | sertraline. The patient was not on any concomitant      |
|            | medications immediately before or during the onset of   |
|            | the suicidal ideation. Her medical history, physical    |
|            | exam, and lab evaluation were unremarkable except for   |
|            | migraine headaches and overweight. Her baseline CDRS-R  |
|            | total score was 72, with an irritability item score of  |
|            | 7 and suicidal ideation item score of 1, and CGI-S      |
|            | rating of 4.                                            |
|            |                                                         |
|            | On day 28 of study treatment, the subject's CDRS-R      |
|            | total score was 30, with irritability item score of 4   |
|            | and suicidal ideation item score of 1. On day 35, the   |
|            | subject experienced suicidal ideation with plan.        |
|            | Reportedly, the subject held a kitchen knife to her     |
|            | neck while alone but did not cut herself and the event  |
|            | was not witnessed. At her next scheduled visit, on day  |
|            | 42, the subject reported the suicidal ideation          |
|            | described above, and she was hospitalized and withdrawn |
|            | from the study. The event was considered resolved 7     |
|            | days later and she was discharged from the hospital in  |
|            | improved condition. The investigator attributed the     |
|            | cause to the depression. The subject had been on stable |
|            | sertraline dosing of 100 mg for 13 days prior to the    |
|            | adverse event.                                          |
+------------+---------------------------------------------------------+
| 5028-1022  | The subject is a 10 year old male with diagnosis of     |
|            | major depression, single episode of 9 months duration   |
| (A0501001) | randomized to double blind sertraline who experienced   |
|            | the adverse event (AE) of suicidal ideation on day 21   |
|            | of the study while receiving 100 mg of sertraline.      |
|            |                                                         |
|            | The subject also had a secondary diagnosis of ADHD for  |
|            | the past 3 years. At baseline, the CDRS-R total score   |
|            | was 82 with an irritability item score of 6 and         |
|            | suicidal ideation item score of 4. The subject was      |
|            | determined to be markedly ill (CGI-S =5). The baseline  |
|            | physical exam and laboratory evaluation was             |
|            | unremarkable. The patient received no concomitant       |
|            | medications during the trial.                           |
|            |                                                         |
|            | On day 3, the patient experienced an AE of mild         |
|            | psychomotor agitation while on sertraline 25mg which in |
|            | the investigator's judgement was due to study drug. The |
|            | AE resolved on day 31. At his scheduled visit on day    |
|            | 18, the patient had a CDRS-R score of 74, and           |
|            | irritability score was 4, suicidal ideation was 2. He   |
|            | then received an increase of sertraline to 2 tabs a day |
|            | (100 mg) on day 19. On day 21, the patient experienced  |
|            | the adverse event of suicidal ideation of moderate      |
|            | intensity which led to the patient being withdrawn from |
|            | the study and hospitalized. Apparently, he was involved |
|            | in an argument with his teacher and he made a comment   |
|            | suggestive to the teacher suggestive of suicidality.    |
|            | The school social worker was not immediately available  |
|            | to assess the child so EMS was called and the subject   |
|            | was hospitalized. His attending physician saw no        |
|            | evidence of suicidality and he was discharged from the  |
|            | hospital 5 days later. In the investigator's judgement, |
|            | the AE was not due to study drug and the causality was  |
|            | school altercation.                                     |
+------------+---------------------------------------------------------+
| 5010-4022  | The subject is a 16 year old female with MDD single     |
|            | episode of 3 years duration who received double blind   |
| (A0501017) | sertraline. The subject had an AE of suicide attempt on |
|            | day 50.                                                 |
|            |                                                         |
|            | The dose of sertraline at AE onset was 150 mg. Her      |
|            | medical history, physical exam and lab evaluation were  |
|            | unremarkable. Concomitant medications taken during the  |
|            | study included fexofenadine and ibuprofen. At baseline, |
|            | her CDRS-R total score was 66, with irritability item   |
|            | score of 7, and suicidal ideation item score of 1.      |
|            |                                                         |
|            | On day 24, the subject had an AE of physical            |
|            | restlessness of moderate severity which did not         |
|            | resolve. No action was taken, and the investigator      |
|            | attributed this AE to study drug which had been         |
|            | increased to 100 mg 9 days before. The visit on day 44  |
|            | was unremarkable -- her CDRS-R score was 44,            |
|            | irritability and suicidal ideation item scores were     |
|            | both 1. On day 50, the subject attempted suicide by     |
|            | multidrug overdose including ibuprofen, acetaminophen,  |
|            | naprosyn, aspirin, and dimenhydrinate of indeterminate  |
|            | quantities. The patient was withdrawn from the study,   |
|            | sertraline was discontinued and the subject was         |
|            | hospitalized, given gastric lavage, and admitted for 2  |
|            | days. At the time of the suicide attempt, the patient   |
|            | had been taking sertraline 150 mg a day and had been at |
|            | that dose since day 30. The causality for the attempt   |
|            | was identified as disease under study. Prior to the     |
|            | attempt, the subject was involved in a family argument  |
|            | regarding school attendance.                            |
+------------+---------------------------------------------------------+
| 5049-3095  | The subject is a 6 year old male with MDD single        |
|            | episode of 2 yrs duration who received double blind     |
| (A0501017) | sertraline treatment. On day 34, the subject attempted  |
|            | suicide.                                                |
|            |                                                         |
|            | The dose of sertraline at AE onset was 100 mg. His      |
|            | medical history and physical exam was unremarkable. The |
|            | subject did not receive any concomitant medications     |
|            | immediately before or during the AE. At baseline, the   |
|            | subject's CDRS-R total score was 58, the irritability   |
|            | item score was 7 and suicidal ideation item score was   |
|            | 3, and judged to be moderately ill (CGI-S =4).          |
|            |                                                         |
|            | On day 16, the subject had an AE of severe agitation    |
|            | which did not resolve. The subject had just increased   |
|            | his dose to 100mg on the prior day. There was no action |
|            | taken by the investigator and the AE was attributed to  |
|            | study drug. On day 29, the subject's CDRS-R total score |
|            | was 42 with an irritability item score of 3 and         |
|            | suicidal ideation item score of 4. Of note, at this     |
|            | study visit was an elevated increase of WBC and         |
|            | neutrophil count that was not noted at baseline,        |
|            | possibly indicating latent infection. On day 34, the    |
|            | subject threatened to jump from a moving vehicle        |
|            | stating that he wanted to kill himself. Later that same |
|            | evening, he expressed suicidal ideation and was         |
|            | hospitalized. The subinvestigator attributed this AE to |
|            | the study drug and coded the event as a suicide         |
|            | attempt. The study drug was discontinued and the        |
|            | subject was hospitalized for 7 days. Events that may    |
|            | have affected the subject were: 1) his grandmother      |
|            | attempted suicide 2 weeks earlier and 2) his mother     |
|            | informed him that he was going to be withdrawn from the |
|            | study and that he was to start psychotherapy. In the    |
|            | A0501017 study report, submitted to the Agency on 14    |
|            | December 2001, the sponsor disputed the attribution to  |
|            | study drug, for the reasons listed, and continues to    |
|            | dispute this attribution.                               |
+------------+---------------------------------------------------------+
| 5061-4329  | The subject is a 17 year old female with MDD, single    |
|            | episode of 4 months duration randomized to placebo      |
| (A0501017) | treatment. The subject had an AE of suicide attempt on  |
|            | day 9.                                                  |
| Placebo    |                                                         |
|            | Her medical history was significant for treated GI worm |
| treatment  | infestation one month prior to screening. Before and    |
|            | during the time of the AE, the subject was not          |
|            | receiving any concomitant medications. At baseline, her |
|            | CDRS-R total score was 45 with irritability and         |
|            | suicidal ideation item scores rated as 1. Her CGI-S     |
|            | rating was 4.                                           |
|            |                                                         |
|            | At day 8, the subject's CDRS-R total score was 45 with  |
|            | irritability and suicidal ideation item scores of 1. On |
|            | day 9, the subject attempted suicide by immolation. Her |
|            | siblings doused the flames immediately. She was left    |
|            | with burns on her abdomen and left shoulder. The        |
|            | subject admitted she was angry with her parents for     |
|            | going away. The subject then subsequently admitted that |
|            | she acted impulsively and had not intended to kill      |
|            | herself. The subject's parents did not report this      |
|            | event until day 15 because they thought that the        |
|            | subject's burns were minor. It was reported that she    |
|            | received burn treatment consisting of tetanus toxoid,   |
|            | silver sulphadiazine and paracetamol. Placebo was       |
|            | permanently discontinued on day 15 due to insufficient  |
|            | clinical response. At the time of the attempt, the      |
|            | subject was taking one placebo tab per day. The AE      |
|            | causality was judged to be MDD.                         |
+------------+---------------------------------------------------------+
| 5062-4321  | The subject is a 15 year old female with diagnosis of   |
|            | MDD, single episode with 6 months duration and          |
| (A0501017) | secondary diagnosis of trichotillomania also of 6       |
|            | months duration who was randomized to double blind      |
| Placebo    | placebo treatment. The subject had two separate adverse |
|            | events of suicide attempt on day 63 and day 66 which    |
| treatment  | were revealed to the investigator at the last study     |
|            | visit (end of week 10).                                 |
|            |                                                         |
|            | Her past medical history was unremarkable. Her physical |
|            | exam was notable for sparse hair over the posterior     |
|            | aspect of her scalp. At baseline, her lab examination   |
|            | was significant for low hemoglobin, hematocrit, and MCV |
|            | consistent with mild iron deficiency anemia which did   |
|            | not correct at the final visit. The subject did not     |
|            | receive any concomitant medications during the trial.   |
|            | Her baseline CDRS-R total score was 72, with an         |
|            | irritability item score of 6 and suicidal ideation item |
|            | score of 4. The CGI-S rating was 5.                     |
|            |                                                         |
|            | On day 59 of the study, the subject's CDRS-R total      |
|            | score was 69, with an irritability item score was 5 and |
|            | suicidal ideation item score of 3. Her CGI-I score was  |
|            | 4, indicating no change from baseline. On day 63, she   |
|            | tried to hang herself and was prevented from doing so   |
|            | by her family. On day 66, the subject took 32 tablets   |
|            | of study drug (placebo) in another attempt. She         |
|            | suffered no side effects following this event but was   |
|            | hospitalized for suicidal ideation. The suicidal        |
|            | ideation resolved 9 days after hospitalization, but she |
|            | remained an inpatient for social reasons. Prior to      |
|            | these attempts, the subject was receiving 4 placebo     |
|            | tablets for at least 16 days, but may have been         |
|            | hoarding the tablets. In the opinion of the             |
|            | investigator, these events were due to the disease      |
|            | under study. The subject was considered to have         |
|            | completed study treatment as she completed the final    |
|            | study visit on the same day and prior to                |
|            | hospitalization.                                        |
+------------+---------------------------------------------------------+

# Analysis and Conclusion

Because there were relatively few events of suicide related behavior in
the Zoloft pediatric placebo-controlled trials, non-statistical
inspection of the numbers and derived arithmetic ratios may be prone to
subject variability. Therefore, statistical evaluations were conducted
to determine whether the observed results were more likely to occur by
chance or a drug-related event.

Figure 3 below summarizes the incidence of suicidal behavior (suicidal
ideations and attempts, respectively) in the placebo-controlled
pediatric studies. As can be seen from both number of subjects and
number of events, the 95% confidence intervals overlap in each instance
and the 95% confidence interval of the difference between treatment
groups includes zero in all cases, demonstrating that there is no
statistical difference detected between treatment groups in terms of
suicide related behavior. Further proof of this is derived from Fisher's
exact test in all instances -- none of the derived p values suggest a
statistically significant difference between treatment groups.

**Figure 3. Suicidal Ideation and Suicide Attempts: Point Estimate and
95% Confidence Intervals of Difference between Sertraline and Placebo**

![](media/image1.wmf){width="5.3902777777777775in"
height="3.8090277777777777in"}

Abbreviations: SA = suicide attempt; SI = suicidal ideation

Square symbol size is representative of and proportional to study sample
size.

These statistical analyses do not demonstrate an association between
Zoloft treatment and suicide related behavior. Despite the relatively
low statistical power, the analysis is appropriate to demonstrate that
the observed difference in incidence of events falls within the range
that arises by chance in this population who are at an inherent risk of
suicide related behavior.

The narratives illustrate that there are confounding factors which need
to be taken into account when examining or attempting analysis of
suicidal behavior. These can include, but are not limited to, presence
or absence of comorbidities such as anxiety disorders or attention
deficit disorder, personal history of suicidal behavior in the past,
family history of suicide attempts, MDD, or bipolar disorder,
situational precipitants, age and other confounds.

The safety analysis of clinical study data from the use of Zoloft in the
treatment of pediatric patients (\<18 years of age) with MDD (or with
OCD) does not support a clear causal association between Zoloft and
suicidal behavior. In the placebo-controlled clinical studies, there was
only one relevant event for which a causal relationship with Zoloft had
been reported by the investigator. However, a critical evaluation of
this case as well as the remaining non-related cases does not detect any
signal or establish any pattern that would suggest a causal relationship
with Zoloft.

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Kessler RC et al. The epidemiology of Major Depressive Disorder; results
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