# Summary Minutes 

# Advisory Committee for Reproductive Health Drugs Meeting

**December 15, 2003**

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 December 15, 2003, meeting of the Advisory
Committee for Reproductive Health Drugs and that these minutes (see
below) accurately reflect what transpired at that meeting.

Approval Date: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

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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., Lorraine Tulman,
Ph.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]{.underline}:**

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 America: Vanessa Cullins

Douglas Rose (representing self)

American College of Nurse Midwives: DeAnn Williams

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]{.underline}**

Folate Nutrition and Metabolism and Influence Barry Shane, Ph.D.

on Neural Tube Defects (NTDs) Professor, Dept. of Nutritional

> Sciences and Toxicology
>
> University of California, Berkeley
>
> Folic Acid and Safety Patrick J. Stover, Ph.D.

Associate Professor of

Nutritional Biochemistry

Cornell University

Folic Acid Fortification in the U.S.: Elizabeth Yetley, Ph.D.

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 National Center on Birth Defects

> 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

Dalhousie University, Halifax, Nova Scotia

> 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.)]{.underline}**

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
>
> Rollins School of Public Health
>
> Emory University
>
> 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
>
> University of North Carolina at Chapel Hill

Oral Contraceptive Use, Pregnancy Andrew M. Kaunitz, M.D.

Intendedness and Folic Acid Intake Professor and Assistant Chairman

University of Florida Health Science Center

Summary and Conclusion Andrew J. Friedman, M.D.

***[Questions to the Committee:]{.underline}***

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%;*

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-   *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 5:00 p.m.