A verbatim
transcript is available and posted on the FDA dockets website at:
http://www.fda.gov/ohrms/dockets/ac/cder03.html#ReproductiveHealth
I certify
that I attended the
Approval
Date: _______________________
________________________________________________ __________________________________________
Jayne E.
Peterson, R.Ph., J.D., Acting Executive Secretary Linda Giudice, M.D., Chair
All external requests for the
a written copy of the meeting transcripts should be submitted to the
CDER, Freedom of Information office.
Prior to the meeting, the members and the
invited consultants had been provided the background material from the FDA and
from Johnson and Johnson, Pharmaceutical Research & Development, LLC (J
& J was an FDA invited participant in the AC meeting). The meeting was called to order by Linda
Giudice, (Committee chair); the conflict of interest statement was read into
the record by Jayne Peterson (Acting Executive Secretary). There were approximately 200 persons in
attendance. There were twelve (12)
speakers for the Open Public Hearing session (see below for a listing of the
speakers).
Attendance:
Advisory
Committee for Reproductive Health Drugs Members Present (voting):
Linda Giudice, M.D. (Chair), Susan Crockett,
M.D., Nancy Dickey, M.D., Scott Emerson, M.D., Ph.D., W. David Hager, M.D.,
Vivian Lewis, M.D., Larry Lipshultz, M.D., George Macones, M.D., Valerie
Montgomery Rice, M.D., Joseph Stanford, M.D.
Advisory Committee for
Reproductive Health Drugs Members Absent:
Arthur
Burnett, Jr., M.D., Charles Lockwood, M.D.,
Advisory Committee for
Reproductive Health Drugs Consultants (voting):
Irwin
Rosenberg, M.D., Ralph Green, M.D., Katherine Wenstrom, M.D., Michael Greene,
M.D., Barry Shane, Ph.D., Tsunenobu Tamura, M.D., Phillip Darney, M.D. Note:
Patrick Stover, Ph.D. was scheduled to present and participate in the
meeting but was unable to attend the meeting (see meeting agenda below). Instead Dr. Barry Shane presented on his
behalf.
Non-Prescription Drugs
Advisory Committee Member Present (voting):
Sonia
Patten, Ph.D.
Acting Industry
Representative (non-voting):
Jonathan Tobert, M.D., Ph.D.
National
Institutes of Health (NIH) Participant (non-voting):
James Mills, M.D., M.S.
Centers
for Disease Control (CDC) Participant (non-voting):
Joseph Mulinare, M.D., MSPH
FDA
Participants (non-voting):
Daniel Shames, M.D., Donna Griebel, M.D., Scott
Monroe, M.D., Lisa Soule, M.D., Jeanne Rader, Ph.D., Elizabeth Yetley, Ph.D.
Open
Public Hearing Speakers:
Spina Bifida Association of America/Spina Bifida
Foundation: Eileen Carlson/Douglas
Sorocco
Reproductive Health Technology Project: Kristen Moore
John Grossman, M.D. (representing self)
National Association of Nurse Practitioners in
Women’s Health: Susan Wysocki
Association of Reproductive Health
Professionals: Felicia Stewart
Association of Women’s Health Obstetric and
Neonatal Nurses: Claudia Ravin
Healthy Mothers/Healthy Babies: Anita Boles
Dr. Sonya Oppenheimer
Planned Parenthood Federation of
Douglas Rose (representing self)
American
American Society of Reproductive Medicine: Richard Falk, M.D.
Issue:
The
public health issues, including the safety and potential clinical benefit,
associated with combining folic acid and an oral contraceptive into a single
combination product. (Note:
The goal of this plan is to reach women of child-bearing potential
either who currently take oral contraceptives and conceive while on the OC or
who discontinue the OC and immediately conceive).
FDA
Presentations
Folate Nutrition and Metabolism and
Influence Barry Shane, Ph.D.
on Neural Tube Defects (NTDs) Professor, Dept. of Nutritional
Sciences and Toxicology
Folic Acid and Safety Patrick
J. Stover, Ph.D.
Associate
Professor of
Nutritional
Biochemistry
Folic Acid Fortification in the
Planning, Implementation, and Monitoring Lead Scientist for Nutrition
Center for Food Safety
and
Applied Nutrition
(CFSAN), FDA
Assessing the Impact of Fortification on the Joe Mulinare, M.D.,
MSPH
Epidemiology of NTDs
and Developmental
Disabilities Centers for Disease Control
and Prevention (CDC)
Folic Acid Supplementation and
Fortification Michiel Van den
Hof, M.D.
in Nova Scotia (via
telecon) Division
Head, Maternal/Fetal Medicine
What is the Minimum Effective Dose of Folic James L. Mills, M.D., M.S.
Acid for Preventing NTDs? Chief, Pediatric
Epidemiology Section
Epidemiology Branch
Div. of Epidemiology, Statiststics and
Prevention Research, NICHD, NIH
Invited Sponsor Presentations (Johnson and
Johnson, Pharaceutical Research & Development, L.L.C.)
Proposal
Background and Overview Andrew
J. Friedman, M.D.
Director, Women’s Health
Care Research Ortho-McNeil Pharmaceutical, Inc.
Neural Tube
Defects: Efficacy and Safety of Godfrey
P. Oakley, Jr., M.D., MSPM
Folic Acid
Visiting Professor, Dept.
of Epidemiology
Need for Increased Folic
Acid Intake Among Anna
Maria Siega-Riz, Ph.D., R.D.
Reproductive
Age Women
Associate
Professor of Maternal and Child
Health and Nutrition
Oral Contraceptive Use, Pregnancy Andrew
M. Kaunitz, M.D.
Intendedness and Folic Acid Intake Professor and
Assistant Chairman
University
of
Summary and Conclusion Andrew
J. Friedman, M.D.
Questions to the Committee:
1.
Are further increases in
folic acid intake, beyond what is available from fortified cereals, likely to
result in public health advances in preventing further neural tube defects?
Vote: Yes:
18 No: 0
The Committee Members felt that folic acid intake above the
current levels being ingested by women of child bearing potential would be
beneficial.
Sources of folic acid include: normal food intake, fortified
cereals and enriched grains, and vitamin supplements. Recommendations for pregnant women
(pre-pregnancy and early pregnancy) are to increase folic acid intake by
400 mcg/day, however, many women do not reach this goal. Adequate folic acid is most important the
first four to six weeks of pregnancy, however, many women are unaware of
this. Data were presented that suggested
that:
·
since the Federal
fortification program was begun in 1998, in general, daily folic acid intake
has been increased by approximately 200 micrograms/day and the incidence of
NTDs in the U.S. has decreased by an estimated 30%;
·further decreases in the NTD
rate may still be possible.
2.
Can we define a subpopulation
among women of reproductive age that needs additional folic acid?
**Note: This question was reworded by the committee
to read, “Is it necessary to define a subpopulation among women of reproductive
age that needs additional folic acid?” and the vote was taken based on this re-wording.
Vote: Yes: 4 No: 14
If yes,
what subpopulation should receive additional folic acid and how would you
identify this
population?
The
majority of the Committee Members felt that all women of reproductive age
(regardless of their current folic acid intake) could be candidates for further
folic acid supplementation and that identification of any specific
subpopulation was not necessary. The
several that felt that subpopulation(s) could be identified mentioned: women taking folate antagonists (such as
valproic acid). Additionally, a few
Committee Members mentioned that because of the concern that women taking folic
acid supplemented vitamins might be already ingesting 1000 mcg/day of folic
acid (which is the daily maximum recommended by the Institute of Medicine) ,
they would exclude these women as candidates for additional folic acid.
3.
Are there any safety issues associated with folic acid
supplementation targeted at reproductive-age women? If so,
Vote: Yes: 7 No: 11
a. What are they?
The Committee Members were somewhat split on this
issue. Several felt strongly that
although toxic levels of the
drug
is per se not a safety issue, the
potential of folic acid to mask pernicious anemia would be a concern. They
also expressed
concern that increased folic acid intake could impact the activity of
antifolate drugs such as antiepileptics (valproic acid) and methotrexate.
b. Would these safety issues not be a concern
below a certain level of
supplementation? If so, what is that level?
4. Would the benefit of prior folic acid use
persist if conception occurs after discontinuation
of folic acid?
Vote: Yes: 12 No: 2 Abstain: 1
If so, for how long will the benefit persist?
The majority of the
Committee Members expressed agreement that even following discontinuation of
folic acid, the
benefits exist. They further agreed that increased red cell
folate levels (following folic acid supplementation)
would be maintained for up to
90 days following discontinuation.
5. Is an oral contraceptive pill a reasonable
delivery vehicle if additional folic acid
supplementation is likely
to provide public health advances in preventing further neural tube
defects?
Vote: Yes: 18 No: 0
a. If so, would 400 mcg be a reasonable dose?
Vote: Yes: 18 No: 0
While the Committee Members voted that 400 mcg of folic acid would be a
reasonable dose to add to an oral
contraceptive pill,
many stated that this dose might not be ideal and that additional studies
should be conducted
to further define a
dose.
b. If 400
mcg is not appropriate, what dose of folic acid should be provided?
The Committee Members
did not provide a recommendation for alternative dosing.
The
meeting adjourned at approximately