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:


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:  _______________________


________________________________________________                    __________________________________________

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).



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:


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

               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.)

               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:


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



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.