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Qualified Health Claims: Letter Regarding Tomatoes and Prostate Cancer (Lycopene Health Claim Coalition) (Docket No. 2004Q-0201)

Back to Qualified Health Claims: Letters of Enforcement Discretion

November 8, 2005

 

F. Kerr Dow, Ph.D.
Vice President Nutrition and Technical Affairs
H. J. Heinz Company
P.O. Box 57
Pittsburgh, Pennsylvania 15230-0057

RE: Qualified Health Claim Petition - Tomato Lycopene, Tomatoes and Tomato Products, which Contain Lycopene, Lycopene in Tomatoes and Tomato Products, Lycopene in Fruits and Vegetables, including Tomatoes and Tomato Products and Reduced Risk of Prostate Cancer (Docket No. 2004Q-0201)

Dear F. Kerr Dow:

This letter responds to the qualified health claim petition received on May 17, 2004, by the Food and Drug Administration (FDA or the agency), submitted by the Lycopene Health Claim Coalition,[1] pursuant to Section 403(r)(4) or 403(r)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. §§ 343(r)(4) or 343(r)(5)(D)). The petition proposed the following qualified health claims:

  1. 1) "Although the evidence is not conclusive, tomato lycopene may reduce the risk of prostate cancer."
  2. 2) "Although the evidence is not conclusive, tomato lycopene may reduce the risk of prostate cancer when consumed as part of a healthy diet."
  3. 3) "Although the evidence is not conclusive, tomato products, which contain lycopene, may reduce the risk of prostate cancer."
  4. 4) "Although the evidence is not conclusive, tomatoes and tomato products, which contain lycopene, may reduce the risk of prostate cancer."
  5. 5) "Although the evidence is not conclusive, tomato products, which contain lycopene, may reduce the risk of prostate cancer when consumed as part of a healthy diet."
  6. 6) "Although the evidence is not conclusive, tomatoes and tomato products, which contain lycopene, may reduce the risk of prostate cancer when consumed as part of a healthy diet."
  7. 7) "Although the evidence is not conclusive, lycopene in tomato products may reduce the risk of prostate cancer."
  8. 8) "Although the evidence is not conclusive, lycopene in tomatoes and tomato products may reduce the risk of prostate cancer."
  9. 9) "Although the evidence is not conclusive, lycopene in tomato products may reduce the risk of prostate cancer when consumed as part of a healthy diet."
  10. 10) "Although the evidence is not conclusive, lycopene in tomatoes and tomato products may reduce the risk of prostate cancer when consumed as part of a healthy diet."
  11. 11) "Although the evidence is not conclusive, lycopene in fruits and vegetables, including tomatoes and tomato products, may reduce the risk of prostate cancer."

In a letter dated May 27, 2004, FDA informed you that the petition was undergoing initial review and that we would follow the interim procedures for qualified health claim petitions as described in the FDA publication entitled "Consumer Health Information for Better Nutrition Initiative" Task Force Final Report, more specifically, the agency's guidance for procedures on qualified health claims.[2] Thus, FDA filed the petition on June 30, 2004 and posted it on the FDA website for a 60-day comment period.

The agency received a total of five comments pertaining to this docket, which included petitions submitted on behalf of Heinz and American Longevity, Inc. The petition submitted on behalf of American Longevity, Inc., requested that the agency authorize health claims or allow qualified health claims characterizing the relationship between consumption of lycopene, tomatoes, and lycopene-containing tomato-based foods, and reduction in the risk of certain forms of cancer, prostate cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and pancreatic cancer. Three of the comments were from individuals and two were from industry. The three comments from individuals supported the proposed claims but did not provide any data to support their conclusions and were not directed to any specific petition. One of the comments from industry was directed specifically to your petition and the other was directed to the petition submitted on behalf of American Longevity, Inc. The comment directed to your petition did not support many of the claims as presented and provided substantial data to support their conclusions. FDA considered all relevant comments in its evaluation of the petition.

This letter sets forth the basis of FDA's determination that the current scientific evidence for the proposed qualified health claim related to consumption of tomatoes and/or tomato sauce, and a reduced risk of prostate cancer is appropriate for consideration as a qualified health claim on conventional foods. This letter also sets forth the basis for FDA's determination that there is no credible evidence to support claims about consumption of tomato lycopene; tomatoes and tomato products which contain lycopene; lycopene in tomatoes and tomato products, or lycopene in fruits and vegetables, including tomatoes and tomato products and a reduced risk of prostate cancer. Finally, this letter sets forth the factors that FDA intends to consider in the exercise of its enforcement discretion for a qualified health claim with respect to consumption of tomatoes and/or tomato sauce and a reduced risk in prostate 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 is 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. 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 that affect how humans respond to the consumption of foods and dietary substances (Institute of Medicine, National Academies of Science, 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.[10] 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 quantity of evidence (number of the various types of studies and sample sizes), 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[11], and the overall consistency[12] of the total body of evidence.[13] Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support the substance/disease relationship, and, if so, determines the ranking that reflects the level of comfort among qualified scientists that such a relationship is scientifically valid.

A. Substance

A health claim characterizes the relationship of any substance and a disease or health-related condition (21 CFR 101.14(a)(1)). A substance means 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 tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in fruits and vegetables, including tomatoes and tomato products; and "tomato lycopene" as the substances of the qualified health claim petition. The petition does not define "tomato lycopene"; however, the agency assumes that the petitioner meant this term to mean lycopene extracted from tomato or tomato products to be used as an ingredient for food or as an ingredient in dietary supplements, as described in an article by Don Hartal and Lorri Danzig provided with the petition and the petitioner's request for a qualified health claim under section 403(r)(5) of the Act (21 U.S.C. 343(r)(5)), which applies to dietary supplements. Tomatoes and tomato products are foods within the definition of food under the Act (21 U.S.C. § 321(f)(1)). Similarly, fruits and vegetables are foods within the definition of food under the Act.[14] Lycopene is an ingredient of foods such as red tomatoes, red tomato-based foods, red or pink grapefruit, watermelon, red sweet peppers, papaya, and pink guava. Lycopene is also a member of the carotenoid family that is marketed as a dietary supplement. Therefore, lycopene is both a food ingredient and a component of food and thus meets the definition of food under the Act (21 U.S.C. § 321(f)(3)). Therefore, the agency concludes that tomatoes, tomato products, and lycopene 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 prostate cancer as the disease that is the subject of the proposed qualified health claim. Cancer is a constellation of more than 100 different diseases, each characterized by the uncontrolled growth and spread of abnormal cells (American Cancer Society, 2004). Therefore, the agency concludes that prostate cancer is a disease as defined in 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 or a food ingredient or a component of a food ingredient whose use at the levels necessary to justify the claim must be 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)). For dietary supplements, the applicable safety provisions require, among other things, that the dietary ingredient not present a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in 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 which 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))).

As discussed in section I.A., the substances requested by the petitioner are (1) tomatoes, (2) tomatoes and tomato products, which contain lycopene, (3) lycopene in tomatoes and tomato products, (4) lycopene in fruits and vegetables, including tomatoes and tomato products, and (5) tomato lycopene.

1. Tomatoes and Tomato Products

For purposes of the health claim regulation, tomatoes and tomato products are not ingredients that are the source of the substance; rather tomatoes and tomato products are the substance. Tomatoes are also a primary ingredient in many tomato products. Tomato products can thus be a source of tomatoes. Tomatoes are foods of natural biological origin that have been widely consumed in the United States for their nutrient properties prior to January 1, 1958, without known detrimental effects, which are subject only to conventional processing as practiced prior to January 1, 1958, and for which no known safety hazard exists. Tomatoes themselves and tomatoes as a food ingredient in tomato products are consistent with FDA's definition of food ingredients ordinarily regarded as "generally recognized as safe" (GRAS) (21 CFR 170.30(d)).

The limited scientific evidence describing the effects of tomatoes and tomato products on prostate cancer, suggests that consumption of one-half to one cup of tomatoes and/or tomato sauce per week may reduce the risk of prostate cancer (discussed in section IV C). Therefore, FDA concludes under the preliminary requirements of 21 CFR 101.14(b)(3)(ii), that the use of tomatoes and/or tomato sauce[15] at the level necessary to justify the claim is safe and lawful.

2. Fruits and Vegetables

It is not necessary for FDA to make any determination about the safety or lawfulness of fruits and vegetables in this letter, because the agency is denying the proposed claim related to "fruits and vegetables" for lack of credible evidence, as discussed in sections II and III.

3. Lycopene

The petition asserts that there is no reason to believe that lycopene consumption would result in harm. Lycopene and other carotenoids serve as a key source of antioxidants. Antioxidants are substances that can prevent or delay the oxidation of other substances and may protect against chronic disease (Institute of Medicine, 2000 p 35-57). There are no specific intake quantities for lycopene proposed in the petition. Instead, the petition cites various articles in the scientific literature stating that, to be effective, lycopene supplementation must be at daily doses of at least 15 mg. No Dietary Reference Intakes (DRIs) have been established for the carotenoid lycopene. However, the Institute of Medicine supports existing recommendations for increased consumption of carotenoid-rich fruits and vegetables (Institute of Medicine, 2000 p 325).

FDA has received two GRAS notifications concerning lycopene, one submitted by LycoRed for tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract, (GRAS notification number 000156), and the other submitted by BASF corporation for synthetic lycopene (GRAS notification number 000119). In the "Agency Response Letter" to the GRAS notifications for the above listed subjects, the agency stated it had no questions at this time regarding the conclusions that tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract or synthetic lycopene are GRAS under their intended conditions of use. FDA further stated that the agency had not made its own determination regarding the GRAS status of the use of tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract or synthetic lycopene and, as always, it is the continuing responsibility of manufacturers to ensure that the food ingredients they market are safe, and are otherwise in compliance with all applicable legal and regulatory requirements (Agency Response Letters to GRAS notifications # 000156 and 000119; (http://www.cfsan.fda.gov/~rdb/opa-g156.html and http://www.cfsan.fda.gov/~rdb/opa-g119.html). Additionally, FDA has received a GRAS notification for lycopene from Blakeslea trispora the review of which is still pending (GRAS notification number 000173). FDA has also recently amended its color additive regulations to provide for the safe use of tomato lycopene extract and tomato lycopene concentrate as color additives in foods (70 FR 43043; July 26, 2005). The action was in response to a petition filed by LycoRed Natural Products Industries.

It is not necessary for FDA to make any determination about the safety or lawfulness of lycopene either as a food ingredient, a component of food or as a dietary supplement in this letter because the agency is denying the proposed claims for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products, and lycopene in fruits and vegetables, including tomatoes and tomato products for lack of credible evidence, as discussed in section II.

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

FDA has identified the following markers to use in identifying risk reduction for purposes of a health claim evaluation involving cancer: incident cases of the particular cancer being studied, and recurrent colon/rectal polyps for colon/rectal cancer. Colon/rectal polyp recurrence has been used as a surrogate marker for colon/rectal cancer and has been used by the National Cancer Institute as a surrogate marker for colon cancer prevention (Schatzkin et al., 1994). To evaluate the potential effects of tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in and fruits and vegetables, including tomatoes and tomato products consumption on cancer risk, FDA considered these markers as indicators or predictors of the disease prostate cancer.

The petition cited 177 publications and or websites as evidence to substantiate the relationship for the claims. These publications consisted of 38 review articles; three abstracts; 13 in vitro studies; ten animal studies; 63 articles that did not measure lycopene, tomatoes or tomato products and/or a type of cancer, the substance and disease that are subject of the proposed claims, (i.e., studies on lycopene bioavailability, transport, relationship to other diseases, other substance (β-carotene[16]); one federal report; one power point presentation from a scientific meeting, eight book chapters; nine websites (i.e., government databases, medical dictionary, general health information); and 31 studies on cancer and lycopene/tomato/tomato products foods (see docket # 2004Q-0201 for bibliography), of which five were intervention studies and 26 were observational studies.

In addition to the studies in your petition, the agency considered two additional intervention studies for prostate cancer (Clinton et al., 1996; Matalaga et al., 2001) and three additional observational studies (Grant et al., 1999; Meyer et al., 1997; Jian et al., 2005).

A. Assessment of Review Articles, Meta-Analyses and Abstracts

Although useful for background information, the review articles, meta-analysis, 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). 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. As a result, the review articles, meta-analysis, and abstracts supplied by the petitioner do 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 submitted with the petition 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 tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomato and tomato products or lycopene in fruits and vegetables, including tomatoes and tomato products. Therefore, FDA cannot draw any scientific conclusions from the animal or in vitro studies regarding tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomato and tomato products or lycopene in fruits and vegetables, including tomatoes and tomato products and the reduction of risk of prostate cancer.

C. Assessment of Intervention Studies

Five intervention studies (Chen et al., 2001; Bowen et al., 2002; Van Breemen et al., 2002; Kucuk et al., 2001; Ansari et al., 2003) were submitted by the petitioner and two studies (Matlaga et al., 2001; Clinton et al., 1996) were identified by the Agency to evaluate the relationship between tomato lycopene; tomatoes or tomato products, which contain lycopene; lycopene in tomatoes and tomato products; and/or lycopene in fruits and vegetables, including tomatoes and tomato products and prostate cancer. However, all seven of these studies used tomatoes or tomato products (e.g., tomato sauce) and/or lycopene as a treatment for men diagnosed with prostate cancer. Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.[17] These claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim. As a result, FDA considers evidence from studies in individuals already diagnosed with prostate cancer 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. Given that such evidence was not available, the agency cannot draw any scientific conclusions from these seven studies.

D. Assessment of Observational Studies

Lycopene

A total of 17 studies[18] evaluated the relationship of lycopene and prostate cancer. The studies can be categorized into three groups: 1) Studies that evaluated lycopene from dietary sources and assessed the risk of cancer based on dietary lycopene intake; 2) Prospective observational and cross-sectional studies that used a single measure of serum lycopene concentration for determining the relationship between serum lycopene and risk of cancer; and 3) Studies that evaluated serum lycopene levels in subjects diagnosed with cancer.

Nine observational studies cited in the petition[19] calculated lycopene intake from estimated dietary intake. The proposed claims regarding lycopene are for a relationship between lycopene as a dietary supplement or lycopene as an ingredient or component of food, tomatoes and tomato products, which contain lycopene, lycopene in tomatoes and tomato products, and lycopene in fruits and vegetables, including tomatoes and tomato products. In observational studies that calculate nutrient intake from conventional food, measures of lycopene intake are based on recorded dietary intake methods such as food frequency questionnaires, diet recalls, or diet records, in which the type and amount of foods consumed are estimated. Estimated lycopene concentration values are then added to the data using typical lycopene concentration values for the food product category based on the USDA National Nutrient Database for Standard Reference, SR 16. A common weakness of observational studies is the limited ability to ascertain the actual food or nutrient intake for the population studied. Furthermore, the lycopene content of foods can vary significantly (e.g., due to food variety, ripening stage of the food, food processing/cooking procedures, or storage (duration, temperature) (Giovannucci et al., 1999; Gartner et al., 1997; Boileau et al., 2002; Shi et al., 2000). Thus, it is difficult to ascertain an accurate amount of the nutrient consumed based on reports of dietary intake of foods.

In addition, lycopene-containing foods contain not only lycopene, but also other nutrients that may be associated with the metabolism of lycopene or the pathogenesis of certain cancers. Because lycopene-containing foods consist of many nutrients and substances, it is difficult to study the nutrient or food components in isolation (Sempos et al., 1999). For studies based on recorded dietary intake of such foods, it is not possible to accurately determine whether any observed effects of lycopene on cancer risk were due to: 1) lycopene alone; 2) interactions between lycopene and other nutrients; 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 lycopene-rich foods.

In fact, 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 the nutrient-containing dietary supplement 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, 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 (The Alpha-Tocopherol and Beta Carotene Cancer Prevention Study Group, 1994; Omenn et al., 1996).[20] These studies illustrate that the effect of 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.[21]

Evidence is also now available that epidemiological studies based on the recorded dietary intake of conventional foods may suggest a benefit for a particular nutrient in that food with respect to a disease but it is subsequently demonstrated in an intervention study that the nutrient itself, when isolated from other nutrients in the food, does not confer a benefit ("Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acid," Institute of Medicine of the National Academies, 2002). For example, previous epidemiological studies (38 out of 48) reported an association between dietary fiber and reduced risk of colon cancer (Lanza 1990; Kromhout et al, 1982). Despite these and other positive findings, three recent clinical intervention trials found no association between dietary fiber and reduced risk of colon cancer (Alberts et al., 2000; Bonithon-Kopp et al., 2000; Schatzkin et al., 2000).

Furthermore, the observational studies that calculated lycopene intake from estimated dietary intake did not specify whether the tomato and/or tomato product intake reported was derived from red tomatoes. There are three varieties of tomatoes (red, green, and yellow) and only red tomatoes contain lycopene (USDA Nutrient Database, http://www.nal.usda.gov/fnic/foodcomp/). Thus, it is not possible to know whether the tomatoes in the studies actually contained lycopene. Nor, for the reasons discussed above, would it be possible to know whether, even if the tomatoes contained lycopene, that the lycopene had any relation to the reported effects. Moreover, the only data on lycopene in fruits and vegetables derived from two observational studies calculating lycopene intake from estimated dietary intake that included pink grapefruit and watermelon. The data on tomatoes and tomato-based products and the data on pink grapefruit and watermelon were combined in these studies. Therefore, it is impossible for FDA to determine whether any reported effects were from the tomatoes or tomato products, which may or may not have contained lycopene, or from the watermelon and pink grapefruit.

For the above reasons, FDA concludes that scientific conclusions cannot be drawn from observational studies on foods for the proposed claims for lycopene as a food ingredient, a component of food, or as a dietary supplement.[22]

Four observational studies evaluated serum lycopene levels and prostate cancer risk.[23] Numerous studies have shown that dietary lycopene intake and serum lycopene levels are poorly correlated; correlation coefficient range r = 0.11-0.45 (Campbell et al., 1994; Michaud et al., 1998; Casso et al., 2000; Neuhouser et al., 2001).[24] In addition, many factors can affect the serum lycopene levels including age, basal metabolic index (BMI), smoking, serum cholesterol levels, and season of the year (Casso et al., 2000; Mayne et al., 1999; Neuhouser et al., 2001). Since serum lycopene levels and dietary levels are poorly correlated and many factors (e.g., BMI, serum cholesterol, smoking, time of year) can alter the serum lycopene measures at a given point in time, scientific conclusions cannot be drawn from these four studies about the relationship between lycopene intake and risk reduction of any type of cancer.

Four studies[25] evaluated serum lycopene levels in subjects with cancer. In addition to the problem that serum lycopene levels are poorly correlated with dietary intake (see above), these studies used subjects diagnosed with different forms of cancer. Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.[26] These claims involve reducing the risk of a disease in people who do not already have the disease that is the subject of the claim. As a result, FDA considers evidence from studies in individuals already diagnosed with prostate cancer 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. Given that such evidence was not available, the agency cannot draw any scientific conclusions from these studies.

Tomatoes and Tomato Products

There were 19 observational studies on tomato and/or tomato product consumption and risk of prostate cancer, consisting of three prospective cohort studies[27], one sub-cohort study[28], 13 case-control studies[29], and two ecological studies.[30] Three studies were a republication of studies already being used in evaluating the proposed claim.[31] One study compared insulin-like growth factors (IGF) and tomato intake.[32] IGF is not a surrogate endpoint for prostate cancer. Therefore, the agency could not draw any scientific conclusions from this study. Finally, two case-control studies provided no information as to whether the food frequency questionnaires in the studies, which were used for the collection of tomato consumption data from study subjects, had been appropriately validated.[33] Validation of the food frequency questionnaire method is essential in order to be able to draw conclusions from the scientific data, as the failure to validate may lead to false associations between dietary factors and diseases or disease-related markers.[34] As a result, these studies provided no information on the accuracy of how tomato intake was measured, and hence, no scientific conclusions could be drawn from them.[35]

Thus, there were 13 observational studies evaluating the relationship between tomatoes or tomato products and prostate cancer. Two large cohort studies conducted in the United States evaluated tomato/tomato sauce intake and prostate cancer risk (Giovannucci et al., 2002; Mills et al., 1989). Both studies received a high methodological quality rating. Giovannucci et al. (2002) used the Health Professionals Follow-Up Study cohort that contained 47,365 males followed for approximately 12 years. In this cohort 2,481 prostate cancer cases were identified during follow-up. Tomato sauce intake was evaluated using three different food frequency questionnaires given at the beginning of the study and at four-year intervals. Consuming one, or greater than one, serving of tomato sauce per week was associated with significant decreased risk of prostate cancer; relative risk 0.80 (95% Confidence Interval (CI) of 0.70-0.91) and 0.77 (95% CI of 0.66-0.90)[36], respectively. Mills et al. (1989) followed a cohort of 14,000 Seventh Day Adventist males for six years, 180 prostate cancer cases were identified during the follow-up. Consuming tomatoes one to four times per week, or greater than five times per week was associated with a significant decrease in prostate cancer incidence; relative risk 0.62 (95% CI of 0.40-0.96) and 0.57 (95% CI of 0.35-0.93), respectively.

One sub-cohort study evaluated tomatoes and prostate cancer risk in 642 prostate cancer cases and 1,668 random healthy subjects from a cohort in the Netherlands (Schuurman et al., 1998). This study was of high methodological quality. Tomato intake (per 25 grams tomatoes) was not associated with prostate cancer, with a relative risk of 1.05 (95% CI of 0.90-1.22). Tomato juice intake (per 25 grams) was not associated with prostate cancer incidence; relative risk of 1.12 (95% CI of 0.96-1.29).

Eight case-control studies evaluated tomatoes and prostate cancer risk and all of the studies received high to moderate methodological quality ratings. Jain et al. (1999) reported that consuming greater than 109 grams of tomatoes per day was associated with a reduced risk of prostate cancer; odds ratio of 0.64 (95% CI of 0.45-0.91). This case-control study was conducted in Canada with 617 prostate cancer cases and 636 controls. Bosetti et al. (2000) conducted a case-control study that included 320 prostate cancer cases and 246 controls in Greece. Decreased intake of cooked tomatoes was associated with an increased risk of prostate cancer; odds ratio of 1.91 (95% CI of 1.20-3.04). However, there was no association between raw tomato intake and prostate cancer risk. Jian et al. (2005) conducted a case-control study in 130 prostate cancer cases and 274 controls from China. Tomato intake was associated with a reduced risk of prostate cancer; odds ratio of 0.16 (95% CI of 0.07-0.38).

Five of the eight case-control studies found no association between tomato consumption and prostate cancer risk (Villeneuve et al., 1999; Key et al., 1997; Hayes et al., 1999; Kolonel et al., 2000; LeMarchand et al., 1991). One case-control study conducted in Canada included 1,623 prostate cancer cases and controls and found no association between prostate cancer and tomatoes or tomato juice consumption; odds ratio of 1.0 (95% CI of 0.7-1.3) (Villeneuve et al., 1999). Another case-control study conducted in England included 328 prostate cancer cases and controls and found no association between prostate cancer and raw or cooked tomato intake; odds ratio of 1.06 (95% CI of 0.55-1.62) and 0.92 (0.59-1.42), respectively (Key et al., 1997). Hayes et al. (1999) conducted a case-control study in the United States with 932 prostate cancer cases and 1,201 controls. Tomato juice and raw/cooked tomato consumption had no association with prostate cancer risk. Kolonel et al. (2000) conducted a case-control study using 1,619 prostate cancer cases and 1,618 controls from a multi-ethnic population from the United States and Canada. There was no association between tomatoes or cooked tomato consumption and prostate cancer risk. Le Marchand et al. (1991) conducted a case-control study in Hawaii with 452 prostate cancer cases and 899 controls. Tomato consumption had no association with prostate cancer risk.

Two ecological studies of moderate methodological quality evaluated tomato consumption and prostate cancer risk (Grant., 1999; Ganmaa et al., 2002). Grant (1999) compared prostate cancer mortality data from 41 countries to the tomato supply for each country. Of the 28 countries that consumed more than five kilocalories per day from tomatoes, there was a strong protective correlation between tomato intake and prostate cancer mortality. Ganmaa et al. (2002) evaluated prostate cancer incidence rates and tomato consumption (based on country intake) for 44 countries. There was no correlation between tomato consumption and prostate cancer.

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 quantity of evidence (number of the various types of studies and sample sizes), 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[37], and the overall consistency[38] of the total body of evidence. Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support the substance/disease relationship, and, if so, determines the ranking that reflects the level of comfort among qualified scientists that such a relationship is scientifically valid.

Lycopene

As discussed in Section II of this letter, no studies provided information about whether lycopene may reduce the risk of prostate cancer. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between lycopene consumption, either as a food ingredient, a component of food, or a dietary supplement, and prostate cancer.[39]

Tomatoes and Tomato Products

As discussed in Section II of this letter, there were 13 observational studies that evaluated the relationship between the consumption of tomatoes or tomato products and prostate cancer: two cohort studies, one sub-cohort study, eight case-control studies, and two ecological studies. Both cohort studies reported a significant reduction in prostate cancer risk with increased consumption of tomato sauce or tomatoes, respectively (Giovannucci et al., 2002; Mills et al., 1989). Furthermore, prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.[40] The cohort studies were conducted in the United States, received high methodological quality ratings, and contained a large number of subjects (greater than 14,000 per study). Two case-control studies (Jain et al., 1999; Bosetti et al., 2000) and one ecological study (Grant, 1999) also reported a protective association between tomatoes and prostate cancer risk. However, five case-control studies (Villeneuve et al., 1999; Key et al., 1997; Hayes et al., 1999; Kolonel et al., 2000; and LeMarchand et al., 1991), one sub-cohort study (Schuurman et al., 1998) and one ecological study (Ganmaa et al., 2002) found no association between tomato intake and prostate cancer risk. Several of these case-control studies were conducted in the United States, received high methodological quality ratings, and each study contained greater than 1,000 subjects.

Based on the above, FDA finds that there is very limited credible evidence for a qualified health claim. FDA concludes that there is a very low level of comfort that a relationship exists between tomatoes and/or tomato sauce and prostate cancer.[41]

IV. Other Enforcement Discretion Factors

For the purposes of this section of the letter, the term "tomato" includes raw, cooked, dried, or canned tomatoes. FDA has not established a standard of identity for tomato sauce, however, the agency's policy on tomato sauce is that it should consist of a spiced tomato product concentrated to contain not less than 8.37 percent salt-free tomato solids, and that it can be made by adding spices to tomato puree (CPG 7109.21). For the purposes of this letter the term "tomato sauce" means a spiced or not spiced tomato product that contains at least 8.37% of salt-free tomato solids.

Factors that FDA intends to consider in the exercise of its enforcement discretion for qualified health claims about tomatoes and/or tomato sauce and prostate cancer used on the label or in the labeling of tomatoes and/or tomato sauce are discussed below.

A. Disqualifying Nutrient Levels

Under the general requirements for health claims (21 CFR 101.14(e)(3)), a food may not bear a health claim if that food exceeds any of the disqualifying nutrient levels for total fat, saturated fat, cholesterol, or sodium established in § 101.14(a)(4). Disqualifying total fat levels for individual foods are above 13.0 g per reference amount customarily consumed (RACC), per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Disqualifying saturated fat levels for individual foods are above 4.0 g per RACC, per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Disqualifying cholesterol levels for individual foods are above 60 mg per RACC, per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g. Disqualifying sodium levels for individual foods are above 480 mg per RACC, per label serving size, and, for foods with a RACC of 30 g or less or 2 tablespoons or less, per 50 g.

Tomatoes and most tomato sauces would not exceed the disqualifying levels for total fat, saturated fat, and cholesterol as specified in 21 CFR 101.14(a)(4). However, some tomatoes or tomato sauces may be disqualified based on their sodium level. FDA intends to consider the exercise of its enforcement discretion for qualified health claims about consumption of tomatoes and/or tomato sauce and reduced risk of prostate cancer on the label or in the labeling of tomatoes, tomato sauce, when the food does not exceed any disqualifying nutrient levels (i.e., total fat, saturated fat, cholesterol and sodium) as specified in 21 CFR 101.14(a)(4).

B. 10 Percent Minimum Nutrient Content Requirement

Under the general requirements for health claims, a conventional food may not bear a health claim unless it contains, prior to any nutrient addition, at least 10 percent of the Daily Value (DV) for vitamin A, vitamin C, iron, calcium, protein, or dietary fiber per RACC (21 CFR 101.14(e)(6)). The purpose of this provision is to prevent the use of health claims on foods with minimal nutritional value.

FDA notes that most tomatoes and tomato sauces will contain at least 10 percent of vitamin A, vitamin C, or both. Therefore, FDA intends to consider the exercise of its enforcement discretion for qualified health claims about tomatoes and/or tomato sauce and prostate cancer, used on the label or in the labeling of tomatoes and/or tomato sauce when the food complies with the 10 percent minimum nutrient contribution requirement as specified in 21 CFR 101.14(e)(6).

C. Minimum Effective Amount of Tomatoes Eligible for the Claim

The general requirements for health claims require 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 the appropriate form to justify the claim. Where no definition of 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)). After considering the available scientific evidence, the agency determined that the minimum effective amount of tomatoes and/or tomato sauce that may result in a reduced risk of prostate cancer is one-half to one cup per week.

V. Agency's Consideration of Disclaimers or Qualifying Language

We considered but rejected use of a disclaimer or qualifying language to accompany the proposed claim for which we found no credible evidence for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products, lycopene in fruits and vegetables, including tomatoes and tomato products, and lycopene as a food ingredient, a component of food, or as a dietary supplement and prostate cancer. We 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 decisive connotation for which qualifying language would result in 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 your petition, and other pertinent scientific evidence, FDA concludes that there is no credible evidence to support a qualified health claim for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in fruits and vegetables, including tomatoes and tomato products, and lycopene as a food ingredient, a component of food, or as a dietary supplement and reduced risk of prostate cancer. Thus, FDA is denying these claims. However, FDA concludes that there is very limited credible evidence for qualified health claims for tomatoes and/or tomato sauce, and prostate cancer provided that the qualified claim is appropriately worded so as to not mislead consumers. Thus, FDA intends to consider exercising its enforcement discretion for the following qualified health claim:

Prostate Cancer
"Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer. FDA concludes that there is little scientific evidence supporting this claim."

FDA intends to consider exercising its enforcement discretion for the above qualified health claim 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 claim, or that may raise safety concerns about the substance that is the subject of the claim.

Sincerely yours,

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


Appendix 1 (Heinz Letter)

See petition (docket #2004Q-0201) for complete reference citation

Observational Studies that evaluated lycopene from dietary sources
Giovannucci et al., 2002
Key et al., 1997
Hayes et al., 1999
Norrish et al., 2000
Cohen et al., 1999
Schuurman et al., 2002
Meyer et al., 1997
Deneo-Pellegrini et al., 1999
Jian et al., 2005

Lycopene serum levels from prospective studies
Gann et al., 1999
Huang et al., 2003
Hsing et al., 1990
Nomura et al., 1997

Serum lycopene measures in subjects diagnosed with cancer
Lu et al., 2001
Vogt et al., 2002
Rao et al, 1999
Cinton et al., 1996

Republication
Giovannucci et al., 1995
Norrish et al., 2000
Tzonou et al, 1999

Used non validated endpoints of cancer
Mucci et al., 2001

Food Frequency Questionnaire Validation not Verified in Study
Norrish et al., 2000
Cohen et al., 1999


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Notes

[1] This coalition consists of the H.J. Heinz Company, LycoRed Natural Products Industries, Ltd., The Morningstar Company, and The Prostate Cancer Foundation.

[2] Interim Procedures for Qualified Health Claims in the Labeling of Conventional Human Food and Human Dietary Supplements, (Attachment E) July 10, 2003. (http://www.cfsan.fda.gov/~dms/nuttf-e.html).

[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). [125 S.Ct. 310 (2004).

[4] See guidance entitled "Interim Evidence-based Ranking System for Scientific Data," July 10, 2003.  [http://www.cfsan.fda.gov/~dms/hclmgui4.html]

[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 Guidance entitled "Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements" (December 22, 1999).  [http://www.cfsan.fda.gov/~dms/ssaguide.html]

[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] See supra, note 4.

[11] 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).

[12] 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."

[13] See supra, note 4.

[14] In this instance, it is not necessary for FDA to determine whether it would be appropriate to consider the broad food category of fruits and vegetables as a substance for purposes of a health claim (see "QHC ANPRM," 68 FR 66040, Nov. 25, 2003), because even if they were considered to be a substance FDA finds that there is no credible evidence to support the claim concerning "fruits and vegetables." Nonetheless, FDA has evaluated information the petitioner submitted concerning fruits and vegetables.

[15] Since there were no other tomato products identified that purported to show an effect, the substance "tomato products" is in effect limited, in this case, to tomato sauce.

[16] While both lycopene and β-carotene are classified as carotenoids, they are structurally different from each other and exhibit different physiological effects.

[17] See supra, note 3.

[18] See Appendix 1

[19] See Appendix 1

[20] Β-carotene and lycopene are both members of the carotenoid family ("Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids," A Report of the Panel on Dietary Antioxidants and Related Compounds, Food and Nutrition Board of the Institute of Medicine, 2000).

[21] With regard to dietary supplements, 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 held 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 the single nutrient supplement.

[22] Therefore, observational studies in foods do not provide any credible evidence for a claim for risk reduction for a single food component because, in fact, the single food component form may decrease, have no effect, or actually increase risk of the disease or health related condition. Additionally, such studies do not provide credible evidence for the single food component as discussed above. For the reasons set forth in Section V, we have concluded that neither a disclaimer nor qualifying language would suffice to prevent consumer deception in these instances because observational studies in food do not provide credible evidence for the proposed claims for tomato lycopene, tomatoes and tomato products, which contain lycopene, lycopene in tomatoes and tomato products, or lycopene in fruits and vegetables, including tomatoes and tomato products and there is no other credible evidence to support these claims.

[23] See appendix 1

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

[25] See appendix 1

[26] See supra, note 3.

[27] In a cohort study, a group of healthy people or cohort is identified and followed up for a certain time period to ascertain the occurrence of disease and or health related events. (Epidemiology Beyond the Basics, page 24, Aspen Publishers, 2000).

[28] A sub-cohort study uses subjects from a defined cohort study. Cases are subjects diagnosed with the disease (i.e. cancer) in the cohort and controls are subjects selected randomly from a sample of the entire cohort at baseline. (Epidemiology Beyond the Basics, Aspen Publishers, 2000.)

[29] 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).

[30] An ecological study examines a possible association between aggregate measure of exposure and disease or mortality (Epidemiology Beyond the Basics, page 17, Aspen Publishing 2000).

[31] See Appendix 1.

[32] See Appendix 1.

[33] See Appendix 1.

[34] "Validation of the food frequency questionnaire method is essential, as incorrect information may lead to false associations between dietary factors and disease or disease-related markers." Cade, J., Thompson, R., Burley, V., and Warm D. Development, Validation and Utilization of Food-Frequency Questionnaires-A Review. Public Health Nutrition, 5: page 573, 2002.  See, also, Subar, A., et al., Comparative validation of the Block, Willett, and National Cancer Institute Food Frequency Questionnaires, American Journal of Epidemiology, 154: 1089-1099, 2001.

[35] "Food frequency questionnaires require validation prior to or as a part of dietary research. The approach taken in most studies is to examine the concordance of food frequency responses with reference instruments such as multiple 24 hour recalls or diet records using measurement error models to estimate the correlations between nutrient intakes measured by food frequency questionnaires and truth."  Subar, A., et al., Comparative validation of the Block, Willett, and National Cancer Institute Food Frequency Questionnaires, American Journal of Epidemiology, 154: 1089-1099, 2001.

[36] Relative risk 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 prospective studies by measuring exposure (e.g. lycopene intake) in subjects with and without disease (e.g. specific type of cancer). An adjusted relative risk controls for potential confounders. Confidence intervals provide a statistical analysis (p value) of relative risk. 95% Confidence intervals that include 1.0 are not statistically significant. "CI" stands for a Confidence interval.

[37] See supra, note 11.

[38] See supra, note 12.

[39] FDA also notes that there were no studies that evaluated the relationship between the consumption of a group of lycopene-containing fruits and vegetables and prostate cancer.

[40] See supra, note 4.

[41] See supra, note 4.