Center for Drug Evaluation and Research
SUMMARY MINUTES OF THE
CDER PSYCHOPHARMACOLOGIC DRUGS ADVISORY
COMMITTEE
AND THE
FDA PEDIATRIC ADVISORY COMMITTEE
Wayne
Goodman M.D. (Chair)
Jean Bronstein, R.N., M.S.
James McGough, M.D.
Lauren Marangell, M.D.
Delbert Robinson, M.D.
Bruce Pollock, M.D., Ph.D.
Barbara Wells, Pharm.D.
Daniel Pine, M.D.
FDA Participants
Russell Katz, M.D.
Thomas Laughren, M.D.
M. Dianne Murphy, M.D.
Anne Trontell, M.D., M.P.H.
Executive Secretary
Anuja M. Patel, M.P.H.
Matthew Rudorfer, M.D.
Irene Ortiz, M.D.
Tana Grady-Weliky, M.D.
Richard Malone, M.D.
Cynthia Pfeffer, M.D.
Gail Griffith, B.A., M.A. (Patient Representative)
Psychopharmacologic
Drugs Advisory Committee Member (Non-voting)
Philip Wang, M.D., M.P.H., Dr. P.H.
Psychopharmacologic
Drugs Advisory Committee Industry Representative (Non-voting)
Dilip Mehta, M.D., Ph.D.
Pediatric Advisory Committee Member (Voting)
Joan Chesney, M.D.
Robert Nelson, M.D., Ph.D.,
Thomas Newman, M.D., .M.P.H.,
Victor Santana, M.D.
Judith O’Fallon, Ph.D.
Michael Fant, M.D., Ph.D.
Deborah Dokken, M.P.A. (Patient-Family Representative)
Pediatric Advisory Committee Consultants
(Voting)
Charles Irwin, Jr., M.D. (CDER SGE)
James Perrin, M.D. (CDER SGE),
Laurel Leslie, M.D., FAAP (CDER SGE)
Robert Gibbons, Ph.D. (CDER SGE)
Norman Fost, M.D., M.P.H. (CBER SGE)
Steven Ebert, Pharm.D. (Consumer Representative for
AIDAC)
Pediatric Advisory Committee Member
(Patient Health Organization Representative - Non-voting)
Richard
Gorman, M.D., FAAP
Guest Pediatric Advisory Committee
Industry Representative (Non-voting)
Samuel
Maldonado, M.D., M.P.H. (AIDAC Industry Representative)
Guest
Speakers (Non-voting)
John March, M.D., M.P.H.
Guests (Non-voting)
Barbara
Stanley, Ph.D.
Madelyn
Gould, Ph.D., M.P.H.
These summary minutes for the
I certify that I attended the
________//S//____________ _____________//S//______________________
Anuja M. Patel, M.P.H. Wayne K. Goodman, M.D.
Executive Secretary Chair
Open Public Hearing Speakers:
· Kenneth Duckworth - National
·
· Ronnie Wilkins -
· Ann Blake Tracy & Marion Goff -
International Coalition for Drug Awareness
· Andrew Chmilewsky
· Susan Furlough
· Lisa van Syckel
· Raul Lagurre
· Gloria Pope - Depression and Bipolar
Support
· Andy Vickery
· Vera Sharav -
· Jennifer Tierney
· Alan Salerian
·
· David Fassler - American Psychiatric
Association
· Tom Woodward
· Sheila McDonald - The Child &
Adolescent Bipolar Foundation
· John Walkup
· Mark Taylor & Donna Taylor
· Kim Witczak
· Karen Barth Menzies
·
·
· Reese Butler -
· Suzanne Vogel-Scibilia
·
Mary
Ellen Winter
·
Beverly
Hatcher
· David Shaffer
· Mark Miller - International Coalition
for Drug Awareness
·
Donald
Farber
·
Allan
Routhier
·
Sharon
McBride
·
Peter
Breggin
·
Bruce
Orr
·
Jerry
Reed - Suicide Prevention Action
·
Chris
Coffin
·
Alice
Erber
·
Leigh
Webb
·
· Nancy Parker
· Richard Schneeberg
·
David
Risinger
·
David
Healy
·
Cynthia
Wainscott - National Mental Health Association
·
Deborah
Gruder
·
Mary
Guardino - Freedom from Fear
·
Terri
Williams
·
Laurie
Yorke
·
Robert
Fritz
·
Stuart
Varon
·
Julie
Zito
·
·
Steve
Rebarber
·
Christopher
Kratochvil
·
Eric
Swan
·
Patty
Weathers – Ablechild
·
Celeste
Steubing
·
Robert
Mann - American Foundation for Suicide Prevention
·
·
Mark
Shapiro
·
Mathy
Milling Downing
·
Peter
Kahn
·
Eileen McGinn
FDA Presentations:
Overview of Issue M.
Dianne Murphy, M.D.
Director,
Office of Pediatric Therapeutics,
Office
of the Commissioner
Russell Katz, M.D.
Director,
Division of Neuropharmacological Drug Products (DNDP), CDER, FDA
Regulatory
History and Background Thomas
Laughren, M.D.
Team
Leader, DNDP, CDER, FDA
Recent
Observational Studies of Diane
Wysowski, Ph.D.
Antidepressants (ADs) and Suicidal Behavior Epidemiologist, Division of Drug
Risk Evaluation, Office of Drug Safety (ODS), CDER, FDA
Brief Report on TADS Trial John March, M.D., M.P.H.
Characteristics of Pediatric Antidepressant Trials Greg Dubitsky, M.D.
Medical
Officer, DNDP, CDER, FDA
Classification of Suicidality Events
OCTAP Appraisal of
Classification Methodology Team Leader, Office of
Counter-Terrorism and Pediatric Drug Development (OCTAP), CDER, FDA
Results of the Analysis of Suicidality in Tarek Hammad, M.D., Ph.D.,
M.Sc., M.S.
Pediatric Trials of Newer Antidepressants Senior Medical Reviewer, DNDP,
CDER, FDA
Comparison between Original ODS and Andrew Mosholder, M.D., M.P.H.
Current DNDP Analyses of Pediatric Epidemiologist, Division
of Drug Risk Evaluation,
Suicidality Data Sets ODS,
CDER, FDA
Citalopram and Escitalopram
Pediatric Safety Data
Sertraline Use in Pediatric
Population: Pfizer
Incorporated
A Risk Benefit Discussion
Antidepressant Use in
Pediatrics Wyeth
Pharmaceuticals
Questions to the Committee:
1. Please
comment on our approach to classification of the possible cases of suicidality
(suicidal thinking and/or behaviors) and our analyses of the resulting data
from the 23+1 pediatric trials involving 9 antidepressant drugs.
Given the caveat that the
data set was inherently limited (e.g., not intended to evaluate suicide as an
endpoint, non-uniform ascertainment of suicide information, relatively small
number of events, etc.) the reclassification enhanced the confidence the
committee had in the data compared to last February. The overall consensus of the committee was
that the classification of the cases of suicidality (suicidal thinking and/or
behaviors) was reliable and valid. The
use of independent suicide experts, training and blinding of source materials
made it a rigorous process. Excellent
inter-rater reliability was demonstrated through agreement in classification
between the
The committee advised the
agency to address the issues of violent behavior and aggression in future data
collection. The committee further
suggested that the agency investigate whether suicidality outcome was related
to lack of response, other somatic adverse events, or dose changes. The committee urged use of reliable and valid
measures of suicidality and possible antecedent behavioral toxicity in
prospective fashion in future clinical trials.
Please see
transcript for details.
2. Do the
suicidality data from these trials support the conclusion that any or all of
these drugs increase the risk of suicidality in pediatric patients?
Prior to voting, the
Committee engaged in discussion regarding this question. The Committee felt that there was a lack of
clarity in the word “suicidality” therefore they redefined “suicidality” as the
“suicidal ideation, attempts and preparatory actions” as indicated in Outcome
3. Additionally, the Committee clarified
that the “trials” in this question refer to the 23+1 pediatric trials as stated
in question 1 where the “+1” corresponds to the TADS trial.
Since there were no completed
suicides in any of the 23+1 trials, the answer is limited to the data presented
from these trials.
Yes= 25 No= 1 Abstain= 1
Please see
transcript for details.
3. If the
answer to the previous question is yes, to which of these 9 drugs does this
increased risk of suicidality apply?
- Please
discuss, for example, whether the increased risk applies to all
antidepressants, only certain classes of antidepressants, or only certain antidepressants.
The
Committee revised the question above into a statement to read:
“The data in aggregate
indicate an increased risk of suicidality, as previously defined, in pediatric
patients. Although there is variability in the results, we are unable to
conclude that any single antidepressant agent is free of risk at this time. Do
you agree?”
The
Committee was unanimously in agreement with the statement above.
Yes= 27 No= 0 Abstain= 0
Please see
transcript for details.
4. If there is
a class suicidality risk that is limited to certain drugs in this class, how
should this information be reflected in the labeling
of each of the products?
-
What, if any, additional regulatory actions should the
Agency take?
The
Committee revised the question above to state:
“Does
the Committee support a “black box” warning for all antidepressants for
pediatric use?”
Yes= 15 No= 8 Abstain=
0
There were a total of 23
votes. Four voting members were absent at the time of the vote. A consensus was
reached by the committee that a med-guide for patients was needed and any
warning should be extended to all antidepressants for all pediatric uses not
just depression. The committee members expressed the need for additional
warnings as congruent with their vote on question #3 but there were various
opinions on what form this warning should assume. Those voting against a “black box” warning
felt that this option might be too alarming and that bold lettering or similar
means would be a more measured response to communicate the possible risk. An advantage cited for the “black box” is
that it might deter marketing through direct to consumer ads.
Please see
transcript for details.
5. Please
discuss what additional research is needed to further delineate the risks and
benefits of these drugs in pediatric patients with psychiatric illness.
The Committee made several
suggestions to the Agency including more efficacy data and more safety data
focusing on suicidality. The committee encouraged future long-term trials
including placebo and fluoxetine as controls. The Committee advised the Agency
to include additional information on the prior history of patients (e.g. personal
and family history of bipolar disorder). The committee strongly felt a need to ensure
that prescribers know how to use antidepressant drugs safely and effectively
with greater attention to medication induced side effects (e.g. possible signs
of behavioral toxicity as reflected by an activation syndrome), risk factors
(e.g. history of bipolar disorder, co morbid anxiety disorder, etc.),
age-appropriate dosing, possible pharmacokinetic factors, and need for close
monitoring. The Committee advised the Agency that children with major
depressive mood disorder (MDD) be further studied by the National Institutes of
Health; such research should aim at better understanding the natural history
and longitudinal course of the disorder, and the risks of no treatment as well
as those associated with pharmacological and non-pharmacological interventions.
Please see
transcript for details.
Following the discussion session, the
meeting adjourned at approximately