PETITIONERS:      Julian M. Whitaker, MD; Durk Pearson and Sandy Shaw; American
     Preventive Medical Association; and Pure Encapsulations, Inc.

ADDRESS:
     c/o Emord & Associates, P.C.
     1050 Seventeenth Street, NW, Suite 600
     Washington, DC 20036

SUBJECT:
     Petition for Health Claim: Vitamin E Dietary Supplements and Heart Disease

Food and Drug Administration

Office of Food Labeling (HFS-150)

200 C Street, SW

Washington, DC 20204

1. Introduction and Statement of Purpose

The undersigned, Julian M. Whitaker, M.D.; Durk Pearson and Sandy Shaw; the American Preventive Medical Association; and Pure Encapsulations, Inc. (collectively, "Petitioners"), pursuant to Section 403 (r)(5)(D) of the Federal Food, Drug & Cosmetic Act (FDCA) (21 USC § 343(r)(5)(D)), submit this petition for a health claim concerning the relationship between the consumption of vitamin E dietary supplements and heart disease. Attached hereto, and constituting a part of this petition, are all of the items specified in 21 CFR § 101.70 (f). The text of the proposed model claim is set forth in section IV of this petition.

Petitioners believe this petition represents a logical and valid evaluation of the scientific studies and clinical trials concerning the relationship between vitamin E and heart disease. Those studies demonstrate that: (1) LDL oxidation increases cardiovascular disease risk, (2) increased consumption of vitamin E inhibits LDL oxidation, and (3) increased consumption of vitamin E, with attendant inhibition of LDL oxidation and platelet adhesion, thus lowers cardiovascular disease risk. The scientific evidence justifies permitting a health claim that links consumption of vitamin E with a reduction in cardiovascular disease risk (See, Pryor Report, Attachment 2).

Such a health claim directly responds to a major public health concern in the United States: cardiovascular disease accounts for more deaths per year than any other disease or group of diseases. 21 CFR § 101.75(b). Moreover, vitamin E offers a safe, inexpensive, readily accessible means for reducing cardiovascular disease risks population wide. (Davey (1998) and Bendich (1997)). Risk factors for heart disease are similar for both men and women (Arnold and Underwood, 1993; Aronow, 1996). Conventional cardiovascular disease risk factors include age, gender, heredity, inactivity, smoking, high cholesterol, hypertension, and diabetes (Aronow, 1996). While some risk factors can be reduced with simple changes in diet and lifestyle, other risk factors, such as age, gender, and heredity, are currently incapable of reduction. Additional factors, such as high cholesterol, hypertension, and diabetes, can require costly and hazardous therapies to reduce risk. By contrast, supplementing the diet with vitamin E is less costly and burdensome. It offers a meaningful reduction of cardiovascular disease risk without a reduction in quality of life. See, Davey (1998), Bendich (1997); Pryor Report. The proposed health claim asserts a feasible means of reducing cardiovascular disease risk and serves U.S. Department of Health and Human Services (DHHS) policy by addressing a significant health problem in the U.S. population. See, 61 Fed. Reg. 296, 297 (Jan. 4, 1996).

A diet supplemented with vitamin E offers health benefits that may reduce the occurrence or severity of cardiovascular disease. (Pryor Report, Attachment 2). Coronary artery disease costs more than $8 billion annually in health-care costs and more than $60 billion annually in lost productivity (Keaney, 1994). Recent studies indicate that a significant number of individuals can benefit from improved cardiovascular outcomes as a result of increased consumption of vitamin E (Tables 1 and 2). (Davey, 1998). Furthermore, experts estimate an annual savings of $5 billion a year can be realized "as a result of reduced CHD hospitalizations associated with vitamin E supplementation" (200-400 IU/day) (Bendich, 1997; Davey, 1998). Those cost savings do not account for savings from decreased physician fees, outpatient services, and prescriptions, or saved lost workproductivity costs. Considering efficacy, cost effectiveness, safety, and the potential lives saved, greater use of vitamin E resulting from awareness of the proposed health claim will serve the national interest and DHHS policy. It is imperative that FDA act rapidly and allow use of the petitioned health claims as soon as possible, thereby minimizing the risk of avoidable cardiac deaths and/or increased heart disease morbidity that can be prevented by increased intake of supplemental vitamin E.

Vitamin E has always been a natural component of the American diet. Vitamin E is found in a variety of conventional foods. 66.4% of dietary vitamin E is obtained from fats and oils. An additional 11.5% come from meats, poultry, fish, eggs, dairy products,, sugars, sweeteners and miscellaneous foods. A total of 77.9% of the dietary sources for vitamin E are within the categories of foods that the Surgeon General has determined should be dramatically reduced by Americans. USDA and DHHS (PHS) Nutrition Monitoring in the United States: An Update Report on Nutrition Monitoring, Sept. 1989 (Kushi, 1999). Even without restricting fat and cholesterol containing foods, it is difficult if not impossible to consumeenough foods in conventional form that contain enough vitamin E to obtain the known heart health benefits. Only a supplemental source of synthetic or natural vitamin E can ensure that efficacious quantitiesof are ingested daily (Pryor Report at 2).

The limited amount of vitamin E available in the average diet and, more significantly, the levels expected to be found in a heart healthy diet low in fat and cholesterol make vitamin E supplementation an essential alternative to achieve population wide cardiovascular disease risk reduction. See, USDA and DHHS, Third Report on Nutrition Monitoring in the United States--Executive Summary, 1995; Pryor Report at 2, Attachment 2. The scientific studies described in this petition directly address this important public health issue and further national and DHHS policies by addressing cost effective means of reducing cardiovascular disease risk.

The underlying scientific data demonstrate that daily consumption of vitamin E will reduce cardiovascular disease risk. More than 40 human studies between 1987 and 1999, when taken as a whole, justify approval of the petitioned claim (Pryor Report at 2, 33; Tables 1 and 2). The scientific data provide substantial evidence of the cardiovascular benefits resulting from daily consumption of vitamin E.

Petitioners believe that the truthful and succinct health information conveyed by their proposed health claim will enable consumers to make prudent and effective choices about their health care and lifestyles. Labeling dietary supplements with the proposed vitamin E health claim would augment previously published statements by DHHS concerning the prevention and treatment of cardiovascular disease. The petitioned claim will accurately impart to consumers the scientific understanding about the relationship between vitamin E and the risks of cardiovascular disease, enabling them to make better informed choices in the marketplace.

Consistent with the decision in Pearson v. Shalala, 164 F.3d 650, (D.C. Cir. 1999), reh’g denied en banc, No. 98-5043, 1999 U.S. App. LEXIS 5954 (Apr. 2, 1999), Petitioners respectfully request that, in its action on this petition, the agency define "significant scientific agreement" in 21 CFR § 101.14 by articulating clearly the principles that guide the agency in reaching its decision such that the Petitioners can perceive the degree, quality, and nature of evidence FDA expects to satisfy its standard. In addition, and consistent with Pearson, if the agency finds the proposed claim not to satisfy "significant scientific agreement," the Petitioners request that the agency authorize the claim nevertheless, with such disclaimer or disclaimers as the agency reasonably deems necessary to avoid a potentially misleading connotation.

This petition seeks FDA approval of the proposed claim for use on dietary supplements of vitamin E manufactured in accordance with U.S. Pharmacopeia (USP) specifications. Vitamin E meets the definition of a "substance" provided by 21 CFR § 101.14(a). "Substance" is defined as a food or a component of food regardless of whether the food is in conventional or dietary supplement form. The subject of this petition is α-tocopherol that is a 16-carbon phenol with three chiral centers. The natural form of α-tocopherol is the isomer 2R, 4΄R, 8R΄- α-tocopherol (RRR- α-tocopherol) and known as d-α-tocopherol. Vitamin E is a component of foods found naturally in conventional foods such as fats, oils, meats, poultry, fish, eggs, dairy products, and sugars.and dairy products. The synthetic form has the chemical name of all-racermic- α-tocopherol or dl-α-tocopherol and contains all eight stereoisomers. Both the natural and synthetic forms of α-tocopherol (vitamin E) inhibit the oxidation of the LDL activities by similar actions (Devaraj, 1996; Pryor Report at 6). The natural vitamin E, however, is more efficient than its synthetic counterpart (Pryor Report at 5-6). For stability and for longer shelf life, supplemental vitamin E is usually formulated as the esters α-tocopherol acetate and/or α-tocopherol succinate. The subject of this petition includes the alpha tocopherol esters such as acetate and succinate (USP 23-NF18 and USP-DI, Attachment 4).

The proposed health claim conforms to the relevant requirements of 21 CFR § 101.14(b). Section 101.14(b) provides:

Conformance with each requirement of 21 CFR § 101.14(b) is discussed below.

In satisfaction of section 101.14(b)(1), the proposed health claim associates supplemental vitamin E with cardiovascular disease. Cardiovascular disease includes diseases of the heart and circulatory system. Coronary heart disease is the most common and serious form of cardiovascular disease primarily affecting the heart muscle and supporting blood vessels. 21 CFR § 101.75(a) (1999). Coronary heart disease is a major public health concern in the United States, primarily because it accounts for more deaths per year than any other disease or group of diseases. 21 CFR § 101.75(b) (1999). Stroke, a closely related cardiovascular disease, is the third leading cause of death in the U.S. See, CDC, www.cdc.gov/nchs/fastat, 1998. The petitioner meets the requirements of 21 CFR § 101.14(b)(1) by associating vitamin E with a disease for which the general U.S. population is at risk. FDA has determined that the adult population is at risk for coronary heart disease and cardiovascular disease.

In conformity with section 101.14(b)(3)(i), vitamin E contributes nutritive value and retains its nutritive attribute when consumed at or above the current Reference Daily Intake (RDI) values. The RDI value for vitamin E is 30 IU/day (21 CFR § 101.9 § 101.9(c)(8)(iv)). The nutritive contribution of vitamin E is widely recognized. The substance is a naturally occurring nutritive component in a wide variety of foods such as fats and oils, meats, poultry, fish, eggs, dairy products, and sugars.and dairy products. FDA recognizes the nutritive values through its nutritional labeling regulation, 21 CFR § 101.9. Section 101.9(c)(8)(iv) states that Vitamin E is essential in human nutrition. The RDI values provided in § 101.9(c)(8)(iv) are an attempt to establish a minimum intake of vitamin E necessary for maintaining adequate nutrition. The proposed health claim promotes intake quantities greater than the RDI values. The nutritive value of the substances are retained at the levels necessary to justify the proposed health claim. Therefore, the proposed health claim meets the requirements of 21 CFR § 101.14(b)(3)(i).

In conformity with section 101.14(b)(3)(ii), vitamin E is both a food and food ingredient and is safe and lawful at the levels necessary to justify the proposed health claim. As mentioned above, vitamin E is a natural ingredient of common foods such as green leafy vegetables, orange juice, and beans.vegetable oils and other high fat content foods. Vitamin E is also commonly sold as a dietary supplement. The FDCA deems dietary supplements a food under 21 U.S.C. §321(ff). Accordingly, vitamin E is both a food and food ingredient according to 21 CFR § 101.14(b)(3)(ii).

Vitamin E is generally recognized as safe and lawful at the levels necessary to justify the proposed health claim. Tocopherols and a -tocopherol acetate are generally recognized as safe when used in accordance with good manufacturing practices (21 CFR §§182.8890 and 182.8892). Vitamin E is generally recognized as safe with no pre-determined daily intake limitation under 21 CFR § 184.1676.

The maximum (safe) daily intake of vitamin E is generally limited to the amount reasonably required to accomplish an intended nutritive effect. 21 CFR § 172.5 (1999). Accordingly, vitamin E is generally recognized as safe at any daily intake level justified for a particular nutritive effect. The safe upper limit for vitamin E has not been established but has generally been set at above 800 IU /day and has been shown to be safe at intake levels up to 3,200 IU per day (Bendich, 1988). The proposed health claim promotes dietary intakes that are well below the safety levels established by the scientific community. Therefore, the proposed health claims comply with the safety and lawfulness requirements of 21 CFR § 101.14(b)(3)(ii).

The safety of the proposed health claim can also be shown when examining the dietary habits of the general U.S. population. Less than 30 % of the American population consume 30 IU or more of vitamin E per day. USDA, Nationwide food consumption survey: continuing survey of food intakes by individuals: men 19-50 years, 1985, and Nationwide food consumption survey: continuing survey of food intakes by individuals: women 19-50 years and their children 1-5 years, 1985, Report Nos. 85-3 and 85-4, Nutrition Monitoring Division, Human Nutrition Information Service, 1986. Since the proposed claim promotes an intake level well within the upper safety limit, even when considering the possibility of increased consumption, any safety concerns of over consumption are mitigated.

In summary, since vitamin E meets the requirements set forth in 21 CFR § 101.14(b), the preliminary requirements of 21 CFR § 101.70 are fully satisfied.

There exists significant agreement among experts who study the field of cardiovascular disease concerning the association between vitamin E and heart disease risk factors. See, Pryor Report, Attachment 2. Results of epidemiological studies support the inverse association between Vitamin E and risk of heart disease. (Kushi, 1999, Steinberg, 1992). Summaries of those meta-analyses and literature surveys discussing the inverse relationship between vitamin E and heart disease risk are presented below:

• A survey of epidemiological and clinical studies indicates that mild to moderately elevated lipid levels respond to 400 IU/day vitamin E supplementation while more severe hyperlipidemia may require 600-1,200 IU/day (Suzukawa, 1998). The authors conclude that supplementation with 400 IU/day of vitamin E, which is sufficient to increase the Vitamin E content of LDL two-fold and significantly decrease LDL oxidizability, may reduce individual risk of CHD.
• A critical review of six epidemiologic studies notes that high-level vitamin E intake or supplementation is associated with a significant reduction in cardiovascular disease (Jha, 1995). Jha’s research revealed that epidemiologic data show that daily high intake of vitamin E for 2 years or more resulted in a relative risk reduction of 31% to 65%. The researchers found the data from randomized clinical trials to be more equivocal. The randomized trials were not specifically designed to assess heart disease, did not provide data on nonfatal cardiovascular end points, may have had insufficient treatment duration, and used suboptimal doses of vitamin E. The health benefits of vitamin E could be significant with very little risk.
• Kushi (1999) examined the results of prospective epidemiologic studies and cohort studies that have examined the association between vitamin E and incidence of heart disease. Kushi concluded that "overall, among the six prospective studies to examine the association of vitamin E intake with coronary disease, all reported some measure of evidence of an inverse association." (Kushi, 1999). Among those six studies, four examined the effect of vitamin E from foods and five addressed the effect of vitamin E from supplements. "The strongest reported association corresponded to an approximate halving of the risk of coronary disease in those who took vitamin E supplements compared to those who did not."
• Buring and Hennekens (1997) surveyed available studies (animal, epidemiological and clinical) that examined antioxidants and the reduction of cardiovascular disease. That comprehensive review concluded that "the totality of evidence from basic research and observational studies is consistent with a small to moderate benefit on CHD risk" by vitamin E intake.
• Kwiterovich (1997) reviewed published studies that examined the influence of antioxidants and vitamin E in particular on heart disease risk. Kwiterovich concluded that the available data and literature supports the recommendation of 200 IU /day of vitamin E to reduce the risk of coronary artery disease.
• Rexrode (1996) conducted an in depth review of prospective cohort studies of vitamin E and relative risk of coronary heart disease. That review revealed that epidemiologic evidence for vitamin E and prevention of cardiovascular disease is generally strong and consistent across populations and in both men and women. A greater effect has been noted in most studies from supplement use than from dietary intake alone.
• Mendis (1998) reviewed the results of three epidemiological studies and two clinical trials. In evaluating the results of those studies, when taken together with other published data, Mendis concluded " Compelling evidence…support the idea that intake of vitamin E above the recommended daily allowance may be beneficial in relation to cardiovascular disease…there is good reason to believe that a high dose of vitamin E may prevent non-fatal myocardial infarction in patients with angina and coronary atherosclerosis."

1. Scientific evidence demonstrates the cardiovascular health benefits of vitamin E.

The Shute brothers of London, Ontario, addressed the therapeutic properties of Vitamin E more than 50 years ago. Vitamin E's cardiovascular protective properties have gained acceptance in the medical community over the past two decades. A recent study of 181 American cardiologists found that more than 44% personally take antioxidant supplements with Vitamin E, the most common antioxidant for cardiovascular health protection (Mehta,1997; Pryor Report at 2-3).

William A. Pryor, PhD, has investigated the field of free radical chemistry for more than 43 years. He has published more than 350 peer-reviewed scientific journal articles and 25 books. He is the co-editor-in-chief of the Elsevier journal Free Radical Biology & Medicine and editor of the annual Vitamin E & Carotenoids, which reviews the health implications of publications concerning vitamin E, carotenoids, and other antioxidant nutrients. Based on his investigations and extensive review of scientific literature, Dr. Pryor has concluded that "the mass of data leaves little doubt that vitamin E provides important and significant protection both to those without diagnosed heart conditions and to those with proven heart disease." (Pryor Report at 32).

Vitamin E’s unique and powerful antioxidative properties protect the vascular system from the pathogenic effects of oxidative events that lead to atherosclerosis (Pryor Report at 6-11; Table 1). Atherosclerosis is the principal cause of heart attacks and stroke (Ross, 1993). Atherosclerosis results from insults to the endothelium and smooth muscle cells of arterial walls. Inflammation plays a role in the development of the fibrous and fibrofatty atherosclerotic lesions. (Ross, 1993). Macrophages have specific receptors for oxidized LDL, readily take up that material, and when overloaded by high oxidized LDL levels, degenerate into the 1993)foam cells found in atherosclerosis plaques. There is significant scientific agreement among qualified experts that there is a direct relationship between platelet adhesiveness and heart disease risk. In addition, growth factors, cytokines and vasoregulatory molecules contribute to the pathogenic process. LDL oxidation, for example, increases monocyte adherence, transmigration, and macrophage formation and activation, thus promoting atherosclerosis development. (Ross, 1993; Steinberg, 1992; Southorn, 1988). Oxidized LDL is potentially more atherogenic than "native" LDL. (Steinberg, 1992; Haberland, 1992). Vitamin E inhibits LDL oxidation that plays a key role in the pathogenesis of atherosclerosis and cardiovascular disease. (Azen, 1996; Azzi, 1998; Haberland, 1992; Henning, 1993; Pryor Report at 6-11).

In addition, vitamin E reduces platelet adhesion associated with transient ischemic attacks and atherosclerosis (Tran, 1996; Yoshikawa, 1998; Kanzhi, 1992; Mark, 1996 and 1997; Martin, 1997; Steiner, 1993; and Freedman, 1996). It protects against cellular damage caused by autoxidation of polyunsaturated fatty acids (PUFA) that are present in most cells and cell membranes and are very susceptible to autoxidation. (Tran, 1996; Esterbauer, 1991; Keaney, 1994; Pryor Report at 9). Vitamin E further protects the body by reducing the damage caused by prostoglandins formed by oxidation of the PUFA arachidonate (Chan, 1993, 1991, 1988; Ferns, 1993). Vitamin E also protects against nitrogen dioxide free radical reactions with PUFA’s. (Chan, 1998; Pryor Report at 8).

There is significant scientific agreement among qualified experts that there is an inverse relationship between the consumption of vitamin E and heart disease risk. Dozens of published scientific articles reporting results of human cohort and controlled clinical trials have examined the vitamin E/cardiovascular disease risk relationship (Table 1). Additional support for the proposed health claim is found in evidence from experimental, animal and other studies (Table 2). By contrast, weak or no associations between vitamin E and heart disease were revealed in the studies listed in Table 3. The results of those studies do not, however, refute the overwhelming evidence in support of the proposed health claim (Pryor Report at 18-24). Many of those studies suffer from severe methodological limitations such as (a) studies limited to a very small sample size; (b) studies involving populations of smokers (that have far higher levels of oxidative stress than non-smokers) or mixed smoker/non-smoker populations; (c) studies using very small doses of vitamin E; and (d) studies failing to measure non-fatal cardiac events or diseases or measuring only non-cardiac endpoints. In addition, many of those studies had very small gradient differences in vitamin E intake making conclusions concerning associations invalid. The beneficial effects of vitamin E in those studies may be hidden and/or counteracted by confounding factors that are known to increase the risk of heart disease such as smoking, high fat intake, high cholesterol levels, and increased systolic and diastolic blood pressures. The serum studies measured plasma levels at a point in time far removed in events (serum frozen for 20 years in some cases). The stability and accuracy of measuring vitamin E concentrations using that method is highly questionable. Most of the authors who reviewed available literature and found that a public health recommendation for increased consumption of vitamin E was not justified did note that the observational and epidemiologic data did indicate an inverse relationship between vitamin E and heart disease. In addition, many of those reviewers made their recommendations on antioxidants in general. When vitamin E is examined, the evidence for the health claim remains compelling (Pryor Report at 27). Lonn (1997), for example, concluded from a review of epidemiologic and clinical trials that the data are inconclusive and should wait before making widespread recommendations for supplements. That conclusion was based on an evaluation of antioxidants in general rather than an evaluation of vitamin E in particular. The researchers’ detailed analyses, however, demonstrate a significant inverse association between Vitamin E use and heart disease, especially among supplement users. Van de Vijer (1997) conducted an extensive review of antioxidants and concluded that "general preventive measures based on antioxidant supplementation are not justifiable on the basis of current knowledge, although there is certainly support for a preventive effect of high doses of vitamin E on cardiovascular disease risk."

Most researchers note that in order to determine the exact extent to which vitamin E intake reduces cardiovascular disease risk would be extremely difficult and cost prohibitive (Tangney, 1997, Pryor Report 33). The available data do not indicate that intake of vitamin E at levels consistent with the proposed health claim poses a health risk and the potential benefits are significant as indicated by the following:

• Large scale prospective studies of more than 40,000 men and 80,000 women reveal that Vitamin E, in doses greater than 100 IU/day through use of supplements, is associated with a significant decrease in the risk of cardiovascular disease (Rimm, 1993 and Stampfer 1993).
• Vitamin E consumption by post-menopausal women is inversely associated with risk of death from heart disease (Kushi, 1996).
• Clinical intervention trials demonstrate that supplementation with vitamin E significantly reduces the risk of recurrent heart attacks (Stephens, 1996 (2,002 randomized patients with angiographically proven atherosclerosis CHAOS Study)).
• Supplementation with vitamin E is protective against the development of atherosclerosis (Azen, 1996).
• Vitamin E supplementation promotes regression of existing atherosclerosis (Hodis, 1995) and reduces platelet aggregation associated with coronary artery disease (Freedman, 1996).
• Supplementation with 300 IU/day of vitamin E improves endothelium-dependent vasodilation and decreased angina attacks in patients with coronary spastic angina (Motoyama, 1998).
• Vitamin E reduces LDL oxidation in CAD patients when included in an atherosclerosis-reversal therapy regimen (Parks, 1998).
• Vitamin E supplementation decreased the risk of fatal coronary events in smokers (Virtamo, 1998).
• Vitamin E supplementation reduced the risk of coronary disease mortality (Losonczy, 1996; Sahyoun, 1996; and Ashwell 1995).
• In case controlled studies, low vitamin E levels are associated with increased risk of coronary artery disease (CAD), independent of other CAD factors (Delport, 1998; Dube, 1998; and Kim, 1996), and greater risk of heart attack in men (Bobak, 1998).
• Other epidemiological and observation studies demonstrate that persons with unstable angina had significantly lower vitamin E levels than control subjects (Kostner, 1997, Miwa, 1996, and Rimersma 1989) and low levels of vitamin E are involved with the early phases of atherosclerosis (Bonithon-Koop, 1997).
• The results of a longitudinal population study of more than 5,100 Finnish men support the hypothesis that vitamin E protects against cardiovascular disease (Knekt, 1994).
• A double blind placebo controlled study demonstrated that Vitamin E in a dose of 500 IU/day will significantly reduce the susceptibility of LDL to oxidation (Simons, 1996).
• Riemersma, R.A., et. al., "Risk of angina pectoris and plasma concentrations of Vitamin A, C, and E and carotene," Lancet. Jan. 1991, Vol. 337, No. 8732, 1-5. A case controlled study of 110 angina sufferers compared to 394 control middle aged men. Plasma concentrations of vitamins C and E and carotene were inversely related to the risk of angina. The ratio of risk indicates that populations with a high incidence of coronary heart disease may benefit from eating diets rich in natural antioxidants, particularly vitamin E. Due to the effect of processing and food preparation, supplementation may be needed to provide the level of nutrients required.

The studies that found a strong association between vitamin E intake and a reduced risk of heart disease examined the effects of both natural and synthetic vitamin E preparations. Natural vitamin E, d-α-tocopherol, consistently demonstrated therapeutic effects at levels of 100-400 IU/day (See Table 1). The threshold level for synthetic vitamin E, dl-α-tocopherol, has been demonstrated to be 400 IU/day (Fuller, 1997; Table 1). The specific dose response studies indicate that 400 IU/day of either d-α-tocopherol or dl-α-tocopherol is needed to significantly decrease LDL susceptibility to oxidation and thus reduce the risk of atherosclerosis and heart disease development (Devaraj, 1997; Jialal, 1995).

In summary, an overwhelming majority of the aforementioned scientific articles support the proposed health claim. The conclusions of the authors demonstrate that there is significant scientific agreement among qualified experts. Those experts repeatedly conclude that there is (1) an inverse relationship between vitamin E and heart disease risk, (2) a direct relationship between LDL oxidation and heart disease risk, (3) an inverse relationship between vitamin E and LDL oxidation, and (4) supplemental quantities of vitamin E show protective effects against cardiovascular disease more conclusively than dietary vitamin E. Accordingly, FDA should respect the well-considered conclusions of scientific experts on the cardiovascular benefits of vitamin E and approve the proposed claims.

4. Analytical Methods

The amount of d-α-tocopherol or dl-α-tocopherol contained in a dietary supplement that may be a candidate for bearing the health claims can be ascertained by standard assay methods (Attachment 3). The USP assay methods described in the USP 23-NF 18 (1995) are applicable to finished products.

Petitioners propose the following Model Claims for Vitamin E and heart disease risk:

• As part of a diethealthy diet low in saturated fat and cholesterol, 400 IU/day of Vitamin E (d-a -tocopherol or dl-a -tocopherol) may reduce the risk of heart disease. Individuals who take anticoagulant medicine(s) should consult their physicians before taking supplemental Vitamin E.
• As part of a healthy diet low in saturated fat and cholesterol, 100 - 400 IU/day of natural Vitamin E (d-a -tocopherol) may reduce the risk of heart disease. Individuals who take anticoagulant medicine(s) should consult their physicians before taking supplemental Vitamin E.
• As part of a healthy diet low in saturated fat and cholesterol, 200 - 800 IU/day of synthetic Vitamin E (dl-a -tocopherol) may reduce the risk of heart disease. Individuals who take anticoagulant medicine(s) should consult their physicians before taking supplemental Vitamin E.

Attached are copies of the scientific studies and other information referenced in, and constituting the basis for, this Petition. To the best of the Petitioners' knowledge, all non-clinical studies relied upon were conducted in compliance with the good laboratory practices regulations set forth at 21 CFR Part 58, and all clinical or other human investigations relied upon were either conducted in accordance with the requirements for institutional review set forth at 21 CFR Part 56 or were not subject to such requirements in accordance with 21 CFR §§ 56.104 or 56.105, and were conducted in conformance with the requirements for informed consent set forth in 21 CFR § 50 et seq. See generally, 21 CFR § 101.70 (c)-(d).

The requested health claim approval contained in this petition is categorically excluded under 21 C.F.R. § 25.24.

For the foregoing reasons, the Petitioners request that the FDA approve the proposed health claims. The Petitioners look forward to working with the FDA in promulgating a regulation authorizing the use of dietary supplement health claims concerning the association between vitamin E and reduction in the risk of heart disease.

Any questions concerning this Petition may be directed to Jonathan W. Emord, Esq., Emord & Associates, P.C., 1050 Seventeenth Street, NW, Suite 600, Washington DC 20036, (202) 466-6937.

The undersigned certify on behalf of the Petitioners that to the best of their knowledge and belief, the Petition includes all information and views on which the Petitioners rely and is a representative and balanced submission that includes unfavorable information as well as favorable information, known by the Petitioners to be pertinent to evaluation of the proposed health claims.

Jonathan W. Emord

Eleanor A. Kolton

1050 Seventeenth Street, N.W., Suite 600

Washington, D.C. 20036

P: (202) 466-6937

F: (202) 466-6938

e-mail: Emordal1@erols.com

Date: July 6, 1999

Table 1: Studies demonstrating the inverse relationship between vitamin E and heart disease risk.

Table 2. Additional studies supporting the role of Vitamin E in reducing heart disease risk.

Table 2. Additional studies supporting the role of Vitamin E in reducing heart disease risk (continued).

Table 3. Studies with conclusions not supportive of effects of Vitamin E on heart disease risk.

Table 3. Studies with conclusions not supportive of effects of Vitamin E on heart disease risk (continued).

1. Armstrong BK, et al., "Commodity consumption and ischemic heart disease mortality, with special reference to dietary practices," J Chron Dis, 28: 455-469, 1975.
2. Arnold AZ and Underwood DA, "Coronary artery disease in women: a risk-factor analysis," Cleveland Clinic J Med, 60:387-392, 1993.
3. Aronow WS and Ahn C, "Risk Factors for New Coronary Events in a Large Cohort of Very Elderly Patients With and Without Coronary Artery Disease," Am J Cardiol, 77: 864-866, 1996.
4. Ashwell M and Buss D, "Vitamin Intake in Great Britain: Association with Mortality Rates for Coronary Heart Disease," Bibl Nutr Dieta, 1995: 128-36, 1995.
5. Artaud-Wild SM et al., "Differences in Coronary Mortality Can Be Explained By Differences in Cholesterol and Saturated Fat Intakes in 40 Countries But Not in France and Finland," Circulation, 88: 2771-79, 1993.
6. Azen SP, et al., "Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering," Circulation, 94: 2369-72, 1996.
7. Azzi A, et al., "Molecular basis of α-tocopherol control of smooth muscle cell proliferation," BioFactors, 7: 3-14, 1998.
8. Bellizzi MC, et al., "Vitamin E and coronary heart disease: the European paradox," Eur J of Clin Nutr, 48: 822-831, 1994.
9. Bendich A, et al., "Interaction of Dietary Vitamin C and Vitamin E on Guinea Pig Immune Responses to Mitogens," J Nutr, 114: 1588-1593, 1984.
10. Bendich A and Machlin LJ, "Safety of oral intake of vitamin E," Am J Clin Nutr, 48:12-9, 1988.
11. Bendich A, Mallick R and Leader S, "Potential health economic benefits of vitamin supplementation," West J Med, 166: 306-12, 1997.
12. Bobak M., et al., "Could antioxidants play a role in high rates of coronary heart disease in the Czech Republic?" Eur J Clin Nutr, 52: 632-6, 1998.
13. Bolton-Smith C, Woodward M and Tunstall-Pedoe H, "The Scottish Heart Study. Dietary intake by food frequency questionnaire and odds ratio for coronary heart disease risk," Eur J Clin Nutr, 46: 85-93, 1992.
14. Bonithon-Kopp C, et al., "Combined effects of lipid perioxidation and antioxidant status on carotid atherosclerosis in a population aged 59-71 y: The EVA Study. Etude sur Viellisement Arteriel. Am J Clin Nutr, 65: 121-7, 1997.
15. Boscoboinik D, et al., "Inhibition of Cell Proliferation by α-Tocopherol," J Biol Chem, 266: 6188-6194.
16. Buring JE and Hennekens CH, "Antioxidant Vitamins and Cardiovascular Disease," Nutr Rev, 55: S53-S60, 1997.
17. Buring JE and Hennekens CH, "The Women’s Health Study: Summary of the Study Design," J Myocardial Ischemia, 4: 27-30, 1992.
18. Carew TE, et al., "Antiatheogenic effect of probucol unrelated to its hypocholesterolemic effect: Evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit," Proc Natl Acad Sci, 84: 7725-7729, 1987.
19. Chan AC and Leith MK, "Decreased prostacyclin synthesis in vitamin E deficient rabbit aorta," Am J Clin Nutr, 34: 2341-47, 1981.
20. Chan AC, "Vitamin E and Atherosclerosis," J Nutr, 128: 1593-6, 1998.
21. Chan AC, "Partners in defense, vitamin E and vitamin C," Can J Physiol Pharamcol, 71: 725-31, 1993.
22. Chan AC, et al., "Effects of dietary vitamin E on the biosynthesis of 5-lipoxygenase products by rat polymorphonuclear leukocytes (PMNL)," Biochem Biophysic Acta, 1005: 265-9, 1989.
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