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This article was originally published in The Tan Sheet

Executive Summary

FOLIC ACID HEALTH CLAIMS FOR NTD PREVENTION ARE ALLOWED BY FDA under a proposed rule slated for publication in the Oct. 12 Federal Register. FDA said it "has tentatively decided to authorize a health claim for folate and neural tube defects (NTDs)" in the labeling of dietary supplements and foods "based on its own review of the totality of the scientific evidence." The notice also proposes to allow fortification of grain products with folic acid. Approval of a folic acid health claim comes almost a year after the Public Health Service recommended that women of childbearing age should consume 400 mcgs daily of folic acid to reduce the risk of conceiving a child with neural tube defects, and about one week after dietary supplement bill sponsors Sen. Orrin Hatch (R-Utah) and Rep. Bill Richardson (D-N.M.) urged FDA Commissioner David Kessler to approve a folic acid health claim "immediately" ("The Tan Sheet" Oct. 4, p. 7). FDA announced the proposal in an Oct. 8 press release. The claim, as proposed by FDA, would generally convey that "women who are capable of becoming pregnant and who consume adequate folate daily may reduce their risk of having a pregnancy affected by spina bifida and other NTDs." The agency provides five sample health claims that may be used. Synonyms for folate may be used in the label statement, such as "folic acid," "folacin," or "folic acid/folate/folacin, a B vitamin." In addition, firms may substitute other terms for NTDs, such as "the birth defect spina bifida," or "birth defects of the brain and spinal cord." FDA also proposed to require that the claim contain a statement that NTDs are "multifactorial in origin" and that NTDs, "while not of high prevalence in the U.S., are very serious birth defects." FDA offered an example of a label statement: "Such birth defects, while not widespread, are very serious." The claim also is required to contain a statement that "some but not all women may benefit from adequate intakes of folic acid" in order to prevent the claim from "misleading women to believe that use of folic acid will prevent all occurrences of NTDs." FDA warned that the health claim should not assert "that a specified amount of folate is more effective in reducing the risk of NTDs than a lower amount," and that the health claim statement should identify sources of folate. Manufacturers can state, for instance, that "adequate amounts of folate may be obtained by making specific dietary choices of folate-rich foods, as well as through use of dietary supplements or fortified breakfast cereals." To ensure that dietary supplements are delivering the folate amounts that they claim to be providing, FDA proposed that all folic acid-containing supplements that bear a health claim must 11 meet the United States Pharmacopeia standards for disintegration and dissolution." Supplements can be "formulated in a manner that prevents rapid dissolution and disintegration, thereby preventing subsequent absorption of the nutrients they contain," the agency explained. If USP standards do not exist, however, FDA allowed that "demonstrations of bioavailability in human or animal studies . . . will fulfill this requirement." FDA said it is prohibiting folic acid health claims on supplement formulas that contain more than 100% of the RDI of vitamin A and vitamin D. The agency noted that "some consumers may try to increase their folate intake through the use of multiple doses of fortified products or vitamin supplements" in light of the health claim, and that, as a result, consumers who take "products that contain both folate and vitamin A or vitamin D" could be exposed to "excessive vitamin A or vitamin D intakes in their attempts to obtain increased amounts of folate." In excessive amounts, vitamin A is potentially teratogenic and vitamin D is potentially toxic, FDA pointed out. FDA also is offering manufacturers the option of identifying "other risk factors" for NTDs, such as a personal history of such a defect, maternal diabetes mellitus, use of the antiepileptic drug valproic It acid, maternal febrile illness, or a close relative with an NTD. FDA did not authorize a health claim for folic acid in its January 1993 final rule implementing the Nutrition Labeling & Education Act for conventional foods. At that time, the agency noted that 11 questions remained about the safety of high intakes of folate by both the target population and other segments of the population who might be unintentionally exposed to high intakes of folic acid if overfortification of the food supply were to occur." In addition, "there were several other unresolved scientific questions that required discussion before a health claim could be authorized," FDA explained. FDA noted that the "strongest evidence" supporting the relationship between folic acid consumption the prevention of NTDs came from an intervention study by the U.K.'s Medical Research Council that "showed that women at risk of recurrence of an NTD- affected pregnancy who consumed a supplement containing .4 mg folic acid daily had a reduced risk of having a child with NTDs." The study, FDA said, "clearly demonstrated for the first time a significant reduction in recurrence of NTDs with high levels of folic acid but not with other vitamins or minerals." The MRC research also "established a specific role for folic acid," the agency added. "In reaching this tentative conclusion" to allow folic acid health claims, FDA acknowledged that it found "significant gaps in existing knowledge about the etiology of NTDs; about how folate, either alone or in combination with other nutrients, reduces the risk of NTDs; and of the dose-response relationship of folate intake to reduction in risk of NTD-affected pregnancies." Despite these uncertainties, FDA said, the evidence is "sufficiently consistent" in favor of a folic acid health claim. FDA also noted that it was swayed by the support of its Folic Acid Subcommittee, which endorsed a folic acid health claim at an April meeting ("The Tan Sheet" April 19, p. 3). Addressing a concern of the Folic Acid Subcommittee that higher doses of folic acid may occasionally mask the hematologic manifestations of vitamin B[12] deficiency and lead to pernicious anemia and nerve damage, FDA said it has "tentatively concluded that safety problems can be resolved by setting a safe upper limit of intake of 1 mg folate/day for all population groups when considering options for food fortification." Under FDA's proposal for fortification of the food supply -- which is also addressed in two separate Oct. 12 proposals that amend the food additive regs and the standards of identity for various food products to allow for a folic acid health claim -- cereal-grain products are fortified at 140 mcg/100g, breakfast cereals at 100 mcg/serving, and folic acid amounts in dietary supplements are retained at 400 mcgs/unit. These levels "could provide folate intakes below I mg folate daily for most persons," FDA said. For fortified foods and dietary supplements that contain more than 25% of the RDI (more than 100 mcgs/supplement), FDA is requiring a statement about "the maximum safe daily limit for folate consumption" to prevent the health claim from "being misleading regarding potential risks from excessive intakes." The agency added that it would consider modifying the upper limit of I mg per day if data submitted in response to the Oct. 12 proposal supported such a change. In addition, FDA requested scientific data on whether individuals who are taking drugs that interfere with folate metabolism are at an increased risk of adverse reactions in light of the proposal. "There are large numbers of patients taking low levels of antifolate drugs on a chronic basis and the current scientific literature on potential adverse effects of significant increases in folic acid intakes . . . is very limited," the agency noted. The proposal carries a 60-day comment period during which FDA is convening its Food Advisory Committee and Folic Acid Subcommittee on Oct. 14-15 to discuss the proposals ("The Tan Sheet" Sept. 27, In Brief). In addition, FDA said it is requesting input from industry specifically on "the number of products that will bear health claims or the effect that folate health claims will have on consumer demand for products containing folic acid."

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