Food and Drug Administration
Center for Drug
Evaluation and Research
Advisory Committee Conference Room 1066,
Steven
Ebert, Pharm. D.
Joan P. Chesney, M.D. Victor Santana, M.D.
David
Danford, M.D. Mark Hudak,
M.D. Richard Gorman, M.D.
Robert Nelson, M.D. Susan
Fuchs, M.D. Judith O’Fallon, Ph.D.
Katherine Wisner, M.D.
Government Employee Industry Representative
Janet Cragan, M.D. (CDC) Sam Maldonado, M.D.
FDA Participants
Dianne Murphy, M.D. Shirley Murphy, M.D. Susan Cummins, M.D.
Solomon Iyasu, M.D.
These summary minutes for the
I certify that I
attended the
_______//S//________________________ __________//S//_____________________
Thomas
H. Perez, M.P.H., R.Ph. Joan
P. Chesney, M.D.
Executive Secretary Chair
The Pediatric Subcommittee of the AntiInfective
Drugs Advisory Committee, of the Food and Drug
Administration, Center for Drug Evaluation and Research met June 9, 2004 Advisory
Committee Conference Room, Rm. 1066, 5630 Fishers Lane, Rockville, MD.
On
The Subcommittee and invited guests received a
briefing document from the FDA in preparation for this meeting.
There were approximately 65 persons present in the
audience at this meeting. The meeting
was called to order at
Presentations
began at
Adverse Event Reports per Section 17 of BPCA Division
of Pediatric Drug Development
Solomon Iyasu, M.D., Lead Medical Officer
Fexofenodine Jane Filie, M.D., Medical Officer
Topotecan and, Temozolomide Susan McCune, M.D., Medical Officer
Ciprofloxacin and, Moxifloxacin Harry Gunkel, M.D., Medical Officer
Fosinopril Larry Grylack, M.D., Medical Officer
Fentanyl ShaAvhree Buckman, M.D., Medical Officer
David J. Lee, Ph.D., Clinical Pharmacology
Reviewer
Div. of Pharmaceutical Evaluation II
D. Elizabeth McNeil, M.D., Medical Officer,
Div. of Anesthetic, Critical Care &
Addiction Drug Products
At
Venlafaxine Hari Sachs, M.D., Medical Officer
There were no participants for
the Open Public Hearing’s morning session.
At
At
Robert
Levin, M.D., Div. of Neuropharmacological Drug Prod.
Katherine Wisner, M.D., Women’s Behavioral Health CARE
At
Update on Congenital Eye Malformations in Infants Solomon Iyasu, M.D.
The afternoon session of the Open Public Hearing began
at
Maternal
SSRI-Use During Pregnancy Philip Sanford Zeskind, Ph.D., Research Professor of Pediatrics
And Neonatal Neurobehavioral
Outcome
After a 10 minute break the meeting
continued at
Pediatric
Research Equity Act (PREA) Update Shirley
Murphy, M.D.
Director,
Division of Pediatric Drug Development
Overview of
IOM Report, Ethical Conduct of Robert Nelson, M.D.
Clinical
Research Involving Children The
Children’s
The
meeting was adjourned at
Pediatric Sub-committee of the Anti-infective Drugs
Advisory Committee Meeting
Questions to the Subcommittee
The
Subcommittee discussed the following questions.
The meeting’s discussion will be made available through the meeting
transcripts and placed on the web in approximately three weeks. Transcripts may be accessed at: www.fda.gov/ohrms/dockets/ac/acmenu.htm.
Adverse Event Reporting
1. The risk management strategy for the Duragesic patch
that you have heard today is very preliminary. Do you have any suggestions or additional
thoughts that you would like to discuss?
The committee
strongly recommends that the Black Box section contain additional language
indicating that:
"inappropriate use may result in serious adverse effects
including death" and highlight the need for qualifications of those
prescribing the medication.
In addition
the committee suggested the following additional points to consider:
Patient
information should be clear and written at a less sophisticated level,
particularly statements regarding continued risk and side effects from the
medication after it has been discontinued.
Format
reorganization of the information to highlight important areas.
Develop
additional risk management communications to hospitals, in particular the
pharmacy department.
Consider
adding a "Pediatric Exclusivity" category of information for trial
information in the labeling for all products that are studied under the
Pediatric Exclusivity provisions. The committee also expressed concern that
important negative information or even acknowledgement of studies conducted in
children is not being noted in all of the labels of products having pediatric
studies.
Consider
future development of products labels with embedded electronic links for
additional details and documentation.
SSRI/SNRI neonatal withdrawal syndrome
2. The FDA is proceeding with class labeling about
neonatal toxicity/withdrawal syndrome related to in-utero exposure to
SSRI/SNRIs. Considering the risk/benefit of SSSR/SNRI use in pregnant women
with depression versus the risk/benefit to the fetus/newborn, how should this
new information on the label be disseminated to child
health practitioners and the public? Please discuss the following options.
a) No further action necessary. Label change is adequate.
b) Dear Health Care Professional Letter (sponsor
responsibility)
c) Prescribe/health care professional education through
professional groups
d) Public Health Advisory (FDA’s responsibility)
The
committee strongly endorsed class labeling for the neonatal toxicity/withdrawal
syndrome related to in utero exposure of SSRI/SNRI’s. The members also strongly supported a package
insert for patients (pregnant or considering pregnancy) which provided detailed
information at the 6th to 8th grade level as to what is
known about the risk/benefit issues for the fetus/newborn and for the mother
when choices have to be made about the use of these agents in pregnancy. The committee did not support a Public Health
Advisory.
Strong
support from the members was also provided regarding professional education
through professional groups regarding the neonatal toxicity/withdrawal
syndrome. In addition to Pediatric,
Obstetric and Psychiatric Professionals, providing information to Family
Medicine practitioners was also strongly emphasized.
3. BPCA does not provide a mechanism for issuing a
written request to study drug therapies for pregnant women. There are no population
based estimates of SSRI/SNRI exposure data in pregnant women and there are no
systematically collected data on neonatal outcomes in infants exposed to these
drugs. Furthermore, determining causality for
neonatal reactions is challenging as the role of drug discontinuation, direct
toxicity (e.g. serotonin syndrome) and/or other drug/substance exposure during
pregnancy is often unclear. Is there a
need for further research to evaluate and characterize the neonatal effects of
in-utero exposure to SSRI/SNRIs? If your answer is yes, in your discussion of
research options, please discuss feasibility and potential sponsors for each
option.
a) Continue evaluating/monitoring post-marketing adverse
event reports
b) Population based prospective study of pregnancies exposed
to anti-depressants and neonatal outcomes
c) Retrospective study of neonatal withdrawal
syndrome/serotonin toxicity
d) Randomized controlled trial of treatment of maternal
depression. If yes, what research questions should be addressed by the trial?
The
members felt there was an urgency to acquire research data clarifying the
nature of the neonatal syndrome. The few
available studies don’t clearly distinguish between a
“behavioral teratogenicity” syndrome resulting from prolonged serotonin
exposure in utero vs. a simple “withdrawal syndrome” resulting from in utero
“serotonin toxicity.” It was felt
that retrospective studies would probably not have precise enough focused
observations to distinguish between these two syndromes, if in fact there are
two separate syndromes.
Although
retrospective studies might provide incidence/prevalence data, the members felt
that prospective detailed, longitudinal and long term studies, including if
possible, in utero physiologic fetal data are urgently needed. For example, information regarding the long
term effects on older children following fetal exposure to SSRI/SNRIs has not
been studied in enough detail.
It
was suggested that the
Although
ideal, the use of randomized controlled trials of SSRIs for the treatment of
maternal depression for the specific
purpose of defining the effects on the fetus and newborn,
is a complex issue which would take much more discussion involving
psychiatrists and obstetricians. From
one of the speakers the members were made aware of a potential study comparing
SSRIs vs. light therapy of depression in pregnancy. Following women who chose no therapy or
alternate pharmacologic or light therapy might provide a control group.