**M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES**

**PUBLIC HEALTH SERVICE**

**FOOD AND DRUG ADMINISTRATION**

**CENTER FOR DRUG EVALUATION AND RESEARCH**

**DATE:** January 5, 2004

**FROM:** Thomas P. Laughren, M.D.

Team Leader, Psychiatric Drug Products

Division of Neuropharmacological Drug Products

HFD-120

**SUBJECT:** Background Comments for February 2, 2004 Meeting of
Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee (Peds AC)

**TO:** Members of PDAC and Peds AC

**Background on Suicidality Associated with Antidepressant Drug
Treatment**

[Longstanding Concern that Antidepressants May be Associated with the
Induction of Suicidality Early in Treatment]{.underline}

One of the goals of the February 2, 2004 meeting of the
Psychopharmacological Drugs Advisory Committee (PDAC) and the Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee (Peds AC) is
to give you an update on the current status of our efforts to better
understand the suicidality data we have received from various drug
development programs involving the use of antidepressant drug products
in pediatric patients.

The occurrence of suicidality in the context of treating patients with
depression and other psychiatric illnesses has been a concern and a
topic of interest and debate for decades. In fact, antidepressant
labeling has, for many decades, carried the following standard language
under Precautions, alerting clinicians to closely monitor patients
during initial drug therapy out of concern for the possible emergence of
suicidality:

> "Suicide: The possibility of a suicide attempt is inherent in major
> depressive disorder and may persist until significant remission
> occurs. Close supervision of high-risk patients should accompany
> initial drug therapy. Prescriptions for Drug X should be written for
> the smallest quantity of tablets consistent with good patient
> management, in order to reduce the risk of overdose."

Of course, this standard Precautions statement does not explicitly warn
of the possibility that antidepressant drugs may have a causal role in
the emergence of suicidality early in treatment. While it is likely
impossible at this point to trace the history of the addition of this
language to antidepressant labeling, I believe that, whether explicit or
not, the statement allows for that interpretation. In fact, as early as
medical school, many physicians learn of this concern, and it has been
part of medical lore for many decades that antidepressants may have an
early activating effect that perhaps gives depressed patients the energy
to follow through on suicidal impulses before the mood improvement
associated with antidepressant treatment takes effect. Following is a
statement from a textbook of psychiatry published over 40 years ago that
is referring to observations in patients during initial treatment with
tricyclic antidepressants \[**Slater and Roth's Clinical Psychiatry, by
Bailliere, Tindall and Cassell; London, 1960, p. 231**\]:

> "With beginning convalescence (following initiation of treatment with
> tricyclic antidepressants), the risk of suicide once more becomes
> serious as retardation fades."

In fact, this particular mechanism proposed to explain a possible
increase in suicidality early in antidepressant treatment is so well
known that it is referred to as the "roll back" phenomenon. However, it
is but one of several mechanisms that have been proposed to explain the
clinical observation that some patients being treated with
antidepressants, particularly early in treatment, may have an increase
in suicidality. This topic was discussed at the September, 1991 meeting
of the PDAC on this same issue, and Dr. Martin Teicher provided a
comprehensive list of the various mechanisms that have been proposed:

-   Roll back phenomenon: view that antidepressants with prominent
    energizing effects may actually increase suicidal behavior in
    severely depressed patients who are suicidal but also have
    psychomotor retardation and are thus inhibited from acting on their
    suicidal thoughts.

-   Paradoxical worsening of depression: view that, in rare patients,
    the depressed mood may actually worsen as a result of antidepressant
    treatment.

-   Akathisia: view that some antidepressants are associated with
    akathisia, and the belief that akathisia may lead to suicidal
    behavior in certain depressed patients.

-   Induction of anxiety and panic attacks: view that certain
    antidepressants may induce anxiety and panic attacks, and that these
    may lead to suicidal behavior in certain depressed patients.

-   Stage shifts: view that antidepressants may lead to switch from
    depression into mixed states in bipolar depressed patients, and this
    may lead to suicidality.

-   Insomnia: view that insomnia associated with certain antidepressants
    may lead to suicidal behavior in certain depressed patients.

While all of these have some plausibility as mechanisms for explaining
the clinical observation of worsening depression or suicidality in
depressed patients being treated with antidepressants, proposing a
mechanism is quite a different matter from demonstrating empirically
that there is a causal association between antidepressant use and
induction of suicidality. Of course, this is the key question we hope to
be able to address with the suicidality data coming from the studies
done with various antidepressant drugs in pediatric patients, i.e., is
there a causal link between antidepressant drug use and suicidality in
pediatric patients with major depressive disorder or other psychiatric
disorders. This is a critically important question to answer, but it is
equally important to answer it in a careful, thoughtful manner. Erring
in either direction would have adverse consequences. Missing a signal of
increased risk of suicidality would result in greater comfort than is
warranted in the safety of these drugs in treating pediatric depression.
On the other hand, a premature decision on the strength of the signal
could result in the overly conservative use of these drugs, or their
lack of availability entirely for the pediatric population. Prematurely
reducing therapeutic options for this serious disease with well
established morbidity and mortality, quite apart from any role that
antidepressant drugs may have, does not seem like a good approach. In
any case, the question is obviously timely and important to fully
address in order to understand how best to use these drugs in the
treatment of pediatric MDD.

If this view that initial antidepressant treatment may be associated
with an actual increase in risk of suicidality is in fact empirically
established, this would, in a sense, confirm a view that is already
widely prevalent in clinical lore, whatever the proposed mechanism.
Despite this fairly widely held view, however, the use of
antidepressants has obviously increased over the years rather than
declined. This fact suggests that, as a group, clinicians may place more
weight on their beliefs in the longer-term benefits of antidepressants
than their concerns about possible early risks of actually increased
suicidal behavior. In fact, the dual findings of an early increase in
the risk of suicidality but also a longer-term benefit for this same
risk with antidepressant treatment would, if both true, not necessarily
be inconsistent. It is quite possible for a drug to have opposite
effects over time, even within the same domain.

[Debate in Recent Years on the Question of Antidepressant-Induced
Suicidality in Adults]{.underline}

The debate on this question with regard to adult depression intensified
in 1990, at which time Martin Teicher, a psychiatrist from Harvard
Medical School, along with several colleagues, published a paper
describing a series of 6 adult patients with depression who, in their
view, became suicidal as a result of being treated with Prozac
(fluoxetine) **(Teicher, et al, 1990)**. This paper and the ensuing
discussion led Lilly, the manufacturer of Prozac, to conduct new
analyses of their controlled trials data for Prozac to explore for the
emergence of suicidality. This renewed interest in the possible
induction of suicidality in association with the use of antidepressant
treatment also led FDA to fully re-evaluate its spontaneous reports
database to try to detect whether or not a signal of increased risk
could be observed. Ultimately, this issue was brought to a PDAC meeting
in September, 1991. This one-day meeting consisted of several hours of
statements made by family members and others in the open public session,
and presentations by representatives from FDA, Lilly, and NIMH.
Statements in the open session were made mostly by family members of
suicide victims whose deaths the families attributed to their taking
Prozac. FDA gave an update on the very substantial number of spontaneous
reports of suicidality in association with Prozac use, but also showed
how the pattern of reporting was clearly linked to the publication of
the Teicher, et al, paper and other publicity about this concern. A
representative from NIMH gave that agency's perspective on this issue,
essentially making the case that depression is a serious disorder that
itself is associated with suicidality, and arguing that the data
available to date did not support the view that antidepressants further
increase the risks of suicidality in this population. Finally, Lilly
presented the results of its analysis of data pooled over its extensive
clinical trials, revealing no signal of increased suicidality in
association with the use of Prozac **(Beasley, et al, 1991)**. At the
end of a long day, a majority of the committee concluded that there was
no clear evidence of an increased risk of suicidality in association
with the use of Prozac, and they did not recommend any changes to Prozac
labeling with regard to this issue.

Over the next several years, additional data were accumulated as
applications for newer antidepressants were submitted and reviewed, and
these drugs came to market. Several groups have, in recent years,
conducted pooled analyses for adult data on completed or attempted
suicides from these programs, in order to continue the search for a
possible signal of risk, either by virtue of being assigned to placebo,
since the ethics of conducting placebo controlled trials in depression
were being challenged, or due to assignment to drug treatment. Arif
Khan, a psychiatrist from the Northwest Clinical Research Center,
Bellevue, Washington, published a paper in 2000 based on adult data he
obtained under FOI from FDA reviews. He concluded that the risk of
completed suicide was the same, regardless of treatment assignment
**(Khan, et al, 2000)**. Jitschak Storosum, a physician from the
Medicines Evaluation Board of the Netherlands, did an analysis of
attempted suicides from adult data available to his group, and he
reached the same conclusion **(Storosum, et al, 2001)**. FDA has done
several analyses on completed suicides for adult data sets provided to
us in response to a request for patient level data sets[^1] for all
relevant studies involving 20 antidepressant drugs studied in 234
randomized controlled trials with MDD. Based on our initial analyses of
these data, we have reached a similar conclusion, i.e., that there does
not appear to be an increased risk of completed suicide associated with
assignment to either active drug or placebo in adults with MDD
**(Hammad, et al, 2003)**.

**Source of Pediatric Suicidality Data**

Regarding pediatric suicidality, it is important first of all to
understand how it is that the various pediatric trials happen to have
been done. These trials were done largely in response to a change in the
Food, Drug and Cosmetic Act that authorized FDA to grant additional
marketing exclusivity (referred to as pediatric exclusivity) to
pharmaceutical manufacturers who were willing to conduct studies of
their drugs as requested by the FDA in pediatric populations. The first
law permitting the pediatric exclusivity incentive was the FDA
Modernization Act (FDAMA, 1997), and this authority to attach additional
marketing exclusivity for such studies was renewed in the Best
Pharmaceuticals for Children Act (BCPA, 2001). In order to qualify for
pediatric exclusivity, sponsors had to conduct pediatric studies
according to the terms of a Written Request from FDA, and submit the
results of those studies in a pediatric supplement. We have reviewed 8
pediatric supplements over the past few years for pediatric drug
development programs involving antidepressant drugs that were conducted
to gain additional marketing exclusivity, and these supplements are the
source of the pediatric suicidality data that are at issue for this
meeting. For completeness, we have included in our review of pediatric
suicidality two studies for a ninth antidepressant drug for which the
studies were not done for exclusivity. Our review includes a total of 24
studies for these 9 drugs, involving a total of over 4000 pediatric
patients.

The 9 drugs involved in our review are:

-   Prozac (fluoxetine)

-   Zoloft (sertraline)

-   Paxil (paroxetine)

-   Luvox (fluvoxamine)

-   Celexa (citalopram)

-   Wellbutrin (bupropion)

-   Effexor (venlafaxine)

-   Serzone (nefazodone)

-   Remeron (mirtazapine)

Of the 24 studies for these 9 drugs, 15 were in MDD, 4 in OCD, 2 in GAD,
1 in SAD, and 2 in ADHD.

**Effectiveness Data for Antidepressants in Pediatric MDD**

While the focus of the discussion at the Feb 2^nd^ PDAC meeting will be
on pediatric suicidality data, it is important to consider the
effectiveness data for these drugs as part of the overall context for
this discussion. Ultimately, this is a risk benefit assessment, so it is
important to know where we stand on the benefit side of this issue. Of
the 7 programs in pediatric MDD (Prozac; Zoloft; Paxil; Celexa; Effexor;
Serzone; Remeron), FDA's reviews of the effectiveness data resulted in
only 1 approval for pediatric MDD, i.e., for Prozac. The efficacy
results from the 15 studies in pediatric MDD are summarized in
**Appendix 1**.

These are sobering findings and certainly raise a question about the
benefits of these drugs in pediatric depression, however, the findings
need to be considered in the context of several other facts.

\(1\) In all but one case for the failed programs, there were only 2
studies in MDD; for the remaining failed program, there were 3 MDD
studies. Among the failed programs there was one program where 1 of the
studies was positive (citalopram), and 2 others where the results, while
negative by the usual standards, were at least trending toward positive
for 1 of the 2 studies (sertraline and nefazodone). Of note, the
published literature gives a somewhat different perspective, suggesting
more positivity in 2 of these programs than was the conclusion at FDA.
One paper describes one of the Paxil studies as positive on most of the
secondary endpoints, while acknowledging that it failed on the primary
endpoint **(Keller, et al, 2001)**. Another paper describes the Zoloft
program as positive, based on a pooling of 2 similarly designed studies
that, when looked at individually, failed **(Wagner, et al, 2003)**.

In adult MDD programs for drugs that are approved for this indication,
overall, the failure rate for studies that appear in every respect to be
adequate trials is about 50%. Thus, if the failure rate were the same in
pediatric MDD, it would not be unexpected to have either 1 or both
studies fail. In fact, since the studies can be considered independent
of one another, the probability of having one or both studies fail in
the 2-study programs is actually 0.75 \[3(0.5 X 0.5)\]; the probability
of both succeeding would be only 0.25 (0.5 X 0.5). Thus, under the best
of circumstances, these very limited programs may have been expected to
mostly fail regarding the goal of obtaining 2 positive studies.
Nevertheless, the overall success rate for positive studies of 20%
(3/15) is clearly a concern.

\(2\) The history of pediatric MDD studies with the tricyclic
antidepressants (TCAs) is uniformly negative. This finding may have
several possible explanations, including flaws in design or conduct, or
the possibility that TCAs simply do not work in pediatric MDD. It is
also possible, however, that there is even greater heterogeneity among
pediatric patients who meet criteria for MDD than is true for adults. If
true, this would also work against obtaining positive studies in
pediatric MDD.

\(3\) The context in which these studies were conducted was not ideal,
in the sense that there was no need to obtain positive results in order
to gain exclusivity. The programs simply had to be conducted according
to the terms of the Written Requests, and the results submitted to meet
deadlines specified in those requests. This is not to suggest that
sponsors of these studies did not design and conduct them with good
intent and according to high standards, but rather, that the mindset was
different than the usual mindset for registration trials. Ordinarily, a
failure of a registration trial to show a drug effect is a complete
loss. That was not the case here and this reality could have influenced
the conduct of the study in subtle ways that might have worked against
getting a positive result, e.g., in recruitment of patients.

\(4\) Finally, there was not the kind of preliminary phase 2 dose
finding exploration for these studies that typically precedes definitive
trials in adult studies. We are routinely asking for such exploration as
part of the Written Requests we are now issuing.

The point I am making is that there are several plausible reasons for
all but one of these programs failing, other than the possibility that
these drugs may have no benefits in pediatric MDD. It is understandable
how some may have reached the conclusion that these studies represent
proof that these drugs, with the exception of Prozac, have no benefits
in pediatric MDD. We at FDA, however, do not view negative studies as
proof of no benefit. In our view, absence of evidence for effectiveness
in most of these programs does not constitute evidence of absence of
benefit for these drugs in pediatric patients, for all the reasons noted
above. Nevertheless, the failure of most of these programs to show a
benefit in MDD does heighten the concern about the possibility of
certain risks that may be associated with these drugs, in particular the
concern about induction of suicidality. In any case, the burden is
clearly upon those who believe these drugs do have benefits in pediatric
MDD to design and conduct studies that are capable of demonstrating such
benefits. I will return later to a possible alternative approach to
acute efficacy studies for demonstrating antidepressant benefits of
these drugs.

**Origins of Present Concern About the Emergence of Pediatric
Suicidality in Association with Antidepressant Use; Initial Regulatory
Response**

[Background to May, 2003 Paroxetine Report]{.underline}

After this brief look at the effectiveness issue, I want now to return
to the issue of the origins of the present concerns about pediatric
suicidality. My approach will be to give a temporal perspective on how
this issue has evolved over the past approximately 7 months. The focus
will be on certain adverse events that were reported in the pediatric
supplements for the various antidepressants, in particular, adverse
events considered to represent suicidality.

First, it is important to comment on the approach used to elicit
treatment emergent suicidality in these trials. In part, investigators
relied on very general prompts, e.g., asking the general question of
"how have things been" at each visit. While this approach is perhaps
somewhat superior to spontaneous reporting, it is likely a distinctly
insensitive approach to eliciting adverse events related to suicidality.
Even in adults with MDD, it generally requires a skilled clinician to
elicit patient reporting of suicidal ideation or behavior, and this
tendency to conceal such ideation and behavior may be even more
prominent in adolescents. On the other hand, all of these trials also
utilized formal instruments for assessing depressive symptoms, each of
them including a suicidality item. However, it is not clear what
elicitation approaches were used in completing these instruments, and
thus, it is not clear whether or not there was specific elicitation with
regard to suicidality. Furthermore, these instruments were not always
done at the times that patients were experiencing events of interest,
since such events occurred at random times. In order to adequately
assess for such emergence of suicidal ideation and/or behaviors, it is
important to have methods that are sensitive to detecting such effects.

In any case, verbatim (investigator) adverse events in any drug
development program, however they are elicited, are coded by subsuming
them under preferred terms in order to capture like events under the
same term, even if patients or investigators had used variable language
to describe the events. For these pediatric trials, adverse events
suggestive of suicidality were coded by the various sponsors for their
programs, using approaches unique to each program, and these data were
examined, along with numerous other adverse events, in the course of our
reviews of the pediatric supplements. FDA's clinical reviews for these
supplements, conducted over a several year period prior to our becoming
aware of a possible signal for the paroxetine program, did not, overall,
suggest a signal for drug treatment-induced suicidality.

The Paxil review, however, did raise a question of data management. The
clinical reviewer for the Paxil supplement noticed that events
suggestive of possible suicidality were subsumed under the preferred
term "emotional lability," rather than under a preferred term more
directly suggestive of suicidality. Other verbatim terms were also
subsumed under "emotional lability," so one of our requests to GSK in
our response letter to their pediatric supplement for Paxil was to ask
them to separate out for us the verbatim terms suggestive of
suicidality. This request was the basis for the additional work done by
GSK on this issue of suicidality that resulted in their submission of a
report on suicidality, first to the UK, and shortly thereafter, to FDA,
on May 22, 2003.

This May 22, 2003 report suggested an increased risk (paroxetine vs
placebo) of various thoughts and behaviors coded as events considered
"possibly suicide related" and also for the subgroup of these events
that met the sponsor's criteria for representing "suicide attempts." The
signal for increased risk was clearest for 1 of the 3 trials involving
pediatric patients with MDD. A summary of the sponsor's findings for the
MDD trials in the Paxil program is included in **Appendix 2.**

[Initial Regulatory Response to Signal of Increased Risk of Suicidality
for Paroxetine]{.underline}

The reaction to this report by the MHRA in the UK was very prompt,
resulting in:

-   A public statement explicitly stating that paroxetine "should not be
    used in children and adolescents under the age of 18 years to treat
    depressive illness," and

-   A labeling change contraindicating paroxetine in pediatric MDD.

FDA's response was soon to follow, with:

-   A public health advisory, stating that: "Although the FDA has not
    completed its evaluation of the new safety data, FDA is recommending
    that Paxil not be used in children and adolescents for the treatment
    of MDD."

-   Despite the strong advisory, we did not take any labeling action,
    and in fact have not taken any action on labeling as of the date of
    this memo.

**Overview of FDA's Ongoing Review of Antidepressants and Pediatric
Suicidality**

[GSK Approach to Accumulating Paroxetine Summary Data]{.underline}

First, I want to describe in some detail the approach GSK took in
evaluating their pediatric clinical trials data for suicidality, since
we modeled our request to sponsors of other antidepressants after the
GSK approach, in order to ensure that we would have similar data from
different programs, for comparative purposes. They focused exclusively
on placebo controlled trials (there were 6 such trials in the GSK
program), and that has been our focus as well. As noted earlier, in
their original pediatric supplement, they had subsumed events suggestive
of suicidality under the preferred term "emotional lability," along with
various other behavioral events. Subsequent to our request for a
separate approach to events suggestive of suicidality, they conducted
the following searches to find events of potential interest:

-   Electronic searches of their database with text strings of
    particular relevance for suicidality:

    -   Search for all events for which the preferred term was either
        "overdose" or "intentional overdose" ([Note]{.underline}: They
        did not include any events for which the preferred term was
        "accidental overdose")

    -   Search of verbatim (i.e., investigator) terms for events that
        had originally been coded with the preferred term "emotional
        lability," in order to find verbatim terms including any of the
        following 15 text strings: "attempt; cut; gas; hang; hung; jump;
        mutilat; overdos; self damag; self harm; self inflict; self
        injur; shoot; slash; suic"

    -   Search of all verbatim terms containing the text string
        "overdose" or "suic" ([Note]{.underline}: They specifically
        excluded any events for which the verbatim term selected was a
        result of the text string occurring in another word that had no
        relevance to suicidality.)

-   They included in their analyses only patients having events that
    occurred either during randomized treatment or in the +30 days
    posttherapy window, and only events they judged to represent
    treatment-emergent events (However, treatment emergent was not
    well-defined and no information was provided for any cases excluded
    for not being considered treatment-emergent). All events meeting
    these criteria were included under the broad category "possibly
    suicide related."

-   GSK then created the subset of patients having events meeting their
    criteria for "suicide attempt" using the following criteria:

    -   A text string suggestive of self-harm

    -   Preferred term "overdose" or "intentional overdose"

    -   They did exclude certain events judged (blindly) by their own
        staff not to represent suicidality, however, no details were
        provided on these patients or for the criteria used in excluding
        cases

[Request for Summary Data for Other Antidepressants]{.underline}

Following our initial review of the Paxil suicidality summary data, we
decided to ask for similar data for the other 8 antidepressants. We
decided that it would be most efficient to ask other sponsors to use a
similar approach to that used by GSK in exploring the Paxil data. Thus,
we issued a letter on July 22, 2003, requesting such summary data for
the placebo controlled pediatric studies for the 8 other antidepressant
products for which such studies had been conducted:

-   Prozac (fluoxetine)

-   Zoloft (sertraline)

-   Luvox (fluvoxamine)

-   Celexa (citalopram)

-   Wellbutrin (bupropion)

-   Effexor (venlafaxine)

-   Serzone (nefazodone)

-   Remeron (mirtazapine)

In this July 22^nd^ letter, we asked the sponsors for these products to
identify "suicide-related events" for their pediatric studies, in a
"blinded" manner, using two search strategies. Since our request was
modeled after the approach GSK had already used, it included many of the
same details provided above:

-   Electronic searches of their database with text strings of
    particular relevance for suicidality:

    -   Search of preferred terms for the following 2 text strings:
        "suic" or "overdos"

        -   [Note]{.underline}: We indicated that they may exclude
            instances coded as accidental overdoses, but asked them to
            provide information on these cases in a separate table.

    -   Search of verbatim (i.e., investigator) terms for the following
        15 text strings: "attempt; cut; gas; hang; hung; jump; mutilat;
        overdos; self damag; self harm; self inflict; self injur; shoot;
        slash; suic"

        -   [Note]{.underline}: We did indicate that terms identified
            using these electronic searches because one of these text
            strings was included in a word that had no relevance to
            suicidality could be excluded.

-   In addition, we asked them to blindly review narratives for any
    deaths and serious adverse events (SAEs) in order to identify any
    additional possible instances of "suicide-related events"

    -   [Note]{.underline}: There were no deaths due to any cause in any
        of the 24 studies included in these pediatric programs

-   We also asked the sponsors to blindly select from among the larger
    set of "suicide-related events" a subset of events that could be
    consider "suicide attempts," defined to include all patients who
    exhibited self-injurious behavior.

-   We asked sponsors to provide a narrative for each patient identified
    as having one or more potential events, and also a table including
    the same information for each such patient.

The letter also asked for analyses for the cases identified using these
approaches similar to those described above for Paxil.

[Re-Review of Suicidality Data from Pediatric Supplements for Other
Antidepressants]{.underline}

While we were waiting for the various sponsors of the antidepressants
other than Paxil to respond with their summary data, we went back to the
summary adverse event data in the pediatric supplements for these other
drugs to re-examine the question of suicidality. The major question of
interest was whether or not there were other antidepressants with
possible signals of increased risk for suicidality, as was observed for
Paxil. There were several limitations to this re-examination. First, the
methods for detecting and coding events were not standard across these
programs. Second, since we wanted to have similar numerator categories
to those used for the Paxil data, for purposes of comparison across drug
programs, we classified any events described in the adverse event
listings, etc for these drug programs into the two categories of
interest: "possibly suicide-related" and "suicide attempt." One obvious
flaw in this approach was that the FDA reviewer was not blinded during
this reclassification process. Nevertheless, it was hoped that this
somewhat crude re-examination of these summary data might shed some
light on the possibility of signals emerging from other antidepressant
programs.

While the methodology for this initial exploration was necessarily
crude, it did provide some further insight into the treatment-emergent
suicidality question across these 9 drug programs. There were several
findings of particular interest resulting from this crude look at the
pediatric supplements data. First, there were signals of increased risk
of suicidality for patients assigned to drug for more than the
paroxetine program, and second, the findings were not consistent across
the studies even within individual programs. Finally, the signals were
coming predominantly from the MDD studies within these programs.

[Wyeth Labeling Change and Dear Health Care Professional Letter for
Effexor, and Regulatory Response]{.underline}

During this period while we were re-examining the suicidality data from
the pediatric supplements and beginning to receive responses to our
requests for summary data from the sponsors for the other
antidepressants, Wyeth, the sponsor for Effexor (venlafaxine) and
Effexor XR, decided to make labeling changes for its products with
regard to suicidality and hostility. This action was based on its
re-analyses of the Effexor pediatric trials data. The labeling change
was the addition of a statement to the Usage in Children/Pediatric Use
section of Precautions to note increased reports of hostility and
suicidality. This labeling change was accompanied by a Dear Health Care
Professional letter (August 22, 2003) noting the findings and also
noting that these products are not recommended for use in pediatric
patients. It should be noted that sponsors have the authority to make
changes of this nature, i.e., that are perceived to strengthen labeling
from the standpoint of safety, without prior approval by FDA.

This action by Wyeth was followed in September, 2003 by a regulatory
response by the MHRA in the UK similar to their response to the report
on paroxetine suicidality data. They issued a public statement advising
that these products should not be used in pediatric MDD, accompanied by
a change in labeling to contraindicate these products in pediatric MDD.
FDA has not taken any regulatory action based on these findings for
venlafaxine, since we view these as preliminary data that require the
same level of more detailed review needed for the other antidepressant
drug products.

[FDA Internal Regulatory Briefing]{.underline}

An important milestone in our consideration of the pediatric suicidality
data was an internal briefing for upper level CDER management held on
September 16, 2003. This briefing was held at a time when we had
available to us only a preliminary review of the summary data for the
Paxil program and a crude re-analysis of suicidality data from the
pediatric supplements, i.e., we had not yet received even the summary
data from the pediatric programs other than Paxil. There were several
agreements reached at this meeting, including two that were of
particular importance for our further plans for addressing this issue.
It was acknowledged that a very broad net had been cast in trying to
capture events of potential interest with regard to possible
suicidality, and questions were raised about what many of these events
actually represented. Thus, there was agreement that it would be useful
to try to have all events of potential interest blindly reclassified by
outside experts in suicidality in order to have greater confidence in
what the signals represented. Second, there was acknowledgement that
there was inconsistency in the signals across individual studies for the
various programs for which signals of increased risk for suicidality
emerged, based on the re-analyses of pediatric supplement data. Thus,
there was also agreement that it would be useful to attempt to obtain
patient level data sets for all of these trials in order to permit a
more refined analyses using adjustment for potentially important
covariates. These agreements strongly influenced the subsequent course
of our efforts to better understand these data.

[Updated FDA Public Health Advisory and Talk Paper]{.underline}

We issued an updated public health advisory and talk paper on October
27, 2003, based on our assessment of the pediatric suicidality data at
that point in time. We indicated that preliminary data suggested an
excess of reports of suicidality for several antidepressant drugs,
however, we noted that additional data and analysis would be needed. We
also noted that we intended to bring this issue to an advisory committee
meeting. We advised caution in the use of any of these drugs in MDD, and
reminded prescribers of the standard language already in antidepressant
labeling alerting clinicians to the need for close supervision of high
risk patients, particularly during initial drug therapy.

[Responses to FDA's Request for Summary Data for Other
Antidepressants]{.underline}

Now I want to return to the summary data for the other antidepressant
drugs. The responses including the requested data and analyses for these
summary data began arriving in late August, and had all arrived by late
September, 2003. Unfortunately, as we began reviewing these responses,
it became clear that different sponsors had interpreted the July 22^nd^
request differently, resulting in our lack of confidence that the cases
of suicidality had been selected for review, classified, and presented
to us using similar approaches for all 8 sponsors. This impression was
confirmed when we spoke to individual sponsors about their approach to
this request. In retrospect, the algorithm we had provided for searching
for potential events and selecting patients with events for the summary
data analyses was not sufficiently detailed to result in a common
understanding. This discovery presented a major hurdle to overcome in
our evaluation of these data, since we needed to have confidence in the
thoroughness and uniformity of the methods used for gathering and
classifying these cases.

I will provide at this point several examples of the kinds of variations
in methods we discovered across the different sponsors. This list of
variations is just a sampling of the types of variations, and should
serve the purpose of making clear why we needed to spend considerably
more time ensuring that all relevant cases had been accumulated, and
that they had been appropriately classified. We felt this was critical
in order for us to complete our assessment of this potential problem.

-   We had hoped to have a complete accounting of potential events
    identified by the search algorithms and SAE narrative reviews,
    however, in no case did a sponsor provide such an accounting. At one
    extreme we were provided narratives only for patients judged by the
    sponsor to have events that represented suicidality, with no
    explanation as to why other patients identified by the algorithms
    might have been excluded. In other cases, more details were provided
    on patients who had been excluded, but none of the reports was
    completely satisfactory in this regard.

-   Although most sponsors conducted the search and selection of cases
    according to our instructions, in no case did they provide us with
    the specific criteria used in excluding cases at various levels of
    the process.

    -   For example, although we invited sponsors to exclude cases that
        might be considered "false positives" in the sense described
        above, i.e., where the text string of interest occurred in a
        longer word that was irrelevant to suicidality, we had expected
        that excluded cases would have been described. Most sponsors did
        not provide such a listing.

    -   We had asked for cases coded as accidental overdose, and for the
        most part received this information, however, we had failed to
        inquire about cases coded as accidental injury, and most
        sponsors did not fully address how they handled these cases. In
        fact, most sponsors simply excluded all cases coded as
        accidental injury, without further review. As an example, after
        we began inquiring about the process of excluding cases, we
        received from one sponsor a line listing of excluded cases that
        included a case of a child who was excluded as accidental injury
        with an event characterized only as "patient stabbed himself in
        the neck with a pencil while taking a test." While this may have
        in fact represented an accidental injury, we decided it would be
        important to know enough details about cases coded as accidental
        injury in order to be confident that such cases were
        appropriately classified and excluded.

    -   At least one sponsor acknowledged that they had conducted some
        of the searching and selection of cases with knowledge of
        treatment assignment, in particular, for the review of narrative
        summaries of SAEs.

    -   Another sponsor acknowledged that they had excluded cases where
        the events that occurred were not considered "treatment
        emergent." These were events suggestive of suicidality but for
        which there was evidence that the event may have also been
        occurring before randomization. No other information had been
        provided about the excluded cases in the sponsor's summary
        submission.

    -   Another finding that raised concern about the approach to case
        exclusion and selection resulted from our comparison of our
        results of suicidality risk for one drug product based on our
        re-review of the pediatric supplements with that sponsor's
        analysis of suicidality based on their reclassification of cases
        in response to our July 22^nd^ request. In this particular
        instance, there was a striking difference in the results of the
        two analysis, i.e., a strong signal emerging from our
        re-examination of the pediatric supplement for that drug
        compared to only a weak signal emerging from the sponsor's
        analysis submitted in response to our July 22^nd^ letter.

-   As noted earlier, for many of the events included in the various
    analyses as representative of suicidality, there were questions
    about whether or not they were appropriately classified as such.
    Many of these were described as instances of very minor self injury
    with no indication of suicidal intent.

-   There were also substantial differences across different programs in
    the selection of cases representing suicide attempts, with some
    sponsors deciding to include essentially all captured events as
    suicide attempts, even though there was clearly not enough
    information in the cases to justify such a classification.

[Decision to Seek Outside Review and Reclassification of
Cases]{.underline}

During this period when we were re-examining the pediatric supplement
data and then beginning to explore the summary data provided to us in
response to our July 22^nd^ letter, it was becoming increasingly clear
that we could not have confidence in the numerator events for the
analyses we were provided by the sponsors, because the methods were not
well-articulated, and the limited details available about the methods
suggested that they varied substantially for different sponsors. Thus,
we essentially confirmed the view already reached tentatively at our
internal regulatory briefing that it would be desirable to have
potential events blindly reclassified by an independent group. We
briefly considered doing this internally, but quickly rejected this
idea, since (1) we clearly did not have the expertise in suicidality to
conduct such a reclassification, and (2) most of those who might
logically be involved in such an effort had already seen many of the
cases. Thus, we began to look outside the agency, and we initiated a
series of discussions with outside experts. We found several experts
interested in such an effort, however, there remained the problem of who
would coordinate the overall effort, establish methods and criteria for
reclassification, etc. Among the experts we discovered in our search was
a group at Columbia University who not only had well-recognized
expertise in adolescent suicidality, but also had developed an approach
to classifying events possibly representative of suicidality that
precisely fit our needs. Thus we have been involved in extensive
discussions with this group in order to establish a contract for having
this reclassification of cases accomplished and also to work out the
details of a standard approach to both finding all relevant cases and
setting up categories for the reclassification effort that would meet
our needs from a regulatory standpoint. At the present time, the
contract is in place and we are in the process of preparing case
material to provide to this group. It is important to note that, while
the Columbia group will serve as the coordinating center for this
effort, experts in adolescent suicidality from several other academic
centers will also participate in the process in order to ensure broad
representation from the expert community. Once we have provided the case
materials to this group, one of the initial goals will be to try to
reach agreement on an approach to classifying events into appropriate
categories.

[Second Request for Identification of Events of Potential Interest with
Regard to Suicidality]{.underline}

As a result of our discussions with sponsors about their submissions in
response to our July 22^nd^ request for summary data on suicidality from
their pediatric studies, and our discussions with the expert group at
Columbia University about the reclassification of these cases, we worked
out a more detailed standard method for sponsors to use in assembling
their data regarding any cases of potential interest detected in the
searches of their pediatric data base. This document was provided to
sponsors for all 9 antidepressant products on Nov 24, 2003. Following is
a summary of key aspects of this new standard:

-   We asked sponsors to confirm that they had conducted an electronic
    search of their preferred terms and verbatim terms using the text
    strings specified in our July 22^nd^ letter, or if not, to describe
    in detail what they had done.

-   We next asked sponsors to provide a complete accounting of the
    winnowing down of the complete list of potential events/patients
    identified by these electronic searches to arrive at the events that
    would need to be blindly reclassified by outside experts. Sponsors
    were asked to provide the total number of patients identified as
    having 1 or more such potential events suggestive of suicidality, as
    a starting point. We then requested that they fully describe the
    exclusions from this list, for the following reasons:

    -   Prerandomization events: Sponsors were to list all patients
        excluded because all of their potential events occurred
        prerandomization.

    -   Events occurring more than 30 days beyond the last dose of
        randomized treatment: Sponsors were to list all patients
        excluded because all of their potential events occurred more
        than 30 days beyond the last dose of randomized treatment.

    -   False positive events: Sponsors were to list all patients
        excluded because all of their potential events could be
        characterized as "false positives" in the sense that a preferred
        or verbatim term was selected because one of the text strings
        occurred within that term and the term has no relevance to
        suicidality, e.g., "gas" in "gastrointestinal."

    -   We asked for summary narratives for all remaining patients with
        potential events, including patients classified as having
        accidental injury or accidental overdose (i.e., using preferred
        terms).

-   In addition, we asked sponsors to provide narratives for all
    patients having one or more serious adverse events (SAE, based on
    regulatory definition) that occurred either in the randomized
    doubleblind phase of the controlled trials or within the +30 days
    beyond the last randomized dose period described earlier.

[Blinded Reclassification of Potential Suicidality Events]{.underline}

We have now received responses to this Nov 24^th^ request from most of
the sponsors, and, as noted, we are in the process of preparing this
information to forward to our outside contractors. We expect to be
working closely with them over the next month in order to reach
agreement on (1) the approach they will use in cleaning and blinding the
narratives for information that might bias their assessment (to be done
by an independent group who will not be involved in the reclassification
of events), (2) the categories into which events will be classified and
the criteria for such placements, (3) the process by which disagreements
will be resolved, or if not resolved, the process for reaching the best
judgement for classifying any particular case. We expect that it will
take at least another several months to complete this reclassification
effort. A member from the Columbia group will be making a presentation
at the Feb 2^nd^ meeting to describe their role in this project in
greater detail.

There is one caveat to this effort. It is ultimately limited by 2
significant problems. First, as noted earlier, the approach to eliciting
suicidal ideation and behavior was of unknown sensitivity. Second, the
approach to identifying potential events may have missed certain events
if they were not classified as serious, since detection for the other
events depended on matching on certain text strings, and the list of
text strings was necessarily limited.

[Interim Overview of Results from Sponsors' Analyses of their Original
Summary Data (i.e., for drugs other than Paxil)]{.underline}

Given that we are not confident in what the numerator data represent in
the summary analyses provided by the sponsors for these pediatric
studies, we will not be presenting detailed results from these analyses
at this time. However, I have included one summary data table
(**Appendix 2**) in order to make two important observations. **Appendix
2** summarizes risk data by individual study for the 15 pediatric major
depressive disorder (MDD) studies for which we have data. While we have
been provided data both for "on-therapy" and for "on-therapy + 30 days"
events, I have focused on the "on-therapy" data, since these are the
least problematic from the standpoint of interpretation. While we do
sometimes utilize an "on-therapy + 30 days" timeframe for capturing
events of interest, this analysis is problematic in this case for two
reasons. First, it may be confounded by discontinuation symptoms
occurring following withdrawal of medication, and second, different
sponsors used different rules in deciding what events to include and
exclude from the +30 days period in their analyses. For simplicity, I
have provided the data for all ages combined, rather than breaking it
out by age group. The table provides risk (percentage of patients having
at least 1 event) and risk ratio (when this can be calculated). Risk is
provided both for the category "possibly suicide-related" and the
subgroup of events classified as "suicide attempts."

I think there are two important observations from this table:

(1) A signal of increased risk on drug is apparent for at least 4 of the
    7 programs, i.e., paroxetine, sertraline, venlafaxine, and
    citalopram, with perhaps a weak signal for nefazodone.

(2) There is inconsistency across the individual studies within the
    programs for which there is an apparent signal, with the exception
    of venlafaxine, where both studies reveal a signal. For paroxetine,
    a signal emerges from 1 study (329), but without even a weak signal
    for the other 2 studies in the program. This is also the case for
    sertraline and citalopram, where a signal emerges from 1 of 2
    studies in each case, with no signal emerging in the other study.
    While fluoxetine is generally without a signal, in the "suicide
    attempts" analysis for study X065 there is actually a signal for
    drug. There are several instances where the risk ratio favors drug
    over placebo.

Overall, I think **Appendix 2** reveals that, while there are signals of
increased risk of events suggestive of suicidality for several of these
drugs, the signals for the most part are coming from a single trial
within each of these programs. An important additional point, however,
is that we are not yet confident in what the identified events
represent.

[Planned Analyses of Patient Level Data for Pediatric
Suicidality]{.underline}

As noted earlier, the observation of inconsistency of the signal across
studies within individual programs based on a crude re-analysis of
suicidality from the pediatric supplements resulted in a recommendation
from our internal regulatory briefing to request patient level data to
permit us to conduct a more refined analysis including adjustment for
potentially important covariates. Since the summary data provided by the
sponors in response to our July 22, 2003 request have confirmed that
finding of inconsistency, we are planning on proceeding with this more
detailed analysis of the suicidality data from these programs. A
standard letter requesting patient level data sets was issued to all
sponsors on October 3, 2003. The variable list was expanded several
times in subsequent weeks, and the final variable list is included as
**Appendix 3**. We have now received all of these data sets from
sponsors, and we are in the process of developing an analysis plan to
explore for excess risk of suicidality using a statistical model that
provides for adjustment of covariates. The numerator events for this
analysis will be identified based on the reclassification of patient
events by our outside experts. A member of our safety group will make a
presentation on the current status of our plans for this analysis at the
Feb 2^nd^ meeting.

**Update on Most Recent Regulatory Action on Antidepressant Treatment of
Pediatric MDD by MHRA**

The MHRA (UK) made a public announcement on Dec 10, 2003 indicating
that, in addition to its earlier contraindications of paroxetine and
venlafaxine in pediatric MDD, it was now contraindicating sertraline,
citalopram, and escitalopram as well for this condition. This
announcement noted that the risk benefit profile is unassessable for
fluvoxamine, and that, in its view, the risk benefit profile is
favorable in pediatric MDD only for fluoxetine.

\[[Note]{.underline}: Nefazodone and bupropion are not approved drug
products in the UK. Mirtazapine is an approved product in the UK,
however, MHRA has offered no comment on the pediatric data for this
drug.\]

**Summary of Issues That Complicate the Anaylsis of the Pediatric
Suicidality Data; Questions for the Committee**

In this section, I will first recap the major issues that have
complicated our attempts to understand the pediatric suicidality data,
and then list the specific issues for which we would like committee
feedback to assist us as we move forward in trying to address this
concern. We are not asking for votes on any particular questions, but
rather, discussion by the committees and any feedback you might have to
offer on our current plans for further exploring these data.

[Ascertainment for Suicidality]{.underline}

One of the concerns about these studies is the fact that they were not
conducted in a manner to fully and adequately assess patients for
emergent suicidality. This is apparent in reviewing the descriptive
information for the events identified as possibly suggestive of
suicidality. These descriptions are frequently sparse and lacking the
kind of detail that would ordinarily be useful in assessing whether or
not the events might legitimately be considered to represent
suicidality. There is, of course, no fix for this problem with regard to
these studies. However, one of our outside experts will address the
issue of how one might develop guidance for more adequate assessment for
emergent suicidality in future studies. We would welcome any advice from
the committees on the development of such guidance.

One might reasonably ask why this would be a concern for these studies,
since, despite the generally inadequate ascertainment, signals for drug
associated suicidality did emerge. In fact, however, one can easily
construct possible explanations for biases being introduced by
inadequate ascertainment that work either for drug or against drug.
Rather than having to speculate about possible bias, it would have been
preferable to have included adequate ascertainment in the first place.

[Possible Failure to Fully Capture All Events of Potential Interest with
Regard to Suicidality]{.underline}

Quite apart from a concern about ascertainment is the issue of the
method used to search the database for events of possible interest. GSK
had developed an algorithm for searching for potential events
representing suicidality in their database, and we proposed a variation
of this to other sponsors. However, this is admittedly a compromise. It
is still conceivable that certain cases of interest might have been
missed by the search methods employed. The only failsafe approach to
identifying all possible events of interest would be to have experts
blindly evaluate every case report form for the more than 4000 patients
who participated in these trials. Since that is not feasible, we welcome
advice from the committee on possible modifications to the search
strategies used for identifiying cases that might have been missed.
Additional searches at this point would further delay the analyses of
these data, and so this needs to be taken into consideration. However,
if the committees feel there are serious deficiencies in the search
methods employed, it would be helpful to hear about alternative
approaches that might be suggested.

[Approaches to Classifying Events into Meaningful Categories for the
Purpose of Further Analysis]{.underline}

As noted, an important next step is to decide on categories into which
events of interest might be classified, along with operational
definitions for such classifications. The approach used by sponsors thus
far has been to classify cases first into a crude category of "possibly
suicide-related," and then a further subgrouping of that broader group
into a "suicide attempt" class. Since we are just now beginning to
address this question with our outside experts, we would welcome any
advice the committees might have on how to classify these events for the
purpose of further analysis.

[Patient Level Data Analysis]{.underline}

There will be a brief presentation by a member of our safety group on
our plans for the patient level data analysis. Since we are in the
preliminary stages of this analysis, this would again be an opportune
time to get feedback on how to approach this analysis. In addition, you
have seen our list of potential covariates for inclusion in this
analysis, and we would welcome any thoughts you might have on this list.
If we have left out important covariates, please let us know, since this
would be the time to try to gather any additional information that you
feel might be helpful in trying to understand these data.

[Future Approaches to Trying to Address the Question of What Benefits
These Drugs Might Have in Pediatric MDD]{.underline}

As noted earlier, the attempts to demonstrate efficacy in short-term
trials for these drugs have not been successful, for the most part. We
would welcome your thoughts on how to interpret and understand these
largely negative results, and also any thoughts you might have on
alternative approaches to demonstrating benefits in this population. An
approach often used in expanding information on effectiveness in adult
MDD populations is the randomized withdrawal design, in which patients
who have responded during open treatment with an antidepressant drug are
randomized to either continuation of drug or switch to placebo. The
endpoint in these trials is typically time to relapse, and the success
rate for these trials is far higher than the roughly 50% success rate in
acute trials in adult MDD. We would welcome your thoughts on whether or
not this design might be useful in evaluating possible benefits of these
drugs in pediatric MDD.

[Feedback on Other Relevant Topics]{.underline}

You should not feel limited to providing feedback on the above topics.
The purpose of this meeting is to give you interim feedback on where we
are at present with our attempts to understand these data, and to gain
your insights into how we might proceed. Thus, we would welcome your
feedback on other issues as well that you feel are relevant to our
continuing evaluation of these data.

+-----------------------------------+-----------------+-----------------+
| **Appendix 1**                    |                 |                 |
|                                   |                 |                 |
| **Summary of Efficacy Results     |                 |                 |
| (Primary Outcomes) for Short-Term |                 |                 |
| Placebo-Controlled Pediatric      |                 |                 |
| Studies in Major Depressive       |                 |                 |
| Disorder**                        |                 |                 |
+-----------------------------------+-----------------+-----------------+
| **Drug Program/Study Number**     | **Age Range**   | **Outcome^1^**  |
|                                   |                 |                 |
|                                   |                 | **(Drug vs      |
|                                   |                 | Placebo)**      |
+-----------------------------------+-----------------+-----------------+
| **Paroxetine/329**                | **12-18**       | **Negative^2^** |
+-----------------------------------+-----------------+-----------------+
| **Paroxetine/377**                | **13-18**       | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Paroxetine/701**                | **7-17**        | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Fluoxetine/HCJE**               | **8-17**        | **Positive**    |
+-----------------------------------+-----------------+-----------------+
| **Fluoxetine/X065**               | **8-17**        | **Positive**    |
+-----------------------------------+-----------------+-----------------+
| **Sertraline/A050-1001**          | **6-17**        | **Trend**       |
+-----------------------------------+-----------------+-----------------+
| **Sertraline/A050-1017**          | **6-17**        | **Negative^3^** |
+-----------------------------------+-----------------+-----------------+
| **Venlafaxine/382**               | **7-17**        | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Venlafaxine/394**               | **7-17**        | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Citalopram/CIT-MD-18**          | **7-17**        | **Positive**    |
+-----------------------------------+-----------------+-----------------+
| **Citalopram/94404**              | **13-18**       | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Nefazodone/CN104-141**          | **12-18**       | **Trend**       |
+-----------------------------------+-----------------+-----------------+
| **Nefazodone/CN104-187**          | **7-17**        | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Mirtazapine/003-004/Study 1**   | **7-17**        | **Negative**    |
+-----------------------------------+-----------------+-----------------+
| **Mirtazapine/003-004/Study 1**   | **7-17**        | **Negative**    |
+-----------------------------------+-----------------+-----------------+

1.  Positive (p[\<]{.underline}0.05); Negative (p\>0.10); Trend
    (0.05\<p[\<]{.underline}0.10)

2.  Keller, et al, 2001; positive on most secondary endpoints

3.  Wagner, et al, 2003; positive on pooling of 2 studies

+-----------------------+-------+-------+-------+-------+-------+-------+
| **Appendix 2**        |       |       |       |       |       |       |
|                       |       |       |       |       |       |       |
| **Risk (%) and Risk   |       |       |       |       |       |       |
| Ratio for Events      |       |       |       |       |       |       |
| Classified as         |       |       |       |       |       |       |
| "Possibly             |       |       |       |       |       |       |
| Suicide-Related" and  |       |       |       |       |       |       |
| "Suicide Attempts"**  |       |       |       |       |       |       |
|                       |       |       |       |       |       |       |
| **in Pediatric        |       |       |       |       |       |       |
| Studies of Major      |       |       |       |       |       |       |
| Depressive Disorder** |       |       |       |       |       |       |
|                       |       |       |       |       |       |       |
| **\[All subjects;     |       |       |       |       |       |       |
| On-Therapy Data\]**   |       |       |       |       |       |       |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Drug/Study Number** | *     |       |       | **"Su |       |       |
|                       | *"Pos |       |       | icide |       |       |
|                       | sibly |       |       | A     |       |       |
|                       | Sui   |       |       | ttemp |       |       |
|                       | cide- |       |       | ts"** |       |       |
|                       | Relat |       |       |       |       |       |
|                       | ed"** |       |       |       |       |       |
+-----------------------+-------+-------+-------+-------+-------+-------+
|                       | **D   | *     | *     | **D   | *     | *     |
|                       | rug** | *Plac | *Risk | rug** | *Plac | *Risk |
|                       |       | ebo** | Ra    |       | ebo** | Ra    |
|                       |       |       | tio** |       |       | tio** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Paroxetine/329**    | **6   | **1   | **    | **5   | **0** | **    |
|                       | .5%** | .1%** | 5.9** | .4%** |       | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Paroxetine/377**    | **3   | **4   | **    | **3   | **4   | **    |
|                       | .9%** | .2%** | 0.9** | .9%** | .2%** | 0.9** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Paroxetine/701**    | **1   | **1   | **    | **1   | **1   | **    |
|                       | .0%** | .0%** | 1.0** | .0%** | .0%** | 1.0** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Fluoxetine/HCCJ**   | **0** | **5   | **    | **0** | **5   | **    |
|                       |       | .3%** | \--** |       | .3%** | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Fluoxetine/HCJE**   | **3   | **3   | **    | **0   | **1   | **    |
|                       | .7%** | .6%** | 1.0** | .9%** | .8%** | 0.5** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Fluoxetine/X065**   | **4   | **4   | **    | **4   | **0** | **    |
|                       | .2%** | .2%** | 1.0** | .2%** |       | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **S                   | **4   | **0** | **    | **1   | **0** | **    |
| ertraline/A050-1001** | .1%** |       | \--** | .0%** |       | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **S                   | **2   | **2   | **    | **2   | **2   | **    |
| ertraline/A050-1017** | .2%** | .2%** | 1.0** | .2%** | .2%** | 1.0** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Venlafaxine/382**   | **6.  | **1.  | **    | **2.  | **1.  | **    |
|                       | 25%** | 18%** | 5.3** | 50%** | 18%** | 2.1** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Venlafaxine/394**   | **7.  | **0** | **    | **1.  | **0** | **    |
|                       | 84%** |       | \--** | 96%** |       | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **C                   | *     | *     | **    | *     | *     | **    |
| italopram/CIT-MD-18** | *1%** | *2%** | 0.5** | *1%** | *1%** | 1.0** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **Citalopram/94404**  | **    | *     | **    | **    | *     | **    |
|                       | 13%** | *8%** | 1.6** | 13%** | *8%** | 1.6** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **N                   | **1   | **0** | **    | **1   | **0** | **    |
| efazodone/CN104-141** | .1%** |       | \--** | .1%** |       | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **N                   | **0   | **0** | **    | **0   | **0** | **    |
| efazodone/CN104-187** | .5%** |       | \--** | .5%** |       | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+
| **                    | **0.  | **1.  | **    | **0** | **1   | **    |
| Mirtazapine/003-045** | 59%** | 14%** | 0.5** |       | .14** | \--** |
+-----------------------+-------+-------+-------+-------+-------+-------+

**Appendix 3**

**\[Note: This was the final variable list submitted to sponsors
(10-28-03) as an update to the original request for patient level data
sets send 10-3-03\]**

We would appreciate your adding these variables to the previously
requested dataset.

HXPSHOSP: This is a Y/N variable indicating that the subject had a
history of psychiatric hospitalization prior to entering the RCT.

SCALESUI: The score of the suicide item for the primary scale used to
rate baseline severity of depression. As part of your response to this
data request, please include the range and meaning of the scores for the
suicide item.

Clarifications of 10/27/03 updated request:

-   Please note that the description of the variable HXSUIATT referred
    to history of suicide attempt[s]{.underline}. The description should
    be corrected to read "attempt" (see table below). In other words, to
    qualify for a "yes" on that variable, a subject need only have had
    one suicide attempt (not multiple).

-   "." Will be added as a response option for missing data for the
    psychiatric history variables

-   In the variable "HXNONCOM", "erratic" compliance is defined as not
    taking the study drug as prescribed.

The changes described above are [highlighted]{.mark} in the following
table.

+--------------+------+--------+--------------------+------------------+
| Variable     | Le   | Type   | Description        | Coding notes     |
| name         | ngth |        |                    |                  |
+--------------+------+--------+--------------------+------------------+
| TRIAL        | NS   | Cha    | Trial ID           | No missing       |
|              |      | racter |                    | values are       |
|              |      |        |                    | allowed in this  |
|              |      |        |                    | variable.        |
+--------------+------+--------+--------------------+------------------+
| CTPID        | NS   | Cha    | Patient ID within  | No missing       |
|              |      | racter | each trial.        | values are       |
|              |      |        |                    | allowed in this  |
|              |      |        |                    | variable         |
+--------------+------+--------+--------------------+------------------+
| UNIQUEID     | NS   | Cha    | A unique ID for    | It should        |
|              |      | racter | every patient      | incorporate both |
|              |      |        |                    | the trial ID and |
|              |      |        |                    | the patient ID   |
|              |      |        |                    | within each      |
|              |      |        |                    | trial.           |
|              |      |        |                    |                  |
|              |      |        |                    | No missing       |
|              |      |        |                    | values are       |
|              |      |        |                    | allowed in this  |
|              |      |        |                    | variable.        |
+--------------+------+--------+--------------------+------------------+
| DIAG         | NS   | Cha    | Condition for      | Should be one of |
|              |      | racter | which patient was  | the diagnoses    |
|              |      |        | being treated      | listed for the   |
|              |      |        | (e.g.,             | corresponding    |
|              |      |        | dementia-related   | trial in the     |
|              |      |        | psychosis or       | "Controlled      |
|              |      |        | schizophrenia).    | Trial File".     |
|              |      |        |                    |                  |
|              |      |        |                    | No missing       |
|              |      |        |                    | values are       |
|              |      |        |                    | allowed in this  |
|              |      |        |                    | variable.        |
+--------------+------+--------+--------------------+------------------+
| DIAGCAT      | 3    | N      | Diagnosis category | 1= major         |
|              |      | umeric |                    | depressive       |
|              |      |        |                    | disorder         |
|              |      |        |                    |                  |
|              |      |        |                    | 2= obsessive     |
|              |      |        |                    | compulsive       |
|              |      |        |                    | disorder         |
|              |      |        |                    |                  |
|              |      |        |                    | 3= social        |
|              |      |        |                    | anxiety disorder |
|              |      |        |                    |                  |
|              |      |        |                    | 4= other anxiety |
|              |      |        |                    | disorder         |
+--------------+------+--------+--------------------+------------------+
| AGE          | 3    | N      | Age of patient in  | . = Missing.     |
|              |      | umeric | years              |                  |
+--------------+------+--------+--------------------+------------------+
| AGECAT       | 3    | N      | Categories of age  | 1= AGE \< 12     |
|              |      | umeric |                    |                  |
|              |      |        |                    | 2= AGE \>= 12    |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| GENDER       | 3    | N      | Patient gender     | 1= Female        |
|              |      | umeric |                    |                  |
|              |      |        |                    | 2= Male          |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| RACE         | 3    | N      | Race               | 1= White         |
|              |      | umeric |                    | Caucasian        |
|              |      |        |                    |                  |
|              |      |        |                    | 2=               |
|              |      |        |                    | A                |
|              |      |        |                    | frican-American\ |
|              |      |        |                    | 3= Hispanic      |
|              |      |        |                    |                  |
|              |      |        |                    | 4= Asian         |
|              |      |        |                    |                  |
|              |      |        |                    | 5= Other         |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| BMI          | 3    | N      | Body mass index    | Calculated as    |
|              |      | umeric |                    | weight in        |
|              |      |        |                    | kg/(height in    |
|              |      |        |                    | meters)^2^       |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| SET          | 3    | N      | Setting at         | 1= Inpatient     |
|              |      | umeric | randomization      |                  |
|              |      |        |                    | 2= Outpatient    |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| LOC          | 3    | N      | Location of trial  | 1= North America |
|              |      | umeric | center             |                  |
|              |      |        |                    | 2= Non-north     |
|              |      |        |                    | America          |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| HXSUIATT     | 3    | N      | The subject had a  | 0=No             |
|              |      | umeric | history of suicide |                  |
|              |      |        | [attempt]{.mark}   | 1=Yes            |
|              |      |        | prior to entering  |                  |
|              |      |        | the RCT            | [. =             |
|              |      |        |                    | Missing]{.mark}  |
+--------------+------+--------+--------------------+------------------+
| HXSUIID      | 3    | N      | The subject had a  | 0=No             |
|              |      | umeric | history of         |                  |
|              |      |        | suicidal ideation  | 1=Yes            |
|              |      |        | prior to entering  |                  |
|              |      |        | the RCT            | [. =             |
|              |      |        |                    | Missing]{.mark}  |
+--------------+------+--------+--------------------+------------------+
| [HXPS        | [3   | [Num   | [The subject had a | [0=No]{.mark}    |
| HOSP]{.mark} | ]{.m | eric]{ | history of         |                  |
|              | ark} | .mark} | psychiatric        | [1=Yes]{.mark}   |
|              |      |        | hospitalization    |                  |
|              |      |        | prior to entering  | [. =             |
|              |      |        | the RCT]{.mark}    | Missing]{.mark}  |
+--------------+------+--------+--------------------+------------------+
| HXSUBAB      | 3    | N      | The subject had a  | 0=No             |
|              |      | umeric | history of         |                  |
|              |      |        | substance abuse    | 1=Yes            |
|              |      |        | prior to entering  |                  |
|              |      |        | the RCT            | [. =             |
|              |      |        |                    | Missing]{.mark}  |
+--------------+------+--------+--------------------+------------------+
| HXHOST       | 3    | N      | The subject had a  | 0=No             |
|              |      | umeric | history of         |                  |
|              |      |        | hostility or       | 1=Yes            |
|              |      |        | aggressive         |                  |
|              |      |        | behavior prior to  | [. =             |
|              |      |        | entering the RCT   | Missing]{.mark}  |
+--------------+------+--------+--------------------+------------------+
| HXIRRAG      | 3    | N      | The subject had a  | 0=No             |
|              |      | umeric | history of         |                  |
|              |      |        | irritability or    | 1=Yes            |
|              |      |        | agitation prior to |                  |
|              |      |        | entering the RCT   | [. =             |
|              |      |        |                    | Missing]{.mark}  |
+--------------+------+--------+--------------------+------------------+
| RANTX        | NS   | Cha    | Name of            | "Your drug       |
|              |      | racter | post-randomization | name",           |
|              |      |        | treatment          | "Placebo", or    |
|              |      |        | assignment         | the name of the  |
|              |      |        |                    | active control   |
|              |      |        |                    | drug             |
|              |      |        |                    |                  |
|              |      |        |                    | No missing       |
|              |      |        |                    | values are       |
|              |      |        |                    | allowed in this  |
|              |      |        |                    | variable.        |
+--------------+------+--------+--------------------+------------------+
| RANTXCAT     | 3    | N      | Category of the    | 1=SSRI           |
|              |      | umeric | drug               |                  |
|              |      |        |                    | 2=non-SSRI       |
|              |      |        |                    |                  |
|              |      |        |                    | 3=placebo        |
+--------------+------+--------+--------------------+------------------+
| DOSE         | 3    | N      | Dose of the        | 0=Placebo        |
|              |      | umeric | post-randomization |                  |
|              |      |        | investigational    | . = Missing      |
|              |      |        | treatment; If a    |                  |
|              |      |        | flexible dose      |                  |
|              |      |        | scheme was used,   |                  |
|              |      |        | then report the    |                  |
|              |      |        | modal dose. If     |                  |
|              |      |        | there were         |                  |
|              |      |        | multiple modal     |                  |
|              |      |        | doses, select the  |                  |
|              |      |        | maximal modal dose |                  |
+--------------+------+--------+--------------------+------------------+
| DFRAN        | 10   | Date   | Date of first dose | Use date format: |
|              |      |        | of randomized      | MM /DD/YYYY,     |
|              |      |        | treatment          | e.g. 3/4/2000    |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| DLRAN        | 10   | Date   | Date of last dose  | Use date format: |
|              |      |        | of randomized      | MM /DD/YYYY e.g. |
|              |      |        | treatment          | 6/14/2000        |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| EXPOSURE     | 3    | N      | Number of days of  | Should represent |
|              |      | umeric | exposure to        | the difference   |
|              |      |        | randomized         | between "DFRAN"  |
|              |      |        | treatment          | and "DLRAN".     |
|              |      |        |                    |                  |
|              |      |        |                    | \                |
|              |      |        |                    | [DLRAN-DFRAN\]+1 |
|              |      |        |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| HXNONCOM     | 3    | N      | There is some      | 0=No             |
|              |      | umeric | evidence in the    |                  |
|              |      |        | subject's medical  | 1=Yes            |
|              |      |        | record or case     |                  |
|              |      |        | report form that   |                  |
|              |      |        | the subject had a  |                  |
|              |      |        | history of erratic |                  |
|              |      |        | compliance with    |                  |
|              |      |        | the study          |                  |
|              |      |        | medication during  |                  |
|              |      |        | the RCT            |                  |
+--------------+------+--------+--------------------+------------------+
| RCTYEARS     | 12   | N      | Exposure in years  | =Exposure/365.25 |
|              |      | umeric |                    |                  |
|              |      |        |                    | . = Missing      |
+--------------+------+--------+--------------------+------------------+
| SEVSCALE[^2] | 3    | N      | Primary scale used | 1=HAM-D          |
|              |      | umeric | to rate baseline   |                  |
|              |      |        | severity of        | 2=CDRS-R         |
|              |      |        | depression         |                  |
|              |      |        |                    | 3=K-SADS-L       |
|              |      |        |                    |                  |
|              |      |        |                    | 4=Kutcher        |
|              |      |        |                    |                  |
|              |      |        |                    | 5=Other          |
|              |      |        |                    |                  |
|              |      |        |                    | 6= NA (if not    |
|              |      |        |                    | measured)        |
+--------------+------+--------+--------------------+------------------+
| BASESEV      | 3    | N      | Baseline severity  | . = Missing      |
|              |      | umeric | score              |                  |
+--------------+------+--------+--------------------+------------------+
| HAMD17       | 3    | N      | Score on HAM-D 17  | . = Missing      |
|              |      | umeric | if performed (or   |                  |
|              |      |        | adapted from HAM-D |                  |
|              |      |        | 21)                |                  |
+--------------+------+--------+--------------------+------------------+
| [SCAL        | [3   | [Num   | [The score of the  | [. =             |
| ESUI]{.mark} | ]{.m | eric]{ | suicide item for   | Missing]{.mark}  |
|              | ark} | .mark} | the primary scale  |                  |
|              |      |        | used to rate       |                  |
|              |      |        | baseline severity  |                  |
|              |      |        | of                 |                  |
|              |      |        | depression]{.mark} |                  |
+--------------+------+--------+--------------------+------------------+
| DURATION     | 3    | N      | Duration of        | . = Missing      |
|              |      | umeric | illness prior to   |                  |
| \[Add        |      |        | randomization in   |                  |
| DURACAT      |      |        | months             |                  |
| variable if  |      |        |                    |                  |
| duration of  |      |        |                    |                  |
| illness was  |      |        |                    |                  |
| recorded as  |      |        |                    |                  |
| a            |      |        |                    |                  |
| categorical  |      |        |                    |                  |
| variable\]   |      |        |                    |                  |
+--------------+------+--------+--------------------+------------------+
| SUIEVENT     | 3    | N      | A suicide-related  | 0= No            |
|              |      | umeric | event as defined   |                  |
|              |      |        | in July 2003       | 1=Yes            |
|              |      |        | submission         |                  |
|              |      |        | occurred during    |                  |
|              |      |        | the RCT            |                  |
+--------------+------+--------+--------------------+------------------+
| SUIATT       | 3    | N      | A suicide attempt  | 0=No             |
|              |      | umeric | as defined in July |                  |
|              |      |        | 2003 submission    | 1=Yes            |
|              |      |        | occurred during    |                  |
|              |      |        | the RCT \[Suicide  |                  |
|              |      |        | attempt is a       |                  |
|              |      |        | subset of          |                  |
|              |      |        | suicide-related    |                  |
|              |      |        | event\]            |                  |
+--------------+------+--------+--------------------+------------------+
| EVENTDC      | 3    | N      | The                | 0=No             |
|              |      | umeric | [                  |                  |
|              |      |        | first]{.underline} | 1=Yes            |
|              |      |        | suicide-related    |                  |
|              |      |        | event occurred     |                  |
|              |      |        | following          |                  |
|              |      |        | discontinuation    |                  |
+--------------+------+--------+--------------------+------------------+
| DAYEVENT     | 3    | N      | The number of days | . = Missing or   |
|              |      | umeric | to the             | patient did not  |
|              |      |        | [                  | have an event    |
|              |      |        | first]{.underline} |                  |
|              |      |        | suicide-related    |                  |
|              |      |        | event counting     |                  |
|              |      |        | from the day of    |                  |
|              |      |        | the first dose.    |                  |
|              |      |        | Counting from the  |                  |
|              |      |        | first day of drug  |                  |
|              |      |        | should occur even  |                  |
|              |      |        | if the event       |                  |
|              |      |        | occurred after the |                  |
|              |      |        | patient            |                  |
|              |      |        | discontinued the   |                  |
|              |      |        | drug.              |                  |
+--------------+------+--------+--------------------+------------------+
| TEAEAG       | 3    | N      | A                  | 0=No             |
|              |      | umeric | treatment-emergent |                  |
|              |      |        | adverse event      | 1=Yes            |
|              |      |        | coded to the       |                  |
|              |      |        | preferred term     |                  |
|              |      |        | agitation occurred |                  |
|              |      |        | during the RCT     |                  |
+--------------+------+--------+--------------------+------------------+
| TEAEHOST     | 3    | N      | A                  | 0=No             |
|              |      | umeric | treatment-emergent |                  |
|              |      |        | adverse event      | 1=Yes            |
|              |      |        | coded to the       |                  |
|              |      |        | preferred term     |                  |
|              |      |        | hostility occurred |                  |
|              |      |        | during the RCT     |                  |
+--------------+------+--------+--------------------+------------------+
| SOURCE       | 4    | Cha    | First 4 letters of |                  |
|              |      | racter | your drug name     |                  |
+--------------+------+--------+--------------------+------------------+

NS=not specified.

**References**

Bailliere, Tindall and Cassell: *Slater and Roth's Clinical Psychiatry*.
London, 1960 (p.231).

Beasley CM, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH,
Heiligenstein JH, et al: Fluoxetine and suicide: a meta-analysis of
controlled trials of treatment for depression. BMJ 1991; 303:685-692.

Hammad T, Mosholder A, Boehm G, Racoosin JA, Laughren T: Incidence of
suicide in randomized controlled trials of patients with major
depressive disorder. Pharmacoepidemiology and Drug Safety 2003; 12:S156
(Abstract)

Keller MB, Ryan ND, Strober M, et al: Efficacy of paroxetine in the
treatment of adolescent major depression: A randomized controlled trial.
J Am Acad Child Adolesc Psychiatry 2001; 40 (7):762-772.

Khan A, Warner HA, Brown WA: Symptom reduction and suicide risk in
patients treated with placebo in antidepressant clinical trials. Arch
Gen Psychiatry 2000; 57:311-317.

Storosum JG, van Zweiten BJ, van den Brink W, Gersons BPR, Broekmans AW:
Suicide risk in placebo-controlled studies of major depression. Am J
Psychiatry 2001; 158:1271-1275.

Teicher MH, Glod C, Cole JO: Emergence of intense suicidal preoccupation
during fluoxetine treatment. Am J Psychiatry 1990; 147:207-210.

Wagner KD, Ambrosini P, Rynn M, et al: Efficacy of sertraline in the
treatment of children and adolescents with major depressive disorder.
JAMA 2003; 290(8):1033-1041.

cc:

HFD-120/TLaughren/RKatz/JRacoosin/PDavid

HFD-040/RTemple

HFD-020/JJenkins

**DOC:** PDAC_Memo_Feb2004_TL02.doc

[^1]: I will distinguish between what I will refer to as [summary
    data]{.underline} and [patient level data]{.underline}. Summary data
    will refer to data tables provided by sponsors that include only
    numbers of events as numerators and either total patients exposed or
    total accumulated person-time as denominators. Patient level data
    will refer to data sets provided by sponsors in response to detailed
    requests made by FDA for electronic data sets structured to include
    one row per patient participating in each study, with multiple
    variables for each patient. Patient level data sets permit
    adjustments for potentially important covariates, while summary data
    do not.

[^2]: HAM-D -- Hamilton Depression Scale; CDRS =Children's Depression
    Rating Scale-Revised ; K-SADS-L = 9 item depression subscale of the
    Schedule for Affective Disorders and Schizophrenia for School Age
    Children- Lifetime version ; Kutcher = Kutcher Adolescent Depression
    Rating Scale