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Petition for Qualified Health Claims: Antioxidant Vitamins C and E and Reduction in the Risk of Site-Specific Cancers, FDA-2008-Q-0299

Back to Qualified Health Claims: Letters of Enforcement Discretion

June 19, 2009

 

Jonathan W. Emord, Esq.
Emord & Associates, P.C.
11808 Wolf Run Lane
Clifton, Virginia 20124

 

RE: Petition for Qualified Health Claims: Antioxidant Vitamins C and E and Reduction in the Risk of Site-Specific Cancers (Docket Number) FDA-2008-Q-0299

 

Dear Mr. Emord:

This letter responds to a health claim petition for qualified health claims received by the Food and Drug Administration (FDA or the agency) on April 9, 2008, which was submitted on behalf of Julian M. Whitaker, M.D., The Coalition to End FDA and FTC Censorship, Durk Pearson and Sandy Shaw, and Youngevity, Inc. The petition was submitted pursuant to Section 403(r)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 343(r)(5)(D)). In the petition, you requested that the agency grant your request for health claims characterizing the relationship between antioxidant vitamins C and E from dietary supplements and reduced risk of several site-specific cancers. The petition proposed the following claims as model health claims for dietary supplements:

Claims for Vitamin C

  1. Vitamin C may reduce the risk of colon cancer. The scientific evidence supporting this claim is persuasive, but not conclusive.
  2. Vitamin C may reduce the risk of squamous cell cancer of the esophagus. The scientific evidence supporting this claim is persuasive, but not conclusive.
  3. Vitamin C may reduce the risk of gastric cancer. The scientific evidence supporting this claim is persuasive, but not conclusive.
  4. Vitamin C may reduce the risk of laryngeal cancer. The scientific evidence supporting this claim is persuasive, but not conclusive.
  5. Vitamin C may reduce the risk of lung cancer. The scientific evidence supporting this claim is convincing, but not conclusive.
  6. Vitamin C may reduce the risk of cancer of the oral cavity. The scientific evidence supporting this claim is persuasive, but not conclusive.
  7. Vitamin C may reduce the risk of pancreatic cancer. The scientific evidence supporting this claim is persuasive, but not conclusive.
  8. Vitamin C may reduce the risk of pharyngeal cancer. The scientific evidence supporting this claim is persuasive, but not conclusive.
  9. Vitamin C may reduce the risk of renal cell cancer. The scientific evidence supporting this claim is persuasive, but not conclusive.
  10. Vitamin C may reduce the risk of cancer of the salivary glands. The scientific evidence supporting this claim is persuasive, but not conclusive.

Claims for Vitamin E

  1. Vitamin E may reduce the risk of bladder cancer. The scientific evidence for this claim is convincing, but not conclusive.
  2. Vitamin E may reduce the risk of brain cancer. The scientific evidence for this claim is persuasive, but not conclusive.
  3. Vitamin E may reduce the risk of cervical cancer. The scientific evidence for this claim is persuasive, but not conclusive.
  4. Vitamin E may reduce the risk of gastric cancer. The scientific evidence for this claim is persuasive, but not conclusive.
  5. Vitamin E may reduce the risk of lung cancer. The scientific evidence for this claim is convincing, but not conclusive.
  6. Vitamin E may reduce the risk of rectal cancer. The scientific evidence for this claim is persuasive, but not conclusive.
  7. Vitamin E may reduce the risk of renal cell cancer. The scientific evidence for this claim is persuasive, but not conclusive.

FDA received an earlier health claim petition for the above qualified health claims, dated February 19, 2008; however, FDA informed you in a letter dated March 4, 2008, that it was not able to acknowledge receipt of that petition and begin its preliminary review because the petition was not complete as required under 21 CFR 101.70. In response, you supplied the needed information in a supplemental submission received by the agency on April 9, 2008. FDA then acknowledged the petition in a letter dated April 24, 2008, which initiated FDA’s preliminary review of the petition. FDA filed the petition for comprehensive review on May 23, 2008, and posted the petition on the FDA website for a 60-day comment period, consistent with the agency’s guidance for procedures on qualified health claims [1]. The agency received two submissions of supplemental information from the petitioner. One submission provided a recent publication that concerned additional findings regarding the Linxian General Population Nutrition Intervention Trial presented with the original petition. The second submission provided an analysis and opinion of a recent publication on the National Cancer Institute SELECT trial. The agency did not receive any comments in response to this petition. FDA considered the information provided in the supplemental submissions from the petitioner in its evaluation of the petition. The initial date for the agency’s response to your petition was January 9, 2008. After mutual agreements, the date for the agency’s response was extended to June 19, 2009.

As noted in the petition, FDA announced its intent in the December 21, 2007 Federal Register (72 FR 72738; Docket No. FDA-2007-N-0152 (formerly Docket No. 2007N-0464)) to reevaluate the scientific evidence, in part, for the existing qualified health claim for antioxidant vitamins C and E and certain cancers (see Docket No. FDA-1991-N-0043 (formerly Docket No. 1991N-0101)). This letter is directed solely to your proposed qualified health claims and not to the reevaluation of the scientific evidence for the existing qualified health claim for antioxidant vitamins C and E and certain cancers as described in the December 21, 2007, Federal Register notice of reevaluation.

This letter sets forth the conclusions from the agency’s review of the scientific evidence for the proposed qualified health claims concerning consumption of vitamin C from dietary supplements and the site-specific cancers listed above, as well as the proposed qualified health claims for vitamin E from dietary supplements and the site-specific cancers listed above.

FDA has determined that the current scientific evidence is appropriate for considering the exercise of enforcement discretion with respect to qualified health claims on dietary supplements concerning the relationship between consumption of vitamin C from dietary supplements and reduced risk of gastric (stomach) cancer and the relationship between consumption of vitamin E from dietary supplements and reduced risk of bladder cancer, colorectal cancer[2], and renal cell cancer.

Accordingly, this letter also sets forth the basis for FDA’s determination that there is no credible scientific evidence supporting qualified health claims on dietary supplements concerning the relationship between consumption of vitamin C from dietary supplements and reduced risk of colon cancer, laryngeal cancer, lung cancer, oral cavity cancer, pancreatic cancer, pharyngeal cancer, renal cell cancer, salivary glands cancer, or squamous cell cancer of the esophagus, nor for qualified health claims concerning the relationship between consumption of vitamin E from dietary supplements and reduced risk of brain cancer, cervical cancer, gastric (stomach) cancer, lung cancer or rectal cancer (excluding colorectal cancer).

Finally, this letter provides the factors that FDA intends to consider in the exercise of its enforcement discretion for qualified health claims concerning vitamin C from dietary supplements and reduced risk of gastric (stomach) cancer and qualified health claims concerning vitamin E from dietary supplements and reduced risk of bladder cancer, colorectal cancer, and renal cell cancer.

I. Overview of Data and Eligibility for a Qualified Health Claim

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 CFR 101.14(a)(1)). The substance must be associated with a disease or health-related condition for which the general U.S. population, or an identified U.S. population subgroup, is at risk (21 CFR 101.14(b)(1)). Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease[3]. In a review of a qualified health claim, the agency first identifies the substance and disease or health-related condition that are the subject of the proposed claim and the population to which the claim is targeted.[4] FDA considers the data and information provided in the petition, in addition to other written data and information available to the agency, to determine whether the data and information could support a relationship between the substance and the disease or health-related condition.[5]

The agency then separates individual reports of human studies from other types of data and information. FDA focuses its review on reports of human intervention and observational studies.[6] In addition to individual reports of human studies, the agency also considers other types of data and information in its review, such as meta-analyses[7], review articles[8], and animal and in vitro studies. These other types of data and information may be useful to assist the agency in understanding the scientific issues about the substance, the disease or health-related condition, or both, but cannot by themselves support a health claim relationship. Reports that discuss a number of different studies, such as meta-analyses and review articles, do not provide sufficient information on the individual studies reviewed for FDA to determine critical elements, such as the study population characteristics and the composition of the products used. Similarly, the lack of detailed information on studies summarized in review articles and meta-analyses prevents FDA from determining whether the studies are flawed in critical elements, such as design, conduct of studies, and data analysis. FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it. Therefore, FDA uses meta-analyses, review articles, and similar publications[9] to identify reports of additional studies that may be useful to the health claim review and as background about the substance-disease relationship.[10] If additional studies are identified, the agency evaluates them individually.

FDA uses animal and in vitro studies as background information regarding mechanisms of action that might be involved in any relationship between the substance and the disease. The physiology of animals is different than that of humans. in vitro studies are conducted in an artificial environment and cannot account for a multitude of normal physiological processes, such as digestion, absorption, distribution, and metabolism, which affect how humans respond to the consumption of foods and dietary substances (Institute of Medicine [IOM], 2005). Animal and in vitro studies can be used to generate hypotheses or to explore a mechanism of action but cannot adequately support a relationship between the substance and the disease.

FDA evaluates the individual reports of human studies to determine whether any scientific conclusions can be drawn from each study. The absence of critical factors, such as a control group or a statistical analysis, means that scientific conclusions cannot be drawn from the study (Spilker et al., 1991; Federal Judicial Center, 2000). Studies from which FDA cannot draw any scientific conclusions do not support the health claim relationship, and these are eliminated from further review.

Because health claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim, FDA considers evidence from studies in individuals diagnosed with the disease that is the subject of the health claim only if it is scientifically appropriate to extrapolate to individuals who do not have the disease. That is, the available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations, and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people. If such evidence is not available, the agency cannot draw any scientific conclusions from studies that use diseased subjects to evaluate the substance-disease relationship.

Next, FDA rates the remaining human intervention and observational studies for methodological quality. This quality rating is based on several criteria related to study design (e.g., use of a placebo control versus a non-placebo controlled group), data collection (e.g., type of dietary assessment method), the quality of the statistical analysis, the type of outcome measured (e.g., disease incidence versus validated surrogate endpoint), and study population characteristics other than relevance to the U.S. population (e.g., selection bias and whether important information about the study subjects -- e.g., age, smoker vs. non-smoker -- was gathered and reported). For example, if the scientific study adequately addressed all or most of the above criteria, it would receive a high methodological quality rating. Moderate or low quality ratings would be given based on the extent of the deficiencies or uncertainties in the quality criteria. Studies that are so deficient that scientific conclusions cannot be drawn from them cannot be used to support the health claim relationship, and these are eliminated from further review.

Finally, FDA evaluates the results of the remaining studies. The agency then rates the strength of the total body of publicly available evidence.[11] The agency conducts this rating evaluation by considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), the methodological quality rating previously assigned, the number of studies and number of subjects per group, whether the body of scientific evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated[12], and the overall consistency[13] of the total body of evidence.[14] Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support the qualified health claim for the substance/disease relationship and, if so, considers what qualifying language should be included to convey the limits on the level of scientific evidence supporting the relationship or to prevent the claim from being misleading in other ways.

A. Substance

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 CFR 101.14(a)(1)). A substance is a specific food or component of a food, regardless of whether the food is in conventional form or a dietary supplement (21 CFR 101.14(a)(2)). The petition identified vitamins C and E as the substances for the proposed claims.

Vitamin C, one of the essential nutrients for all humans and a few other mammals that lack the ability to biosynthesize the compound from glucose, is a component of fruits and vegetables and is also added to some processed foods as an antioxidant (IOM, 2000, Chapter 5). Approximately 90 percent of dietary vitamin C comes from fruits and vegetables, and the vitamin C content of foods may vary depending on the seasonality, location, stage of maturity, cooking practices, and storage time (IOM, 2000, Chapter 5). Vitamin E is a fat-soluble vitamin and exists in eight different forms; alpha, beta, gamma, and delta tocopherol and alpha, beta, gamma, and delta tocotrienol. Each form has its own biological activity, which is the measure of potency or functional use in the body. Alpha-tocopherol is the most biologically active because it is the only form of vitamin E that is specifically maintained in human plasma (IOM, 2000, chapter 6). The Dietary Reference Intakes (DRIs) for vitamin E are for alpha-tocopherol only and do not include amounts obtained from the other seven naturally occurring forms historically called vitamin E (IOM, 2000).[15] Vitamin E is found in edible vegetable oils, unprocessed cereal grains, nuts, fruits, and meats, especially in the fatty portion (IOM, 2000, Chapter 6).

Therefore, the agency concludes that the substances identified in the petition, vitamins C and E, are components of food and meet the definition of “substance” in the health claim regulation (21 CFR 101.14(a)(2)).

B. Disease or Health-Related Condition

A disease or health-related condition means damage to an organ, part, structure, or system of the body such that it does not function properly or a state of health leading to such dysfunctioning (21 CFR 101.14(a)(5)). The petition has identified the following site-specific cancers as the diseases that are the subject of the proposed claims: bladder cancer, brain cancer, cervical cancer, colon cancer, gastric (stomach) cancer, laryngeal cancer, lung cancer, cancer of the oral cavity, pancreatic cancer, pharyngeal cancer, rectal cancer, renal cell cancer, cancer of the salivary glands, and squamous cell cancer of the esophagus.

Cancer is a constellation of more than 100 different diseases, each of which is characterized by the uncontrolled growth and spread of abnormal cells (American Cancer Society, 2008). Cancer is categorized into different types of diseases based on the specific organ and tissue site (National Cancer Institute). Cancers at different sites have different risk factors, treatment modalities, and mortality risk (American Cancer Society, 2008). Both genetic and environmental (including diet) risk factors may affect the risk of different types of cancers. Risk factors may include a family history of a specific type of cancer, cigarette smoking, alcohol consumption, overweight and obesity, exposure to ultraviolet or ionizing radiation, exposure to cancer-causing chemicals, and dietary factors. The etiology, risk factors, diagnosis, and treatment for each type of cancer are different (Hord and Fenton, 2007; Milner, 2006). Since each form of cancer is a different disease based on organ site, risk factors, treatment options, and mortality risk, each form of cancer must be individually evaluated in a health claim petition. As a result, the agency considered whether the studies supported the potential substance/disease relationship for specific types of cancer (e.g., lung cancer, brain cancer, cervical cancer, etc.), each of which constitutes a disease under 21 CFR 101.14(a)(5).

C. Safety Review

Under 21 CFR 101.14(b)(3)(ii), if the substance is to be consumed at other than decreased dietary levels, the substance must be a food, a food ingredient, or a component of a food ingredient whose use at levels necessary to justify a claim has been demonstrated by the proponent of the claim, to FDA’s satisfaction, to be safe and lawful under the applicable food safety provisions of the Act.

FDA evaluates whether the substance is “safe and lawful” under the applicable food safety provisions of the Act. For conventional foods, this evaluation involves considering whether the ingredient that is the source of the substance is generally recognized as safe (GRAS), approved as a food additive, or authorized by a prior sanction issued by FDA (see 21 CFR 101.70(f)).

Dietary ingredients in dietary supplements, however, are not subject to the food additive provisions of the Act (see section 201(s)(6) of the Act (21 U.S.C. § 321(s)(6)). Rather, they are subject to the adulteration provisions in section 403 of the Act (21 U.S.C. § 342) and, if applicable, the new dietary ingredient provisions in section 413 of the Act (21 U.S.C. § 350b), which pertain to dietary ingredients which were not marketed in the United States before October 15, 1994.[16] The applicable adulteration provisions of the Act require, for example, that the dietary ingredient not present a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in the labeling or, if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use (section 402(f)(1)(A) of the Act (21 U.S.C. 342(f)(1)(A))). Further, a dietary supplement must not contain a poisonous or deleterious substance that may render the supplement injurious to health under the conditions of use recommended or suggested in the labeling (section 402(f)(1)(D) of the Act (21 U.S.C. 342(f)(1)(D))).

The IOM has conducted a risk assessment of dietary vitamins C and E as part of a larger project to evaluate the human requirements and safety of antioxidant nutrients (IOM, 2000) (hereafter the 2000 IOM Report). As part of this risk assessment, the 2000 IOM Report established Tolerable Upper Intake Levels (ULs) for vitamins C and E at various life stages. The UL is the highest level of nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population.

Vitamin C

The review of the literature in the 2000 IOM Report indicates that high vitamin C intakes are associated with low toxicity. Possible adverse effects associated with very large doses of vitamin C (greater than 3,000 mg per day) include: diarrhea and gastrointestinal disturbances, increased oxalate excretion and kidney stone formation, increased uric acid excretion, pro-oxidant effects, systematic conditioning (rebound scurvy), increased iron absorption leading to iron overload, reduced vitamin B12 and copper status, increased oxygen demand, and erosion of dental enamel.

Using osmotic diarrhea and related gastrointestinal disturbances as the clinically defined critical endpoints, the 2000 IOM Report identified the lowest-observed-adverse-effect level (LOAEL) at 3,000 mg per day for adults 19 years and older. The 2000 IOM Report established 2,000 mg per day of vitamin C as the UL for individuals aged 19 years and older by dividing the LOAEL of 3,000 mg per day by an uncertainty factor of 1.5. An uncertainty factor of 1.5 was selected because there is little uncertainty regarding the range of vitamin C intakes that are likely to induce osmotic diarrhea. The UL for vitamin C in other life-stage groups younger than 19 years are: for children 1 to 3 years, 400 mg per day; for children 4 to 8 years, 650 mg per day; for children 9 to 13 years, 1,000 mg per day; and for children 14 to 18 years, 1,800 mg per day. Further, the 2000 IOM Report stated that it was not possible to establish a UL for infants from birth up to 12 months.

The 2000 IOM Report relied on data from the Third National Health and Nutrition Examination Survey (NHANES III), which shows that the mean and ninety-ninth percentile of dietary vitamin C intake from food in all individuals are 105 and 201 mg per day, respectively. Data from NHANES III also shows that the mean and ninety-ninth percentile of total vitamin C intake (food plus supplements) in all individuals are 167 and 1,131 mg per day, respectively. The highest reported total intakes at the ninety-ninth percentile for men and women aged 51 to 70 years are 1,302 and 1,236 mg of vitamin C per day, respectively, both of which are below the UL for vitamin C for adults aged 19 years and older. Based on these data, the 2000 IOM Report concluded that the risk of adverse effects resulting from excess total intake of vitamin C (food plus supplements) appears to be very low at the highest intake in the United States population.

Supplement use is high in the United States (Radimer, et al. 2004). Over one-half (52 percent) of the adult population aged 20 years and above reported taking a dietary supplement,[17] according to data from NHANES 1999-2000 (Radimer, et al. 2004). Data from NHANES 1999-2000 also show that thirty-five percent of adults reported taking a multivitamin/multimineral supplement,[18] and 12.4 percent reported taking a vitamin C supplement[19] (Radimer, et al. 2004). Supplemental vitamin C can be obtained from multivitamin/multimineral supplements and vitamin C-containing supplements.[20] The vitamin C intake recommended on the labels of common multivitamin/multimineral supplements was between 30 and 1,000 mg per day.[21] The most frequent amount of recommended vitamin C intake form multivitamin/multimineral supplements was 120 mg per day.[22] Five recommended intakes of vitamin C were observed on the labels of vitamin C-containing supplements: 60, 250, 500, 1,000 and 3,000 mg per day.[23] The most frequently recommended intake for vitamin C-containing supplements was 500 mg of vitamin C per day.[24] Only one of the vitamin C-containing supplements reviewed recommended a daily intake of 3,000 mg of vitamin C per day, which is above the UL for vitamin C for adults 19 years and older. If the unusual vitamin C-containing supplement that recommended a daily intake of 3,000 mg of vitamin C is excluded, the range of vitamin C recommended on the label of multivitamin/multimineral and vitamin C-containing supplements is 30 to 1,000 mg per day. If the mean dietary intake of vitamin C from food in all individuals in the United States was added to this range of recommended vitamin C intakes on the labels of multivitamin/ multimineral and vitamin C-containing supplements, the total daily intake of vitamin C (135 to 1,105 mg of vitamin C per day) would be well below the UL for vitamin C, which is 2,000 mg per day, for adults aged 19 years and older.

The IOM identified possible adverse effects associated with doses of vitamin C at levels greater than 3,000 mg per day. Thus, FDA does not consider it appropriate to exercise its enforcement discretion for a dietary supplement that recommends an intake of vitamin C of 3,000 mg/day to bear a qualified health claim about vitamin C and reduced risk of a particular cancer. That level of intake, along with additional dietary sources of vitamin C, may result in possible adverse effects. As discussed in section IV of this letter, FDA is considering, as a factor in the exercise of its enforcement discretion, the recommended level of intake of vitamin C in the labeling of dietary supplements.

Based on the systematic risk assessment of vitamin C in the 2000 IOM Report and the observation that the maximum daily amount of vitamin C recommended on the label of most multivitamin/multimineral and vitamin C-containing supplements does not exceed 1,000 mg,[25] the agency believes that the daily dietary intake from the combined amount of vitamin C from diet and such dietary supplements would likely be kept below the UL of 2,000 mg per day for vitamin C. Therefore, FDA concludes at this time, under the preliminary requirements of 21 CFR 101.14(b)(3)(ii), that the use of vitamin C in dietary supplements, at levels necessary to justify the qualified health claim described in section IV of this letter, that recommend a daily intake of 1,000 mg of vitamin C or less in the labeling, is safe and lawful under the applicable provisions of the Act.

Vitamin E

There is no evidence of adverse effects from the consumption of vitamin E naturally occurring in foods; therefore, the determination of a UL for vitamin E in the 2000 IOM Report is limited to evidence concerning intake of alpha-tocopherol as a supplement, food fortificant, or pharmacological agent.

The review in the 2000 IOM Report noted that some uncontrolled studies have found various adverse effects associated with excess intake of vitamin E, which include fatigue, emotional disturbances, thrombophlebitis (i.e., inflammation of the veins), breast soreness, creatinuria, altered serum lipid and lipoprotein levels, gastrointestinal disturbances, and thyroid effects. Side effects have been reported with extended intakes of 1,600 to 3,200 mg of vitamin E per day, but these effects are not severe and subside rapidly upon reducing the dosage or discontinuing use. The 2000 IOM Report also stated that vitamin E supplementation may increase the risk of prolonged bleeding for individuals routinely ingesting non-steroidal anti-inflammatory drugs, such as aspirin, and anticoagulant drugs, or for individuals who have a vitamin K deficiency. Another potential concern about the safety of supplemental vitamin E raised in the 2000 IOM Report is the apparent increase in mortality from hemorrhagic stroke observed in the Alpha-Tocopherol Beta-Carotene (ATBC) Cancer Prevention Study in Finnish male smokers consuming 50 mg per day of alpha-tocopherol for 6 years (ATBC Cancer Prevention Study Group, 1994). However, the findings regarding hemorrhagic stroke in the ATBC study were considered preliminary and provocative but not convincing until the findings are corroborated or refuted in further large-scale clinical trials.

The 2000 IOM Report established 1,000 mg of any form of supplemental alpha-tocopherol[26] per day as the UL for individuals aged 19 years and older based on the potential adverse effect of an increased tendency to hemorrhage. The 2000 IOM Report also noted that caution must be exercised in judgments regarding the safety of supplemental doses of vitamin E over multi-year periods, as available human data are based on small studies of relatively short duration. The UL for vitamin E in other life-stage groups younger than 19 years are: for children 1 to 3 years, 200 mg of any form of supplemental alpha-tocopherol per day; for children 4 to 8 years, 300 mg of any form of supplemental alpha-tocopherol per day; for children 9 to 13 years, 600 mg of any form of supplemental alpha-tocopherol per day; and for children 14 to 18 years, 800 mg of any form of supplemental alpha-tocopherol per day. Data from NHANES III shows that the mean and ninety-ninth percentile of dietary vitamin E intake in all individuals are 7.5 and 16 mg of alpha-tocopherol per day, respectively.

Data from NHANES III also shows that the mean and ninety-ninth percentile of total vitamin E intake (food plus supplements) in all individuals are 21 and 327 mg of alpha-tocopherol per day, respectively. The highest reported daily intake at the ninety-ninth percentile is 407 mg of alpha-tocopherol in women aged 51 to 70 years, which is below the UL of 1,000 mg of any form of supplementary alpha-tocopherol per day. Based on these data, the 2000 IOM Report concluded that the risk of adverse effects resulting from excess total intake of vitamin E (food plus supplements) appears to be very low at the highest intake in the United States population.

According to data from the NHANES 1999-2000 survey, 12.7 percent of adults aged 20 years and above report taking vitamin E supplements[27] (Radimer et al., 2004). Supplemental vitamin E can be obtained from multivitamin/multimineral supplements and vitamin E-containing supplements.[28] Alpha-tocopherol is the form generally used in vitamin E supplements. The range of vitamin E intake recommended on the label of multivitamin/multimineral supplements is between 6.75 and 308 mg of alpha-tocopherol per day.[29] The most frequently recommended vitamin E intake is 67 mg of alpha-tocopherol per day.[30] The range of vitamin E intake recommended on the label of vitamin E-containing supplements is between 20 and 670 mg of alpha-tocopherol per day, and the most frequently recommended intake is 268 mg of alpha-tocopherol per day.[31] If the mean dietary intake of vitamin E in all individuals in the United States was added to the range of recommended vitamin E intakes on the label of multivitamin/multimineral and vitamin E-containing supplements, the total daily intake of vitamin E (14 to 677 mg of alpha-tocopherol per day) would be below the UL for vitamin E, which is 1,000 mg of any form of supplemental alpha-tocopherol per day, for adults aged 19 years and older.

Based on the systematic risk assessment of vitamin E in the 2000 IOM Report and the observation that the maximum daily amount of vitamin E recommended on the label of multivitamin/multiminerals and vitamin E-containing supplements is 670 mg of alpha-tocopherol per day,[32] the agency believes that the combined amount of vitamin E from diet and such dietary supplements would likely be kept below the UL of 1,000 mg per day for vitamin E. Therefore, FDA concludes at this time, under the preliminary requirements of 21 CFR 101.14(b)(3)(ii), that the use of vitamin E in dietary supplements, at levels necessary to justify the qualified health claims described in section IV of this letter, that recommend a daily intake of 670 mg or less in the labeling, is safe and lawful under the applicable provisions of the Act.

II. The Agency’s Consideration of a Qualified Health Claim

FDA has identified the following endpoints, including surrogate endpoints, to use in identifying risk reduction for purposes of a health claim evaluation involving cancer: cases of the site-specific cancer being studied, and recurrent adenomatous[33] colorectal polyps[34] for colorectal cancer. Adenomatous colorectal polyp recurrence has been used as a surrogate endpoint for colorectal cancer risk (Schatzkin et al., 1994). To evaluate the potential effects of supplemental vitamin C or vitamin E on colorectal cancer risk, FDA considered these endpoints as indicators or predictors of disease.

The petition cited 207 publications as evidence to substantiate the relationship for the proposed claims (see Docket # FDA-2008-Q-0299). Several of the publications were provided in duplicate copies. These 207 publications consisted of 1 animal study, 5 in vitro studies, 3 news releases or editorials, 13 book chapters, review articles, or meta-analyses; and 14 studies that evaluated a different substance (e.g., beta-carotene) or disease (e.g., prostate cancer, breast cancer) than identified in the proposed claims (Appendix 1). In addition, the petition provided 17 human intervention and 134 observational studies that evaluated the relationship between vitamin E or vitamin C intake and the proposed site-specific cancers claims.

In addition to the above publications, FDA identified 17 intervention (Albanes et al., 1996, 2000; Dawsey et al., 1994; DeCosse et al., 1989; De Sanjose et al., 1996; Gaziano et al., 2009; Greenberg et al., 1994; Heart Protection Study Collaboration Group 2002; Hercberg et al., 2004; Hofstad et al., 1998; Kaugars et al., 1994; Lippman et al., 2009; Malila et al., 1999; McKeown-Eyssen et al., 1988; Taylor et al., 1994; Virtamo et al., 2003; Wang et al., 1994) and 21 observational (Breuer-Katschinski et al., 2001; Chow et al., 1992; Dong et al., 2008; Eichholzer et al., 1992; Enger et al., 1996; Farrow et al., 1990; Giuliano et al., 1997; Knekt et al., 1988c, 1991b; Longnecker et al., 1992; Malila et al., 2002a; Mayne et al., 2001; Schober et al., 1987; Stahelin et al., 1987; Vena et al., 1992; Wu et al., 2002 [Nurses’ Health Study and Health Professionals Follow-Up Study]; Zatonski et al., 1991; Zeegers et al., 2001; Zheng et al., 1995; Ziegler et al., 1990) studies that evaluated the relationship between vitamin E or vitamin C intake and the proposed site-specific cancer claims.

A. Assessment of Review Articles and Abstracts

Although useful for background information, review articles and abstracts do not contain sufficient information on the individual studies that they reviewed and, therefore, FDA could not draw any scientific conclusions from this information. FDA could not determine factors such as the study population characteristics or the composition of the products used (e.g., food, dietary supplement) from this information. Similarly, the lack of detailed information on studies summarized in review articles and meta-analyses prevented FDA from determining whether the studies are flawed in critical elements such as design, conduct, and data analysis. FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it. As a result, review articles and abstracts did not provide information from which scientific conclusions can be drawn regarding the substance-disease relationships claimed by the petitioner.

B. Assessment of Animal and In Vitro Studies

FDA uses animal and in vitro studies as background information regarding mechanisms of action that might be involved in any relationship between the substance and the disease, and they can also be used to generate hypotheses or to explore a mechanism of action, but they cannot adequately support a relationship between the substance and the disease in humans. FDA did not consider the animal or in vitro studies as providing any supportive information about the substance-disease relationship because such studies cannot mimic the normal human physiology that may be involved in the risk reduction of any type of cancer, nor can the studies mimic the human body's response to the consumption of vitamins E and C. Therefore, FDA cannot draw any scientific conclusions from the animal or in vitro studies regarding vitamin E or C intake and the reduction of risk of any type of cancer.

C. Assessment of Intervention Studies

FDA evaluated 34 reports of intervention studies that were designed to evaluate the relationship between vitamin C or E intake and site-specific cancers (see Appendix 1). Scientific conclusions could not be drawn from 32 of these 34 reports for the reasons discussed below.[35]

There was one report of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) trial that evaluated the relationship between supplements containing vitamin E (30 mg), vitamin C (120 mg), and other nutrients (selenium, beta-carotene, and zinc) compared to a placebo and risk of all cancers combined and site-specific cancers (Hercberg et al., 2004). There were no screening tests for any of the cancers conducted prior to the intervention. Because this study did not confirm that all subjects were free of any cancers, including the cancer of interest (oral cavity), prior to the intervention, this study may have involved subjects who had this site-specific cancer, and, therefore, the result with respect to this cancer may be biased.[36] Furthermore, no statistical analysis was conducted for oral cavity cancer. Statistical analysis of the study findings is a critical factor because it provides the comparison between subjects consuming vitamin E or C and those not consuming vitamin E or C, to determine whether there is a reduction in cancer risk. Thus, when appropriate statistical analysis is not performed, it is not possible to determine whether the results showed a difference in risk between the two study groups (Spilker, 1991). For the above reasons, this study provided no information about whether vitamin E or C supplement use may reduce the risk of oral cavity cancer, and no scientific conclusions could be drawn from it.

There were eight reports of one trial, the Alpha-Tocopherol, Beta-Carotene Cancer (ATBC) Prevention study, that evaluated the relationship between supplemental vitamins E and beta- carotene and cancer (the ATBC Study Group, 1994; Albanes et al., 1996, 2000; Malila et al., 1999, 2002b; Varis et al., 1998; Virtamo et al., 2000, 2003). The ATBC trial was a randomized, double-blind, placebo-controlled trial that was conducted in southwestern Finland between 1985 and 1993. This study included 29,133 (50- to 69-year-old) male smokers (five or more cigarettes daily at entry) receiving either a placebo, alpha-tocopherol (50 mg) alone, beta-carotene (20 mg) alone, or both alpha-tocopherol and beta-carotene daily for 5 to 8 years. One report provided initial cancer- and mortality-related findings of the ATBC trial (the ATBC Study Group, 1994). The findings for the entire duration of the ATBC trial are published in six reports (Albanes et al., 1996, 2000; Malila et al., 1999, 2002b; Varis et al., 1998; Virtamo et al., 2000). One study analyzed post-intervention (May 1993-April 1999) effects of alpha-tocopherol on total and site- specific (i.e., lung, gastric) cancer incidence (Virtamo et al., 2003). While lung cancer was the primary outcome measured (Albanes et al., 1996; Virtamo et al., 2003)[37] , post-hoc analyses were conducted to examine other (secondary)[38] cancers (bladder, colorectal, gastric) for which the study was not designed to evaluate (Albanes et al., 1996, 2000; Malila et al., 1999, 2002b; Varis et al., 1998; Virtamo et al., 2000, 2003). These six reports did not screen for prevalent cases of site-specific cancers (e.g., bladder, colorectal, gastric) at the beginning of the trial. Consequently, the results with respect to cancers other than lung cancer may be biased due to an uneven distribution of prevalent cases in the treatment versus the placebo group. Uneven distribution of important patient or disease characteristics between groups may lead to mistaken interpretation (Spilker, 1991). If there was a significant difference between the intervention and placebo group, it would not be possible to determine whether this difference was due to a difference in the number of subjects at the beginning of the study in each group who had a certain cancer or due to the vitamin E intervention. Therefore, scientific conclusions could not be drawn from six of these eight reports about the relationship between supplemental vitamin E intake and reduced risk of bladder, colorectal, and gastric cancer.

Three randomized trials evaluated the impact of supplementation on total cancer (Heart Protection Study Collaborative Group, 2002; Lonn et al., 2005; Lee et al., 2005). Two studies were designed to specifically evaluate the effect of vitamin E supplementation on total cancer incidence and mortality (Lonn et al., 2005; Lee et al., 2005), while assessment of site-specific cancer incidence (lung and colorectal) was subsidiary. Another study assessed the impact of a supplement containing vitamins E and C and beta-carotene on coronary events, total cancer, and mortality (Heart Protection Study Collaborative Group, 2002). The primary outcomes of this study were major coronary events and fatal or non-fatal vascular events, while assessment of site-specific cancers (stomach, lung) was subsidiary. Significantly, the three studies above did not screen for prevalent cases of any cancers, including lung, colorectal, and stomach cancers, at the beginning of the trial. Because these studies did not confirm that all subjects were free of any cancers, including the cancers of interest (lung, colorectal, and stomach), prior to the intervention, this study may have involved subjects who had these site-specific cancers and, therefore, the results with respect to these cancers may be biased. Thus, scientific conclusions could not be drawn from these three studies about the relationship between vitamins E or C intake and lung, colorectal, and stomach cancer risk.

Two randomized placebo-controlled trials evaluated the impact of supplementation on prostate cancer or total cancer in men (Gaziano, et al., 2009; Lippman et al., 2009). Lippman et al. (2009) was designed to specifically evaluate the effect of vitamin E supplementation on prostate cancer incidence in healthy men (not one of the proposed claims). Site-specific cancer incidence (lung and colorectal) was a secondary endpoint of this study. This study did not screen for prevalent cases of either of these site-specific cancers at the beginning of the trial. Gaziano et al. (2009) was designed to specifically assess the effect of long-term vitamin E or C supplementation on prostate and total cancer, respectively. Other cancers (bladder, colorectal, lung, pancreatic) were also evaluated. Significantly, Gaziano et al. (2009) did not screen for prevalent cases of any cancers, including colorectal, lung, bladder, and pancreatic cancers, at the beginning of the trial. Therefore, as discussed above, because these studies did not confirm that all subjects were free of the cancers of interest (lung, colorectal, bladder, pancreatic) prior to the intervention, this study may have involved subjects who had these site-specific cancers and, therefore, the results with respect to these cancers may be biased. Thus, scientific conclusions could not be drawn from these two studies about the relationship between vitamin E or C intake and colorectal, lung, bladder, and pancreatic cancer risk.

Two double-blind, placebo-controlled, randomized intervention studies evaluated the relationship between combined vitamin E and C supplement intake and colorectal cancer (Greenberg et al., 1994; McKeown-Eyssen et al., 1988). Because subjects did not receive vitamins E or C as single supplements, these studies were not designed to measure the independent role of vitamin E or vitamin C in reducing the risk of colorectal cancer. There is evidence from human intervention studies of an interaction between vitamins E and C (Bruno et al., 2005, 2006; Hamilton et al., 2000). Two randomized supplement intervention studies (Bruno et al., 2005, 2006) have demonstrated that plasma alpha-tocopherol disappearance rates are inversely correlated with plasma ascorbic acid (vitamin C) concentration in smokers, as opposed to non-smokers, indicating that vitamin C could spare vitamin E from oxidation or reduce the vitamin E radical to regenerate vitamin E; hence, the presence of vitamin C may result in less depletion of vitamin E. About 80% of the subjects in the McKeown-Eyssen et al. (1988) study were smokers. Greenberg et al. (1994) did not report on their subjects’ smoking status, which indicates that some of the study subjects may have been smokers. Furthermore, another randomized intervention study in a group of healthy non-smoker men and women showed that supplementation with ascorbic acid increased the level of plasma alpha-tocopherol and that supplementation with alpha-tocopherol was associated with an increase in plasma ascorbic acid concentration (Hamilton et al., 2000). The study concluded that these results are supportive of an interaction between vitamins C and E in humans (Hamilton et al., 2000). Based on the above reported interaction between vitamin C and vitamin E, the independent roles of vitamin E and vitamin C on colorectal cancer cannot be determined from these two studies, in which vitamins E and C were given to subjects as a combined supplement (Greenberg et al., 1994; McKeown-Eyssen et al., 1988). Therefore, scientific conclusions cannot be drawn from these two studies about the relationship between vitamin E or vitamin C supplement use and risk of colorectal cancer.

Another placebo-controlled intervention trial conducted in Norway measured colorectal polyp recurrence in males and females given a multi-nutrient supplement containing vitamins C and E, selenium, beta-carotene, and calcium (Hofstad et al., 1998). Based on the above reported interaction between vitamin C and vitamin E, the independent roles of vitamin E and vitamin C on colorectal cancer cannot be determined from this study, in which vitamins E and C were given to subjects as a combined supplement. Therefore, no scientific conclusions could be drawn from this study about the independent effect of vitamin E or vitamin C on risk of colorectal cancer.

One intervention trial randomized 209 Italian men and women who had at least one colorectal polyp removed prior to the intervention. The intervention trial included a group taking a supplement containing vitamins A, E, and C (number of subjects (n) =70) and a control group receiving no treatment (n =78) (Roncucci et al., 1993). Three colonoscopy exams were planned for each subject between 6 to 8, 12 to 18, and 24 to 36 months after the initial examination. The average subject trial time was reported to be 17.8 + 13.1 months (mean + standard deviation); however, the period between colonoscopy exams within the treatment groups did not follow the planned interval. Approximately 30% of the participants in the supplement group dropped out after one colonoscopy and before one year of supplementation. The study article indicated that only 26 percent of the subjects in the supplement group had their final colonoscopy between 24 and 65.5 months after the intervention. The differences in the treatment time make this study difficult to evaluate because each subject in the intervention group did not receive the same amount of the assigned supplement. Moreover, the high dropout rate in this study makes the results difficult to interpret and can introduce bias because it changed the number of subjects in the intervention group and may also have changed the group’s composition relative to the control group. Furthermore, this study was not placebo-controlled. Including a placebo in a supplementation trial prevents a subject from knowing whether he or she is receiving the substance or not. Additionally, if an intervention but not a placebo is used in a clinical trial, there is no statistical test to demonstrate that the intervention was effective. The observed changes (if any) may have been due to a placebo effect (Spilker, 1991, Chapter 9). This study also did not investigate subjects’ usual dietary and supplement intake (e.g., vitamins C or E). Thus, it is not known whether one group took more supplements or consumed foods that are more protective of some cancers (e.g., fruits and vegetables) or ingested potentially more harmful high-fat foods than the other groups. Additionally, the study protocol did not have a means of determining compliance with the vitamin supplement-dosing regimen other than asking patients if they had adhered to the treatment schedule. Therefore, it is not known if all the subjects received their assigned treatments. Due to the shortcomings described above, this study is so deficient in quality that is considered to be of low-quality design. Furthermore, based on the above reported interaction between vitamin C and vitamin E, the independent roles of vitamin E and vitamin C on colorectal cancer cannot be determined from this study, in which vitamins A, C, and E were given to subjects as a combined supplement. Therefore, the supplements containing vitamins A, C, and E could not be used to independently assess the effect from vitamin E or vitamin C alone. Based on the above reasons, scientific conclusions could not be drawn from this study about the relationship between vitamin E or vitamin C intake and risk of colorectal cancer.

Five reports were on two randomized nutrition intervention trials (Dysplasia Trial and General Population Trial) conducted in the Linxian region of China that examined the benefit of vitamin E or vitamin C in reducing the risk of esophageal, stomach (gastric), and colorectal cancer (Blot et al., 1993; Dawsey et al., 1994; Li et al., 1993; Taylor et al., 1994; Wang et al., 1994). In the General Population trial, 29,584 adults aged 40-69 years from four Linxian communes were randomly assigned to either receive a placebo, supplemental ï�¡-tocopherol (30 mg), ï�¢-carotene (15 mg) and selenium (50 ï�­g/day), or vitamin C (120 mg) and molybdenum (30 ï�­g). In the second trial, the Dysplasia Trial, 3,318 adults aged 40-69 years from three Linxian communes were randomly assigned into two groups: one received a placebo, and the other group received a multiple vitamin and mineral supplement including vitamins C (180 mg) and E (60 mg). Linxian, China, has one of the world’s highest rates of esophageal cancer,[39] with mortality rates of this cancer exceeding the national U.S. average incidence for whites by as much as 100-fold (Blot et al., 1993). Furthermore, the risk factors for stomach cancer are very different between the United States and China.[40] Additionally, there is substantial scarcity of food in the region, and this has led to several micronutrient deficiencies (e.g., vitamins A, C, riboflavin) and blood levels of vitamin C and E that are consistently low in this population compared to Western levels (Yang et al., 1984, 1985). Thus, because the study subjects were Linxian residents, it is not possible to determine if a potential benefit of these vitamins is a result of correcting a vitamin C and/or E deficiency. Scientific conclusions about the role of vitamin C or vitamin E in reducing the risk of esophageal, stomach (gastric), or colorectal cancer could not be drawn from these studies because the study population had subclinical (prior to clinical symptoms of a disease/condition being observed) malnutrition, and a strikingly high prevalence of esophageal and gastric cancer, with risk factors that are different from those in the United States.

Ten intervention studies measured endpoints[41] other than validated surrogate endpoints of cancer risk for certain site-specific cancers, including colorectal, oral, and gastric cancer (Benner et al., 1993a; Cahill et al., 1993; Correa et al., 2000; De Sanjose et al., 1996; Henning et al., 1991; Kamangar et al., 2006; Kaugars et al., 1994; Paganelli et al., 1992; Zaridze et al., 1993; You et al, 2006). Because they did not measure a validated surrogate endpoint, scientific conclusions about the relationship between vitamin C or vitamin E intake and risk of colorectal, oral, or gastric cancer could not be drawn from these studies.

DeCosse et al. (1989) measured the impact of vitamins C and E on already existing rectal polyps (mean number of polyps was 11) in 62 patients with Familial Adenomatous Polyposis (FAP)[42] who had a total colectomy. These patients had already had their colon removed and had numerous rectal polyps. Therefore, the agency could not draw any scientific conclusions from this population, since this subset of the U.S. population has a genetic predisposition to colorectal cancer and, therefore, the results of studies involving this population cannot be extrapolated to reach conclusions about potential effects on the general U.S. population.

Based on the above discussion, scientific conclusions could be drawn from two of the 34 reports that evaluated the proposed claims concerning a relationship between vitamin C or vitamin E intake and risk of site-specific cancers (Albanes et al., 1996; Virtamo et al., 2003).

Vitamin C

Colorectal Cancer

The majority of published research did not differentiate between colon and rectal cancers; therefore, the agency evaluated colon and rectal cancer together in this review.[43] There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of colorectal cancer.

Squamous Cell Cancer of the Esophagus[44]

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of squamous cell cancer of the esophagus.

Gastric (Stomach) Cancer 

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of gastric cancer.

Laryngeal Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of laryngeal cancer.

Lung Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of lung cancer.

Oral Cavity Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of oral cavity cancer.

Pancreatic Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of pancreatic cancer.

Pharyngeal Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of pharyngeal cancer.

Renal Cell Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of renal cell cancer.

Salivary Glands Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of salivary glands cancer.

Vitamin E

Bladder Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of bladder cancer.

Brain Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of brain cancer.

Cervical Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of cervical cancer.

Colorectal Cancer

The majority of published research did not differentiate between colon and rectal cancers; therefore, the agency evaluated colon and rectal cancer together in this review.[45] There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of colorectal cancer.

Gastric (Stomach) Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of gastric cancer.

Lung Cancer

Albanes et al. (1996) was a high quality randomized, double-blind, placebo controlled primary-prevention trial that evaluated whether daily supplementation with alpha-tocopherol (vitamin E), beta-carotene, or both would reduce the incidence of lung cancer across subgroups of participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC study). A total of 29,133 men, aged 50-69 years, who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both alpha-tocopherol and beta-carotene, or a placebo daily for a median of 6.1 years (April 1985-April 1993). By the end of the study, 894 men were identified with lung cancer (204 in the vitamin E group and 208 in the placebo group). No overall statistically significant effect was observed on lung cancer from vitamin E supplementation. The relative risk[46] for vitamin E was 0.99 (Confidence Interval (CI) = 0.87-1.13)[47]. During a six-year post-trial follow-up (May 1993-April 1999) among the 25,283 ATBC participants (free of lung cancer when the post-trial period began), 1,037 lung cancer cases were reported (Virtamo et al., 2003). No statistically significant overall difference in lung cancer incidence was observed during the post-trial period between alpha-tocopherol recipients and non-recipients (259 in vitamin E group; 250 in the placebo group; relative risk = 1.03; CI = 0.91 -1.16). Vitamin E supplementation did not have a statistically significantly effect on lung cancer risk in this population.

Renal Cell Cancer

There were no intervention studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of renal cell cancer.

D. Assessment of Observational Studies

Assessment of Vitamin C and Vitamin E Intake

Dietary Intake

The proposed claims are for a relationship between vitamin C or vitamin E from dietary supplements and a reduced risk of site-specific cancers. In observational studies that calculate nutrient intake from conventional food, measures of vitamins C or E intake are based on recorded dietary intake methods such as food frequency questionnaires (FFQ), diet recalls, or diet records, in which the type and amount of foods consumed are estimated. A common weakness of observational studies is the limited ability to ascertain the actual food or nutrient intake for the population studied as a result of poor memory, over or underestimation of portion sizes, and recall bias (Flegal, 1999). Furthermore, the nutrient content of foods can vary (e.g., due to demographics (soil composition), food processing/cooking procedures, or storage (duration, temperature)). In the case of vitamin E, dietary intake estimates from observational studies are particularly prone to difficulties in obtaining accurate measurements (IOM, 2000, Chapter 6). Most nutrient databases do not distinguish among the alpha-, beta-, gamma-, and delta- forms of tocopherols that occur in food (IOM, 2000, Chapter 6). Only alpha-tocopherol is retained in the body and is the most bioactive form (IOM, 2000, Chapter 6). Vitamin E intakes are dependent on the types and amounts of oils in the diet; some vegetable oils contain more gamma- than alpha-tocopherol. For example, soybean and corn oils contain 10 times more gamma-tocopherol than alpha-tocopherol (IOM, 2000, Chapter 6). About half of the tocopherol content in oils such as wheat germ, sunflower, cottonseed, canola, and olive is in the form of alpha-tocopherol (IOM, 2000, Chapter 6). Accurate information on both amounts and composition of oils used in food processing and preparation is often not gathered in interviews or known by most study respondents. Often energy and fat intakes are underreported by participants in the national surveys (i.e., National Health and Nutrition Examination Survey (NHANES)) (IOM, 2000, Chapter 6).

There are adequate food composition databases for quantifying the amount of vitamin C in various foods; nevertheless, the definite intake levels vary according to food handling and cooking practices (Mayne, 2003). For example, vitamin C can be destroyed in foods when they are exposed to high temperatures or cooked in large amounts of water (Mayne, 2003). Also, the vitamin C content of foods can vary depending on the growing conditions, season of the year, and the stage of maturity (IOM, 2000, Chapter 5). Thus, to accurately estimate intake of vitamins C and E requires direct chemical analysis of the diet consumed, which is not done when assessing vitamins C and E intake in observational studies.

Conventional foods and multi-nutrient supplements contain not only vitamin C or vitamin E but also contain additional nutrients that may be associated with the metabolism of vitamin C and/or vitamin E or the pathogenesis of various cancers. Because foods and multi-nutrient supplements consist of many nutrients and substances, it is difficult to study the nutrient or food components in isolation (Sempos et al., 1999). See Sempos et al. (1999) and Willett (1990; 1998) regarding the complexity of identifying the relationship between a specific nutrient within a food and a disease. For studies based on recorded dietary intake of such foods or multi-nutrient supplements, it is not possible to accurately determine whether any observed effects of vitamin C or vitamin E on cancer risk were due to: 1) vitamin C or vitamin E alone; 2) interactions between vitamin C or vitamin E and other nutrients or substances; 3) other nutrients acting alone or together; or 4) decreased consumption of other nutrients or substances contained in foods displaced from the diet by the increased intake of vitamin C or vitamin E rich foods. Moreover, evidence demonstrates that in a number of instances, epidemiological studies based on the recorded dietary intake of conventional foods may indicate a benefit for a particular nutrient with respect to a disease, but it is subsequently demonstrated in an intervention study that a dietary supplement containing that nutrient does not confer a benefit or actually increases risk of the disease (Lichtenstein and Russell, 2005). For example, previous epidemiological studies reported an association between fruits and vegetables high in beta-carotene and a reduced risk of lung cancer (Peto et al., 1981). However, subsequent intervention studies—specifically, the Alpha-Tocopherol and Beta-Carotene Prevention Study (ATBC) and the Carotene and Retinol Efficiency Trial (CARET)—demonstrated that beta-carotene supplements increase the risk of lung cancer in smokers and asbestos-exposed workers, respectively (ATBC, 1994; Omenn et al., 1996). These studies illustrate that a nutrient provided as a dietary supplement exhibits different health effects compared to when it is consumed among many other food components. Furthermore, these studies demonstrate the potential public health risk of relying on results from epidemiological studies, in which the effect of a nutrient is based on recorded dietary intake of conventional foods as the sole source for concluding that a relationship exists between a specific nutrient and disease risk; the effect could actually be harmful.

In Pearson v. Shalala, the D.C. Circuit noted that FDA had “logically determined” that the consumption of a dietary supplement containing antioxidants could not be scientifically proven to reduce the risk of cancer where the existing research had examined only foods containing antioxidants, as the effect of those foods on reducing the risk of cancer may have resulted from other substances in those foods (164 F.3d 650, 658 (D.C. Cir. 1999)). The D.C. Circuit, however, concluded that FDA’s concern with granting antioxidant vitamins a qualified health claim could be accommodated by simply adding a prominent disclaimer noting that the evidence for such a claim was inconclusive given that the studies supporting the claim were based on foods containing other substances that might actually be responsible for reducing the risk of cancer. Id. The court noted that FDA did not assert that the dietary supplements at issue would “threaten consumer's health and safety.” Id. at 656. There is, however, a more fundamental problem with allowing qualified health claims for nutrients in dietary supplements based solely on studies of foods containing those nutrients than the problem the D.C. Circuit concluded could be cured with a disclaimer. As noted above, even if the effect of the specific component of the food constituting the dietary supplement could be determined with certainty, recent scientific studies have shown that nutrients in food do not necessarily have the same beneficial effect when taken in the form of a dietary supplement. See Lichtenstein and Russell (2005). Indeed, not only have studies on single nutrient supplements established that the benefits associated with the dietary intake of certain nutrients do not materialize when the nutrients are taken as a supplement, but some of these studies have actually indicated an increased risk for the very disease the nutrients were predicted to prevent. Id. Thus, an observational study based on food provides no information from which scientific conclusions may be drawn for a single nutrient supplement.

Therefore, observational studies in foods and multi-nutrient supplements do not provide any credible evidence for a claim for risk reduction for a nutrient taken as a supplement because, in fact, the nutrient in supplement form may decrease, have no effect on, or actually increase risk of the disease or health-related condition. For the reasons set forth in Section V, Agency’s Consideration of Disclaimers or Qualifying Language, FDA has concluded that neither a disclaimer nor qualifying language would suffice to prevent consumer deception in these instances because observational studies in food or multi-nutrient supplements do not provide credible evidence of risk reduction for a nutrient provided in a dietary supplement.

The agency will consider findings from observational studies that examined a supplement containing only vitamin C or vitamin E.[48] Such studies do not present the same degree of problems as studies involving foods or multi-nutrient dietary supplements containing other substances that may have a possible role in protecting against certain types of cancer. Rather, observational studies about single supplements of vitamin C or vitamin E are more reliable than those involving foods or multi-nutrient dietary supplements because they are based on a specific nutrient supplement and can therefore provide a more accurate measure of vitamin C or vitamin E intake. FDA has considered only observational studies involving single-nutrient supplements in which any known confounders have been identified and accounted for.

Blood (plasma or serum) Vitamins C or E

Alpha-tocopherol is the only form of vitamin E that is specifically maintained in human serum or plasma.[49] In general, serum or plasma vitamin E (alpha-tocopherol) concentrations are poorly correlated with vitamin E intake and are affected by many confounding factors (Gibson, 1990; IOM., 2000, Chapter 6; Mayne, 2003; Traber, 2006). For example plasma vitamin E increases with increasing plasma lipid concentration (Gibson, 1990; Mayne, 2003; Traber, 2006). Numerous studies have shown that dietary vitamin E intake and serum or plasma vitamin E levels are poorly correlated; correlation coefficients (r)[50] range between 0.05 and 0.48 (Boeing et al., 1997; Dixon et al., 2006; Ford and Sowell, 1999; Galan et al., 2005; Kabagambe et al., 2001; Kardinaal et al., 1995; White et al., 2001). Several other studies have reported a stronger but still marginal correlation (r = 0.31- 0.60) between total vitamin E intake (diet and supplement) and serum or plasma vitamin E levels (Ascherio et al., 1992; Dixon et al., 2006; Jacques et al., 1993; McNaughton et al., 2005; Stryker et al., 1988; Tangney et al., 2004; White et al., 2001). These higher associations were suggested to be largely due to vitamin E supplement intake. Dietary and supplement vitamin E intake in these studies were based on subjects’ food recall using food frequency questionnaires (FFQ) or 24-hour recall method, and vitamin E values were estimated from nutrient composition databases. As discussed above (see “Dietary Intake”), these assessment intake methods cannot be considered reliable indicators of vitamin E intake due to the unacceptable level of variation and bias toward underreporting. Additionally, while supplement use increases the correlation between total vitamin E intake and plasma E levels, the correlation is still marginal, and most of the variation in plasma vitamin E levels cannot be attributed to vitamin E intake. Furthermore, plasma alpha-tocopherol levels do not increase linearly with vitamin E supplement intake. It has been reported that plasma alpha-tocopherol concentrations rarely increase more than three-fold in response to vitamin E supplementation, regardless of dose size ((Dimitrov et al., 1991; Traber et al., 1994, 1998). This suggests a limitation in plasma vitamin E concentrations, which could occur because the tocopherol binding protein can become saturated with alpha-tocopherol (Traber et al., 1994). Additionally, many confounding factors are reported to affect the circulating level of vitamin E, including age, gender, energy intake, fat intake, serum lipid levels (cholesterol, triglycerides), smoking, body mass index (BMI), and ethnicity (Ford and Sowell, 1999; Gibson, 1990; Mayne, 2003; White et al., 2001). Based on the above, circulating levels of vitamin E are not a reliable surrogate measure of dietary or supplemental vitamin E intake.

A serum or plasma level of vitamin C is difficult to interpret as a marker of vitamin C intake unless frank deficiency is present (IOM, 2000, Chapter 5; Gibson, 1990). Vitamin C deficiency is generally rare in developed countries such as the United States. Several studies have shown that dietary vitamin C intakes and serum or plasma C levels are poorly to moderately correlated; r = 0.14 to 0.50 (Boeing et al., 1997; Bolton-Smith et al., 1991; Galan et al., 2005; Jacques et al., 1993; Tangney et al., 2004). Similar to vitamin E, many factors can affect serum vitamin C levels, including acute and chronic infection, smoking, body weight, and seasonal variations (Gibson, 1990; Mayne, 2003). Serum or plasma measures of vitamin C also pose interpretive problems when intake is outside of typical dietary ranges. There is a direct relationship between plasma vitamin C and recent vitamin C intakes between 50 and 90 mg/day (Mayne, 2003). However, intakes of vitamin C above these levels, which are readily attainable in the U.S. population diet (e.g., 200 mg/day), may increase renal-clearance rate (IOM, 2000, Chapter 5; Mayne, 2003). Dose-dependent absorption and renal regulation limit plasma C levels when intakes are high and conserve C body stores when intakes are low (IOM, 2000, Chapter 5). Therefore, plasma C may predict intake at low levels but not at higher dietary levels or in supplement users (IOM, 2000, Chapter 5; Mayne, 2003). Furthermore, there is a high fluctuation in blood C levels in response to current intake; thus, a fasting blood sample is required (Mayne, 2003). Based on the above, circulating levels of vitamin C are not a reliable surrogate measure of dietary or supplemental vitamin C intake.

Since circulating vitamin C or vitamin E levels and intake levels are poorly correlated, and many factors (e.g., BMI, serum lipid level, smoking) can alter the serum or plasma vitamin C or vitamin E concentration at a given point in time, scientific conclusions cannot be drawn from studies that used blood vitamin C or E levels as a biomarker of intake.

Observational Studies

FDA evaluated a total of 155 observational studies that investigated the relationship between vitamin C or vitamin E and cancer risk for the proposed site-specific cancers. Scientific conclusions could not be drawn from 144 of the observational studies for one or more of the reasons discussed below (see Appendix 1).[51]

Seventy-nine studies evaluated the relationship between estimated intakes of vitamin C or vitamin E from dietary sources and risk reduction of site-specific cancers (Appendix 1). For the reasons discussed above, scientific conclusions could not be drawn from these 79 studies about the relationship between supplemental vitamins E or C and risk reduction of such cancers.

Thirteen observational studies did not assess vitamins C or E intake from single-nutrient supplement sources. These studies collected information on intake of vitamins C or E either from multi-nutrient supplements, a combination of vitamin C or E from a multi-nutrient supplement plus vitamin C or E from a single supplement, or a combination of a vitamin E- or C-containing supplement plus dietary intake data. For the reasons discussed above, scientific conclusions about supplemental vitamin C or E intake and reduced risk of site-specific cancers could not be drawn from these thirteen observational studies (Appendix 1).

Three studies assessing vitamin E or vitamin C intake from single-nutrient supplement sources did not provide confidence intervals for determining statistical significance or risk between different groups (Terry et al., 2000; Yong et al., 1997; Ziegler et al., 1990). Statistical analysis of the study findings is a critical factor because it provides the comparison between subjects consuming vitamin E or C and those not consuming vitamin E or C to determine whether there is a reduction in cancer risk. When statistics are not performed on the specific substance/disease relationship, it cannot be determined whether there is a difference between groups (Spilker, 1991, Chapter 70). As a result, because these studies provided no information about whether vitamin E or C from supplement sources reduces the risk of site-specific cancer, no scientific conclusions could be drawn from them.

Dabrowska-Ufniarz et al. (2002) evaluated the vitamin C concentration in gastric juice in patients with precancerous lesions of the stomach and gastric cancer. Because this study did not measure a validated surrogate endpoint, scientific conclusions about the relationship between vitamin C consumption and risk of gastric cancer could not be drawn.

Barone et al. (1992) assessed the relationship between vitamin C intake and both cancer of the oral cavity and esophageal cancer. However, for the purpose of this petition, the study was only utilized to evaluate the relationship between vitamin C intake and cancer of the oral cavity. One of the proposed claims was for a relationship between vitamin C supplement intake and risk of squamous cell cancer of the esophagus. This study assessed esophageal cancer, rather than squamous cell cancer of the esophagus, which is a particular type of esophageal cancer;[52] therefore, scientific conclusions about the relationship between vitamin C consumption and risk of squamous cell cancer of the esophagus could not be drawn.

White et al. (1997) assessed the relationship between vitamin C or vitamin E supplement intake and colorectal cancer incidence among U.S. men and women. This study assessed intake of vitamin E from single-nutrient supplements. However, the study measured vitamin C intake from a combination of single-nutrient supplements plus multi-nutrient supplements or supplements containing vitamins A, C, and E and folic acid. This study did not provide information as to what other substances were included in the multi-nutrient supplements and, therefore, the agency cannot determine whether the multi-nutrient supplements contained substances that may affect the metabolism of vitamin C or the pathogenesis of colorectal cancer. Moreover, based on the reported interaction between vitamin E and C discussed above, the supplements containing vitamins A, C, and E and folic acid could not be used to assess the independent effect of vitamin C on colorectal cancer. Thus, this study was used only to evaluate the relationship between vitamin E supplement intake and reduced risk of colorectal cancer.

Forty-eight observational studies measured serum or plasma concentration as a biomarker of vitamin C or vitamin E intake (Appendix 1). For the reasons discussed above, serum or plasma C or E are not reliable biomarkers of vitamin C or vitamin E intake. Therefore, scientific conclusions cannot be drawn about the relationship between vitamin C or vitamin E intake and risk of cancers from these 48 studies.

Thus, scientific conclusions could be drawn from 11 of 155 observational studies that evaluated the relationship between vitamins C or E intake from a single-nutrient supplement source and risk of the proposed site-specific cancer (Barone et al., 1992; Holick et al., 2005; Hu et al., 2003; Jacobs et al., 2002a, 2002b; Mayne et al., 2001; Michaud et al., 2000; Whelan et al., 1999; White et al., 1997; Wu et al., 2002 [Nurses’ Health Study and Health Professionals Follow-Up Study]).

Vitamin C

Colorectal Cancer

FDA identified one moderate methodological quality case-control[53] study that evaluated the relationship between supplemental vitamin C and incidence of recurrent polyps (Whelan et al., 1999). This study evaluated the relationship between single vitamin C supplementation and the incidence of recurrent polyps in men and women (average age = 65.5 years). Average duration of vitamin usage ranged from 9.8 to 12.2 years. Overall, 183 subjects were diagnosed with recurrent colorectal polyps and 265 subjects were without a recurrent colorectal polyps. There was no statistically significant association between supplemental vitamin C intake and risk of polyp recurrence (odds ratio[54] = 0.696; CI = 0.445 - 1.09).

Squamous Cell Cancer of the Esophagus

The agency identified one moderate methodological quality case-control study that reported on vitamin C supplement intake and the risk of squamous cell cancer of the esophagus (Mayne et al., 2001).

Results from a population-based case-control study in U.S. men and women (age 30-79 years) indicate that vitamin C supplement use (at least once a week for 6 months or longer) did not have a statistically significant association with reduced risk of squamous cell cancer of the esophagus (cases = 26; odds ratio = 0.71; CI = 0.51 -1.22) (Mayne et al., 2001). Approximately 81 percent of the subjects were male and 21 percent were nonwhite. However, the data were not stratified based on gender or race. The overall number of cases of histologically confirmed squamous cell cancer of the esophagus was 206.

Gastric (Stomach) Cancer

FDA identified one high methodological quality prospective cohort study (Jacobs et al., 2002b) and one moderate methodological quality case-control study (Mayne et al., 2001) that evaluated the relationship between vitamin C supplement intake and risk of gastric cancer incidence or mortality.

Jacobs et al. (2002b) followed a cohort among 1,045,923[55] U.S. adult participants (460,737 men and 585,186 women) in the Cancer Prevention Study II (CPS-II) to examine the association between regular use[56] of individual vitamin C supplements at enrollment and gastric cancer mortality. During the 16 years of follow-up, 1,725 cases of stomach cancer death occurred (1,127 in men and 598 in women). After adjustment of multiple potential gastric cancer risk factors, vitamin C use was not reported to decrease the risk of gastric cancer mortality (162 deaths; relative risk = 0.83; CI = 0.68 - 1.01). However, a statistically significant association between vitamin C use and gastric cancer risk reduction was observed in those (men and women combined) who reported using vitamin C for less than 10 years (66 deaths; relative risk = 0.68; CI = 0.51 - 0.91) and not for those who took supplements for more than 10 years (65 deaths; relative risk = 1.00; CI = 0.73 - 1.38). Regardless of duration of vitamin C supplement use, when the cohorts were stratified by gender, no statistically significant effect was observed on gastric cancer mortality (men: ≥ 10 years; 44 deaths; relative risk = 1.04; CI = 0.71 - 1.53; women: ≥ 10 years; 21 deaths; relative risk = 0.94; CI = 0.54 – 1.64).

Mayne et al. (2001) was a multicenter case-control study of U.S. men and women who were 30 -79 years of age and were diagnosed with gastric cancer from 1993 to early 1995. Based on 255 cases of gastric cardia cancer[57], 352 cases of non-cardia gastric cancer, and 687 controls, there was no statistically significant association between vitamin C supplement use (at least once a week for 6 months or longer) and risk of gastric cardia cancer (cases = 47; odds ratio = 0.71; CI = 0.48 - 1.07). However, vitamin C supplement use was associated with a statistically significant lower risk for noncardia gastric cancer (cases = 62; odds ratio = 0.60; CI = 0.41 - 0.88).

Laryngeal Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of laryngeal cancer.

Lung Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of lung cancer.

Oral Cavity Cancer

FDA identified one case-control study that evaluated the relationship between vitamin C supplement intake and oral cavity cancer incidence (Barone et al., 1992).

Barone et al. (1992) was a high methodological quality case-control study that was part of an ongoing tobacco-related cancer study involving eight hospitals in four major U.S. cities. A total of 290 oral cavity cancer cases and 576 controls were identified. There was no statistically significant difference in the risk of oral cavity cancer between supplemental vitamin C users and those who did not take vitamin C (48 cases, 100 controls; odds ratio = 1.2; CI = 0.7 - 2.0). Stratification by smoking status or duration of vitamin C use (1- 9 years or ≥ 10 years) did not change the association.

Pancreatic Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of pancreatic cancer.

Pharyngeal Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of pharyngeal cancer.

Renal Cell Cancer[58]

FDA identified one moderate methodological quality case-control study that evaluated the relationship between vitamin C supplement use and incidence of renal cell cancer (Hu et al., 2003).

Hu et al. (2003) was a case-control study that collected data on incident cases of renal cell cancer in Canadian men and women from the National Enhanced Cancer Surveillance System (NECSS). A total of 1,279 (691 male and 588 female) histologically confirmed cases of renal cell carcinoma and 5,370 (2,696 male and 2,674 female) controls were identified. The data were stratified by gender and duration of supplement use (1-5 years or > 5 years). There was no statistically significant relationship between risk of renal cell cancer and vitamin C supplement use even in those who reported taking vitamin C supplements for more than 5 years (males: 87 cases; odds ratio = 0.8, CI = 0.6 - 1.0; females: 99 cases; odds ratio = 0.8; CI = 0.6 - 1.0).

Salivary Glands Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of cancer of salivary glands.

Vitamin E

Bladder Cancer

FDA identified one high quality prospective cohort study (Jacobs et al., 2002a) and two moderate (Holick et al., 2005; Michaud et al., 2000) methodological quality prospective studies that evaluated the relationship between supplemental vitamin E and risk of bladder cancer incidence or mortality.

Jacobs et al. (2002a) followed a cohort of 991,522[59] U.S. adult participants (446,227 men and 545,295 women) in the Cancer Prevention Study II (CPS-II) to examine the association between bladder cancer mortality and vitamin E single-supplement use at enrollment. During the 16 years follow-up, a total of 1,289 cases of bladder cancer death occurred (962 in men and 327 in women). Regular[60] vitamin E supplement use (at enrollment) had a statistically significant association with reduction of bladder cancer mortality only in those (men and women combined) that took vitamin E supplement for 10 years or more (24 deaths; relative risk = 0.60; CI = 0.37 - 0.96). No risk reduction was observed in those (men and women combined) who had been vitamin E supplement users for less than 10 years (60 deaths; relative risk = 1.04; CI = 0.77 - 1.40). Regardless of duration of vitamin E supplement use, when the cohorts were stratified by gender, no statistically significant effect was observed on bladder cancer mortality (men: ≥ 10 years; 19 deaths; relative risk = 0.63; CI = 0.37 - 1.08; women: ≥ 10 years; 5 deaths; relative risk = 0.52; CI = 0.19 – 1.40).

Holick et al. (2005) reported a total of 237 cases of bladder cancer incidence during 20 years of follow-up (1980 - 2000) among 88,796 women enrolled in the Nurses’ Health Study. The data were stratified based on years of supplement use (never users; past users; current: < 5, 5-9, and > 10 years). The first questionnaire was sent out in 1980 and duration of supplement use was updated biennially. Individual vitamin E supplement use was not associated with a statistically significant decreased risk of bladder cancer incidence even in women who had reported taking vitamin E supplements for more than 10 years (cases = 9; relative risk = 0.72; CI = 0.37 - 1.42).

Michaud et al. (2000) examined the relationship between the duration of single supplement vitamin E use and risk of bladder cancer among 51,529 men in the prospective Health Professionals Follow-up study (1986 - 1998). The first questionnaire was sent out in 1986 and duration of supplement use was updated biennially. During 12 years of follow-up, 320 cases of bladder cancer were diagnosed. There was no statistically significant association between duration (≤ 5, 6-9, or ≥ 10 years) of current vitamin E supplement use and risk of bladder cancer compared to those who reported not using vitamin E supplements (e.g., ≥ 10 y: 27 cases; relative risk = 0.68; CI = 0.45 - 1.03).

Brain Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between supplemental vitamin E intake and risk of brain cancer.

Cervical Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of cervical cancer.

Colorectal Cancer

FDA identified two case-control studies (Whelan et al., 1999; White et al., 1997) and one article on two prospective cohort studies (Wu et al., 2002) that reported on the relationship between supplemental vitamin E and incidence of colorectal cancer or polyp recurrence.

Whelan et al. (1999) was a moderate methodological quality case-control study that assessed the relationship between vitamin E supplementation and the incidence of recurrent polyps in males and females (average age = 65.5). Average duration of vitamin usage ranged from 9.8 to 12.2 years. Overall, 183 subjects were diagnosed with recurrent colorectal polyps and 265 subjects were without recurrent colorectal polyps. Supplemental vitamin E intake was associated with a statistically significant decreased risk of polyp recurrence (34 cases; odds ratio = 0.61; CI = 0.38 - 0.98).

White et al. (1997), a moderate methodological quality case-control study, assessed single vitamin E supplement use and colorectal cancer incidence among U.S. men and women. Overall, 444 cases and 427 controls were included. Supplement use was assessed using questions regarding frequency, duration, and dose per day of vitamin E supplement intake during a 10-year period ending 2 years before the cases had been diagnosed. A statistically significant association between single vitamin E supplement use (≥ 200 IU) and reduced risk of colorectal cancer incidence was observed (26 cases, 47 controls; odds ratio = 0.43; CI = 0.40-0.91).

Wu et al. (2002) reported on the results of two prospective cohort studies that evaluated vitamin E supplement intake and risk of colorectal cancer. These studies were of high methodological quality and followed 87,998 females from the Nurses’ Health Study for 16 years and 47,344 males from the Health Professionals Follow-up Study for 10 years. Among men and women, 399 and 626 colorectal cancer cases were identified, respectively. Data for both cohorts were analyzed for different amounts of supplement intake at the baseline (≤ 250 IU; 300 - 500 IU; or ≥ 600 IU) and by duration (1 – 4, 5 – 9, ≥ 10 years) of high dose vitamin E (300 IU and up).[61] No significant association was observed between vitamin E and risk of colorectal cancer in either men or women at any level of supplement intake at the baseline (e.g., ≥ 600 IU: women - 11 cases, relative risk = 0.78; CI = 0.43 - 1.42; men - 11 cases, relative risk = 0.70; CI = 0.39 -1.29). No significant association between duration (1 – 4, 5 – 9, ≥ 10 years) of high-dose (300 IU and up) vitamin E supplement use and risk of colorectal cancer compared to non-vitamin E supplement users was observed in women (e.g., ≥ 10 years, 37 cases, relative risk = 0.87; CI = 0.61 - 1.22). A significant association was seen only among men who had used high-dose (300 IU and up) vitamin E supplements for 1 to 4 years (47 cases; relative risk = 0.71; CI = 0.52 - 0.98).

Gastric (Stomach) Cancer

FDA identified one high methodological quality prospective cohort study (Jacobs et al., 2002b) and one moderate methodological quality case-control study (Mayne et al., 2001) that evaluated the relationship between supplemental vitamin E and risk of gastric cancer incidence or mortality.

Jacobs et al. (2002b) was a prospective cohort study that followed 1,045,923[62] U.S. adult men and women in the Cancer Prevention Study II (CPS-II) from 1982-1998 to examine the association between gastric cancer mortality and regular use[63] of vitamin E supplements at enrollment. During the 16 years of follow-up, 1,725 cases of gastric cancer death occurred (1,127 in men and 598 in women). After adjustment of multiple potential gastric cancer risk factors, vitamin E supplement use was not statistically significantly associated with risk of gastric cancer mortality (130 deaths; relative risk = 1.02; CI = 0.82 - 1.27).

Mayne et al. (2001) was a multicenter case-control U.S. study of men and women (30 -79 years of age) who were diagnosed with gastric cancer from 1993 to early 1995. Based on 255 cases of gastric cardia cancer,[64] 352 cases of noncardia gastric cancer, and 687 controls, there was no statistically significant association between single vitamin E supplement use (at least once a week for 6 months or longer) and risk of gastric cardia cancer (cases = 34; odds ratio = 0.86; CI = 0.54 - 1.37) or noncardia gastric cancer (cases = 51; odds ratio = 0.88; CI = 0.58 - 1.33).

Lung Cancer

There were no observational studies from which scientific conclusions could be drawn about the relationship between vitamin E intake and risk of lung cancer.

Renal Cell Cancer

FDA identified one moderate methodological quality case-control study that evaluated the relationship between vitamin E supplement use and incidence of renal cell cancer (Hu et al., 2003).

Hu et al. (2003) was a case-control study that collected data on incident cases of renal cell cancer in Canadian men and women from the National Enhanced Cancer Surveillance System (NECSS). Overall, 1,279 (691 male and 588 female) histologically confirmed cases of renal cell carcinoma and 5,370 (2,696 male and 2,674 female) population controls were identified. The data were stratified by gender and duration of supplement use (1 -5 years or > 5 years). Among males, only those who were taking vitamin E for more than 5 years showed a statistically significant reduction in risk of renal cell cancer (50 cases; odds ratio = 0.7, CI = 0.5 - 0.9). However, among females, a statistically significant inverse association was observed between vitamin E supplement use and risk of renal cell cancer, regardless of duration of supplement use (1-5 years: 71 cases; odds ratio = 0.6, CI = 0.4 - 0.8; or > 5 years: 60 cases; odds ratio = 0.6, CI = 0.4 - 0.8).

III. Strength of the Scientific Evidence

Below, the agency rates the strength of the total body of publicly available evidence. The agency conducts this rating evaluation by considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), the methodological quality rating previously assigned, the number of studies and number of subjects per group, whether the body of scientific evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated[65], and the overall consistency[66] of the total body of evidence. Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support a qualified health claim for the substance/disease relationship and, if so, considers what qualifying language should be included to convey the limits on the level of scientific evidence supporting the relationship or to prevent the claim from being misleading in other ways.

Vitamin C

Colorectal Cancer

As discussed in section II, the evidence for a relationship between vitamin C intake and risk of colorectal cancer is based on one moderate methodological quality case-control study (Whelan et al., 1999).

Whelan et al. (1990) was a case-control study that evaluated the relationship between single vitamin C supplementation and the incidence of recurrent polyps in men and women (average age = 65.5 years). No statistically significant association between vitamin C intake and a decreased risk of polyp recurrence was observed. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C intake and reduced risk of colorectal cancer.

Squamous Cell Cancer of the Esophagus

As discussed in section II, the evidence for a relationship between vitamin C intake and risk of squamous cell cancer of the esophagus is based on one moderate methodological quality case-control study (Mayne et al., 2001).

This study reported no statistically significant association between vitamin C intake and risk of squamous cell cancer of the esophagus (26 cases) (Mayne et al., 2001). Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C intake and reduced risk of squamous cell cancer of the esophagus.

Gastric (Stomach) Cancer

As discussed in section II, the evidence for a relationship between vitamin C intake and risk of gastric cancer incidence or mortality is based on one high methodological quality prospective cohort study (Jacobs et al., 2002b) and one moderate methodological quality case-control study (Mayne et al., 2001).

Of the two above studies, Mayne et al. (2001) observed a statistically significant association between vitamin C supplement use and noncardia gastric cancer risk (62 cases), but not between vitamin C supplement use and gastric cardia cancer (47 cases). Jacobs et al. (2002b) reported no association between vitamin C supplement use at enrollment and risk of stomach cancer mortality (162 cases) unless the data were stratified by period of supplement use, in which case a statistically significant association between vitamin C intake and reduced risk of stomach cancer mortality was observed only in those who took supplements for less than ten years (66 cases).

The Mayne et al. (2001) study was retrospectively designed (case-control), while Jacob et al. (2002b) was a prospective cohort study with a much larger sample size. Prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.[67] The reported individual findings of Mayne et al. (2001) and Jacobs et al. (2002b) have not been replicated, and replication of scientific findings is important in order to substantiate results.[68] Furthermore, consistency of findings among similar and different study designs is important for evaluating the strength of the scientific evidence.[69]

Based on the above, FDA concludes that there is very limited credible evidence for a relationship between vitamin C supplement intake and reduced risk of gastric cancer and that the existence of a relationship between vitamin C supplement intake and reduced risk of gastric cancer is highly uncertain.

Laryngeal Cancer

As discussed in section II, there were no studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of laryngeal cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of laryngeal cancer.

Lung Cancer

As discussed in section II, there were no studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of lung cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of lung cancer.

Oral Cavity Cancer

As discussed in section II, the evidence for a relationship between supplemental vitamin C intake and the risk of oral cavity cancer incidence is based on one high methodological quality case-control study (Barone et al., 1992). The study reported no statistically significant association between vitamin C supplementation and risk of oral cavity cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of oral cavity cancer.

Pancreatic Cancer

As discussed in section II, there were no studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of pancreatic cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of pancreatic cancer.

Pharyngeal Cancer

As discussed in section II, there were no studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of pharyngeal cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of pharyngeal cancer.

Renal Cell Cancer

As discussed in section II, the evidence for a relationship between vitamin C intake and risk of renal cell cancer is based on one moderate methodological quality case-control study (Hu et al., 2003). This case-control study found that there was no statistically significant association between vitamin C supplement intake and risk of renal cell cancer (Hu et al., 2003). Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of renal cell cancer.

Salivary Glands Cancer

As discussed in section II, there were no studies from which scientific conclusions could be drawn about the relationship between vitamin C intake and risk of salivary glands cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin C supplement intake and reduced risk of cancer of salivary glands.

Vitamin E

Bladder Cancer

As discussed in section II, the evidence for a relationship between vitamin E intake and risk of bladder cancer incidence or mortality is based on one high methodological quality prospective cohort study (Jacobs et al., 2002a) and two moderate methodological quality prospective cohort studies (Holick et al., 2005; Michaud et al., 2000).

Of the three above studies, two studies reported no statistically significant association between vitamin E supplement use and bladder cancer incidence in men (27 cases) or women (9 cases) even when subjects reported taking supplements for more than 10 years (Michaud et al., 2000; Holick et al., 2005). The third study showed a reduction in bladder cancer mortality in those (men and women combined) who took vitamin E supplements for 10 years or more (24 cases), but no statistically significant relationship was observed in those who took vitamin E supplements for a shorter duration of time (< 10 years; 60 cases) (Jacobs et al., 2002a). However, when data were stratified by gender, no significant association was observed between vitamin E supplement use (regardless of duration) and risk reduction of bladder cancer mortality.

The reported findings of Jacobs et al. (2002a) have not been replicated, and replication of scientific findings is important in order to substantiate results.[70] Furthermore, consistency of findings among similar and different study designs is important for evaluating the strength of the scientific evidence.[71]

Based on the above, FDA finds that there is very limited credible evidence for a relationship between vitamin E supplement intake and bladder cancer and that the existence of a relationship between vitamin E supplement intake and reduced risk of bladder cancer is highly unlikely.

Brain Cancer

As discussed in Section II, there were no studies that evaluated the relationship between vitamin E intake and risk of brain cancer. Therefore, FDA concludes that there is no credible evidence for a claim about vitamin E supplement intake and reduced risk of brain cancer.

Cervical Cancer

As discussed in Section II, there were no studies that evaluated the relationship between vitamin E intake and risk of cervical cancer. Based on the above, FDA concludes that there is no credible evidence for a claim about vitamin E supplement intake and reduced risk of cervical cancer.

Colorectal Cancer

As discussed in Section II, the evidence for a relationship between vitamin E intake and risk of colorectal cancer or recurrent polyps is based on four observational studies (Whelan et al., 1999; White et al., 1997; and the Nurses’ Health Study and Health Professionals Follow-Up Study (2 studies evaluated in Wu et al., 2002)).

One high quality prospective cohort study showed a statistically significant association between the risk of colorectal cancer incidence and high-dose vitamin E supplement use (300 IU and up) for shorter durations (1-4 years) in men only (47 cases) (Health Professionals Follow-Up Study, evaluated in Wu et al., 2002). The two moderate quality case control studies in both men and women showed a statistically significant association between vitamin E supplement use and incidence of colorectal cancer (26 cases) (White et al., 1997) or polyp recurrence (34 cases) (Whelan et al., 1999).

The White et al. (1997) and Whelan et al. (1999) studies were retrospectively designed, while the two studies evaluated in Wu et al. (2002) were prospective cohort studies with a much larger sample size. Prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.[72] The Health Professionals Follow-Up Study, evaluated in the Wu et al. article (2002), did not observe any significant association between longer-duration supplement use (5 years and up) and colorectal cancer incidence in men. Furthermore, the Nurses’ Health Study, evaluated in the Wu et al. article (2002), observed no statistically significant association between vitamin E supplement use and reduced risk of colorectal cancer in women, regardless of supplement dose or duration of use. The reported findings of Wu et al. (2002) have not been replicated, and replication of scientific findings is important in order to substantiate results.[73] Consistency of findings among similar and different study designs is important for evaluating the strength of the scientific evidence.[74]

Based on the above, FDA concludes that there is very limited credible evidence for a qualified health claim about vitamin E supplement intake and colorectal cancer risk. Furthermore, based on the strength of the credible evidence, the agency concludes that the relationship between vitamin E supplement intake and reduced risk of colorectal cancer is highly unlikely.

Gastric (Stomach) Cancer

As discussed in section II, the evidence for a relationship between vitamin E intake and risk of gastric cancer incidence or mortality is based on one high methodological quality prospective cohort study (Jacobs et al., 2002b) and one moderate methodological quality case-control study (Mayne et al., 2001).

Jacobs et al. (2002b) did not observe a statistically significant relationship between vitamin E supplement intake and the risk of stomach cancer mortality (130 cases). The case-control study, based on 255 cases of gastric cardia cancer and 352 cases of noncardia gastric cancer, also did not observe a statistically significant association between vitamin E supplement use and gastric cardia cancer or noncardia gastric cancer (Mayne et al., 2001). Therefore, FDA concludes that there is no credible evidence for a claim about vitamin E supplement intake and reduced risk of gastric cancer.

Lung Cancer

As discussed in section II, the evidence for a relationship between vitamin E intake and risk of lung cancer is based on one intervention study (Albanes et al., 1996) and one post-intervention follow-up trial (Virtamo et al., 2003).

Albanes et al. (1996) was a high quality randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol (50 mg) would reduce the incidence of lung cancer across subgroups of participants in the ATBC study. No overall statistically significant effect on the incidence of lung cancer was observed with vitamin E supplementation. Furthermore, the 6-year post-trial follow-up did not show any statistically significant late preventive effects of vitamin E on lung cancer (Virtamo et al., 2003).

Based on the above, FDA concludes that there is no credible evidence for a claim about vitamin E supplement intake and reduced risk of lung cancer.

Renal Cell Cancer

As discussed in section II, the evidence for a relationship between vitamin E intake and risk of renal cell cancer is based on one moderate methodological quality case-control study (Hu et al., 2003).

This case-control study reported a beneficial relationship between vitamin E intake and risk of renal cell cancer in women (131 cases), regardless of duration of vitamin use (Hu et al., 2003). For men (139 cases), however, the negative association was seen only in those who took vitamin E supplements for more than 5 years (n =50).

The findings by Hu et al. (2003) have not been replicated, and replication of scientific findings is important in order to substantiate results.[75] Because there is only one observational study in support of the claim, there is very little data from which to conclude whether such a relationship actually exists.

Based on the above, FDA concludes that there is very limited credible evidence for a relationship between vitamin E intake and risk of renal cell cancer and that the existence of a relationship between vitamin E supplement intake and reduced risk of renal cell cancer is highly uncertain.

IV. Other Enforcement Discretion Factors

A qualified health claim on the label or in the labeling of vitamin C or vitamin E dietary supplements is required to meet all applicable statutory and regulatory requirements under the Act, with the exception of the requirement that a health claim meet the significant scientific agreement standard and the requirement that the claim be made in accordance with an authorizing regulation.

Qualifying level of vitamins C and E in dietary supplements

The general requirements for health claims provide that, if the claim is about the effects of consuming the substance at other than decreased dietary levels, the level of the substance must be sufficiently high and in an appropriate form to justify the claim. Where no definition for “high” has been established, the claim must specify the daily dietary intake necessary to achieve the claimed effect (see 21 CFR 101.14(d)(2)(vii)).

Since a “high” definition is established for both vitamins C and E as defined in 21 CFR 101.54(b), which is 20 percent or more of the RDI for vitamins C and E, the agency intends to consider exercising enforcement discretion for dietary supplements bearing a qualified health claim about vitamin C and reduced risk of gastric (stomach) cancer when the dietary supplement contains vitamin C at a level that meets or exceeds the requirement for a “high” level of vitamin C. The agency also intends to consider exercising enforcement discretion for dietary supplements bearing a qualified health claim about vitamin E and reduced risk of bladder cancer, colorectal cancer, or renal cell cancer when the dietary supplement contains vitamin E at a level that meets or exceeds the requirement for a “high” level of vitamin E. A “high” level of vitamin C, based on the current RDI, is 12 mg or more per reference amount customarily consumed under the current regulation, and the “high” level of vitamin E is 6 IU or more per reference amount customarily consumed under the current regulation.

As discussed in section I.C. of this letter, the range of intakes recommended on the labels of most dietary supplements containing vitamin C is 30 to 1,000 mg per day. The combined daily intake of vitamin C from such supplements and dietary sources would be below the level determined by the IOM to pose possible adverse health effects. Therefore, FDA intends to exercise enforcement discretion for qualified health claims about supplemental vitamin C and gastric (stomach) cancer on dietary supplements that recommend an intake of 1,000 mg or less of vitamin C per day. The range of intakes recommended on the labels of dietary supplements containing vitamin E is 6.75 to 670 mg of alpha-tocopherol per day, and the combined daily intake of vitamin E from such supplements and dietary sources would also be below the level determined by the IOM to pose possible adverse health effects. Therefore, FDA intends to exercise enforcement discretion for qualified health claims about supplemental vitamin E and bladder, colorectal, or renal cell cancer on dietary supplements that recommend an intake of 670 mg or less of alpha-tocopherol per day.

V. Agency’s Consideration of Disclaimers or Qualifying Language

FDA considered but rejected use of a disclaimer or qualifying language to accompany the proposed claims for which we found no credible evidence for a relationship between vitamins C or E and certain site-specific cancers. There was no credible evidence for consumption of vitamin C from dietary supplements and reduced risk of colorectal cancer, laryngeal cancer, lung cancer, oral cavity cancer, pancreatic cancer, pharyngeal cancer, renal cell cancer, salivary glands cancer or squamous cell cancer. There also was no credible evidence for consumption of vitamin E from dietary supplements and reduced risk of brain cancer, cervical cancer, gastric (stomach) cancer, or lung cancer. FDA concluded that neither a disclaimer nor qualifying language would suffice to prevent consumer deception in these instances, where there is no credible evidence to support the claims. Adding a disclaimer or incorporating qualifying language that effectively characterizes the claim as baseless is not a viable regulatory alternative because neither the disclaimer nor the qualifying language can rectify the message conveyed by the unsubstantiated claim. See, e.g., In re Warner-Lambert Co., 86 F.T.C. 1398, 1414 (1975), aff’d, 562 F.2d 749 (D.C. Cir. 1977) (pro forma statements of no absolute prevention followed by promises of fewer colds did not cure or correct the false message that Listerine will prevent colds); Novartis Consumer Health, Inc. v. Johnson & Johnson-Merck Consumer Pharms. Co., 290 F.3d 578, 598 (3d Cir. 2002) (“We do not believe that a disclaimer can rectify a product name that necessarily conveys a false message to the consumer”); Pearson v. Shalala, 164 F.3d 650, 659 (D.C. Cir. 1999) (the court stated that, where the weight of the evidence was against the claim, FDA could rationally conclude that the disclaimer “The FDA has determined that no evidence supports this claim” would not cure the misleadingness of a claim). In such a situation, adding a disclaimer or qualifying language does not provide additional information to help consumer understanding but merely contradicts the claim. Resort Car Rental System, Inc. v. FTC, 518 F.2d 962, 964 (9th Cir.) (per curiam) (upholding FTC order to excise “Dollar a Day” trade name as deceptive because “by its nature [it] has a decisive connotation for which any qualifying language would result in a contradiction in terms”), cert denied, 423 U.S. 827 (1975); Continental Wax Corp. v. FTC, 330 F.2d 475, 480 (2d Cir. 1964) (same); Pasadena Research Labs v. United States, 169 F.2d 375 (9th Cir. 1948) (discussing “self-contradictory labels”). In the FDA context, courts have repeatedly found such disclaimers ineffective. See, e.g., United States v. Millpax, Inc., 313 F.2d 152, 154 & n.1 (7th Cir. 1963) (disclaimer stating that “no claim is made that the product cures anything, either by the writer or the manufacturer” was ineffective where testimonials in a magazine article promoted the product as a cancer cure); United States v. Kasz Enters., Inc., 855 F. Supp. 534, 543 (D.R.I.) (“The intent and effect of the FDCA in protecting consumers from . . . claims that have not been supported by competent scientific proof cannot be circumvented by linguistic game-playing”), judgment amended on other grounds, 862 F. Supp. 717 (1994).

VI. Conclusions

Based on FDA’s consideration of the scientific evidence submitted with the petition and other pertinent scientific evidence, FDA concludes that there is no credible evidence to support qualified health claims for vitamin C and a reduced risk of colon cancer, laryngeal cancer, lung cancer, oral cavity cancer, pancreatic cancer, pharyngeal cancer, renal cell cancer, salivary glands cancer, and squamous cell cancer of the esophagus. Thus, FDA is denying claims specific to vitamin C and these cancers. FDA also concludes that there is no credible evidence to support qualified health claims for vitamin E and a reduced risk of brain, cervical, gastric, and lung cancers. Thus, FDA is denying claims specific to vitamin E and these cancers. However, FDA concludes that there is very limited credible evidence for a qualified health claim for vitamin C dietary supplements and gastric cancer, provided that the qualified claim is appropriately worded so as to not mislead consumers. Furthermore, FDA concludes that there is very limited credible evidence for qualified health claims for vitamin E dietary supplements and bladder, colorectal, and renal cell cancers, provided that the qualified claims are appropriately worded so as to not mislead consumers.

Thus, FDA intends to consider exercising its enforcement discretion for the following qualified health claims:

  1. Vitamin C
  2. Gastric (Stomach) Cancer
    “One weak study and one study with inconsistent results suggest that vitamin C supplements may reduce the risk of gastric cancer. Based on these studies, FDA concludes that it is highly uncertain that vitamin C supplements reduce the risk of gastric cancer.”
  3. Vitamin E
  4. Bladder Cancer
    “One small study suggests that vitamin E supplements may reduce the risk of bladder cancer. However, two small studies showed no reduction of risk. Based on these studies, FDA concludes that it is highly unlikely that vitamin E supplements reduce the risk of bladder cancer.”
  5. Colorectal Cancer
    “Two weak studies and one study with inconsistent results suggest that vitamin E supplements may reduce the risk of colorectal cancer. However, another limited study showed no reduction of risk. Based on these studies, FDA concludes that it is highly unlikely that vitamin E supplements reduce the risk of colorectal cancer.”
  6. Renal Cell Cancer
    “One weak and limited study suggests that vitamin E supplements may reduce the risk of renal cell cancer. FDA concludes that it is highly uncertain that vitamin E supplements reduce the risk of renal cell cancer.”

FDA intends to consider exercising its enforcement discretion for the above qualified health claims when all factors for enforcement discretion identified in Section IV of this letter are met.

Please note that scientific information is subject to change, as are consumer consumption patterns. FDA intends to evaluate new information that becomes available to determine whether it necessitates a change in this decision. For example, scientific evidence may become available that will support significant scientific agreement, that will support a qualified health claim for those claims that were denied, that will no longer support the use of the above qualified health claims, or that may raise safety concerns about the substances that are the subject of the claims.

Sincerely,

 

Barbara O. Schneeman, Ph.D.
Director, Office of Nutrition, Labeling
and Dietary Supplements
Center for Food Safety and Applied Nutrition

 

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Appendix 1

Please see Docket # FDA-2008-Q-0299 for the following studies and documents. The parenthetical indicates the source of the study or document (i.e., Petition (P) and FDA (F)).

Animal studies

Kaul et al., 1998 (P)

In Vitro studies

Zhang et al., 2002 (P) Onogi et al., 1998 (P)
Cooney et al., 1993 (P) Shigenaga et al., 1990 (P)
Lima et al., 2008 (P)  

News releases/editorials/commentary

Benner and Hng 1993b (P) Marnett et al., 1987 (P)
Ennever and Paskett 1993 (P)  

Review Articles

Ames, 1983 (P) Patterson et al., 1997 (P)
Block et al., 1992 (P) Ramakrishnan et al., 2007 (P)
Cerutti et al., 1994 (P) Shklar et al., 2000 (P)
Kamat and Lamm 1999 (P) Wattenberg et al., 1990 (P)
Kappus and Diplock 1992 (P) Young and Lee 1999 (P)
Newberne et al., 1990 (P)  

Pooled or Meta analysis

Cho et al., 2006 (P)
Bardia et al., 2008 (P)

Studies measured endpoints other than surrogate endpoints of cancer risk

Intervention Studies

Benner et al., 1993a (P) Kaugars et al., 1994 (F)
Cahill et al., 1993 (P) Kamangar et al., 2006 (P)
Correa et al., 2000 (P) Paganelli et al., 1992 (P)
De Sanjose et al., 1996 (F) Zaridze et al., 1993 (P)
Henning et al., 1991 (P)  

Observational Studies

Dabrowska-Ufniarz et al., 2002 (P)

Intervention studies that included post hoc analysis of secondary cancers

ATBC, 1994, (P) Lonn et al., 2005 (The HOPE and HOPE-Too Trial) (P)
Albanes et al., 2000 (F) Malila et al., 1999 (F)
Gaziano et al., 2009 (F) Malila et al., 2002b (P)
Hercberg et al., 2004 (F) Varis et al., 1998 (P)
Heart Protection Study Collaboration Group 2002 (F) Virtamo et al., 2000 (P)
Lee et al., 2005 (P) Virtamo et al., 2003 (F)
Lippman et al., (2009 (F)  

Vitamins E and/or C deficient population / high risk / not possible to apply to the general US population

Intervention Studies

Blot et al., 1993 (P) Taylor et al., 1994 (F)
Dawsey et al., 1994 (F) Wang et al., 1994 (F)
Li et al., 1993 (P)  

Intervention studies conducted on subjects who were not cancer-free or had genetic predisposition

DeCosse et al., 1989 (F)

Intervention studies with low quality design

Roncucci et al., 1993 (P) (also used multi-nutrient supplements)

Intervention studies used multi-nutrient supplements

Hofstad et al., 1998 (F)

Observational studies that evaluated different substance or site-specific cancers than requested in the proposed claims

Bala et al., 2001(P) Landa et al., 1994 (P)
Bohlke et al., 1999 (P) Mannisto et al., 1999 (P)
Deneo-Pellegrini et al., 1999 (P) Negri et al., 1996 (P)
Eichholzer et al., 1999 (P) Ronco et al., 1999 (P)
Favero et al., 1998 (P) Torun et al., 1995 (P)
Hunter et al., 1993 (P) Yuan et al., 1995 (P)
Jumaan et al., 1999 (P) Zhang et al., 1999 (P)

Observational studies conducted inappropriate/or no statistical analysis

Terry et al., 2000 (P) Ziegler et al., 1990 (F)
Yong et al, 1997 (P)  

Observational studies that estimated supplemental vitamin E or C from various supplement sources (multi-nutrients plus single nutrient)

Bostick, et al., 1993 (P) Shibata et al., 1992 (P)
Brown et al., 1998 (P) Silverman et al., 1998 (P)
Bruemmer et al., 1996 (P) Slatore et al., 2007 (P)
Dong et al., 2008 (F) Voorrips et al., 2000 (P)
Gridley et al., 1992 (P) Zeegers et al., 2001 (F)
Hansson et al., 1994 (P) Zheng et al., 1995 (F)
Preston-Martin et al., 1998 (P)  

Observational studies that estimated vitamins E and/or C intake from dietary sources intake

Bandera et al., 1997 (P) La Vecchia et al., 1995 (P)
Boeing et al., 1991 (P) La Vecchia et al., 1997 (P)
Boeing et al., 1997 (P) Lee et al., 1998 (P)
Bollschweiler et al., 2002 (P) Le Marchand et al., 1989 (P)
Botterweck et al., 2000 (P) Le Marchand et al., 1995 (P)
Buiatti et al., 1989 (P) Lindblad et al., 1997 (P)
Buiatti et al., 1990 (P) Lopez-Carrillo et al., 1999 (P)
Chiu et al., 2003 (P) Lysy et al., 1996 (P)
Chow et al., 1992 (F) McLaughlin et al., 1988 (P)
De Lorgeril et al., 1998 (P) Michaud et al., 2002 (P)
De Stefani et al., 1999 (P) Murtaugh et al., 2004 (P)
De Stefani et al., 2000 (P) Negri et al., 2000 (P)
De Stefani et al., 2002 (P) Neuhouser et al., 2003 (P)
De Stefani et al., 2006 (P) Nouraie et al., 2005 (P)
De Stefani et al., 2007 (P) Ocke et al., 1997 (P)
Enger et al., 1996 (F) Olsen et al., 1994 (P)
Ekstrom et al., 2000 (P) Pandey et al., 1995 (P)
Farrow et al., 1990 (F) Qiu et al., 2005 (P)
Ferraroni et al., 1994 (P) Ramon et al., 1993 (P)
Feskanich et al., 2000 (P) Riboli et al., 1991 (P)
Fontham et al., 1988 (P) Satia-Abouta et al., 2003 (P)
Freudenheim et al., 1990 (P) Satia et al., 2005 (P)
Genkinger et al., 2004 (P) Shibata et al., 1994 (P)
Gonzalez et al., 1994 (P) Sichieri et al., 1996 (P)
Harrison et al., 1997 (P) Smigel et al., 1993 (P)
Herrero et al., 1991 (P) Steinmetz et al., 1993 (P)
Hertog et al., 1996 (P) Stolzenberg-Solomon et al., 2002 (P)
Horn-Ross et al., 1997 (P) Suzuki et al., 2006 (P)
Hu et al., 1994 (P) VanEenwyk et al., 1991 (P)
Hu et al., 1999 (P) Vena et al., 1992 (F)
Ji et al., 1995 (P) Verreault et al., 1989 (P)
Ji et al., 1998 (P) Wideroff et al., 1998 (P)
Kaaks et al., 1998 (P) Wright et al., 2004 (P)
Kim et al., 2005 (P) You et al., 1988 (P)
Knekt et al., 1991a (P) Yong et al., 1997 (P)
Kune et al., 1993 (P) Zatonski et al., 1991 (F)
Lagiou et al., 2004 (P) Zhang et al., 1997 (P)
Launoy et al., 1998 (P) Zheng et al., 1992a (P)
La Vecchia et al., 1988 (P) Zheng et al., 1992b (P)
La Vecchia et al., 1994 (P)  

Observational studies that used blood vitamins E and/or C as a biomarker of intake

Batieha et al., 1993 (P) Knekt et al., 1988c (F)
Battisti et al., 2000 (P) Knekt et al., 1991b (F)
Breuer-Katschinski et al., 2001 (F) Knekt et al., 1993 (P)
Buijsse et al., 2005 (P) Kumagai et al., 1998 (P)
Charpiot et al., 1989 (P) LeGardeur et al., 1990 (P)
Chen et al., 1992 (P) Lehtinen et al., 1999 (P)
Comstock et al., 1991 (P) Longnecker et al., 1992 (F)
Comstock et al., 1997 (P) Loria et al., 2000 (P)
Cuzick et al., 1990 (P) Malila et al., 2002a (F)
Eichholzer et al., 1992 (F) Menkes et al., 1986 (P)
Eichholzer et al., 1996 (P) Palan et al., 1996 (P)
Gackowski et al., 2005 (P) Ratnasinghe et al., 2000 (P)
Giuliano et al., 1997 (F) Schober et al., 1987 (F)
Goodman et al., 1998 (P) Stahelin et al., 1987 (F)
Goodman et al., 2003 (P) Stryker et al., 1990 (P)
Goodman et al., 2007 (P) Taylor et al., 2003 (P)
Harris et al., 1991 (P) Tsubono et al., 1999 (P)
Ho et al., 1998 (P) Webb et al., 1997 (P)
Ito et al., 2005a (P) Woodson et al., 1999 (P)
Ito et al., 2005b (P) Wright et al., 2006 (P)
Jenab et al., 2006a (P) Yalcin et al., 2004 (P)
Jenab et al., 2006b (P) You et al., 2000 (P)
Knekt et al., 1988a (P) Yuan et al., 2004 (P)
Knekt et al., 1988b (P) Zhang et al., 1994 (P)

 


Notes

[1] “Interim Procedures for Qualified Health Claims in the Labeling of Conventional Human Food and Human Dietary Supplements” (July 10, 2003), http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/ GuidanceDocuments/FoodLabelingNutrition/ucm053832.htm.

[2] Cancer that begins in the colon (the longest part of the large intestine) is called colon cancer, and cancer that begins in the rectum (the last several inches of the large intestine) is called rectal cancer. Cancer that affects either of these organs may also be called colorectal cancer (www.cancer.gov; “Colorectal Cancer Prevention”). The National Cancer Institute (NCI) often reports colon or rectal cancer as colorectal cancer, and the risk factors and genetic factors that are identified with each of these cancers are not reported to be different. Also, the clinical trials conducted by the NCI combine these two cancers together as colorectal cancer. With respect to the proposed claims for colon and rectal cancer, the majority of the studies from which conclusions could be drawn did not differentiate between colon and rectal cancers. Therefore, the agency evaluated colon and rectal cancer together. Colorectal polyp recurrence has been used as a surrogate endpoint for colorectal cancer risk by the scientific community and has been used by NCI as a surrogate endpoint for colorectal cancer risk (Schatzkin et al., 1994).

[3]See Whitaker v. Thompson, 353 F.3d 947, 950-51 (D.C. Cir 2004) (upholding FDA’s interpretation of what constitutes a health claim), cert. denied, 125 S. Ct. 310 (2004).

[4]See Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims January 2009, http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/ GuidanceDocuments/FoodLabelingNutrition/ucm073332.htm.

[5]For brevity, “disease” will be used as shorthand for “disease or health-related condition” in the rest of the section.

[6]In an intervention study, subjects similar to each other are randomly assigned to either receive the intervention or not to receive the intervention, whereas in an observational study, the subjects (or their medical records) are observed for a certain outcome (i.e., disease). Intervention studies provide the strongest evidence for an effect. See supra, note 4.

[7]A meta-analysis is the process of systematically combining and evaluating the results of clinical trials that have been completed or terminated (Spilker, 1991).

[8]Review articles summarize the findings of individual studies.

[9]Other examples include book chapters, abstracts, letters to the editor, and committee reports.

[10]Certain meta-analyses may be used as part of the health-claim review process. See supra, note 4.

[11]See supra, note 4.

[12]Replication of scientific findings is important for evaluating the strength of scientific evidence (An Introduction to Scientific Research, E. Bright Wilson Jr., pages 46-48, Dover Publications, 1990).

[13]Consistency of findings among similar and different study designs is important for evaluating causation and the strength of scientific evidence (Hill A.B. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300); See also Systems to Rate the Scientific Evidence, Agency for Healthcare Research and Quality http://www.ahrq.gov/clinic/epcsums/strengthsum.htm#Contents, defining “consistency” as “the extent to which similar findings are reported using similar and different study designs.”

[14]See supra, note 4.

[15]The other forms of vitamin E do not contribute towards meeting the vitamin E requirement because, although absorbed, they are not converted to alpha-tocopherol in humans and are recognized poorly by the alpha-tocopherol transfer protein in the liver (IOM, 2008, chapter 6).

[16]The term “dietary ingredient” is defined in section 201(ff)(1) of the Act (21 U.S.C. § 321(ff)(1)) and includes vitamins; minerals; herbs and other botanicals; dietary substances for use by man to supplement the diet by increasing the total daily intake; and concentrates, metabolites, constituents, extracts, and combinations of the preceding types of ingredients.

[17]Examples include vitamins, minerals, botanicals, amino acids, and enzymes.

[18]Multivitamin/multiminerals as used in this paper (Radimer, et al. 2004) means the supplement contains 3 or more vitamins, with or without 1 or more minerals.

[19]The term “vitamin C supplement” as described in the study Radimer, et al. 2004 means a specifically named single vitamin (in this case, vitamin C), which may include other ingredients. Examples include vitamin C with rose hips and vitamin C with citrus bioflavonoid complex.

[20]Memorandum to the file, “Determination of Amounts of Vitamins C and E in Common Dietary Supplement Products”, prepared by Jill Kevala, November 20, 2008. For purposes of this letter, the term “vitamin C-containing supplement” means a dietary supplement that contains only vitamin C or vitamin C with other non-vitamin ingredients.

[21]See supra, note 20.

[22]See supra, note 20.

[23]See supra, note 20.

[24]See supra, note 20.

[25]See supra, note 20.

[26]Based upon conversion factors identified in the 2000 IOM Report, this equates to about 1500 IU of natural vitamin E or about 2200 IU of synthetic (all racemic) vitamin E. The conversion factors are as follows: (mg of alpha-tocopherol in food, fortified food, or multivitamin = 0.67 X IU of the RRR-α-tocopherol or = 0.45 X IU of the all rac-α-tocopherol]) (IOM, 2000, Chapter 6).

[27]The term “vitamin E supplements” as in the study cited (Radimer, et al. 2004) means a specifically named single vitamin (in this case, vitamin E), which may include other ingredients. Examples include vitamin E with selenium and vitamin E with primrose oil.

[28]See supra, note 20. For purposes of this letter, the term “vitamin E-containing supplement” means a dietary supplement that contains only vitamin E or vitamin E with other non-vitamin ingredients.

[29]See supra, note 20.

[30]See supra, note 20.

[31]See supra, note 20.

[32]See supra, note 20.

[33]An adenomatous polyp is a noncancerous polyp that starts in gland-like cells of the epithelial tissue (thin layer of tissue that covers organs, glands, and other structures within the body). College of American Pathologists [http://www.cap.org/apps/docs/reference/myBiopsy/ColonAdenomatous.html].

[34]A polyp is defined as a growth that protrudes from a mucous membrane. National Cancer Institute, Dictionary of Cancer Terms [http://www.cancer.gov/dictionary/].

[35]In this section, significant flaws in the reports of intervention studies from which scientific conclusions could not be drawn are generally discussed. Such studies may have other flaws in addition to those specifically mentioned, such as flaws related to the use of multi-nutrient dietary supplements in the intervention group.

[36]Bias is defined as the result of systematic error in the design or conduct of a study. There are many forms of bias that can influence the interpretation of data (Spilker, B., Guide to Clinical Studies, pages 612-636, Raven Press, 1991). As a consequence of bias, the observed results of a study may be different from the true results (Epidemiology Beyond the Basics, pages 125-126, Aspen Publishing, 2000).

[37]These two studies investigated the relationship between vitamin E and lung cancer (primary outcome), as well as secondary outcomes (other cancers). They are both included for evaluating the relationship between vitamin E and lung cancer (under vitamin E, this section).

[38]Intervention studies screen for prevalent cases of the disease (“primary” endpoints) at the beginning of the study to minimize bias. Intervention studies may evaluate the outcomes of other diseases as “secondary” endpoints but do not screen for these diseases at the onset of the study.

[39]Esophageal and gastric cancers have been considered as a single clinical endpoint for incidence and mortality rate calculations in Linxian. The reason for the clustering of esophageal/gastric cancer in Linxian is unknown (Blot et al., 1993).

[40]The precise etiology of gastric cancer is unknown; however, two factors, high salt intake and Helicobacter pylori (H. pylori) infection, are associated with an increased risk of the disease and are external risk factors of gastric cancer. High salt intake and the incidence of H. Pylori infection are more prevalent in China and Japan than in the United States (Hohenberger et al., 2003; Key et al., 2004).

[41]These endpoints included rectal or colonic crept cell proliferation, regression or progression of oral leukoplakia and esophagitis, H. pylori seropositivity, progression or regression of the gastric precancerous process (multifocal nonmetaplastic atrophy and intestinal metaplasia), plasma and gastric juice antioxidant levels, and glutathione blood levels and other oxidant defense indices.

[42]Familial adenomatous polyposis (FAP) is a rare inherited disorder characterized by early onset of hundreds of adenomatous polyps of the colon and rectum. Unless FAP is treated, it usually leads to colorectal cancer by age 40. FAP accounts for less than 1 percent of all colorectal cancer cases. (http://www.cancer.gov/cancertopics/wyntk/colon-and-rectal/page4).

[43]See supra, note 2.

[44]Cancer that begins in the esophagus is divided into two major types, squamous cell carcinoma and adenocarcinoma, depending on the type of cells that are malignant. Squamous cell carcinomas arise in squamous cells that line the esophagus. These cancers usually occur in the upper part of the esophagus. Adenocarcinoma usually develops in the glandular tissue in the lower part of the esophagus. (National Cancer Institute, “What You Need to Know About Cancer of the Esophagus”; http://www.cancer.gov/cancertopics/wyntk/esophagus/page4).

[45]See supra, note 2.

[46]Relative risk (RR) is expressed as the ratio of the risk (incidence) in exposed individuals to that in unexposed individuals (Epidemiology Beyond the Basics, page 93, Aspen Publishers, 2000). It is calculated in observational studies by measuring exposure (e.g., vitamin C supplements) in subjects with and without disease (e.g., specific type of cancer). An adjusted relative risk controls for potential confounders.

[47]Confidence intervals provide a statistical analysis of relative risk. 95% Confidence intervals that include 1.0 are not statistically significant.

[48]Vitamin E supplements are generally synthetic forms of alpha-tocopherol (Mayne, 2003).

[49]Although both alpha and gamma tocopherols are absorbed, only alpha-tocopherol is preferentially secreted by the liver into the plasma for transport to tissues, while gamma-tocopherol is preferentially metabolized and excreted in the urine (IOM, 2000, Chapter 6).

[50]Correlation coefficients range from -1 (negative correlation) through +1 (positive correlation). The closer the coefficient is to one, the stronger the correlation; the closer it is to zero, the weaker the correlation.

[51]In this section, significant flaws in the reports of observational studies from which scientific conclusions could not be drawn are generally discussed. Such studies may have other flaws in addition to those specifically mentioned, including studying populations that are not relevant to the general U.S. population (e.g., malnourished populations or populations that have risk factors of a specific disease that are not relevant to disease risk in the U.S.), failure to provide adequate statistical analysis (e.g., failing to provide confidence intervals), failure to adjust data for appropriate confounders (e.g., serum lipids or smoking); or measuring blood vitamin E and C concentrations in people already diagnosed with cancer.

[52]See supra, note 44.

[53]In a case-control study, a group of cases are identified as the individuals in whom the disease of interest was diagnosed during a given year and controls are selected from individuals who do not have the disease in the same time period (Epidemiology Beyond the Basics, page 29, Aspen Publishers, 2000).

[54]The odds ratio reflects the odds of developing a disease in exposed compared to unexposed individuals (Epidemiology Beyond the Basics, page 29, Aspen Publishers, 2000). It is calculated in case-control studies by measuring disease (e.g., specific type of cancer) development in subjects based on exposure (e.g., vitamin C).

[55]This cohort excluded those with a history of cancer other than non-melanoma skin cancer and those with no data on vitamin supplement use.

[56]Participants reporting use of vitamin C or vitamin E supplements 15 or more times a month were categorized as “regular” users of that vitamin supplement.

[57]The two different types of gastric cancer are gastric cardia cancer and noncardia gastric cancer. The gastric cardia is the upper portion of stomach (closest to the esophagus) (American Cancer Society, “What Is Stomach Cancer?”, http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_stomach_cancer_40.asp).

[58]Kidney cancer includes renal cell carcinoma (cancer that forms in the lining of very small tubes in the kidney that filter the blood and remove waste products) and renal pelvis carcinoma (cancer that forms in the center of the kidney where urine collects) (National Cancer Institute, “What You Need to Know About Kidney Cancer,” http://www.cancer.gov/cancertopics/types/kidney).

[59]This cohort excluded those with a history of cancer other than non-melanoma skin cancer and those with no data on vitamin supplement use or cigarette smoking.

[60]See supra, note 56

[61]Low-dose vitamin E supplement users (≤ 250 IU supplementation per day) were excluded from the analysis.

[62]See supra, note 55

[63]See supra, note 56

[64]See supra, note 57

[65]See supra, note 12

[66]See supra, note 13

[67]See supra, note 36

[68]See supra, note 12

[69]See supra, note 13

[70]See supra, note 12

[71]See supra, note 13

[72]See supra, note 36

[73]See supra, note 12

[74]See supra, note 13

[75]See supra, note 12