FDA panel gives nod to adding folic acid to OC

A pill designed to prevent unintended pregnancy and birth defects is moving closer to commercial reality following a Food and Drug Administration (FDA) advisory committee’s unanimous vote to back such a combination product.

The agency’s Reproductive Health Drugs Advisory Committee concluded at its Dec. 15, 2003, meeting that the proposed product, under development by Ortho-McNeil Pharmaceutical of Raritan, NJ, would be an appropriate way to prevent neural tube defects (NTDs) in infants born to women who accidentally become pregnant while taking oral contraceptives (OCs) or become pregnant shortly after stopping pill use.

Despite a unanimous vote on the concept of the product, some panel members called for dose ranging studies to determine the proper dose for NTD prevention, which led to an 11-7 vote that there are no significant safety issues concerning use of the dose of folic acid in combination with the Pill.

Ortho-McNeil now awaits a meeting with the FDA’s Division of Urologic and Reproductive Drug Products to determine its next step, says Andrew Friedman, MD, the company’s director of women’s health research. Any studies that will be done in regard to dosing will be discussed with the FDA, says Friedman. The company will know more about what studies are necessary following its consultation with the agency, he states.

Why a combined pill?

The Washington, DC-based Institute of Medicine and U.S. Public Health Service now recommend that every woman capable of becoming pregnant consume 400 mcg synthetic folic acid daily in addition to a diet rich in natural folates.1 Despite a grain fortification program, which began in 1998, as well as a public awareness campaign on vitamin supplementation, just 20% of women participating in a 2002 March of Dimes survey knew that folic acid could prevent certain birth defects. The proportion who stated that they took a vitamin supplement containing folic acid daily increased from 25% in 1995 to only 31% in 2002.2.

Despite the high efficacy of OCs, approximately 1 million women per year become pregnant while using the Pill; half of these unintended pregnancies are continued to term, says Felicia Stewart, MD, adjunct professor in the department of obstetrics, gynecology, and reproductive sciences at the University of California San Francisco and co-director of the Center for Reproductive Health Research & Policy, also in San Francisco. Stewart testified at the FDA committee meeting on behalf of the Washington, DC-based Association of Reproductive Health Professionals.

Because NTDs develop very early in pregnancy (18-30 days after conception), often before a pregnancy is recognized, it is essential that intake of folic acid be established in advance, she notes.

"An oral contraceptive supplemented with folic acid offers a convenient and effective means of providing protection against NTDs for unintended pregnancies or other pregnancies for which advance folic acid intake may not have been adequate," she explains.

Since women do not plan to become pregnant while taking OCs, many of them are not motivated to take 400 mcg folic acid daily to prevent NTDs in their offspring, says Susan Wysocki, RNC, NP, president and chief executive officer of the Washington, DC-based National Association of Nurse Practitioners in Women’s Health. In addition, these women often have a delay in the diagnosis of pregnancy and would not be seen or counseled by their health care professional until well after the time when the neural tube has closed, she notes.

"Providing the Public Health Service-recommended 400 mcg daily dose of folic acid to these women via a passive method — i.e., women taking OCs that contained folic acid to prevent pregnancy — would be guaranteed to provide 400 mcg daily to women without changing prescription-writing or pill-taking behavior," states Wysocki, who also testified at the FDA committee meeting. "Chronic use of a combination OC/folic acid product would increase body folate stores and could prevent NTDs in unplanned pregnancies that occur while taking OCs and in pregnancies that occur within several months after discontinuing OCs."

Is it safe to use?

Questions were raised at the committee hearing as to potential disadvantages of a combination product. High doses of folic acid can mask a vitamin B deficiency; however, this deficiency occurs most often in older women and not among women of reproductive age, states Wysocki.

Introduction of a combination product will create a new opportunity for providers and women to consider preconception health recommendations, says Stewart.

"By bringing attention to the importance of folic acid, the combination product will remind the clinician to counsel women about other recommendations — about diet, and avoidance of harmful substances such as alcohol and tobacco — that can help contribute to a healthy pregnancy," she notes.

References

1. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC; 2000.

2. March of Dimes Birth Defects Foundation. Folic acid and the prevention of birth defects: A national survey of pre-pregnancy awareness and behavior among women of childbearing age, 1995-2002. Conducted by the Gallup Organization. White Plains, NY: March of Dimes Foundation; May 2002. Publication No. 31-1677-02.