U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Nutritional Products, Labeling, and Dietary Supplements
October 10, 2000

Letter Regarding Dietary Supplement Health Claim for Folic Acid

With Respect to Neural Tube Defects

(Docket No. 91N-100H)

Jonathan W. Emord, Esq.
Emord and Associates, P.C.
1050 Seventeenth Street, NW
Suite 600
Washington, DC 20036

RE: Health Claim: Folic Acid and Neural Tube Defects (Docket No. 91N-100H)

Dear Mr. Emord:

This letter is in reference to the court decision directing the Food and Drug Administration (FDA) to reconsider whether to authorize use of your proposed claim "0.8 mg of folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form" in dietary supplement labeling (Pearson v. Shalala, 164 F.3d 650 (D.C. Cir. 1999)). FDA will address in separate letters the other three health claims that the court directed FDA to reconsider.

I. Procedure and Standard for Evaluating the Claim

In reconsidering your claim and the three other health claims that were the subject of Pearson, FDA proceeded as described in the October 6, 2000, Federal Register notice entitled "Food Labeling; Health Claims and Label Statements for Dietary Supplements; Update to Strategy for Implementation of Pearson Court Decision." 65 Fed. Reg. 59,855 (2000). As noted below in section III, FDA gathered new scientific evidence on the claims by contracting for a literature search and publishing two notices in the Federal Register soliciting comments and data. After reviewing the updated body of evidence on the claims, FDA applied the "significant scientific agreement" standard by which the health claim regulations require the agency to evaluate the scientific validity of claims. Under this standard, FDA may issue a regulation authorizing a health claim only "when it determines, based on the totality of publicly available scientific evidence (including evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific procedures and principles), that there is significant scientific agreement, among experts qualified by scientific training and experience to evaluate such claims, that the claim is supported by such evidence." 21 C.F.R. § 101.14.

For claims that did not meet the significant scientific agreement standard, FDA next considered whether to exercise enforcement discretion for qualified claims about the substance-disease relationship. Consistent with the Pearson decision, the agency considered whether consumer health and safety would be threatened by the claim, and, if not, whether the evidence in support of the claim was outweighed by evidence against the claim, either quantitatively or qualitatively. See 164 F.3d at 650, 659 & n.10. If the evidence for the claim outweighed the evidence against the claim and there was no health or safety threat, the agency went on to consider whether a qualified claim could meet the general health claim requirements of 21 C.F.R. § 101.14, other than the requirement to meet the significant scientific agreement standard, and the requirement that the claim be made in accordance with an authorizing regulation. These requirements were not challenged in Pearson and therefore still apply.

In the October 6 notice, FDA explained that it would consider exercising enforcement discretion for a dietary supplement health claim that did not meet the significant scientific agreement standard if the scientific evidence for the claim outweighed the scientific evidence against the claim, if the claim included appropriate qualifying language, and if the other criteria listed in the notice were met. In that event, the agency explained, FDA would send a letter to the petitioner outlining the agency's rationale for its determination that the evidence did not meet the significant scientific agreement standard and stating the conditions under which the agency would ordinarily expect to exercise enforcement discretion for the claim. See 65 Fed. Reg. at 59,856. The agency also stated that, conversely, if the scientific evidence for the claim did not outweigh the scientific evidence against the claim, or the substance posed a threat to health, or the other criteria for the exercise of enforcement discretion were not met, FDA would issue a letter denying the claim and explaining its reasons for doing so. See 65 Fed. Reg. at 59,856.

Although the deadlines for FDA action in 21 C.F.R. § 101.70(j) apply to health claims that are submitted by petition, they do not apply to the four claims that were the subject of Pearson. FDA is reconsidering those claims under a court order that sets no specific deadlines but clearly contemplates prompt action because of First Amendment concerns and the agency's obligation to comply with court orders as soon as possible. Accordingly, even though the deadlines in § 101.70(j) do not apply, FDA is using them as a guideline. Section 101.70(j)(2) requires the agency to issue a denial or a proposed regulation to authorize the health claim within 190 days of submission of the petition summarizing the scientific evidence relevant to the claim. FDA is issuing this decision letter on October 10, 2000, 190 days after the close of the second comment period for the submission of scientific evidence relevant to the claim.

II. Summary of Review

On March 5, 1996, FDA authorized a health claim for folate and neural tube defects (NTD's). ⁽¹⁾ 61 Fed. Reg. 8750 (1996) (codified at 21 C.F.R. § 101.79). FDA concluded that the evidence available at the time demonstrated that folate, as both folic acid and naturally occurring food folate, reduces the risk of NTD's, which are brain and spinal cord birth defects. At the same time, FDA concluded that a claim that a specific amount of folate from one source was more effective than a specific amount from another source was misleading. The agency concluded that the scientific literature did not support the superiority of any one source of folate over others, and that the data were insufficient to provide a basis for stating that a specific amount of folate is more effective than another amount. Because of this limitation in the evidence, in the health claim regulation for folate and NTD's, FDA prohibited use of a claim that a specified amount of folate per serving from one source is more effective in reducing the risk of NTD's than a lower amount per serving from another source (see 21 C.F.R. § 101.79(c)(2)(i)(G)) (pursuant to Pearson, FDA revoked this provision on October 3, 2000, see 65 Fed. Reg. 58,917, 58,918 (2000)).

In response to Pearson, FDA has reconsidered the scientific evidence on the amount, source, and type of folate in foods relative to reduced risk of NTD's that has become available since the agency concluded the folate-NTD rulemaking in 1996. The agency conducted both its original 1993-96 scientific evaluation and its evaluation of the evidence that has become available since that time in a manner consistent with the principles and procedures articulated in FDA's Guidance for Industry: Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements (December 1999).

Based on its review of the scientific evidence, FDA finds that (1) the evidence does not show that 800 micrograms (mcg) folic acid per day is more effective in reducing the risk of NTD's than 400 mcg folic acid; (2) the evidence does not show that dietary supplements are more effective in reducing the risk of NTD's than foods in common form; and (3) the available evidence consistently shows that 400 mcg folic acid daily is a highly effective dose. FDA concludes from this review that the totality of publicly available scientific evidence demonstrates the lack of significant scientific agreement with respect to the comparative claim of effectiveness. FDA has also concluded that the weight of the evidence is against the proposed comparative claim. However, FDA concludes that the weight of the evidence supports the use of certain statements in conjunction with the currently authorized claim to inform consumers of the nature of the evidence relative to recommended intakes and ways to achieve these intakes. Accordingly, FDA intends to exercise its enforcement discretion with respect to the use of qualified claims about the strength of the evidence relative to the effective level and sources useful in meeting that level.

III. Review of the Scientific Evidence

A. 1993-1996 Scientific Review

Section 101.79(c)(2)(i)(G) of FDA's 1996 folate-NTD health claim regulation stated that "The claim shall not state that a specified amount of folate per serving from one source is more effective in reducing the risk of neural tube defects than a lower amount per serving from another source." FDA included this provision for the reasons described below.

In its proposal of October 14, 1993 (58 Fed. Reg. 53,254, 53,289 (1993)), FDA proposed that a health claim relating intake of folate and risk of NTD's not state that a specified amount of folate is more effective in reducing the risk of NTD's than a lower amount. This proposed requirement was consistent with the available data showing that reduction in risk of NTD's has been associated with general dietary improvement, which was assumed to increase folate intake by unspecified amounts (58 Fed. Reg. at 53,282).

In § 101.79(c)(2)(ii)(B) of its October 14, 1993 proposal, FDA also proposed to require that health claims relating intake of folate and decreased risk of NTD's identify sources of folate by stating that adequate amounts of folate may be obtained by eating folate-rich foods, as well as through use of dietary supplements or fortified breakfast cereals (58 Fed. Reg. at 53,289). Several studies have shown that among women with a prior NTD-affected pregnancy who improved their poor diets to diets with adequate intakes of all nutrients in a subsequent pregnancy, there was a 50 percent reduction in recurrence of NTD's (Laurence, 1983). In addition, several studies have shown that among non-users of supplements, significant gradients (i.e., trends) in reduction of risk of NTD's are associated with increased intakes of folate and other nutrients (Bower and Stanley, 1989; Werler et al., 1993). The study of Milunsky et al. (1989) showed that among non-users of supplements, diets providing 100 mcg or more folate/day were associated with reduced risk of NTD's. Thus, in its October 14, 1993 proposal, FDA tentatively concluded that claims that fail to reveal that adequate amounts of folate can be obtained through attention to dietary choices would be misleading (58 Fed. Reg. at 53,282-83). As stated in footnote 1 above, the October 14, 1993 proposal became a final regulation for dietary supplements by operation of law.

The agency received comments addressing the separate issues of source of folate and amount of folate in response to its October 14, 1993 proposal, which it addressed in its March 5, 1996 final rule (61 Fed. Reg. at 8759-60). For example, several comments stated that health claims should not contain statements that adequate diets cannot provide sufficient folate, or that only fortified foods or supplements can provide adequate folate. Other comments, however, stated that evidence that folate-rich diets reduce the risk of neural tube defects is suggestive while evidence that folic acid containing supplements reduce the risk of neural tube defects is conclusive (61 Fed. Reg. at 8759). The agency evaluated these comments and concluded that, based on its review of the scientific literature, including the studies summarized above and cited in its proposal (Bower and Stanley, 1989; Laurence, 1983; Milunsky et al., 1989; and Werler et al., 1993), the proposed limitation in § 101.79 on statements that specific sources are superior to others was appropriate because the scientific literature does not support the superiority of any one source of folate over others. Both folate from conventional foods and folic acid from fortified foods or dietary supplements are converted into functional, metabolically active coenzyme forms for use in the body (61 Fed. Reg. at 8759-60).

For these reasons, FDA stated in its March 5, 1996 final rule that, in the absence of the limitation, manufacturers would be free to put statements that would be false and misleading in their labeling. The agency's conclusion was consistent with the Public Health Service's (PHS) (DHHS/PHS, 1992) recommendation that advises that careful selection of foods is one means by which women can increase their folate intakes (61 Fed. Reg. at 8760).

Comments received by the agency in response to its October 14, 1993 proposal also addressed issues of the amount of folate that would be appropriate for a health claim. The agency summarized and addressed these comments in its March 6, 1996 final rule. Several comments stated that claims should not indicate that a specific amount of folate is more effective than another amount. Several comments noted that dose/response data to justify such statements do not exist, and that scientists do not yet know the requisite folate level that will protect the fetus from an NTD. Other comments disagreed, stating that claims should indicate that experts recommend 400 mcg folate per day or 100 percent of the Daily Value when referring to adequate amounts of folate. Another comment stated that while the 400 mcg level is admittedly imprecise, it is the amount recommended by the PHS (61 Fed. Reg. at 8760).

The agency evaluated these comments and concluded that, based on its review of the scientific literature, dose/response data were insufficient to provide a basis for stating that a specific amount of folate is more effective than another amount. The quantitative results from the studies of Milunsky et al. (1989), Bower and Stanley (1989) and Werler et al. (1993) suggest that amounts lower than the PHS recommendation of 400 mcg may be protective (61 Fed. Reg. at 8760).

After reviewing all comments that it received and the available scientific literature, FDA concluded in its March 5, 1996 final rule that the comments did not provide a basis for the agency to change its position prohibiting statements in the claim that imply that specific amounts of folate are superior to other amounts because such statements are inconsistent with the scientific data. FDA's conclusion was consistent with information provided in the PHS recommendation that states that amounts of folate lower than 400 mcg may reduce the risk of neural tube defects and that additional research is needed to establish the minimum effective dose (DHHS/PHS, 1992). The agency concluded that a contrary position would permit false statements to appear on product labels (61 Fed. Reg. at 8760).

Thus, in the March 5, 1996 final rule, for the reasons stated above, FDA prohibited in § 101.79 (c)(2)(i)(G) claims that a specified amount of folate per serving from one source is more effective in reducing the risk of neural tube defects than a lower amount per serving from another source.

B. Current Scientific Review

In reconsidering the claim at issue in Pearson, FDA reviewed the evaluation of the relationship between folate intake and NTD's provided by the Institute of Medicine of the National Academy of Sciences (IOM/NAS) in 1998. FDA also reviewed the literature that has been published since the agency issued the final rule on March 5, 1996, using a contract literature search completed in June 2000, as well as the comments and information submitted to the docket by the public in response to two Federal Register notices. ⁽²⁾ 65 Fed. Reg. 48841 (1999); 65 Fed. Reg. 4252 (2000). There were two new publications that IOM/NAS did not review and that provided additional data on folate and risk of NTD's (Berry et al., 1999; Stevenson et al., 2000). Other information from the scientific literature and submitted to the docket did not provide additional data with which to evaluate the claim.

Finally, FDA considered the wording of your proposed claim and evaluated issues relative to sub-components of the claim.

1. Evaluation of relevant data by IOM/NAS (1998)

IOM/NAS (1998) recently evaluated the available data on risk of NTD's associated with periconceptional (i.e., from at least one month before conception through at least the first six weeks of pregnancy) use of folate. IOM/NAS (1998) reviewed the single randomized trial on the effect of periconceptional vitamin supplementation on risk of a first occurrence of an NTD (Czeizel and Dudas, 1992) and 6 case-control studies that provided data on this topic (Bower and Stanley, 1989; Mills et al., 1989; Milunsky et al., 1989; Mulinare et al., 1988; Werler et al., 1993; and Shaw et al., 1995). IOM/NAS (1998) noted that in the United States, the risk reduction achieved with a daily supplement of 400 mcg of folic acid, the most usual dose in multivitamins, was 70 percent in New England (Werler et al., 1993) and 35 percent in California (Shaw et al., 1995) in unselected populations of women with average daily dietary folate intake of about 300 mcg.

IOM/NAS (1998) also reviewed all published data bearing on the question of risk of NTD's associated with different levels of dietary folate intake. Data from the observational studies of Werler et al. (1993) and Shaw et al. (1995) indicate a statistically significant decreasing relative risk of NTD's with increasing dietary folate intake expressed as "approximate dietary folate equivalents" among unsupplemented women (i.e., among women not consuming a dietary supplement of folic acid). IOM/NAS (1998) noted that a tentative relative risk curve can be drawn using results from the studies of Werler et al. (1993) and Shaw et al. (1995). Such a curve shows a quasilinear decreasing relative risk for NTD's for approximate dietary folate equivalent values between 100 mcg and 400 mcg/day. No further decrease in relative risk was observed for higher intake values (IOM/NAS, 1998).

In considering all of the available data relating risk of NTD's to periconceptional use of folic acid-containing supplements, IOM/NAS (1998) noted, at 256, that "it is not clear whether supplements at doses lower than 400 mcg of folic acid/day provide the same level of protection as 400 mcg of folic acid/day, or whether higher doses are associated with increased risk reduction." IOM/NAS (1998) also provided recommendations for reduction in risk of NTD's. IOM/NAS (1998) concluded that, despite the fact that there are still uncertainties about (1) the relationships among folate intake, red cell folate and risk of NTD's and (2) the extent to which the effect of food folate should be distinguished from the effect of folic acid, the available evidence was sufficient to support a recommendation to reduce the risk of NTD's. IOM/NAS (1998) recommended, at 259, that "women capable of becoming pregnant consume 400 mcg of folate daily from supplements, fortified foods, or both, in addition to consuming food folate from a varied diet." IOM/NAS (1998) noted that the evidence for a protective effect from folate supplements is much stronger than that for food folate. This conclusion is based on the fact that most trials have been conducted using dietary supplements, the majority of which contain, among other ingredients, the Recommended Dietary Allowance (RDA) level of 400 mcg folic acid, or have involved questioning women about their use before or during the early months of pregnancy of such dietary supplements. IOM/NAS (1998) stated, at 259, that "[i]t is certainly conceivable that, if taken in adequate quantity, food folate will be shown to be as effective as folic acid, but it remains to be demonstrated."

2. New data since IOM/NAS (1998)

The most recent data regarding amounts of folate needed to reduce the risk of NTD's are those of Berry et al. (1999) and Stevenson et al. (2000). The results of Berry et al. (1999) of the effects of treatment of more than 130,000 women of childbearing age in two distinct geographical areas of China with 400 mcg folic acid from the time of marriage through the first trimester of pregnancy showed that periconceptional intake of 400 mcg folic acid/day reduced the risk of NTD's in areas with high rates of this defect and in areas with low rates of NTD's. With periconceptional use of 400 mcg folic acid/day, rates of NTD's in women in the northern area of study fell from 4.8/1000 to 1.0/1000. In the southern study area, rates of NTD's fell from 1.0/1000 to 0.6/1000 with daily periconceptional use of 400 mcg folic acid.

Stevenson et al. (2000) recently described the results of a three-pronged program in South Carolina that included statewide comprehensive surveillance for NTD's, a folic acid supplementation program for women who have had an NTD-affected pregnancy, and a folic acid education program for all women of reproductive age. In addition, a cohort of control mothers, randomly selected from among all registrants at delivery hospitals in South Carolina, was used to determine the frequency of folic acid use during the periconceptional period. Finally, telephone surveys of women in their childbearing years were used to estimate changes in folic acid use in South Carolina during 1996, 1997 and 1998, the last three years of the project.

Among the cohort of control mothers (see above), the use of folic acid before conception increased from 8 percent to 30 percent during the first 5 years of the project (1992-1997). Most vitamin users (90 percent) took 400 mcg of folic acid as part of an over-the-counter multivitamin preparation. Ten percent of vitamin users took prescription prenatal vitamins containing 800 mcg of folic acid. The results of the telephone surveys during 1996, 1997 and 1998 indicated that 25.2 percent, 34.4 percent and 35 percent, respectively, of women of childbearing age were taking folic acid 4 or more times weekly. Estimated intakes of folic acid by women who consumed folic acid 4 or more times weekly from multivitamin preparations containing 400 mcg folic acid per unit would be in the range of 230-400 mcg folic acid daily.

Stevenson et al. (2000) reported that over a 6-year period of surveillance (1992-1998) in South Carolina, a recognized region of high NTD-risk in the United States, prevalence rates for NTD's decreased from 1.85 to 0.95 cases per 1000 live births and fetal deaths. The authors noted that despite some uncertainties regarding the specific reasons for the high rate of NTD's in South Carolina and for the decrease in rates during the surveillance period, the temporal relationship between the reduction in NTD rates and the increased utilization of folic acid supplements by women in South Carolina is in agreement with the known protective effect of folate against these birth defects.

IV. Evaluating Issues Relative to Comparative Components of the Claim

In the Federal Register of March 5, 1996 (61 Fed. Reg. at 8752), FDA authorized the use on the labels and in the labeling of food, including dietary supplements, of health claims about the relationship between adequate intake of folate and risk of NTD's (use of the claim had been authorized previously for dietary supplements, see footnote 1 above). Because the agency has already dealt with the health claim relationship between folate and risk of NTD's, it will not re-evaluate the relationship here. Rather, it is the comparative elements of your proposed claim that are at issue.

Your proposed claim states: "0.8 mg of folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form." There are two general aspects of the proposed claim. First, your claim compares the effectiveness of 0.8 mg of folic acid to that of lower amounts. Next, it compares dietary supplements to foods in common form as a source of the vitamin. The agency has considered the available evidence about these comparisons in this section.

A. The claim that 0.8 mg folic acid is more effective than a lower amount

Your proposed health claim

"0.8 mg of folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form"

includes a comparative claim that 0.8 mg folic acid is more effective than a lesser amount.

This comparison implies a dose/response relationship between folic acid intake and reduced risk of an NTD-affected pregnancy.

The most definitive evidence for evaluating this dose/response question would be provided by randomized clinical trials in which the effect of varying intakes of folic acid on risk of NTD-affected pregnancies could be compared within a defined study population. This type of study would minimize confounding due to effects of dietary factors other than folic acid on the outcome. It would also minimize confounding caused by non-dietary factors that could affect outcome (e.g., differences in baseline risk or folate nutritional status among population groups). Unfortunately, this type of study has not been done. In the absence of this type of study, we compared results across available studies to determine whether, in their totality, results were suggestive of a dose/response relationship.

The strongest available evidence for evaluating the effectiveness of different levels of folate intake is provided by randomized controlled trials, particularly those that use a test product that contains only folic acid so that the effectiveness of folic acid alone can be isolated and quantified. As noted in FDA's October 14, 1993 proposal (58 Fed. Reg. at 53258-59) and in IOM/NAS (1998), two clinical trials in which folic acid was used as the test substance were available (IOM/NAS, 1998, citing Laurence et al., 1982; Wald et al., 1991). Of these two trials, the strongest data come from the randomized controlled Medical Research Council intervention trial, which showed that women at risk of a recurrence of an NTD-affected pregnancy who consumed a supplement containing 4 mg (4,000 mcg) folic acid daily throughout the periconceptional period had a significantly reduced risk (72 percent) of having another pregnancy affected with an NTD (Wald et al., 1991). Prior to the Medical Research Council trial, Laurence et al. (1981) had conducted a smaller randomized controlled trial in Wales, the results of which showed that a 60 percent reduction in risk of a recurrent NTD was achieved when women with a prior NTD-affected pregnancy consumed 4 mg (4,000 mcg) folic acid daily for at least 1 month before conception and throughout the first trimester of pregnancy.

In a recently available clinical trial, Berry et al. (1999) reported that in a geographic area of China considered to be a high NTD-risk area, the risk of an NTD-affected pregnancy decreased from 4.8/1000 to 1.0/1000 (i.e., about 80 percent) when women used 400 mcg folic acid from the time of marriage through the first trimester of pregnancy. The reduction in risk in a geographic area in China of lower risk of NTD's decreased from 1.0/1000 to 0.6/1000 (i.e., about 40 percent) when women used supplements containing 400 mcg folic acid in the same manner as described above. Thus, factors other than folate intakes may affect the magnitude of the risk reduction.

FDA places lesser weight on the outcome of randomized clinical trials in which the test substance, i.e. folic acid, is fed as part of a multivitamin/multimineral dietary supplement preparation. In this case, it is not possible to determine whether any observed effectiveness is due solely to folic acid, or is also affected by other nutrients in the test product. In a trial that examined the effect of periconceptional use of 800 mcg folic acid plus multivitamins or a trace element supplement on the risk of an NTD-affected pregnancy in Hungarian women with no prior history of affected pregnancies, no cases of NTD (complete protective effect) were observed in the group taking folic acid plus multivitamins compared with six cases that occurred in the group taking the trace element supplement (Czeizel and Dudas, 1992).

Two nonrandomized controlled trials were also cited in FDA's October 14, 1993 proposal (58 Fed. Reg. at 53258-59) and in IOM/NAS (1998). In general, these types of studies are given lesser weight than randomized controlled trials because they are more subject to bias. For example, without randomization of study participants to treatment and control groups, subjects who are most likely to have a favorable outcome independent of any intervention may be preferentially selected to receive the intervention being studied (selection bias). The nonrandomized trial by Smithells et al. (1983) showed that women with a prior history of a NTD-affected pregnancy who consumed 0.36 mg (360 mcg) folic acid plus multivitamins periconceptionally had an 86 percent reduction in risk of NTD's. In addition to the potential for selection bias in this trial, the test product was a multivitamin product, thus confounding our ability to determine whether the observed effects were due to folic acid alone or were also affected by other nutrients in the supplement product. In a small, nonrandomized trial in Cuba, women at high risk of a recurrence of an NTD-affected pregnancy who consumed 5 mg of folic acid daily had no recurrences (Vergel et al., 1990).

Observational studies are generally given lesser weight than clinical trials because of the difficulty of accurately estimating intakes of the substance of interest (i.e., folic acid) and because of the difficulty of isolating the effect of that substance from that of other dietary factors (e.g., other nutrients in a multivitamin/mineral supplement and variations in dietary folate intakes). Additionally, these types of studies often do not provide a sufficient basis for determining whether a substance/disease association reflects a causal rather than a coincidental relationship. However, several observational studies were reviewed in FDA's October 14, 1993 proposal (58 Fed. Reg. at 53259) and in the IOM/NAS (1998) report, and FDA has considered their usefulness for evaluating dose/response relationships. In general, caution must be exercised in estimating intake levels from case control reports. Intakes are subject to recall bias, because in these studies, mothers are asked, some time after the birth of their child, to provide information on a product that they took prior to and during early pregnancy. Recall times of several years may be required depending on when subjects were interviewed relative to their date of conception. Moreover, product brand name and composition information is often sketchy and unreliable.

Of the available case control studies, two provided no information with which to estimate quantitative intakes from supplements, indicating only whether or not a supplement was consumed (Bower and Stanley, 1989; Milunsky et al., 1989). Thus, these studies are not useful for evaluating a dose/response relationship. In its efforts to identify an effective intake for NTD-risk reduction, IOM/NAS (1998) focused its review on the case control studies of Werler et al. (1993) and Shaw et al. (1995). IOM/NAS noted that, in the United States, the risk reduction achieved with a daily supplement of 400 mcg folate, the most usual dose in multivitamin preparations, was 70 percent in New England (Werler et al., 1993) and 35 percent in California (Shaw et al., 1995) in unselected populations with average daily dietary folate intake of about 300 mcg. IOM/NAS (1998) noted the inherent problems in estimating intakes from these studies by noting that the estimated intakes assumed a high level of compliance with supplementation. Based upon their review of these two studies, IOM/NAS (1998) stated that "[i]t is not clear whether supplements at doses lower than 400 mcg/day of folic acid provide the same level of protection as 400 mcg/day or whether higher doses are associated with increased risk reduction." The IOM/NAS (1998) also reviewed these two case control studies for information on estimating dose/response data for food folates. They noted a quasilinear decreasing NTD risk for dietary folate values from 100 and 400 mcg/day but no further risk reduction at higher dietary intake levels.

Studies that look at changes in population parameters (e.g., trends in nutrient intake) over time are among the least persuasive types of studies as it is not possible to determine whether observed changes indicate a causal connection or are coincidental. The recent study of Stevenson et al. (2000) showed a strong temporal association between a decline in rates of NTD's (about 50 percent) and an increased use of folic acid supplements. In the study, 90 percent of women who used supplements reported that they used supplements that contained the RDA-level of 400 mcg folic acid 4 times or more per week (estimated average intakes in the range of 230-400 mcg/day).

Having reviewed the currently available scientific evidence, FDA concludes that the dose/response relationship between folic acid intake and reduced risk of NTD's is unclear. FDA notes that the IOM/NAS (1998) reached similar conclusions in its independent review of the available evidence. The most persuasive type of study, i.e., dose response within a study population, has not been done. The best data available (Laurence et al., 1982; Wald et al., 1991; Berry et al., 1999) do not show a dose-related response to folic acid above 400 mcg/day. Accordingly, FDA concludes that the weight of scientific evidence does not support the conclusion that 800 mcg folic acid/day is more effective than 400 mcg folic acid/day, or lesser amounts (230-400 mcg) (Stevenson et al., 2000), in reducing the risk of NTD's.

B. The claim that dietary supplements are more effective than foods in common form

Your proposed health claim

"0.8 mg of folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form"

implies that dietary supplements are a more effective delivery vehicle than are conventional foods. FDA has identified two possible aspects of this comparison: a) compositional issues, e.g., dietary supplements contain more of the vitamin or are subject to fewer losses of the vitamin than are foods and b) issues of physiologic effectiveness, e.g., the folic acid ingredient in dietary supplements is physiologically superior to the naturally occurring folate in foods. In evaluating these comparisons, we note that the same commercial vitamin form ("folic acid") is added to both dietary supplements and fortified foods. The forms of the vitamin that occur naturally in foods are more complex molecules and will be referred to as "food folate."

1. Compositional issues

An increasing number of conventional foods are fortified and thus provide the same form of folic acid as is found in dietary supplements. Moreover, some of these foods also provide amounts of folic acid similar to those commonly found in dietary supplements. For example, certain fortified breakfast cereals provide 400 mcg folic acid (100 percent of the RDA) per serving, the same amount found in many dietary supplements. In addition, there is a large body of evidence regarding the stability of folic acid added to cereal-grain products (Gregory, 1989). Reports have described the stability of folic acid in fortified breads, vitamin-mineral premixes, and grains, as well as the stability of folic acid when baked (Gregory, 1989). The high degree of stability of folic acid in foods of high moisture content has also been demonstrated (Colman, 1982; Day and Gregory, 1983). To date, there are no data supporting the concept that folic acid is unstable or unavailable when added to cereal-grain products. Such fortified foods have been shown to affect positively folate nutritional status in individuals who consume them. For example, in a study of 75 individuals, Malinow et al. (1998) reported that plasma folate increased proportionally with folic acid content when the individuals consumed breakfast cereals fortified with 127, 499 and 665 mcg folate/30 g for 5 weeks (i.e., 32, 120, and 166 percent of the daily value, respectively). In addition, based upon measurements of indices of folate status in individuals consuming currently fortified foods and comparing the data with data obtained from the same individuals prior to fortification, Jacques et al. (1999) reported that fortification of enriched grain products with folic acid was associated with a substantial improvement in folate status in a population-based sample of middle-aged and older adults. These data demonstrate that fortified foods are an effective vehicle for the delivery of folic acid, as reflected in the IOM/NAS recommendation that women capable of becoming pregnant consume 400 mcg of folate daily, from fortified foods or supplements or both, in addition to consuming food folate from a varied diet.

The court in Pearson quoted Diet and Health: Implications for Reducing Chronic Disease Risk 67 (Committee on Diet and Health, Food and Nutrition Board 1989) to the effect that "'losses [of folic acid] in cooking and canning foods can be very high due to heat destruction,'" and stated that this conclusion appeared to it to be credible evidence supporting the claim at issue. Pearson, 164 F.3d at 658-59. This statement from Diet and Health does not support the claim. In fact, many foods that are good sources of food folate are minimally processed or are eaten raw (e.g., a wide variety of fruits (including citrus fruits), dark green leafy vegetables that are often eaten in salads, and nuts). Others are good sources of folate even when processed before being consumed. Although there may be losses during processing (e.g., during milling of grains), nutrition labeling regulations require that label declarations of vitamin content be based on amounts that are present in the marketed food, 21 C.F.R. § 101.9(g)(4). In addition, nutrients lost during processing can be restored (see FDA's fortification policy, 21 C.F.R. § 104.20(c)). This policy is the basis of cereal-grain fortification: the vitamins lost during milling are restored in the finished products.

It is true that some vitamins, minerals, and other nutrients may be lost from some foods during home cooking, particularly when such foods are cooked in large volumes of water and the water is poured off. However, enriched foods that may lose vitamins, minerals, or other nutrients during cooking and preparation, such as enriched rice, are frequently labeled "To retain vitamins do not rinse before or drain after cooking" or they bear no cooking directions calling for washing or draining (see 21 C.F.R. § 137.350 (c) and (e)). Other enriched foods are precooked and are labeled with directions for preparation that, if followed, will avoid washing away or draining off of enriching ingredients. These instructions serve to aid consumers in minimizing potential cooking losses.

Moreover, some processing steps actually increase the availability of food folate. For example, organ meats such as beef and chicken liver are among the richest sources of folate and contain 140-1810 mcg folate/100 grams (Combs, 1998). Cooking of such meats alters the organic matrix of the meat (by, for example, denaturing the protein) and liberates matrix-bound folates for absorption. A heating step is incorporated into the current methods of folate analysis for the purpose of liberating matrix-bound folates (Rader et al., 2000). Thus, "processing" does not always lead to loss of food folates.

In summary, the same chemical form of folic acid is added to both fortified foods and dietary supplements. Some fortified foods contain an amount of folic acid equivalent to that contained in many dietary supplements. Labeling requirements and practices provide vitamin content information that reflects the amount of vitamin in a finished product and thus prevent consumers from being misled about the vitamin content of marketed foods regardless of processing losses that may have occurred. Other labeling requirements and practices provide information to help consumers reduce folic acid losses during cooking. A "blanket" statement that cooked and processed foods are lower in folic acid content than supplements is misleading.

2. Issues of physiologic effectiveness

"Folate" is the generic term for all forms of the vitamin and includes both naturally occurring "food folate" and the synthetic form of "folic acid" that is added to fortified foods and dietary supplements. The comparison of interest in this section is a comparison of the naturally occurring "food folate" to the synthetic "folic acid" form.

Once consumed, both food folate and folic acid are converted into the same functional, metabolically active coenzyme forms for use in the body (Combs, 1998). The metabolic needs for the B vitamin, folate, are met from body pools of the coenzymes, regardless of whether these coenzymes are derived from naturally occurring food folates or from synthetic folic acid added to foods and used in dietary supplements. Both food folates and folic acid are effective in maintaining the clinical indicators of folate nutritional status, e.g., serum and red blood cell folate levels and normal serum levels of homocysteine (IOM/NAS, 1998).

The similar effectiveness of folic acid added to foods in conventional form and folic acid in dietary supplements is the basic tenet of the national folic acid fortification program, which mandated folic fortification of "enriched" cereal grain products to increase baseline intakes of this vitamin among women of childbearing age to reduce their risk of NTD's. 61 Fed. Reg. 8781 (1996); see also 61 Fed. Reg. 8797 (1996). The similar effectiveness is also the basis for the conclusions of the IOM/NAS (1998), which recommends that women of child-bearing age consume 400 mcg of folate daily from supplements, fortified foods, or both. There is no basis to believe that folic acid delivered by dietary supplements and folic acid delivered by fortified foods differ significantly in their ability to function metabolically as the folate vitamin.

However, folic acid and food folate may differ in bioavailability (e.g., absorption characteristics). IOM/NAS (1998) considered issues of bioavailability when determining the requirements for folate. It noted that the bioavailability of folate ranged from about 100 percent for folic acid supplements taken on an empty stomach to about 50 percent for food folate. Supplements taken with foods have an estimated bioavailability of 85 percent. IOM/NAS (1998) noted that in order to be comparable with food folate, only half as much folic acid is needed if taken on an empty stomach. Differences in bioavailability alone are an insufficient basis on which to determine effectiveness, however. Once absorbed, both food folate and folic acid are converted to the same metabolically active reduced derivatives. Therefore, the relative importance of bioavailability cannot be considered in isolation, but must be evaluated within the context of total vitamin intakes relative to intakes required to achieve the desired physiologic effect, e.g., reduction in risk of NTD's.

In summary, both food folate and folic acid added to dietary supplements and to fortified foods are effective in meeting the body's physiological needs for the folate vitamin. IOM/NAS (1998) did note that the available evidence for a protective effect from folic acid is much stronger than that for food folate. This evidence is derived from four randomized controlled clinical trials that used folic acid-containing dietary supplements as their test substance and from observational studies that questioned women about their use of multivitamin or multivitamin/multimineral dietary supplements. A few observational studies obtained information on dietary intakes and observed decreasing risk of NTD's with increasing intakes of food folate. Because folic acid and naturally occurring food folate are converted into the same functional, metabolically active coenzyme forms for use in the body, the evidence for a protective effect from folic acid also supports the same protective effect for naturally occurring folate.

V. Agency's Consideration of Significant Scientific Agreement

Having reviewed the currently available scientific evidence, including the recent report of the IOM/NAS (1998), FDA concludes that, based on the totality of the scientific evidence, there is not significant scientific agreement among qualified experts that:

"0.8 mg of folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form."

FDA concludes that a dose/response relationship between folic acid intake and reduced risk of NTD's has not yet been defined. Moreover, FDA concludes that the weight of the scientific evidence does not support the conclusion that 800 mcg folic acid/day is more effective than lower amounts in reducing the risk of NTD's. FDA also concludes that a claim of superior effectiveness of dietary supplements to foods in common form relative to reduced risk of NTD's is not consistent with the available scientific evidence.

The scientific evidence does not support the superiority of 800 mcg folic acid daily over other doses and sources. There is no well designed study to determine this issue. Moreover, comparisons of results across available studies of varying rigor, test doses, and sources show quite different magnitudes of reduced risk of NTD's in different population groups. There are limited studies on the effectiveness of graded intakes of dietary folate. Additionally, a recent population surveillance study showed effectiveness in reducing NTD risk with intakes of 400 mcg or less per day. In their totality, these studies show no dose-related response between 400 mcg and 4,000-5,000 mcg folic acid per day. Most studies do not provide any information on which to evaluate dose-related response below 400 mcg/day. However, the available evidence consistently shows that 400 mcg folic acid/day is a highly effective dose. As with all nutrients, intakes above the effective dose would not be expected to add additional benefit. Therefore, given the lack of evidence of a dose-related response above 400 mcg/day, and the paucity of evidence on the effectiveness of intakes below 400 mcg/day, FDA finds that the comparison that "0.8 mg is more effective than lower amounts" is not supported by the available scientific evidence.

The comparison in your proposed claim implying superiority of dietary supplements over foods as a source of the vitamin folate is also not consistent with the available scientific evidence. Many fortified foods contain the same form of folic acid as in dietary supplements, and in some cases, amounts similar to those found in dietary supplements. Labeling information ensures that consumers are not misled as to the vitamin content of foods and supplements, and also provides information, when applicable, to help consumers minimize losses of the vitamin during home food preparation. Although folic acid and food folate may differ in bioavailability, the impact of these differences can be meaningful only within the context of the total diet. Adequate intakes of bioavailable folate, regardless of source, are effective in reducing risk of NTD's. Inadequate intake of bioavailable folate can be corrected by increased intakes of folic acid from fortified food and/or dietary supplements. Increasing intakes of dietary folate to meet these needs is also likely to be effective, given known mechanisms of vitamin function and metabolism.

FDA, therefore, concludes that your proposed claim is not supported by the available evidence. The statement that 0.8 mg folic acid daily is more effective than lower amounts is not supported by the evidence. The implication that supplements are better sources than food relative to effectiveness is not accurate in its generality and is not meaningful unless total intakes from all sources can be compared against a known effective intake level. In the absence of data to establish definitively the optimum effective intake level, the relative significance in meeting that level of various sources cannot be assessed. FDA's conclusions are consistent with the recent recommendations of the IOM/NAS (1998) which reflect the current uncertainties in the available data that are discussed above.

VI. Agency's Consideration of a Qualified Claim

As discussed above, your proposed claim states that 0.8 mg folic acid is more effective than a lesser amount of folic acid, which statement is not supported by the weight of the evidence. Your proposed claim also implies that dietary supplements are more effective than foods in common form, which is not supported by the weight of the evidence. FDA is not aware of any statement that could adequately qualify this proposed claim, which is misleading in these two ways.

A qualifying statement such as that suggested by the court in Pearson, "The evidence in support of this claim is inconclusive," is inadequate because the weight of the evidence is against both aspects of the proposed claim, as discussed above. The qualifying statement, "The FDA has not evaluated this claim," is false because FDA has evaluated the proposed claim. In any case, the qualifying statement does nothing to remedy the claim's basic untruthfulness.

Therefore, FDA has determined that your proposed claim is inherently misleading and cannot be made non-misleading with a disclaimer or other qualifying language. See Pearson, 164 F.3d at 659. Therefore, use of the proposed claim is prohibited by the Federal Food, Drug, and Cosmetic Act. A dietary supplement that bears the proposed claim will be subject to regulatory action as a misbranded food under 21 U.S.C. § 343(a)(1) and (r)(1)(B); as a misbranded drug under 21 U.S.C. § 352(a) and (f)(1); and as an unapproved new drug under 21 U.S.C. § 355(a).

However, FDA recognizes that the available studies and the recent conclusions of IOM/NAS (1998) support the use of certain statements in conjunction with the currently authorized claim to inform consumers of the nature of the evidence relative to recommended intakes and ways to achieve these intakes. For example, the IOM/NAS (1998) recommendation identifies an intake of 400 mcg/day and also indicates that this amount should be obtained from fortified foods and/or a supplement, in addition to food folate from a varied diet. The IOM/NAS (1998) also states that the scientific evidence that folic acid reduces the risk of NTD's is stronger than the evidence for the effectiveness of food folate.

The agency also concludes that an appropriately qualified claim would not threaten consumer health or safety. Because your proposed claim itself cannot be adequately qualified, as discussed above, the agency is providing examples of appropriately qualified claims.

The agency believes that including the IOM/NAS (1998) recommendation with the health claim authorized by § 101.79 is one satisfactory way to make this claim. The agency also believes that there are other statements (given as examples below) that may be included with the health claim about the relationship of folate and NTD's authorized by § 101.79. Accordingly, the agency intends to exercise its enforcement discretion with respect to a dietary supplement that bears such health claims, provided that use of the claim otherwise complies with the requirements of §§ 101.14 and 101.79. Should new data shift the weight of the evidence against this claim, the agency would no longer exercise its enforcement discretion with respect to use of the claim in dietary supplement labeling, and would inform you of that by letter.

For example, the agency intends to exercise its enforcement discretion with respect to use of the following claims in dietary supplement labeling:

Example 1: Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth defect. The Institute of Medicine of the National Academy of Sciences recommends that women capable of becoming pregnant consume 400 mcg folate daily from supplements, fortified foods, or both, in addition to consuming food folate from a varied diet.

Example 2: Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth defect. The scientific evidence that 400 mcg folic acid daily reduces the risk of such defects is stronger than the evidence for the effectiveness of lower amounts. This is because most such tests have not looked at amounts less than 400 mcg folic acid daily.

Example 3: Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth defect. Women capable of becoming pregnant should take 400 mcg folate/day from fortified foods and/or a supplement, in addition to food folate from a varied diet. It is not known whether the same level of protection can be achieved by using only food that is naturally rich in folate. Neither is it known whether lower intakes would be protective or whether there is a threshold below which no protection occurs.

Example 4: Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth defect. Women capable of becoming pregnant should take 400 mcg of folate per day from a supplement or fortified foods and consume food folate from a varied diet. It is not known whether the same level of protection can be achieved by using lower amounts.

With respect to other requirements for health claims on the relationship between folate and risk of NTD's, the agency noted in its final rule of March 5, 1996 (61 Fed. Reg. at 8762), that the benefits of folate intake from food and dietary supplements can only be obtained if the folate is available for absorption and metabolism in the body. Dissolution and disintegration are necessary preconditions for absorption and subsequent metabolism. Digestive processes ensure that conventional foods are digested and that components are liberated for absorption. However, dietary supplements, including folate-containing supplements, can be manufactured in a manner that inhibits dissolution and disintegration (e.g., extremely compressed preparations), and the digestive processes may be insufficient to ensure the liberation of the components for absorption and utilization by the body. A claim on a dietary supplement that does not disintegrate or dissolve would be misleading because the supplement would not meet the preconditions necessary to ensure that the nutrient that is the subject of the claim is available for absorption. For these reasons, the agency adopted § 101.79(c)(2)(ii)(B), which states that to bear the folate NTD health claim, dietary supplements must meet the United States Pharmacopeia (USP) standards for disintegration and dissolution, except that if there are no applicable USP standards, the folate in the dietary supplement must be shown to be bioavailable under the conditions of use stated on the product label.

Sincerely, Christine J. Lewis, Ph.D. Director Office of Nutritional Products, Labeling, and Dietary Supplements Center for Food Safety and Applied Nutrition

¹ Use of such a health claim on dietary supplements had been authorized previously when the agency's October 14, 1993 proposal became a final regulation by operation of law. 59 Fed. Reg. 433 (1994).

² FDA received two comments after the close of the comment period. The agency was not obligated to and did not consider the late comments. All other comments were considered.

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