Food and Drug Administration

**Center for Drug Evaluation and Research**

**SUMMARY MINUTES OF THE**

# Psychopharmacologic Drugs Advisory Committee Meeting and the Pediatric Subcommittee of the anti-infective drugs advisory committee

##### 

##### February 2, 2004

# Members Present (Voting)

Matthew Rudorfer, M.D. (Chair)

Tana Grady-Weliky, M.D.

Irene Ortiz, M.D.

Richard Malone, M.D.

Andrew Leon, Ph.D.

Philip Wang, M.D., M.P.H., Dr. PH

Wayne Goodman, M.D.

James McGough, M.D.

Jean Bronstein, R.N., M.S. (Consumer Representative)

**FDA Participants**

Robert Temple, M.D.

Russell Katz, M.D.

Thomas Laughren, M.D.

M. Dianne Murphy, M.D.,

Susan Cummins, M.D., M.P.H.,

Anne Trontell, M.D., M.P.H.

**Executive Secretary**

Anuja M. Patel, M.P.H.

# Consultants to the Psychopharmocologic Drugs Advisory Committee (Voting)

Gail Griffith, B.A., M.A. (Patient Representative)

Cynthia Pfeffer, M.D.

**Psychopharmacologic Drugs Advisory Committee Consultant
(non-voting):**

Daniel Pine, M.D.

David Shaffer, M.D.

Psychopharmacologic Drugs Advisory Committee Industry Representative
(Non-voting):

Dilip Mehta, M.D., Ph.D.

**Pediatric Subcommittee Consultant Members of the Anti-Infective
Advisory Committee (voting):**

Joan Chesney, M.D.

Robert Nelson, M.D. Ph.D.

Victor Santana, M.D.

David Danford, M.D.

Robert Fink, M.D.

Mark Hudak, M.D.

Susan Fuchs, M.D.

Richard Gorman, M.D., FAAP

Norman Fost, M.D., M.P.H. (CBER Consultant)

AIDAC Members of the Pediatric Subcommittee of the Anti-Infective
Advisory Committee (voting):

Mary Glode, M.D.

Judith O'Fallon, Ph.D.

Steven Ebert, Pharm.D. (Consumer Representative)

**Pediatric Subcommittee of the Anti-Infective Advisory Committee
Consultants (voting):**

Charles Irwin, Jr., M.D.

James Perrin, M.D.

Laurel Leslie, M.D., FAAP

Elizabeth Andrews, Ph.D.

**Pediatric Subcommittee of the Anti-Infective Advisory Committee Acting
Industry Representative (non-voting):**

Samuel Maldonado, M.D., M.P.H.

**Cardio-Renal AC Members Absent:**

None

**Guest Speaker (non-voting):**

Kelly Posner, Ph.D

These summary minutes for the February 2, 2004, meeting of the
Psychopharmacologic Drugs Advisory Committee and the Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee were
approved on March 4, 2004.

I certify that I attended the February 2, 2004, meeting of the
Psychopharmacologic Drugs Advisory Committee and the Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee meeting and
that these minutes accurately reflect what transpired.

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\_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Anuja M. Patel, M.P.H. Matthew Rudorfer, M.D.

Executive Secretary Chair

On February 2, 2004, the Psychopharmacologic Drugs Advisory Committee
and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory
Committee met in open session at the Holiday Inn, at 8120 Wisconsin
Avenue, in Bethesda, Maryland. The Committees discussed reports of the
occurrence of suicidality (both suicidal ideation and suicide attempts)
in clinical trials for various anti-depressant drugs in pediatric
patients with major depressive disorder (MDD). The Committees also
considered optimal approach to the analysis of data from these trials,
as well as further research needs to address these issues.

Prior to the meeting, the members and the invited consultants had been
provided the background material from the FDA and written statements
submitted by the public. The meeting was called to order by Matthew
Rudorfer, M.D. (Committee Chair); the Conflict of Interest Statement was
read into the record by Anuja M. Patel, M.P.H. (Executive Secretary).
There were approximately 450 persons in attendance. There were
approximately 54 speakers for the Open Public Hearing session.

# 

**Open Public Hearing Speakers:**

-   David Antonuccio, Ph.D. and Irving Kirsch, Ph.D.

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-   Lisa VanSyckel

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-   Anne Blake Tracy, Ph.D.

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-   Mark Miller

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-   Jay and Corey Baadsgaard

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-   Joyce Storey

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-   Jennifer and Jame Tierney

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-   Donna Taylor

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-   Shannon Baker

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-   Dawn Rider and Vincent Boehm , A.S.P.I.R.E

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-   Sara Bostock

-   Vera Sharav, The Alliance for Human Research Protection

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-   Cynthia Brockman

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-   Tod and Eileen Shivak

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-   Suzanne Vogel-Scibilia, M.D., The National Alliance of the Mentally
    Ill

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-   Dennis Winter

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-   Steve Cole

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-   Allan Routhier

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-   Daniel Safer, M.D.

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-   Julie Magno Zito, Ph.D., UMD School of Pharmacy

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-   Joseph Glenmullen, M.D.

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-   Linda Cheslek

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-   Jeff Avery

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-   Harry Skigis

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-   Rosie Meysenburg

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-   Rachel Adler and Sheila McDonald, Child and Adolescent Bipolar
    Foundation

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-   Andy Vickery

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-   Pepper Draper

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-   Donald Marks, M.D., Ph.D.

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-   Leah Harris M.A.

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-   Donald Farber, Esq., Law Office of Donald J. Farber

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-   Lorraine, Robert, and Jonathan Slater

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-   Sharon McBride

-   David Fassler, M.D. American Psychiatric Association

-   Lawrence Diller, M.D.

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-   Thomas Moore, M.D.

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-   Pamela Wild

-   Karen Menzies

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-   Amy Coburn

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-   Gary Cheslek, M.D.

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-   Paul Domb and Matthew Piepenburg

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-   Terri Williams

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-   Glenn McIntoch

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-   Delnora Duprey

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-   Joe Pittman

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-   Richard Mack

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-   Gloria and Noah Wright

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-   Marion Goff

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-   Sherri Walton, Mental Health Association of Arizona

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-   Peter Breggin, M.D.

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-   Robert Fritz

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-   Lawrence Greenhill, M.D., American Academy of Child & Adolescent
    Psychiatry

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-   Tom Woodward

FDA Presentations:

Overview of Issues Russell Katz, M.D.

> Director, Division of Neuropharmacological Drug Products, FDA

Pediatric Drug Development Dianne Murphy, M.D.

> Director, Office of Counter-Terrorism and Drug Development, FDA

Pediatric Depression and Its Treatment Cynthia Pfeffer, M.D.

Weill Medical College of Cornell University

Suicide and Related Problems in Adolescents David Shaffer, F.R.C.P.
(Lond), F.R.C. Psych

Columbia University

Pediatric and adolescent Antidepressant Gianna C. Rigoni, Pharm.D., M.S.

Drug Use in the U.S. Epidemiologist, Office of Drug Safety, FDA

One Year Post-Exclusivity Mandated Adverse Event Solomon Iyasu, M.D.,
M.P.H

Review for Paroxetine and Citalopram Lead Medical Officer, Division of
Pediatrics Drug Development, FDA

Office of Drug Safety Data Resources for the Study of Andrew Mosholder,
M.D., M.P.H.

Suicidal Events Epidemiologist, Office of Drug Safety, FDA

Regulatory History on Antidepressants and Suicidality Thomas Laughren,
M.D.

and Update on Current Plans for Analysis of Pediatric Team Leader,
Division of Neuropharmacological Drug Products, FDA

Suicidality Data Neuropharmacological Drug Products, FDA

Suicidality Classification Project Kelly Posner, Ph.D.

Columbia University

Plans for Analysis of Patient Level Data for Tarek Hammad, M.D., Ph.D.,
M.Sc., M.S.

Pediatric Studies Safety Reviewer, Division of Neuropharmacological Drug
Products, FDA

Questions to the Committee:

**Topics Directly Pertinent to Continuing Evaluation of Data from
Pediatric Controlled Trials:**

1.  **Possible Failure to Fully Capture All Events of Potential Interest
    with Regard to Suicidality**

**The first step in the process of evaluation for suicidality was to
find events of potential interest. GSK (Glaxo Smith Kline) had developed
an algorithm for searching for events possibly representing suicidality
in their database, and FDA proposed a variation of this to other
sponsors. However, this was admittedly a compromise. It is conceivable
that certain cases of interest might have been missed by the search
methods employed. The only fail safe 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, FDA welcomes advice from
the committee on possible modifications to the search strategies used
for identifying cases that might have been missed. Additional searches
at this point would further delay the analyses of these data, and 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.**

*The overall consensus of the Committees was that the FDA should proceed
with the planned re-analysis of the data once a team of mental health
experts at Columbia University and elsewhere have reclassified the
cases. The re-analysis, however, may not yield accurate results. The
Committees' concern in this respect reflected impressions that the data
had been collected during the medication trials in a fashion that would
not easily allow the generation of an accurate estimate of adverse
behavioral reactions associated with suicidal behavior or ideation.
Despite these concerns, the statisticians on the Committees felt that
the methodological concepts learned from the re-analyses will be
valuable. The Committees encouraged the Agency to go back and examine
data on adverse effects in individual study participants for signs of
what has been labeled the "stimulation" or "activation" syndrome. These
terms have been used to refer to a constellation of behaviors, including
agitation, restlessness, hyperactivity, and disinhibition. In severe
cases, probably representing a very small percentage of treated
patients, the clinical picture may resemble frank akathisia, accompanied
by considerable subjective distress. Treatment-emergent mood lability,
irritability, or hostility should also be noted. The Committees
encouraged study of these and related phenomena. In particular, the
Committees inquired about whether the presence of these behaviors may be
associated with drug levels or with suicidal ideation, suicidal
behavior, or impulsive acts, and the response of such behaviors to drug
discontinuation or dosage change (either decrease or increase). Although
not necessarily available in the planned data re-analysis, the
Committees recommended the use of clearer inclusion/exclusion criteria,
the collection of additional data including drug concentrations for
pharmacokinetic analysis, and more established endpoints in future
antidepressant clinical trials in children and adolescents. With respect
to study entry criteria and endpoints, the Committees encouraged an
evaluation of study quality. This could be accomplished partially by
examining the degree to which cross-site reliability was established in
each individual study for the rating of criteria and endpoints. In
addition, the Committee felt that off-label prescription including
dispensing of antidepressant medication samples, by non-psychiatrists is
problematic. Therefore, improved labeling information, highlighting
potential side effects of greatest concern, was suggested by the
Committee.*

*In conceptualizing future plans for re-analysis of data on adverse
behavioral reactions, some discussion focused on defining the boundaries
of events that should be considered indicative of suicidal behavior.
Committee members recognized the need to define these boundaries more
precisely than in the reviewed studies and offered some guidelines. In
particular, some Committee members recommended that "cutting" should not
be considered a symptom of suicidal behavior.*

*The Chair summarized the consensus of the committee stating that
although individual members had reservations about the limitations of
the existing database, the Committee endorses the continuation of the
re-classification of data with some additional measures as mentioned
above. The Committee advised the FDA to attempt to recreate the process
of identifying cases of suicide-related events and look for multiple
different types of definitions that may be subsumed under "stimulation
(or activation) syndrome." This would necessarily require keeping
definition(s) as broad as possible.*

2.  **Approaches to Classifying Events into Meaningful Categories for
    the Purpose of Further Analysis**

**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 sub-grouping 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.**

*The consensus of the Committees was that a level of certainty and
variability in analysis be included in the reclassification of data. The
Committees were concerned that the general quality of the data, as they
were originally collected, was relatively low. This complicates any
effort of reclassification. Efforts at re-creating the methodology used
at various sites of the different trials are important for understanding
the specific information that was actually gathered in each data set.
The Committees encouraged the identification of treatment-emergent
agitation and related behaviors as potentially relevant mediators of
self-harm ideation or actions.*

3.  **Patient Level Data Analysis**

**Since we are in the preliminary stages of designing an appropriate
analysis of patient level data, this would 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.**

*As noted, the Committees did have suggestions for additional covariates
that might be collected from these databases to assist in designing an
appropriate analysis plan. Individual committee members provided
multiple suggestions to approaches to identifying covariates, and
mentioned the potential value of evaluating observed events in relation
to time of dosing or other intervention changes. Committee members
expressed an interest in seeing data from various patient-level
variables. These included a broader array of adverse effect variables,
related to the broader "stimulation/activation" syndrome described
above, as well as potential patient-level data that may have moderated
therapeutic or adverse effects delineated in the available studies.
Committee members inquired specifically about data on co-morbid
psychopathology, such as anxiety or disruptive behavior disorders,
adverse environmental events, and family history or other variables that
may relate to the risk for bipolar disorder. In sum, the Committee felt
that extending the analysis of patient level data beyond the focus
specifically on suicidality related or mediating variables would be of
value. These would include family history of mood and other mental
disorders, pretreatment pre-morbid conditions such as hypomanic/manic
symptoms or akathisia, careful delineation of the diagnosis where
possible, e.g. unipolar vs. bipolar depression vs. schizophrenia
spectrum, comorbidities (other mental and physical disorders, substance
use), administration of other medications. As noted, particular
attention to the presence of signs and symptoms of treatment-emergent
agitation and activation is recommended, to include time to development
and severity of such behaviors both pre- and post- treatment in both
patients on medication and control group members.*

**Topics of Future Interest**

4.  **Ascertainment for Suicidality**

**As we reviewed the descriptive information for the events identified
by sponsors as possibly suggestive of suicidality, it became apparent
that ascertainment for emergence of suicidality was not optimal. The
case descriptions were 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. Of course,
these studies were not designed with that goal in mind. Indeed, patients
who were judged to be suicidal at screening were excluded. Nor did we
emphasize such assessment for suicidality in our Written Requests for
these pediatric programs. Furthermore, 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.**

*The Committee's consensus was that the review of the available data
pointed to the pressing need for more research on this topic in new
samples of children and adolescents studied in randomized controlled
trials. In such future studies, the Committee noted the importance of
including children on various other medications while gathering
high-quality data on adverse events. The Committee also recognized the
importance of including placebos in such trials, in order to sort out
the disease from the treatment and to evaluate the data accurately.
Particular focus on behavioral toxicity early in treatment, including
various forms of dysphoric activation, as noted above, is recommended
for more definitive assessment in future clinical trials to try to
capture instances of treatment-emergent difficulties that might precede
or occur in association with frank suicidality. Pressing methodological
issues for future clinical trials include the desirability of
standardizing assessment instruments to capture suicidality or
antecedent adverse effects of interest and permit better analysis across
sites and across trials. Such measures should include self-assessment
instruments for use by patients and their parents/guardians.*

5.  **Future Approaches to Trying to Address the Question of What
    Benefits These Drugs Might Have in Pediatric MDD**

*Due to time constraints the Committee did not discuss this item
completely. The Committee was mixed on the idea of drug-discontinuation
designs. Some Committee members clearly recognized the potential
superior statistical power in this design, given results from studies
using this design in adults. Other Committee members noted that this
design does not address key questions concerning the safety and efficacy
of delivering antidepressants as opposed to other treatments for a child
or adolescent presenting for the first time with symptoms of an
untreated major depressive disorder. To the extent that this question
remains central, it may be important to utilize various research designs
beyond a randomized withdrawal design.*

**In answering these questions please keep in mind that the FDA does not
regulate the practice of medicine, but is responsible for providing
information on the safety and efficacy of the products it regulates. As
a reminder, the FDA issued a Public Health Advisory on October 27, 2003,
which stated:**

**"FDA emphasizes that these drugs must be used with caution.
Prescribers are reminded of the following statement present in all
antidepressant labeling:**

**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".**

*The Committee discussed the need to consider revising this statement,
in light of recent data. As noted, there was a consensus of the
Committee that labeling include a more prominent warning of the risk of
behavioral toxicity, particularly dysphoric agitation/activation, early
in the course of antidepressant treatment. It was also noted that the
last statement in the existing warning cited above, emphasizing the risk
of medication overdose, is a legacy of the tricyclic antidepressant era,
and is no longer appropriate, as drug overdose per se as a means of
suicide is not a concern with the SSRIs and other newer antidepressants.
Similarly, a bolded warning in all current Selective Serotonin Reuptake
Inhibitor (SSRI) labeling regarding the necessity to avoid a potentially
fatal drug-drug interaction with monoamine oxidase (MAO) inhibitor
antidepressants, while true, may well not reflect current medical
practice, which entails only rare use of MAO inhibitors. Consideration
to replacement of these outdated warnings with labeling more
representative of modern medical practice and concern is recommended.*

6.  **A public meeting is planned in late summer to discuss the results
    of further analyses of the controlled trials. Until that time,
    should the FDA provide additional advice to practicing physicians
    regarding the use of these drugs?**

-   **If your answer is yes, please provide specific information on what
    that advice should be.**

*The Committee advised the FDA to issue a warning in the interim to the
physicians and the public on the potential side effects of the SSRIs and
other newer antidepressants. The Committee advised the FDA to inform the
public and health care workers including pediatricians and family
practitioners of the level of concern regarding possible harm to a
minority of children on antidepressants and the signs associated with
the side effects. Specifically, the Committee felt that the necessity of
close follow-up, with monitoring for emergent adverse effects, during
the first weeks of treatment of children and adolescents with
antidepressants should be stated explicitly. Parents or other
responsible adults should be informed of the signs and symptoms of the
"activation syndrome" and of the urgency of having the child seen by
physician should such behaviors emerge, especially early in the
treatment course.*

*The Committee advised the FDA to inform the public and health care
workers, including pediatricians and family practitioners, that the data
on the efficacy of SSRIs for pediatric major depression is less
compelling than Committee members had recognized prior to recent events
discussed by the Committee. The Committee is concerned that health care
workers are unaware of the fact that the strong majority of randomized
controlled trials of SSRIs do not demonstrate superiority over placebo
in the treatment of major depression in children and adolescents. The
Committee felt that it was important for the FDA to communicate this
fact as it bears on the risk-benefit ratio for the use of SSRIs in
pediatric major depression.*

7.  **Should FDA involve other professional organizations in the
    community? If so, how should FDA involve these organizations? What
    messages should these organizations provide?**

> *The Committee felt that the Agency should involve all health care
> organizations whose membership includes physicians and other medical
> personnel who might prescribe or be asked questions about
> antidepressant use in children and adolescents. Such health care
> professionals would include pediatricians, child and adult
> psychiatrists and psychologists, internists, family practitioners,
> emergency room, intensive care, and rehabilitation physicians, nurse
> practitioners, pharmacists, and physicians' assistants. Other
> professionals who work with young people, including teachers and
> social workers, should also be included. Examples of such professional
> organizations cited by Committee members include medical organizations
> such as the American Academy of Pediatrics (AAP) and the American
> Association of Family Practitioners (AAFP), and similar organizations
> representing the other health care professions. Professional
> publications, e.g. [Pediatric News]{.underline}, while heightening
> awareness of the prevalence of depression and risk of suicide, may
> play a role in informing health care workers and family members of the
> relative benefits and risks, including possible side effects, of
> antidepressant drugs.*
>
> *These organizations and the Agency should provide information to
> health care providers through a variety of sources, including
> newsletters and the Internet, as well as face-to-face meetings and
> panel discussions.*
>
> *In addition, the organizations should also inform and educate parents
> so that when they make collaborative decisions with their child's
> physician they are fully informed and understand completely the
> serious potential risks of the drug. The adults responsible for the
> young person being treated with antidepressants should be aware of the
> small but real risk of an "activation syndrome" developing in their
> children and informed of the need to be vigilant about this concern
> and to immediately contact the prescribing health care professional
> should any behavioral toxicity emerge during treatment.*
>
> Following the discussion session, the meeting adjourned at
> approximately 6:15 PM.

#