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:
FROM: Thomas P.
Laughren, M.D.
Team
Leader, Psychiatric Drug Products
Division
of Neuropharmacological Drug Products
HFD-120
SUBJECT: Background Comments for
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
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:
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
The debate on this question with regard to adult depression
intensified in 1990, at which time Martin Teicher, a psychiatrist from
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
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 2nd 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
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
This
Initial Regulatory Response to Signal of Increased Risk of Suicidality
for Paroxetine
The reaction to this report by the MHRA in the
·
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
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:
o Search for all events for which the preferred
term was either “overdose” or “intentional overdose” (Note: They did not include any events for which the
preferred term was “accidental overdose”)
o 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”
o Search of all verbatim terms containing the
text string “overdose” or “suic” (Note: 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:
o A text string suggestive of self-harm
o Preferred term “overdose” or “intentional
overdose”
o 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
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
·
Prozac
(fluoxetine)
·
Zoloft
(sertraline)
·
Luvox
(fluvoxamine)
·
Celexa
(citalopram)
·
Wellbutrin
(bupropion)
·
Effexor
(venlafaxine)
·
Serzone
(nefazodone)
·
Remeron
(mirtazapine)
In this July 22nd 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:
o Search of preferred terms for the following 2
text strings: “suic” or “overdos”
§
Note: We indicated that they may exclude instances
coded as accidental overdoses, but asked them to provide information on these
cases in a separate table.
o 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: 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”
o Note: 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
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
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 (
This action by Wyeth was followed in September, 2003 by a regulatory
response by the MHRA in the
FDA Internal Regulatory Briefing
An important milestone in our consideration of the pediatric
suicidality data was an internal briefing for upper level CDER management held
on
Updated FDA Public Health Advisory and Talk Paper
We issued an updated public health advisory and talk paper on
Responses to FDA’s Request for Summary Data for Other
Antidepressants
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 22nd
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.
Decision to Seek Outside Review and Reclassification of Cases