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U.S. Department of Health and Human Services

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Letter Responding to Health Claim Petition dated January 27, 2004: Green Tea and Reduced Risk of Cancer Health Claim (Docket number FDA-2004-Q-0427)

February 24, 2011

Sections

  1. Overview of Data and Eligibility for a Qualified Health Claim
  2. The Agency’s Consideration of a Qualified Health Claim
  3. Strength of the Scientific Evidence
  4. Other Enforcement Discretion Factors
  5. Agency's Consideration of Disclaimers or Other Qualifying Language
  6. Conclusions

References

Appendix 1 – August 19, 2008, Letter of Denial of Administrative Reconsideration


 

Sin Hang Lee, MD
Fleminger, Inc.
160 Hawley Lane, Suite 205
Trumbull, CT 06611

RE: Health Claim Petition: Green Tea and Reduced Risk of Cancer Health Claim
(Docket No. FDA-2004-Q-0427)

Dear Dr. Lee:

This is an amended response to the health claim petition dated January 27, 2004, submitted to the Food and Drug Administration (FDA or the agency), on behalf of Fleminger, Inc., as supplemented by your letter of May 21, 2004, pursuant to Section 403(r)(4) and 403(r)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. §§ 343(r)(4) and 343(r)(5)(D)). The petition requested that the agency authorize a qualified health claim characterizing the relationship between the consumption of green tea and a reduced risk of cancer. This petition proposed as a model qualified health claim: “Daily consumption of 40 ounces of typical green tea containing 710 µg/ml of natural (-)-epigallocatechin gallate (EGCG) may reduce the risk of certain forms of cancer. There is scientific evidence supporting this health claim although the evidence is not conclusive.”

FDA filed the petition on March 18, 2004 as a qualified health claim petition and posted the petition in the FDA docket system for a 60-day comment period, consistent with the agency's interim guidance for procedures on qualified health claims.1 The agency received one comment on the petition. The comment was from a consumer. The comment expressed support for the approval of the petition in a one-sentence statement. FDA considered the comment in its evaluation of the petition.

On June 30, 2005, FDA issued the original response letter (herein referred to as “the 2005 Response Letter”) that set forth the results of FDA’s scientific review of the evidence for the proposed qualified health claim regarding the consumption of green tea and the reduced risk of certain cancers. The letter also set forth the factors that FDA intends to consider in the exercise of its enforcement discretion for qualified health claims regarding the consumption of green tea and a reduced risk of breast cancer and the consumption of green tea and a reduced risk of prostate cancer. Finally, the letter also set forth the basis for FDA’s determination that there is no credible evidence to support a claim with respect to other types of cancer. The 2005 Response Letter informed you that FDA intended to consider exercising enforcement discretion for the following qualified health claims:

  • Two studies do not show that drinking green tea reduces the risk of breast cancer in women, but one weaker, more limited study suggests that drinking green tea may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer.
  • One weak and limited study does not show that drinking green tea reduces the risk of prostate cancer, but another weak and limited study suggests that drinking green tea may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of prostate cancer.

After FDA issued the 2005 Response Letter, you submitted to the agency a petition for administrative reconsideration, dated August 5, 2005, and supported by letters to the agency, dated July 1, 5, and 6, 2005, on behalf of Fleminger, Inc., pursuant to 21 C.F.R. § 10.33.  In your petition for administrative reconsideration, you requested that FDA modify the language of our conclusions to read as follows:

  • Drinking green tea equivalent to that consumed by Asian Americans may reduce the risk of breast cancer in women. There is credible evidence supporting this claim although the evidence is limited.
  • Drinking green tea equivalent to that consumed by the residents living in Hangzhou, China may reduce the risk of prostate cancer. There is credible evidence supporting this claim although the evidence is limited.

On August 19, 2008, FDA issued a letter (herein referred to as “the 2008 Response Letter”) denying your request for reconsideration of the agency actions set forth in the 2005 Response Letter (Appendix 1). In the 2008 Response Letter, the agency determined that your arguments did not demonstrate that the agency failed to consider or adequately consider relevant information or views contained in the administrative record for the decisions in the June 30th letter. Therefore, the agency determined that your request did not meet the criteria for administrative reconsideration as provided for in 21 C.F.R. § 10.33(d)(1).

In a September 10, 2008 letter to FDA, you acknowledged that the 2008 Response Letter “re-affirms . . . that the FDA intends to continue its consideration of the exercise of enforcement discretion only for the two claims set out in the [2005 Response Letter].” Nonetheless, you wrote that you:

recognize[d] that [FDA’s] clarification of the FDA ruling reiterates a qualified green tea health claim language for the Agency’s discretion enforcement consideration [sic] for the time being as follows:

Green tea may reduce the risk of cancer of the breast and the prostate. There is credible evidence supporting this claim although the evidence is limited.

We understand the language quoted above to reflect your intent to remove from your proposed claims any reference to the quantity or quality of green tea consumed by a given population (e.g. “green tea equivalent to that consumed by Asian Americans”).

On its own initiative, FDA has reevaluated the conclusions set forth in the 2005 and 2008 Response Letters, in light of a recent court ruling regarding qualified health claims, Alliance for Natural Health US v. Sebelius, 714 F. Supp. 2d 48 (D.D.C. 2010). In conducting this review, FDA has evaluated the claim language that you proposed in your petition for reconsideration and September 10, 2008 letter, because in those submissions, you revised the claim language that you originally requested. This amended response letter supersedes the previously issued 2005 and 2008 Response Letters. Therefore, the agency intends to exercise enforcement discretion for the qualified health claims on green tea and reduced risk of cancer as specified in this amended response letter.

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 C.F.R. § 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 C.F.R. § 101.14(b)(1)). Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.2 In a review of a qualified health claim, the agency first identifies the substance and disease or health-related condition that are the subject of the proposed claim and the population to which the claim is targeted.3 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.4

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.5

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,6 review articles,7 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 publications8 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.9 The agency conducts this rating evaluation by
considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), study category , 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 replicated10, and the overall consistency11 of the total body of evidence.12 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.

For the agency to consider a proposed health claim to be scientifically valid, the total body of publicly available scientific evidence supporting the substance-disease relationship must meet the standard for significant scientific agreement set forth in section 403(r)(3)(B)(i)of the Act (21 U.S.C. § 343(r)(3)(B)(i)). FDA’s determination of “significant scientific agreement” represents the agency’s best judgment as to whether qualified experts would likely agree that the scientific evidence supports the substance/disease relationship that is the subject of a proposed health claim.13 To meet this standard, there must be (1) evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific procedures and principles, and (2) significant scientific agreement, among experts qualified by scientific training and experience to evaluate health claims, that the claim is supported by such evidence. Where the “significant scientific agreement” standard is met, FDA authorizes a claim that, in most cases, states that the substance “may reduce the risk of” the specific disease or health-related condition.14

FDA may issue a letter of enforcement discretion as to a qualified health claim where the evidence for a substance/disease relationship is credible but does not meet the standard for significant scientific agreement set forth in section 403(r)(3)(B)(i) of the Act (21 U.S.C. § 343(r)(3)(B)(i)), provided that the claim is accompanied by a disclaimer or otherwise qualified in such a way as to not mislead consumers.15

A. Substance

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 C.F.R. § 101.14(a)(1)). A substance means a specific food or component of food, regardless of whether the food is in conventional form or a dietary supplement (21 C.F.R. § 101.14(a)(2)). The petition identified "typical green tea containing 710 mcg/ml of natural (-)-epigallocatechin gallate (EGCG)" as the substance that is the subject of the proposed claim. None of the scientific data evaluated by the agency identified specific amounts of EGCG in green tea. Therefore, the agency considered the relationship between green tea and a reduced risk of certain types of cancers. Green tea is an article used for drink and, therefore, meets the definition of food under the Act (21 U.S.C. § 321(f)(1)). Green tea is a brewed beverage made by infusing hot water with the dried natural tea leaves of Camellia sinensis (also referred to as Thea sinensis). Green tea differs from other types of tea, such as black or oolong, in that green tea is made with unfermented tea leaves, while black and oolong tea is made with fermented leaves. Therefore the agency concludes that green tea is a specific food and thus meets the definition of substance in the health claim regulation (21 C.F.R. § 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 C.F.R. § 101.14(a)(5)). The petition has identified cancer as the disease that is the subject of the proposed 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). Cancer is categorized into different types based on the specific organ site. Cancers at different organ sites have different risk factors, treatment modalities, and mortality risk (American Cancer Society, 2004). Both genetic and environmental risk factors may affect the risk of different types of cancers. Risk factors may include a family history of a specific type of cancer, cigarette smoking, alcohol consumption, overweight and obesity, exposure to ultraviolet or ionizing radiation, exposure to cancer-causing chemicals, and dietary factors. The etiology, risk factors, diagnosis, and treatment for each type of cancer are unique. 16 Since each form of cancer is a unique disease based on organ site, risk factors, treatment options, and mortality risk, each form of cancer must be individually evaluated in a health claim petition. As a result, the agency considered whether the studies supported the potential substance - disease relationship for any type of cancer, each of which constitutes a disease under 21 C.F.R. § 101.14(a)(5).

C. Safety Review

Under 21 C.F.R. § 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 levels necessary to justify a claim must be demonstrated by the proponent of the claim, to FDA's satisfaction, to be safe and lawful under 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 GRAS, approved as a food additive, or authorized by a prior sanction issued by FDA (see 21 C.F.R. § 101.70(f)). Dietary ingredients in dietary supplements, however, are not subject to the food additive provisions of the act (see section 201(s)(6) of the Act (21 U.S.C. § 321(s)(6)). Rather, they are subject to the adulteration provisions in section 402 of the Act (21 U.S.C. § 342) and, if applicable, the new dietary ingredient provisions in section 413 of the Act (21 U.S.C. § 350b), which pertain to dietary ingredients that were not marketed in the United States before October 15, 1994. The term “dietary ingredient” is defined in section 201(ff)(1) of the Act and includes vitamins; minerals; herbs and other botanicals; dietary substances for use by man to supplement the diet by increasing the total daily intake; and concentrates, metabolites, constituents, extracts, and combinations of the preceding types of ingredients.

Tea is a beverage that is among the most ancient beverages in the world. It is the second most highly consumed beverage in the world, after water, with oolong tea making up about 2% of tea consumption, green tea about 20%, and black tea almost 80% (NCI, DCPC Chemoprevention Branch and Agent Development Committee, 1996). The petition proposes a qualified health claim for reduced risk of various types of cancer based on the consumption of 40 ounces (five cups) of green tea per day, and evidence cited in the petition shows that in some populations 10 cups of green tea per day is consumed regularly (Graham, 1992).

The petition asserts that green tea is generally recognized as safe (GRAS) pursuant to section 409 of the Act. Tea (Thea sinensis) is listed in 21 C.F.R. § 182.20 as GRAS for its intended use.  Although compounds found in green tea have been observed to have interactions with certain nutrients and drugs, inclusion of green tea as part of the diet has not generally been associated with adverse effects. The polyphenols in green tea may interfere with the absorption of inorganic iron, and the vitamin K in green tea may influence the efficacy of the anticoagulant warfarin, although these interactions can be mediated by the addition of ascorbic acid to the diet and by the regulation of the drug dosage, respectively (Institute of Medicine, National Academies of Science, 2001).

Based on the above, FDA concludes under the preliminary requirements of 21 C.F.R. § 101.14(b)(3)(ii) that the use of green tea as described in the qualified health claims discussed in section IV, is safe and lawful.

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 green tea consumption on cancer risk, FDA considered these markers as indicators or predictors of disease.

The petition cited 220 publications as evidence to substantiate the relationship for this claim (see Docket No. FDA-2004-Q-0427). These publications consisted of 65 review articles, 2 abstracts, 1 meta-analysis, 12 in vitro studies, 12 animal studies, 92 observational studies that did not evaluate the substance and disease relationship, and 36 observational studies which did evaluate the relationship between green tea and cancer.

In addition to the studies in your petition that the agency considered, FDA considered three additional observational studies from a literature search which it conducted (Suzuki et al., 2004; Jian et al., 2004; Sonoda et al., 2004).

Below, we assess all of the available scientific information identified in relation to the proposed claim.

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 which 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 green tea. Therefore, FDA cannot draw any scientific conclusions from the animal or in vitro studies regarding green tea and the reduction of risk of any type of cancer.

C. Assessment of Intervention Studies

No intervention studies were submitted by the petitioner relating green tea and cancer risk reduction. Furthermore, the agency could not identify any relevant intervention studies from an independent literature search which it conducted.

D. Assessment of Observational Studies

There were 92 observational studies that evaluated a general category of food (e.g., tea) and not the specific substance of the claim (i.e., green tea). Because these studies did not assess the substance that is the subject of the proposed claim, they did not provide information from which scientific conclusions could be drawn regarding the substance - disease relationship.

FDA identified 39 observational studies that evaluated the relationship between green tea and one or more cancers. These studies consisted of seven prospective cohort studies,17 one nested case-control study,18 and 31 case-control studies.19 Below, the agency discusses the observational studies for each specific cancer type, because each individual cancer is considered its own unique disease, as discussed in Section I B above.

Breast Cancer
Five studies evaluated green tea consumption and breast cancer risk (Inoue et al., 2001; Nakachi et al., 1998; Suzuki et al., 2004 (consisting of two separate cohort studies); and Wu et al., 2003). The subjects in two of these studies (Inoue et al., 2001; Nakachi et al., 1998) had already been diagnosed with breast cancer. Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.20 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 breast 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 two studies (Inoue et al., 2001; Nakachi et al., 1998).

The remaining three studies were considered to be of high methodological quality (Suzuki et al., 2004 (consisting of two separate studies); and Wu et al., 2003). Suzuki et al. (2004) included two separate cohort studies from Japan to evaluate the relationship between green tea consumption and the risk reduction of breast cancer. Cohort I contained 14,409 subjects and 103 cases were followed for nine years. Drinking up to five cups of green tea per day was not significantly associated with breast cancer risk; relative risk 0.96 (95% CI 0.50-1.86).21 Cohort II contained 20,595 subjects and 119 cases with seven years of follow-up. Green tea consumption (greater than five cups per day) was not significantly associated with breast cancer incidence; relative risk 0.85 (95% CI 0.43-1.66).

Wu et al. (2003) was a case-control study that evaluated green tea intake and breast cancer risk in female Asian Americans living in Southern California, and used 501 cases and 504 controls. Drinking more than 85.7 milliliters of green tea per day was significantly associated with a decreased risk of breast cancer; odds ratio 0.47 (95% CI 0.26-0.85).

Prostate Cancer
Two case-control studies evaluated green tea and prostate cancer risk (Jian et al., 2004; Sonoda et al., 2004). Both studies received high methodological quality ratings. Jian et al. (2004) evaluated green tea intake and prostate cancer using 130 cases and 274 controls from China.   Drinking more than three cups of green tea per day was significantly associated with a reduced risk of prostate cancer; odds ratio 0.27 (95% CI 0.15-0.48).22 Sonoda et al. (2004) included 140 Japanese prostate cancer cases and controls. Drinking two to over ten cups of green tea per day was not significantly associated with prostate cancer risk; odds ratio 0.67 (95% CI 0.27-1.64) (for the group that drank at least ten cups of green tea per day).

Gastric Cancer
Sixteen studies evaluated the relationship between green tea and gastric cancer risk (Mu et al., 2003; Galanis et al., 1998; Hoshiyama et al., 2002; Koizumi et al., 2003; Tsubono et al., 2001; Hoshiyama et al., 2004; Hoshiyama et al., 1992; Inoue et al., 1998; Inoue et al., 1994; Ji et al., 1996; Kono et al., 1988; Lee et al, 1990; Setiawan et al., 2001; Tajima et al., 1985; Ye et al., 1998; and Yu et al., 1995). One of these studies did not use statistics to evaluate the specific relationship between green tea and gastric cancer risk (statistics measured other parameters in the study) (Mu et al., 2003). Statistical analysis of the relationship is a critical factor because it provides the comparison between subjects consuming green tea and those not consuming green tea, to determine whether there is a reduction in cancer risk.  Thus when statistics are not performed on the specific substance/disease relationship we are unable to determine if there is a difference between the two groups. As a result, this study provided no information about how green tea may reduce the risk of gastric cancer; hence, no scientific conclusions could be drawn from it.

Eleven of the studies provided no information as to whether the food frequency questionnaires in the studies, which were used for the collection of green tea consumption data from study subjects, had been appropriately validated (Galanis et al., 1998, Hoshiyama et al., 2004; Hoshiyama et al., 1992; Inoue et al., 1998; Inoue et al., 1994; Ji et al., 1996;; Lee et al, 1990; Setiawan et al., 2001; Tajima et al., 1985; Ye et al., 1998; and Yu et al., 1995). 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.23 As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence, no scientific conclusions could be drawn from them.24

Of the four remaining studies (Hoshiyama et al., 2002; Koizumi et al., 2003; Tsubono et al., 2001; and Kono et al., 1988), three were prospectively designed cohort studies (Hoshiyama et al., 2002; Koizumi et al., 2003; Tsubono et al., 2001;) and the remaining study was case-control designed (Kono et al., 1988). 

The three prospectively designed cohort studies received high methodological quality ratings.
Hoshiyama et al. (2002) followed a cohort of 30,370 males and 42,481 females from Japan for approximately nine years of follow-up with the endpoint being death from stomach cancer. The adjusted relative risk  for drinking greater than ten cups of green tea and stomach cancer mortality was 1.0 for men (95% confidence intervals (CI) 0.5-2.0) and 0.7 for women (95% CI 0.3-2.0).  These associations are not statistically significant. Tsubono et al. (2001) included 26,611 Japanese men and women and evaluated the relationship between green tea intake and risk of gastric cancer. After a seven year follow-up, 419 subjects were diagnosed with gastric cancer. An adjusted relative risk of 1.4 (95% CI 1.0-1.9) was observed between drinking less than one cup of green tea per day and drinking five cups of green tea per day, indicating that there was not a statistically significant association. Koizumi et al. (2003) included 39,604 Japanese men and women followed for nine years. In a combined analysis of the Tsubono et al. (2001) cohort and the Koizumi et al. (2003) cohort, there was no association between drinking more than five cups per day of green tea and gastric cancer risk; adjusted relative risk of 1.06 95% CI 0.86-1.30) (Koizumi et al., 2003).

One case-control study evaluated green tea consumption and gastric cancer risk (Kono et al., 1988). It received a moderate methodological quality rating. Kono et al. (1988) included 139 stomach cancer cases and 2,574 hospital controls (controls taken from hospitalized patients without cancer) as well as 278 population controls (controls from the general population) from Japan. There was no association between green tea intake and cancer risk when the cases were compared to the hospital controls; adjusted odds ratio of 0.5 (95% CI 0.3-1.1).  However, an association was reported when the cancer cases were compared to the population controls; odds ratio 0.3 (95% CI 0.1-0.7).

Lung Cancer
Four case-control studies evaluated the relationship between green tea and lung cancer (Chengyu et al., 1992; Le Marchand et al., 2000; Tewes et al., 1990; Zhong et al., 2001). Three of the studies provided no information as to whether the food frequency questionnaires in the studies, which were used for the collection of green tea consumption data from study subjects, had been appropriately validated. 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. As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusions could be drawn from them.25

The remaining study, a case control, received a high methodological quality rating (Le Marchand et al., 2000). Le Marchand et al. (2000) conducted a case-control study in Hawaii with 582 lung cancer cases and 582 controls. Green tea intake had no association with lung cancer incidence, and the adjusted odds ratio for the highest quartile of green tea intake was 0.9 (95% CI 0.5-1.6) compared to the lowest quartile of green tea intake.

Colon/Rectal Cancer
Seven studies evaluated the relationship between colon/rectal cancer and green tea intake (Miller et al., 1983; Tajima et al., 1985; Watanabe et al., 1984; Kono et al., 1991; Ji et al., 1997; Inoue et al., 1998; and Kato et al., 1990). One study measured green tea consumption and colon/rectal cancer incidence. However, the study did not calculate the odds ratio26 for colon/rectal cancer incidence and green tea intake. Without an odds ratio, it is not possible to determine if green tea intake reduced the risk of colon/rectal cancer. Therefore, the substance/disease relationship could not be evaluated in this study. As a result, this study provided no information about how green tea may reduce the risk of colon/rectal cancer; hence, no scientific conclusions could be drawn from it (Miller et al., 1983).

Five of the studies (Tajima et al., 1985; Watanabe et al., 1984; Ji et al., 1997; Inoue et al., 1998; and Kato et al., 1990) provided no information as to whether the food frequency questionnaires in the studies, which were used for the collection of green tea consumption data from study subjects, had been appropriately validated. 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.27 As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusions could be drawn from them.28

The remaining study received a high methodological quality rating (Kono et al., 1991). Kono et al. conducted a case-control study with 80 Japanese men with adenoma colon/rectal polyps and 1,180 polyp-free men to evaluate green tea intake and risk of colon/rectal polyps, a surrogate marker for colon/rectal cancer. There was no association between green tea consumption (greater than or equal to five cups per day) and polyp occurrence.

Esophageal Cancer
Four studies evaluated the relationship between green tea and esophageal cancer risk (Mu et al., 2003; Wang et al., 1999; Inoue et al., 1998 and Gao et al., 1994). One of these studies did not use statistics to evaluate the specific relationship between green tea and esophageal cancer risk (statistics measured other parameters in the study) (Mu et al., 2003). Statistical analysis of the relationship is a critical factor because it provides the comparison between subjects consuming green tea and those not consuming green tea, to determine whether there is a reduction in cancer risk.  Thus, when statistics are not performed on the specific substance disease relationship we are unable to determine if there is a difference between the two groups. As a result, this study provided no information about how green tea may reduce the risk of esophageal cancer; hence, no scientific conclusions could be drawn from it.

The remaining three studies (Wang et al., 1999; Inoue et al., 1998 and Gao et al., 1994) provided no information as to whether the food frequency questionnaires in the studies, which were used for the collection of green tea consumption data from study subjects, had been appropriately validated. 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.29 As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusions could be drawn from them.30

Pancreatic Cancer
Three case-control studies evaluated the relationship between pancreatic cancer and green tea consumption (Goto et al., 1990; Ji et al., 1997; and Mizuno et al., 1992). None of the three studies provided information as to whether the food frequency questionnaires in the studies, which were used for the collection of green tea consumption data from study subjects, had been appropriately validated. 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.31 As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusions could be drawn from them.32

Ovarian Cancer
One case-control study (Zhang et al. 2002) evaluated the relationship between green tea consumption and risk of ovarian cancer. It did not provide any information as to whether the food frequency questionnaire in the study, which was used for the collection of green tea consumption data from study subjects, had been appropriately validated. 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.33 As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusions could be drawn from them.34

Liver Cancer
One study (Mu et al., 2003) evaluated the relationship between green tea consumption and risk of liver cancer. This study did not use statistics to evaluate the specific relationship between green tea and liver cancer risk (statistics measured other parameters in the study) (Mu et al., 2003). Statistical analysis of the relationship is a critical factor because it provides the comparison between subjects consuming green tea and those not consuming green tea, to determine whether there is a reduction in cancer risk.  Thus when statistics are not performed on the specific substance disease relationship we are unable to determine if there is a difference between the two groups. As a result, this study provided no information about how green tea may reduce the risk of liver cancer; hence, no scientific conclusions could be drawn from it.

Bladder Cancer
One study (Wakai et al., 1993) evaluated the relationship between green tea consumption and risk of bladder cancer. However, the subjects in this study had already been diagnosed with bladder cancer. Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease. 35 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 bladder 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) that 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 this study (Wakai et al., 1993).

Skin Cancer
One study (Hakim et al., 2000) evaluated the relationship between green tea consumption and skin cancer incidence. However, the study did not calculate the odds ratio36 for skin cancer incidence and green tea intake. Without an odds ratio, it is not possible to determine if green tea intake reduced the risk of skin cancer.  Therefore, the substance/disease relationship could not be evaluated in this study. As a result, this study provided no information about how green tea may reduce the risk of skin cancer; hence, no scientific conclusions could be drawn from it.

Combined Analysis of Various Forms of Cancer
Two prospective cohort studies in Japan evaluated green tea intake and total cancer incidence (Nagano et al., 2002; Imai et al., 1997). These studies did not provide any information as to whether the food frequency questionnaire in the study, which was used for the collection of green tea consumption data from study subjects, had been appropriately validated. 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.37 As a result, these studies provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusions could be drawn from them.38 In addition the studies combined all forms of cancer into one single analysis. As discussed in Section I, each form of cancer is a unique disease based on organ site, risk factors, treatment options, and mortality risk. Hence, it is not possible to draw any scientific conclusions regarding individual cancer risks from studies that combine multiple forms of cancer into a single analysis. Nagano et al. (2001) did evaluate the risk of some individual forms of cancer in this publication as well as total cancers combined (e.g., stomach, colon/rectal, liver/ pancreatic, lung, breast and bladder); however, as stated above, the study did not provide any information on the validation of the food frequency questionnaire. As a result, the study provided no information on the accuracy of how green tea intake was measured, and hence no scientific conclusion could be drawn from it.

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), study category, 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 replicated39, and the overall consistency40 of the total body of evidence. Based on the totality of the scientific evidence, FDA determines whether such evidence is credible to support a qualified health claim for the substance/disease relationship, and, if so, considers a disclaimer or other qualifying language that should be included to convey the limits on the level of scientific evidence supporting the relationship or to prevent the claim from being misleading in other ways.

Breast Cancer
As discussed in Section II of this letter, three studies provided information about whether green tea may reduce the risk of breast cancer. Although two Japanese cohort studies found no association between green tea consumption and breast cancer (Suzuki et al., 2004 (consisting of two separate studies), one case-control study reported that, with green tea consumption, there was a reduction in breast cancer risk in Asian-Americans from California (Wu et al., 2003). However, the reported findings of Wu et al., 2003 have not been replicated, and replication of scientific findings is important in order to substantiate results.41 Moreover, consistency of findings among similar and different study designs is important for evaluating the strength of the scientific evidence.42 Furthermore, prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.43

The scientific evidence for a claim about green tea and a reduced risk of breast cancer thus is negligible. Based on FDA's review of the strength of the total body of publicly available scientific evidence for such a claim, FDA finds that there is very little credible evidence to support this claim, and therefore ranks the evidence at the lowest level for a qualified health claim.44 Given the state of the evidence, FDA concludes that it is highly unlikely that green tea may reduce the risk of breast cancer.

Prostate Cancer
As discussed in Section II of this letter, two studies provided information about whether green tea may reduce the risk of prostate cancer. These involved two case-control studies from China and Japan, respectively (Jian et al., 2004; Sonoda et al., 2004). Each of the two studies were small (fewer than 150 cases each) in size and both received high methodological quality ratings. Although Sonoda et al. (2004) reported no association, Jian et al. (2004) reported a decrease in prostate cancer risk with green tea intake. However, the reported findings of Jian et al., (2004) have not been replicated, and replication of scientific findings is important in order to substantiate results.45  Moreover, consistency of findings among similar and different study designs is important for evaluating the strength of the scientific evidence.46 Furthermore, both of the studies are retrospectively designed (case-control).  Prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.47

The scientific evidence for a claim about green tea and a reduced risk of prostate cancer thus is negligible. Based on FDA's review of the strength of the total body of publicly available scientific evidence for such a claim, FDA finds that there is very little credible evidence to support this claim, and therefore ranks the evidence at the lowest level for a qualified health claim.48 Given the state of the evidence, FDA concludes that it is highly unlikely that green tea may reduce the risk of prostate cancer.

Gastric Cancer
As discussed in Section II of this letter, four studies provided information about whether green tea may reduce the risk of gastric cancer. All of these studies were conducted in Japan. None of the three prospectively designed cohort studies that evaluated green tea and gastric cancer risk reported an association between green tea and gastric cancer risk reduction (Hoshiyama et al., 2002; Koizumi et al., 2003; Tsubono et al., 2001).  The three cohort studies collectively represented well in excess of 100,000 men and women. The one case-control designed study had ambiguous results (Kono et al., 1988) in that there was a protective association for green tea consumption and gastric cancer when population controls were used (278 men and women), but not when hospital controls were used (2574 men and women). The more reliable and largest studies (the three prospective cohorts) reported no relationship between green tea consumption and gastric cancer. The reported findings from the case-control study (Kono et al., 1998) suggested a beneficial relationship for only the population based controls.

As previously mentioned, a health claim characterizes the relationship between a substance and a disease or health-related condition (21 C.F.R. § 101.14(a)(1)), and the substance for which the health claim is requested 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 C.F.R. § 101.14(b)(1)).

The incidence of gastric cancer is high in Japan, while the incidence is very low in the United States (Hoenberger et al., 2003). Cancer is caused by external (e.g., dietary intake and infections)49 and internal factors50 (e.g., genetics, hormones, immune function). An estimated 50-80% of human cancer is caused by external factors.51 Different external or internal causal factors may alter the etiology of cancer in different populations. The precise etiology of gastric cancer is unknown, however two factors, high salt intake and Helicobacter pylori (H. pylori) infection, are associated with an increased risk of the disease and are external risk factors of gastric cancer.52 High salt intake and the incidence of H. Pylori infection are more prevalent in Japan than in the United States (Hoenberger et al., 2003; Key et al., 2004). High salt intake and H. Pylori infection are forms of bias53 for the green tea and gastric cancer relationship in Japan in that they each affect the risk of developing gastric cancer independent of green tea consumption.  Therefore, because of these two external factors, subjects in the studies conducted in Japan are not appropriate subjects when trying to determine whether there may be a reduction in risk of gastric cancer in the U.S. population. Accordingly, results of studies on the Japanese population cannot be extrapolated to reach conclusions about potential effects on the U.S. population.
Thus, studies from the U.S. or other applicable countries (countries with H. Pylori infection rates and salt intake that are similar to the United States) are needed as part of the total body of evidence to evaluate green tea consumption and gastric cancer risk.  The agency could find no studies that evaluated green tea and gastric cancer risk in people in the United States or other applicable populations. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between green tea consumption and gastric cancer.

Lung Cancer
As discussed in Section II of this letter, one study provided information about whether green tea may reduce the risk of lung cancer (Le Marchand et al., 2000). This case-control study found no association between green tea consumption and lung cancer. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between green tea consumption and lung cancer.

Colon/Rectal Cancer
As discussed in Section II of this letter, one study provided information about whether green tea may reduce the risk of colon/rectal cancer (Kono et al., 1991). This case-control study found no association between green tea and colon/rectal cancer. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between green tea consumption and colon/rectal cancer.

Esophageal, Pancreatic, Ovarian, Liver, Bladder, Skin Cancers, and Combined Analysis of Various Cancers
As discussed in Section II of this letter, no studies provided information about whether green tea may reduce the risk of any of these cancers. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between green tea consumption and any of these cancers.

IV. Other Enforcement Discretion Factors

Qualified health claims on the label or in the labeling of green tea are required to meet all applicable statutory and regulatory requirements under the Federal Food, Drug, and Cosmetic Act, with the exception of the requirement that a health claim meet the significant scientific agreement standard and the requirement that the claim be made in accordance with an authorizing regulation. Other exceptions to the general requirements for health claims that FDA intends to consider in the exercise of its enforcement discretion for qualified claims about green tea and reduced risk of both breast cancer and prostate cancer are discussed below, along with enforcement discretion factors specific to the green tea qualified health claims.

A. Disqualifying Nutrient Levels

Under the general requirements for health claims (21 C.F.R. § 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.

All types of non-herbal brewed teas are similar in nutrient composition and the nutrient profile is described in the USDA Nutrient Database for Standard Reference as one item (e.g. “Tea, brewed, prepared with tap water”). Non-herbal brewed tea is composed mostly of water; 99.7g per 100g and 236.29g per 8 fl. oz. (U.S. Department of Agriculture, Agricultural Research Service. 2010. USDA Nutrient Database for Standard Reference, Release 23. Nutrient Data Laboratory Home Page, http://www.nal.usda.gov/fnic/foodcomp/search). Green tea does not exceed the disqualifying nutrient levels for total fat, saturated fat, cholesterol, and sodium specified in 21 C.F.R. § 101.14(a)(4) and, therefore, FDA does not need to consider the exercise of its enforcement discretion for qualified health claims concerning green tea and breast cancer and green tea and prostate cancer to be used on the label or in the labeling of green tea when not used as an ingredient in other foods.

Green tea is also present as an ingredient for other foods. These other foods are primarily other beverages, such as tea blends and tea-juice blends, but can also include certain desserts, such as ice creams and cakes. FDA intends to consider the exercise of its enforcement discretion for qualified health claims for green tea and breast cancer and for green tea and prostate cancer to be used on the label or in the labeling of green tea-containing foods when the food does not exceed any of the disqualifying nutrient levels for fat, saturated fat, cholesterol, and sodium.

B. 10% Minimum Nutrient Content Requirement

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

FDA has previously exempted certain foods from the 10% minimum nutrient content when it has been determined that such exemptions could assist consumers in maintaining healthy dietary practices. For example, the agency exempted spreads and dressings for salads from this requirement in the plant sterol/stanol esters and CHD health claim interim final rule (65 FR 54686 at 54711). More recently, FDA considered a qualified health claim for walnuts and a reduced risk of CHD, even though walnuts did not meet the minimum 10% nutrient requirement (Walnuts and Heart Disease Letter of Enforcement Discretion, http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm072910.htm).

Green tea is composed of 99.7% water and contains no vitamin A, vitamin C, calcium, protein or fiber. It does contain 0.05 mg iron per RACC, which is well short of the 1.8mg required for the 10% minimum nutrient requirement for iron. Therefore, green tea does not meet the 10% minimum nutrient content requirement of 21 C.F.R. § 101.14(e)(6). However, as an essentially non-caloric food composed mostly of water, inclusion of green tea in the diet does not negatively affect the caloric balance of the diet and does not impede in any significant way the ability of consumers to maintain healthy dietary practices. Therefore, FDA intends to consider the exercise of its enforcement discretion for green tea that does not meet the 10% minimum nutrient content requirement in 21 C.F.R. § 101.14(e)(6). However, green tea-containing foods may not share this unique non-caloric attribute with brewed green tea. Therefore, FDA does not intend to consider the exercise of its enforcement discretion for green tea-containing foods that do not meet the requirements of § 101.14(e)(6).

The general requirements for health claims provide that, if the claim is about the effects of consuming the substance at other than decreased dietary levels, the level of the substance must be sufficiently high and in an appropriate form to justify the claim.  Where no definition for "high" has been established, the claim must specify the daily dietary intake necessary to achieve the claimed effect (see 21 C.F.R. § 101.14(d)(2)(vii)). However, the agency finds that this provision cannot be applied to either the qualified health claim for green tea and reduced risk of breast cancer or the qualified health claim for green tea and reduced risk of prostate cancer because the scientific evidence for these relationships is not conclusive, and does not support the establishment of a recommended daily dietary intake level, or even a possible level of effect for the general U.S. population.  Therefore, the agency continues to consider any label or labeling suggesting a level of green tea to be useful in achieving a reduction in the risk of breast or of prostate cancer for the general healthy population to be false and misleading under Section 403(a) of the Act.

V.  Agency's Consideration of Disclaimers or Other Qualifying Language

A. Background

Where the evidence for a substance/disease relationship is credible but does not meet the “significant scientific agreement” standard, FDA considers a disclaimer or other qualifying language that should accompany the claim to ensure the claim is truthful and not misleading. Such a disclaimer or other qualifying language may prevent consumers from being misled about the strength of the scientific evidence in support of the claim. Health claims have the potential to mislead consumers because a significant number of consumers rely upon health claims on food packages when deciding to buy a product.54 Moreover, studies have shown that a significant number of consumers assume that the claims on labels are accurate.55 Further, representations relating a product to an issue of public concern as a means to induce purchases may take on exaggerated importance in the public mind, and thus may be more likely to mislead (58 Fed. Reg. at 2394 (citing FTC v. Pharmtech Research, Inc., 576 F. Supp. 294, 301 (D.D.C. 1983) (advertisements for food supplements were misleading where they “played on the average consumer's well-founded fear of cancer”)).

The appropriate disclaimer or other qualifying language will depend upon the level of scientific evidence that supports a claim.56 FDA issues a letter of enforcement discretion as to the claim, along with the appropriate disclaimer or other qualifying language.57

As set forth above, the scientific support for a relationship between green tea and reduced risk of breast cancer is negligible, as is the scientific support for a relationship between green tea and reduced risk of prostate cancer. To accurately convey this scant level of scientific evidence, the 2005 Response Letter sets forth claims that describe the evidence and state the agency’s conclusion that the claimed health benefit is “highly unlikely.” For example, the qualified health claim for the relationship between green tea and breast cancer states: “Two studies do not show that drinking green tea reduces the risk of breast cancer in women, but one weaker, more limited study suggests that drinking green tea may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer.”

A recent court decision objected to similarly detailed language in the context of a qualified health claim regarding selenium and a reduced risk of prostate cancer.58 The court concluded that such an approach “replaced plaintiffs’ claim entirely” and “effectively negates any relationship between prostate cancer risk and selenium intake.”  Alliance for Natural Health US, 714 F. Supp. 2d at 71. Instead, the court directed the FDA to consider the possibility of permitting the proposed claim with the addition of “‘short, succinct, and accurate disclaimers.’” Id. (quoting Pearson v. Shalala, 130 F. Supp. 2d 105, 120 (D.D.C. 2001).

In light of the decision in Alliance for Natural Health US, FDA has revised the qualified health claim language set forth in the 2005 Response Letter. In developing alternative claim and disclaimer language, FDA has considered evidence from recent consumer research relevant to qualified health claims.

B. Disclaimers for Claims Regarding Breast and Prostate Cancer

1. Fleminger’s Proposed Claims

Your petition for reconsideration proposed the following claims:59

“Drinking green tea equivalent to that consumed by Asian Americans may reduce the risk of breast cancer in women.”

“Drinking green tea equivalent to that consumed by the residentsliving in Hangzhou, China may reduce the risk of prostate cancer.”

Your September 10, 2008, letter to FDA, in turn, sets forth the following proposed claim:

“Green tea may reduce the risk of cancer of the breast and the prostate. There is credible evidence supporting this claim although the evidence is limited.”

We understand your September 10, 2008, letter to reflect your intent to remove from your proposed claims any reference to the quantity or quality of green tea consumed by a given population (e.g. “green tea equivalent to that consumed by Asian Americans”). Further, because breast cancer and prostate cancer are independent diseases, we use “or” instead of “and” in the proposed claim. In this amended response to your health claim petition, FDA therefore considers the following proposed claim:

       “Drinking green tea may reduce the risk of breast or prostate cancer.”

2. Fleminger’s Proposed Disclaimer

You proposed the following disclaimer to accompany each claim:

“There is credible evidence supporting this claim although the evidence is limited.”

FDA concludes that your proposed disclaimer does not accurately convey the weakness of the scientific evidence regarding a relationship between green tea and a reduced risk of breast or prostate cancer.

Based on the presence of the claim, “Drinking green tea may reduce the risk of breast or prostate cancer,” in food labeling, consumers are likely to assume that FDA has endorsed the claim and that the claim is supported by reliable scientific evidence. Research has shown that consumers assume that the government evaluates and approves regulated products, even when that is not the case. A 2002 FDA national survey has shown that between 35.0 and 57.0 percent of consumers, either with or without use experience with dietary supplements, mistakenly believed that the government regulates the manufacturing and pre-approves the marketing of these products (FDA, 2007).   Consumers who make that mistaken, yet common assumption are likely to further assume that a claim stating that a substance “may reduce the risk of” a disease has been endorsed by FDA, and must be supported by reliable scientific evidence in order to earn the agency’s endorsement. See Simeon Mgmt. Corp. v. FTC, 579 F.2d 1137, 1145 (9th Cir. 1978) (affirming FTC determination that consumers’ assumption of government regulation may lead them to assume that claims of safety and effectiveness on drug products are “based, not on the advertiser's own opinion, but on a determination by the FDA”); see also Am. Home Prods. Corp. v. FTC, 695 F.2d 681, 697-698 (3d Cir. 1982) (“Pervasive government regulation of drugs, and consumer expectations about such regulation, lend drug claims all the more power to mislead”).60 Indeed, FDA uses that same claim format for health claims that are supported by the rigorous standard of “significant scientific agreement.”61 See 21 C.F.R. Part 101 Subpart E.

The risk of consumer deception is particularly acute where, as here, the scientific support for the claim is scant, and thus there is a very low likelihood that the substance actually may reduce the risk of the disease. Under these circumstances, a strong disclaimer is essential in order to make clear that FDA does not endorse the claim and that there is very little scientific evidence for the claim.

Your proposed disclaimer that characterizes the evidence as “credible” but “limited” is misleading because it suggests that the evidence is stronger than it really is. For breast cancer, two studies using a stronger methodology (prospective studies) showed no relationship between consumption of green tea and risk of breast cancer, compared to only one study using a less reliable study design (case-control study) that showed a possible relationship. Importantly, the one less reliable study in support of the claim has not been replicated. For prostate cancer, one less reliable case-control study showed no relationship between consumption of green tea and risk of prostate cancer, and another equally less reliable study showed a possible relationship. As with the breast cancer claim, the less reliable study in support of the prostate cancer claim has not been replicated. Because the evidence is so negligible and the claimed health benefit therefore is unlikely, consumers should be informed that there is very little scientific evidence and that, for that reason, FDA does not agree that green tea may reduce the risk of breast or prostate cancer.

3. FDA Disclaimer

As set forth in the Conclusion, FDA will consider exercising enforcement discretion for the health claim, “Drinking green tea may reduce the risk of breast or prostate cancer,” that is accompanied by the following disclaimer:

“FDA does not agree that green tea may reduce that risk because there is very little scientific evidence for the claim.”

This “short, succinct, and accurate” disclaimer corrects for consumer deception in the following two ways:

  • It prevents consumers from assuming that FDA endorses the health claim, and
  • It accurately conveys the level of scientific support for this claim.

We discuss each function in turn.

a. Preventing the Mistaken Assumption that FDA Endorses the Claim

Disclaimer language that states “FDA does not agree” with the claim prevents consumers from erroneously assuming that the health claim reflects FDA’s determination that the scientific evidence, taken as a whole, shows that green tea is likely to reduce the risk of breast or prostate cancer. As set forth above, many consumers assume that FDA evaluates and approves products regulated by the agency. See FDA (2007). The existence of this incorrect assumption by consumers has been recognized in case law as the proper subject of a corrective disclaimer. See Pearson v. Shalala, 164 F.3d 650 (D.C. Cir. 1999) (suggesting that disclaimer language could address consumers’ mistaken assumption that FDA had authorized the claim); see also Simeon, 579 F.2d at 1145-47 (affirming FTC determination that the failure to disclose the absence of FDA approval for a drug product rendered advertisements deceptive in violation of the Federal Trade Commission Act).

The disclaimer statement that “FDA does not agree” with the claim makes clear that FDA does not endorse the claim, and prevents consumers from making the incorrect assumption that FDA has reviewed the available evidence and agrees with the claim.

b. Accurately Conveying the Strength of the Scientific Evidence

The disclaimer, “FDA does not agree that green tea may reduce that risk because there is very little scientific evidence for the claim,” accurately conveys the strength of the scientific evidence because it helps consumers distinguish among claims that are supported by different levels of scientific evidence. To be effective, the disclaimer must enable consumers to distinguish between the very limited level of scientific support for the green tea qualified health claim, and the stronger level of scientific support for many other qualified health claims, and for health claims that FDA authorizes by regulation.

Consumer research confirms that a statement of FDA’s assessment of the strength of the evidence can be effective in allowing consumers to accurately distinguish between different levels of scientific support. In a study (Hooker and Teratanavat, 2008) in which subjects viewed health claims on a fictitious product label, respondents reported that they had greater confidence in the scientific support for unqualified health claims, compared to claims that were qualified with statements that included, “The FDA concludes that there is little scientific evidence supporting this claim.” A separate study (Kapsak et al., 2008) found that the following text enabled respondents to meaningfully distinguish between the highest two levels and lowest two levels of scientific support: “[Component] may reduce the risk of [disease]. FDA evaluated the scientific evidence and gave it a ‘[Letter]’ rating, based on a scale from A (strongest evidence) to D (weakest evidence).” These studies indicate that consumer confusion is lessened both by a statement of FDA’s characterization of the evidence (e.g. “very little scientific evidence”), and by a clear statement of FDA’s conclusion after evaluating the evidence (whether a letter grade or a statement that “FDA does not agree” that the substance may result in the claimed health benefit).

Based on this consumer research, FDA expects that the disclaimer statement for which it intends to exercise enforcement discretion will enable consumers to distinguish between the scant evidence underlying the green tea claim, and the more robust scientific support for qualified health claims supported by stronger scientific evidence and unqualified health claims supported by “significant scientific agreement.” The disclaimer “accurately reflects the strength of the evidence at issue,” Alliance for Natural Health US,714 F. Supp. 2d at 71, by informing consumers that FDA would not reach the scientific conclusion set forth in the claim based on the available evidence, and thus helps prevent consumers from mistakenly believing that the evidence is stronger than it is.

C. Disclaimers for Claims Regarding Cancers Other Than Breast and Prostate Cancer

FDA considered but rejected the use of a disclaimer or other qualifying language to accompany the proposed claims for green tea and cancers other than breast cancer and prostate cancer.  FDA concluded that neither a disclaimer nor other 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 other qualifying language that effectively characterizes the claim as baseless is not a viable regulatory alternative because neither the disclaimer nor other qualifying language can rectify the false 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 other 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 and other information submitted with your petition, and other pertinent scientific evidence and information, FDA concludes that there is no credible evidence to support qualified health claims for green tea consumption and a reduced risk of gastric, lung, colon/rectal, esophageal, pancreatic, ovarian, and combined cancers. Thus, FDA is denying those claims. However, FDA concludes that there is very little credible evidence for a qualified health claim specifically for green tea and risk of breast or prostate cancer. To avoid misleading consumers, this claim must be accompanied by disclaimer language. Therefore, FDA intends to consider exercising enforcement discretion for the following qualified health claim with the accompanying disclaimer:

Drinking green tea may reduce the risk of breast or prostate cancer. FDA does not agree that green tea may reduce that risk because there is very little scientific evidence for the claim.

Because this letter supersedes the 2005 and 2008 Response Letters, the health claim set forth above is the only claim for which FDA intends to consider exercising enforcement discretion as to the relationship between green tea and any form of cancer.

We note that FDA issued a Warning Letter to you dated February 22, 2010, that identified several violations of the Federal Food, Drug, and Cosmetic Act in connection with your marketing of green tea products. Among other things, your web site made health claims other than those for which FDA stated, in the 2005 Response Letter, that it intended to consider exercising enforcement discretion. It appears that you continue to market green tea using such claims.

If you continue to market green tea products using health claims other than the one for which FDA intends to consider exercising enforcement discretion, FDA may take enforcement action, including injunctions against manufacturers or distributors of illegal products, or seizures of such products, without further notice.

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 the claims that have been denied, that will no longer support the use of the above qualified health claim, or that raises safety concerns about the substance that is the subject of the claim.

Sincerely,

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

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Appendix 1 – August 19, 2008, Letter of Denial of Administrative Reconsideration

Sin Hang Lee, MD
Fleminger, Inc.
160 Hawley Lane, Suite 205
Trumbull, CT 06611

RE: Petition for Reconsideration: Letter Responding to Health Claim Petition Dated January 27, 2004: Green Tea and Reduced Risk of Cancer Health Claim (Docket No. 2004Q-0083)

Dear Dr. Lee,

This letter responds to your petition for administrative reconsideration of the decision by the Food and Drug Administration (FDA or the agency) regarding the health claim petition dated January 27, 2004, and supplemented May 21, 2004, for qualified health claims for green tea and reduced risk of certain cancers (Docket No. 2004Q-0083). Your petition for administrative reconsideration, dated August 5, 2005, and supported by your letters to the agency, dated July 1, 5, and 6, 2005, was submitted to the agency, on behalf of Fleminger, Inc., pursuant to 21 C.F.R. § 10.33. You requested that the agency reconsider its decision issued in a letter to you, dated June 30, 2005 (herein referred to as “the June 30th letter”). That letter was a response to the health claim petition filed by you, on behalf of Fleminger, Inc., requesting that the agency authorize a qualified health claim characterizing the relationship between the consumption of green tea and a reduced risk of cancer.

The June 30th letter set out the agency's determination that there was no credible evidence to support qualified health claims for the relationship between green tea consumption and a reduced risk of gastric, lung, colon/rectal, esophageal, pancreatic, ovarian, and combined cancers. Thus, FDA denied these claims. However, FDA did conclude that there was very limited credible evidence for qualified health claims specifically for the consumption of green tea and breast cancer and for the consumption of green tea and prostate cancer, provided that the qualified claims were appropriately worded so as to not mislead consumers. Thus, the June 30th letter sets out FDA's intent to consider exercising enforcement discretion for the following two qualified health claims:

“Two studies do not show that drinking green tea reduces the risk of breast cancer in women, but one weaker, more limited study suggests that drinking green tea may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer.”

“One weak and limited study does not show that drinking green tea reduces the risk of prostate cancer, but another weak and limited study suggests that drinking green tea may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of prostate cancer.”

Agency Decision on Your Request for Reconsideration

Under 21 C.F.R. § 10.33, interested persons may request that the Commissioner reconsider a decision rendered on a petition. 21 C.F.R. § 10.33 provides that a request for reconsideration shall be granted if the Commissioner determines that all the following apply: (1) the petition demonstrates that relevant information or views contained in the administrative record were not previously or not adequately considered; (2) the petitioner's position is not frivolous and is being pursued in good faith; (3) the petitioner has demonstrated sound public policy grounds supporting reconsideration; and (4) reconsideration is not outweighed by public health or other public interests. A petition for reconsideration may not be based on information or views not contained in the administrative record on which the decision was made. See 21 C.F.R. § 10.33(e).  

An interested person who wishes to rely on information or views not included in the administrative record must submit them with a new health claim petition. If a request for reconsideration is granted, under 21 C.F.R. § 10.33(i), the Commissioner shall review and rule on the merits of the matter. As discussed below, you set out several arguments in support of your request for reconsideration of the June 30th letter. However, none of your arguments demonstrates that the agency failed to consider or adequately consider relevant information or views contained in the administrative record for the decisions in the June 30th letter. Therefore, we have determined that your request for reconsideration does not meet the criteria in 21 C.F.R. § 10.33(d)(1). Therefore, the agency denies your request for reconsideration of the June 30th agency letter.62 Your arguments in support of your request for reconsideration are addressed below.

1. In section I of your August 5, 2005 petition for reconsideration, you argue that the claims contain confusing language. In support of your argument, you cite a number of media and industry reports and opinions of FDA's determination in the June 30th letter.

The intent of a qualified health claim is to be truthful and not misleading by accurately describing the state of the science supporting the claim. FDA's determinations must be guided by the state of the science supporting a given health claim. After an extensive scientific review of all the publicly available evidence, the agency believes that the two aforementioned claims most accurately describe the very limited credible evidence supporting the relationships between the consumption of green tea and reduced risk of breast and prostate cancer. To avoid confusion or mischaracterization of FDA's conclusions, the agency published the June 30th letter on the Internet at http://www.cfsan.fda.gov/~dms/qhc-gtea.html. By publishing the letter, FDA provided the public with unfiltered access to the agency's reasoning in evaluating the petition, as well as to the precise language of the two claims determined by the agency to be truthful and not misleading.

Your argument does not demonstrate that the agency failed to consider or adequately consider relevant information or views contained in the administrative record as required in 21 C.F.R. § 10.33(d)(1) to grant a request for reconsideration. Furthermore, the information you use to support your arguments, the media and industry reports and opinions issued after the June 30th letter, are not relevant here. Such reports and opinions are not part of the administrative record for the June 30th letter. As previously stated, a petition for reconsideration cannot be based on information and views not contained in the administrative record for the June 30th letter.

2. In section II of your August 5, 2005 petition for reconsideration, you argue that two studies (Suzuki et al., 2004; Sonoda et al., 2004) included in FDA's review of your qualified health petition should not have been considered by FDA because they were published after the submission of your petition and were not included in your original petition.63

FDA's scientific review of a petition is not limited to information included in the original petition. As described in sections I and II(G) of FDA's guidance on qualified health claims, the Interim Procedures for Qualified Health Claims in the Labeling of Conventional Human Food and Human Dietary Supplements, claims will be based on the extent to which the totality of the publicly available evidence supports the claims. As further specified in the guidance, in addition to information and views included in the petition, the agency receives comments during the official comment period. Furthermore, in its evaluation of every health claim or qualified health claim petition, the agency conducts a literature search for additional publicly available evidence relevant to its scientific review that is not included in either the petition or comments to ensure that any claims are based on the totality of publicly available evidence. The studies you contend should not have been considered, Suzuki et al. (2004) and Sonoda et al. (2004) were obtained by the agency in the literature search conducted as part of the scientific review of your petition. This detail is described on page six, in Section II, of the June 30th letter. All the studies considered by the agency are included in the administrative record.

The fact that the agency identified two studies through its literature search that were not included in your original qualified health claim petition does not demonstrate that the agency failed to consider or adequately consider relevant information or views contained in the administrative record as required in 21 C.F.R. § 10.33(d)(1) to grant a request for reconsideration.

3. In section III and IV of your August 5, 2005 request for administrative reconsideration and in sections I, II, III, and IV of your July 5, 2005 letter, you question the agency’s scientific review of the studies about the green tea and breast or prostate cancer qualified health claim. You outlined the following concerns:

a) You assert that Suzuki et al. (2004) is a short communication.

Agency’s Response:

The short communication by Suzuki et al. (2004) provided sufficient information about the two studies for the agency to evaluate them individually based on the scientific review process described in section I of the June 30th letter. Therefore, the fact that the communication is short does not demonstrate that the agency failed to consider or adequately consider relevant information or views contained in the administrative record of the June 30th letter.

b) You assert that Suzuki et al. (2004) consists of two cohort studies that are flawed because “…in Japan at the time of the survey, the majority of patients with cancer were not told the true diagnosis…and that the diagnosis of adenocarcinoma had been histologically confirmed in 80 percent of the cases.” You cite to Tsubono et al. (2001) as the basis for your assertion.

Agency’s Response:

Tsubono et al. (2001) used the same cohort as Suzuki et al. (2004) but evaluated gastric cancer whereas Suzuki et al. (2004) evaluated breast cancer. The Suzuki et al. (2004) article states “through population based cancer registries, 103 incident cases of breast cancer were identified in cohort 1 and 119 in cohort 2.” Suzuki et al. (2004) does not mention using questionnaires to assess cancer status or that only 80% of the breast cancer cases were histologically confirmed. The author in Tsubono et al. (2001) states, “[w]e ascertained the incidence of cancer by means of computerized linkage with the records in the Miyagi Prefectural Cancer Registry, one of the earliest and most accurate population-based cancer registries in Japan.” The article also states that “we did not inquire about a history of cancer in the questionnaire, because in Japan at the time of the survey, the majority of patients with cancer were not told the true diagnosis, and hence the accuracy of self-reports was thought to be low.” Tsubono et al. (2001) further states that “the diagnosis of adenocarcinoma had been histologically confirmed in 80% of the cases.” This quote, however, refers to gastric cancer cases described in the prior sentence. Tsubono et al. (2001) does not refer to the number of breast cancer cases histologically confirmed and was not used for the breast cancer claim. Your arguments regarding the Suzuki et al. study do not demonstrate that the agency did not consider or adequately consider relevant information or views in the administrative record of the June 30th letter.

c) You note that the number of breast cancer cases in cohort II cited in Suzuki et al. (2004) does not match the number of breast cancer cases discussed in another article (Nakaya et al., 2003) using the same cohort.

Agency’s Response:

There are several legitimate reasons why the number of cancer cases evaluated in two separate studies using the same data could vary. Research articles evaluating different exposure factors (e.g., green tea or personality traits) may have different inclusion/exclusion criteria which could change the number of cancer cases. For example, if a subject did not answer the question regarding green tea intake, the subject could not be used in the analysis for green tea but may be used in the analysis for personality characteristics and cancer. Your argument regarding the different number of breast cancer cases in the cohorts in the two studies does not demonstrate that the agency failed to consider or adequately consider relevant information or views in the administrative record of the June 30th letter.

d) You question why the agency characterized the Wu et al. (2003) study as weak in the claim language even though it received a high methodological quality rating.

Agency’s Response:

The methodological quality rating only concerns whether the methods used were appropriate for the particular study design type. By contrast, the study design type rating addresses the fact that some design types provide stronger evidence than others. For example, a randomized, controlled intervention trial can establish a causal relationship between a substance and a disease, whereas case-control studies can only show an association and cannot prove causality.

Suzuki et al. (2004) reported on two cohort studies, whereas Wu et al. (2003) was a case-control study. As we stated in the June 30th letter, “prospectively designed studies provide stronger evidence for an association than case-control studies since there are fewer forms of bias.” Hence, case-control studies provide weaker, more limited evidence for a substance and disease relationship than cohort studies. A weaker (e.g., less reliable) study can be of high methodological quality, but because of its limited reliability, provides weaker evidence than a prospective cohort study. FDA clearly considered this issue in the June 30th letter and your questions do not demonstrate that the agency failed to consider or adequately consider relevant information or views in the administrative record.

e) You note that the Wu et al. (2003) study has more cancer cases and used in-person interviewers to collect data compared to the Suzuki et al. (2004) studies which had fewer cancer cases and used a self-administered questionnaire.

Agency’s Response:

As discussed above in the response to (3)(d), case-control studies, like Wu et al. (2003), are inherently weaker (e.g., less reliable) as a result of study design than prospective cohort studies, such as Suzuki et al. (2004). The number of cases and controls included in each study is relevant to weighing the total strength of the evidence, but cannot overcome the limitations of the weaker case-control study design type where, as here, both studies are of high methodological quality. Again, this argument does not demonstrate that we failed to consider or adequately consider relevant information in the administrative record.

f) You argue that in-person interviews used by Wu et al. (2003) are superior to mailed self-administered questionnaires used in the Suzuki et al. (2004) cohort studies.

Agency’s Response:

We incorporate by reference the response above to (3)(d), setting out that case-control studies are inherently of weaker study design type than prospective cohort studies. Both the Wu et al. (2003) and Suzuki et al. (2004) studies received high methodological quality ratings. Both studies used validated questionnaires to assess green tea consumption and the agency considered both in-person interviewer and self-administered questionnaires equal in ascertaining exposure status of the subjects.  The methodological difference you note cannot overcome the limitations of the weaker case-control study design type where, as here, both studies are of high methodological quality. This argument also does not demonstrate that the agency failed to consider or adequately consider relevant information in the administrative record.

g) You claim that some studies are more relevant than others in considering the total body of evidence in support of a relationship between green tea and cancer because some study populations had access to higher quality green tea than others. Your assertions along this line include the following.

  • The articles by Suzuki et al. (2004) and Sonoda et al. (2004) should not have been used by the FDA because they were conducted in northern rural Japan where the quality of green tea consumed is of poor quality.
  • Green tea consumers in Los Angeles know where to get quality green teas because they are descended from the Middle Kingdom of China, which values quality green tea, as opposed to the residents of Miyagi, Japan who filled out the Suzuki et al. (2004) questionnaire.
  • The Sonoda et al. study finding no relationship between consumption of green tea and reduced risk of prostate cancer is flawed because the cases came from two regions of Japan that consume green tea of very different quality because of different access to quality green tea - one region borders a famous tea producing region, the other does not produce tea.
  • Jian et al. should have received more consideration because it was conducted in a region of China that has access to high-grade green tea with more EGCG by weight than lower quality green tea.

In support of your arguments, you reference a picture of a tea peddler in Hangzhou, China and a map of tea producing regions of Japan and two studies (Fujiki et al. 2002; Fujiki 2005) which you claim are relevant to the question of quality of green tea consumed in different locations of Japan and its effects on cancer prevention.

Agency’s Response:

The agency evaluates qualified health claim petitions based on the publicly available science in the administrative record. None of the studies from which scientific conclusions can be drawn provided the nutrient composition or other characteristics, such as quality, of the green tea consumed in their particular study. Hence, it is not possible to assess the “quality" of green tea in any of the studies. We also note that the picture and map you reference in support of your assertions were not included in your original petition and cannot be considered in connection with this request for reconsideration. See 21 C.F.R. § 10.33(e). Your assertions do not demonstrate that the agency failed to consider or adequately consider relevant information or views in the administrative record of the June 30th letter.

4. In your letters to the agency, dated July 1, 2005 and July 6, 2005, you propose revisions to the claim language considered by FDA for enforcement discretion to include reference to the content level of epigallocatchin gallate (EGCG) in the green tea.

In support of your proposal, you reference the National Cancer Institute’s (NCI) Chemopreventive Branch and Agent Development Committee's recommendation on the quality and quantity of green tea to be consumed for potential anticancer benefits entitled “Clinical development plan: tea extracts, green tea polyphenols, epigallocatechin gallate.” and published in the Journal of Cellular Biochemistry 26S:236-257 (1996) ("NCI Article"). The article was included with your original health claim petition.

Agency Response:

As stated in the June 30th letter, “None of the scientific data evaluated by the agency identified specific amounts of EGCG in green tea. Therefore, the agency considered the relationship between green tea and a reduced risk of certain types of cancers.” The Clinical Development Plan developed by NCI summarizes the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. The NCI article references an article by Yang et al. (1993) which documented the contents of typical green tea. The NCI article (Chemopreventive Branch and Agent Development Committee, 1996) states “There are a number of different types of green and black tea. They differ in genetic variety and production methods to yield, for example those with high theaflavin content or strong aroma.” Therefore, the agency does not believe that the 1996 NCI article represents a standard for green tea set by the NCI. Your argument regarding the NCI article also does not demonstrate that we failed to consider or adequately consider all relevant information or views in the administrative records of the June 30th letter.

Agency Conclusions

For all the reasons set out above, FDA denies your petition for reconsideration. The agency concludes that your petition does not satisfy the requirements for reconsideration because none of the issues raised in your petition demonstrates that the agency failed to consider or adequately consider relevant information or views contained in the administrative record, as required by 21 CFR § 10.33(d)(1).

Although 21 C.F.R. § 10.33(d) gives the Commissioner the discretion to grant a request for reconsideration when the Commissioner determines that it is in the public interest and in the interest of justice, the agency believes that granting the request on this basis is not warranted here in light of the extensive scientific review that underlies the June 30th letter. Moreover, even if your request for reconsideration were granted, reconsideration of the decision set out in the June 30th letter would result in the same decision. The scientific evidence is clear that there was no credible evidence to support qualified health claims for a relationship between consumption of green tea and a reduced risk of gastric, lung, colon/rectal, esophageal, pancreatic, ovarian, and combined cancers and very limited credible evidence for the qualified health claims for consumption of green tea and reduced risk of prostate and breast cancer.

As noted in the June 30th letter, 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 the claims that have been denied, that will no longer support the use of the above qualified health claims, or that raises safety concerns about the substance that is the subject of the claims. Until such time that FDA evaluates new information, you may continue to rely on FDA's June 30th letter for the agency's current evaluation of the state of the total body of evidence in support of a relationship between consumption of green tea and reduced risk of different cancers.  At this time, FDA intends to continue its consideration of the exercise of enforcement discretion only for the two claims set out in the June 30th letter.

Sincerely,

David J. Horowitz, Esq.
Assistant Commissioner for Policy
Food and Drug Administration


1 The interim procedures have since been finalized (Guidance for Industry: FDA's Implementation of "Qualified Health Claims": Questions and Answers; Final Guidance) and can be found at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/
ucm053843.htm

2 See Whitaker v. Thompson, 353 F.3d 947, 950-51 (D.C. Cir 2004) (Reh'g en banc denied on March 9, 2004) upholding FDA's interpretation of what constitutes a health claim.

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

4 For brevity, "disease" will be used as shorthand for "disease or health-related condition" in the rest of the section.

5 In an intervention study, subjects similar to each other are randomly assigned to either receive the intervention or not to receive the intervention, whereas in an observational study, the subjects (or their medical records) are observed for a certain outcome (i.e., disease). Intervention studies provide the strongest evidence for an effect. See supra, note 3.

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

7 Review articles summarize the findings of individual studies.

8 Other examples include book chapters, abstracts, letters to the editor, and committee reports.

9 See supra, note 3.

10 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).

11 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).

12 See supra, note 3.

13 Id.

14 See 21 C.F.R. § 101.72 et seq.

15 See supra, note 1.

17 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).

18 A nested-case control study uses subjects from a defined cohort. Cases are subjects diagnosed with the disease (i.e. cancer) in the cohort and controls are subjects selected from individuals at risk each time a case (i.e. cancer) is diagnosed. (Epidemiology Beyond the Basics, page 34, Aspen Publishers, 2000).

19 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).

20 See supra, note 2.

21 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. green tea 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.

22 Odds ratio is the odds of developing the disease in exposed compared to unexposed individuals (Epidemiology Beyond the Basics, page 29, Aspen Publishers, 2000). It is calculated in case control studies by measuring disease (e.g. specific type of cancer) development in subjects based on exposure (e.g. green tea). Adjusted odds ratio 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.

23 “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.

24 “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.

25 See supra, note 21.

26 See supra, note 19.

27 See supra, note 20.

28 See supra, note 21.

29 See supra, note 20.

30 See supra, note 21.

31 See supra, note 20.

32 See supra, note 21.

33 See supra, note 20.

34 See supra, note 21.

35 See supra, note 2.

36 See supra, note 19.

37 See supra, note 20.

38 See supra, note 21.

39 See supra, note 10.

40 See supra, note 11.

41 See supra, note 10.

42 See supra, note 11.

43 See supra, note 3.

44 See supra, note 3.

45 See supra, note 10.

46 See supra, note 11.

47 See supra, note 3.

48 See supra, note 3.

49 External causal factors are environmental, lifestyle, nutritional or cultural factors (e.g. smoking chemical, radiation, dietary factors socioeconomic factors, and specific viruses).

50 Internal causal factors are genetic, gender, race or inherent factors (metabolism and pH).

51 Cancer Prevention and Control, Chapter 6, page 83, edited by Greenwald P., Kramer B., Weed D. Marcel Dekker Publishing, 1995.

53 Bias is defined as the result of systematic error in the selection of study participants and as a consequence the observed results of a study may be different from the true results (Epidemiology Beyond the Basics, pages 125-126 Aspen Publishing, 2000).

54 2005-2006 National Health and Nutrition Examination Survey. See question DBQ780 at: http://www.cdc.gov/nchs/data/nhanes/nhanes_05_06/sp_dbq_d.pdf

55 FDA 2008 Health and Diet Survey. See questions C11 and C15 at:http://www.fda.gov/Food/ScienceResearch/ResearchAreas/ConsumerResearch/ucm193895.htm

56 See Guidance for Industry: Evidence-Based Review System of the Scientific Evaluation of Health Claims, at 8 (“The health claim language should reflect the level of scientific evidence with specificity and accuracy”), available at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/
ucm073332.htm
.

57 See supra, note 1.

58 Specifically, the court considered the following claim language: "Two weak studies suggest that selenium intake may reduce the risk of prostate cancer. However, four stronger studies and three weak studies showed no reduction in risk. Based on these studies, FDA concludes it is highly unlikely that selenium supplements reduce the risk of prostate cancer." Alliance for Natural Health US, 714 F. Supp. 2d at 71.

59 We discuss the claim and accompanying disclaimer language that you proposed in your petition for reconsideration, because that submission revised the language that you originally requested.

60 FDA regulates labeling claims not only for dietary supplements and drugs, but also for conventional foods like green tea. FDA has no reason to believe that consumers have different assumptions as to FDA endorsement for claims in each of these product categories.

61 “Significant scientific agreement” means that the Secretary (and, by delegation, FDA) has “determine[d], based on the totality of the evidence (including evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific procedures and principles), that there is significant scientific agreement, among experts qualified by scientific training and experience to evaluate such claims, that the claim is supported by such evidence.” 21 U.S.C. § 343(f)(3)(B)(i).

62 21 C.F.R. § 10.33(d) requires that all four criteria be met for a request for reconsideration to be granted. Because we have determined that your request does not meet 21 C.F.R. § 10.33(d)(1), it is not necessary for us to address the other criteria in 21 C.F.R. § 10.33(d).

63 We note that your petition for reconsideration incorrectly refers to FDA's July 28, 2005 letter as a "ruling." You contend that the "ruling" in the letter dictates that FDA should not have considered the Suzuki et al., 2004 and Sonoda et al., 2004 studies because they were not made public until after the date of your submission. FDA's July 28, 2005 letter was correspondence intended to provide clarification on the reconsideration process under 21 C.F.R. § 10.33 and does not constitute an agency ruling on any matter. The letter suggests that you review FDA's regulations at 21 C.F.R. § 10.33 if you wish to submit a request for reconsideration and states that "if you wish to rely on information or views not previously included in the record of your January 17, 2004 petition … you would need to submit a new petition, rather than seeking only reconsideration." This statement correctly states the requirement in 21 C.F.R. § 10.33(e) that a petition for reconsideration may only be based on information contained in the administrative record on which the decision was made. The studies in question were appropriately included in the administrative record for the June 30th letter.