Qualified health claim: A claim authorized by the US Food and Drug Administration (FDA) that must be supported by credible scientific evidence regarding a relationship between a substance (specific food or food component) and a disease or health-related condition. Both of these elements -- a substance and a disease -- must be present in a health claim, An example of an authorized health claim is: "Calcium may reduce the risk of osteoporosis."
For example, in 2004 the FDA announced a qualified health claim for the reduced risk of coronary heart disease (CHD) on conventional foods that contain eiscosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega-3 fatty acids.
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Last Editorial Review: 5/13/2016
Package labels need to comply with labeling requirements set forth by the Code of Federal Regulations (CFR) and with the need to protect the public from misleading health claims and from dangerous ingredients. Regarding the need to protect the public, a problem is that, unlike prescription medicines, foods and dietary supplements do not require FDA approval before marketing.1 Consequently, FDA continuously monitors marketed products for unauthorized ingredients, such as anabolic steroids, weight loss drugs, and stimulants.2, 3 Most of FDA's monitoring is initiated by FDA itself, while complaints filed by physicians and consumers also initiate FDA's monitoring.
In this review, the term “section” and the section symbol (§) refer to a section within Title 21 of the CFR. The CFR is a body of administrative law, where a different Title of the CFR is used by a different agency of the federal government. These agencies include FDA, USPTO, and USDA.
As a consequence of FDA's monitoring of foods and dietary supplements, FDA issues warning letters to the manufacturers of various products. The majority of warning letters issued come from “routine workplan inspections” by FDA that include food label reviews, rather than from complaints originating from consumers or competitors.4-6 Before FDA issues a given warning letter, it is checked for consistency with warning letters issued by the various divisions of FDA's Center for Food Safety and Applied Nutrition (CFSAN). What is checked for consistency is letters issued by, for example, Office of Nutrition, Labeling, and Dietary Supplements and Office of Compliance.7
Package labels for foods, beverages, and dietary supplements contain a Principal Display Panel (PDP). The PDP is the part of the package that faces the consumer when stocked on the grocery shelf. Package labels also include a Nutrition Facts panel (or Supplement Facts panel) which lists ingredients, the Daily Value (DV; where relevant), and serving size.8 In the United States, there have been 3 eras of labeling where different reference values were used on the label: from 1941 to 1972 when Minimum Daily Requirements were used, from 1973 to 1993 when Recommended Daily Allowances (RDAs) were used, and since 1993 when DVs were used.9 DVs are published in FDA's Guidance for Industry.10 The term DV is used to refer to 2 different concepts, namely, Daily Reference Value (DRV) and Reference Daily Intake (RDI).11 DRV is derived in a way that is different than the derivation of RDI.
Package labels may contain writing that takes the form of one or more of the following claims:
Disease claims include statements such as “recommended for obesity,” in view of the fact that obesity is considered to be a disease, while the corresponding structure/function claim may be “recommended for weight loss.” Disease claims more typically take the form of statements such as “cures cancer and diabetes.” Where a package label includes a disease claim, the disease claim almost always inspires the FDA reviewer drafting the warning letter to characterize the product as a drug, and also to characterize the product as a “new drug.” “New drug” refers to the fact that a given product has not been FDA-approved, that is, approved by way of an application called a New Drug Application (NDA). A large proportion of FDA's warning letters against foods and dietary supplements concern inappropriate disease claims, and a small proportion of FDA's warning letters concern dietary supplements that contain pharmaceutically active drugs. Because FDA's warning letters against foods and dietary supplements usually refer to FDA's rules for approving drugs, this essay outlines FDA's approval process for drugs. By “drugs” what is meant is medicines for treating or preventing diseases.
“Structure/function” claims take the form of, for example, “promotes the development of lean muscle.” This type of claim refers to a benefit relating to biochemistry or physiology, not relating directly to any disease. “Health claims” address benefits for healthy consumers (not to consumers with an illness). For example, a health claim can take the form of, “calcium may reduce the risk of osteoporosis.” “Nutrient content” claims take the form of, for example, “loaded with,” “rich concentration,” “high in,” and “good source of.”
When FDA reviews the package label on a marketed product, the decision tree that is taken involves the step of determining if the product is a “conventional food” or a “dietary supplement.” This determination is made even if the package label contains words, such as “food” or “dietary supplement.” Depending on the outcome of this determination, FDA may complain about other aspects of the label, for example, representations in the Nutrition Facts panel or Supplement Facts panel. Also, depending on the outcome of this determination, FDA may consider if an ingredient in question is generally recognized as safe (GRAS).
The authority for labeling of foods and dietary supplements takes the form of sections in Title 21 of the United States Code (USC) and in Title 21 of the CFR. The subject matter of 21 USC §343, which concerns misbranded foods, encompasses much of the subject matter of this review. The subject matter of 21 USC §342, in particular, 21 USC §342(a)(2)(C), concerns adulterated foods. Adulterated foods are described in this review in the material on food additives.
However, the USC and the CFR provide little context, and hence their meaning may not be apparent to industry personnel who draft package labels. In addition to the CFR, FDA provides additional guidance for labeling in the form of various Guidance for Industry publications.12-18 However, FDA's Guidance for Industry publications are somewhat fragmentary, include only a moderate amount of detail, and cover only a small percentage of all labeling issues.
This review fulfills the unmet need for a comprehensive guide for most of the issues in drafting or evaluating package labels for foods and dietary supplements. To this end, the author reviewed all of FDA's warning letters from the years 2002 to 2015. The author also acquired guidance by directly contacting a number of FDA officials. Moreover, the author submitted questions to FDA's Food and Cosmetic Information Center (FCIC) at the CFSAN and received corresponding responses from experts in FDA regulations.
To provide a definition, the term “represented” is used to refer to the goal of the manufacturer, that is, in representing the product as a conventional food, dietary supplement, or drug. The term “characterized” is used in this review to refer to FDA's decision on the nature of the product, for example, whether a product represented as a conventional food was considered by FDA to be characterized by the package label as a conventional food, dietary supplement, or drug.
FDA's warning letters are distinguished from FDA's Form 483 letters. Although both types of letters have overlapping subject matter, they differ in procedure. Form 483 letters are issued with a minimal amount of review while, in contrast, warning letters are issued by FDA only after high-level review by attorneys employed by FDA.19 This essay concerns warning letters sent to manufacturers of foods and dietary supplements. An essay on FDA's warning letters sent to investigators engaged in FDA-regulated clinical trials that evaluate drugs, is also available.20
The abbreviations used in this essay are listed in Table 1.
|AIA||America Invents Act|
|CFR||Code of Federal Regulations. The CFR provides rules, also known as administrative laws.|
|CFSAN||Center for Food Safety and Applied Nutrition|
|DRV||Daily reference value|
|FDA||U.S. Food and Drug Administration|
|FCIC||Food and Cosmetic Information Center|
|FTC||Federal Trade Commission|
|GRAS||Generally recognized as safe|
|IND||Investigational New Drug. The IND is a submission to FDA where the goal is to acquire permission to initiate a clinical trial on a new drug.|
|NDA||New Drug Application. The NDA is a submission to FDA where the goal is to gain FDA approval to market a new drug.|
|NDI||New dietary ingredient|
|NDIN||New dietary ingredient notification|
|NOD||National Organic Program|
|OFPA||Organic Foods Protection Act|
|PDP||Principal display panel|
|RACC||Reference amount customarily consumed|
|RDA||Recommended daily allowance|
|RDI||Reference daily intake|
|USC||United States Code. The USC consists of laws, also known as statutes.|
|USDA||United States Department of Agriculture|
|USPTO||United States Patent and Trademark Office|
Format and content of the package label
Package labels include a PDP, an information panel, and any additional writing and pictures (Figure 1).21 The PDP is the portion of the package label most likely to be seen by the consumer at the time of purchase. The PDP must contain the statement of identity and this name must be the “common or usual name of the food.” Examples of “common or usual names” that are not appropriate include “cancer herb”22 and “evaporated cane juice.”23
The information panel is the label panel immediately to the right of the PDP, as seen by the consumer facing the product (Figure 1).24 The CFR provides diagrams of exemplary Nutrition Facts panels (21 CFR §101.9) and Supplement Facts panels (21 CFR §101.36). The PDP must contain the statement identity (the name of the food) and the net quantity. The information panel (usually the side panel) includes the Nutrition Facts panel (or Supplements Facts panel) and the name and address of the manufacturer. Only those nutrients listed in FDA's nutrition regulations, as mandatory or voluntary components of the nutrition label, may be included in the Nutrition Facts panel (21 CFR §101.9(c)). The 5 core nutrients, total fat, cholesterol, sodium, total carbohydrates, and protein, must always appear in the Nutrition Facts panel regardless of amounts present in the food.
A warning letter against a cherry juice product is exemplary, in that it ties together relations between the PDP, information panel, and Nutrition Facts panel. FDA complained that “[t]he percent juice statement ‘100% Pure Cherry Juice’ on your Michigan Montmorency 100% Pure Cherry Juice Super Concentrate product should not be declared within the Nutrition Facts panel. This declaration must be placed on the information panel, as required by 21 CFR 101.30(e), and may also appear on the principal display panel under 21 CFR 101.30(f).”25
The requirement for a Nutrition Facts panel is illustrated by a warning letter against “New Century Foods Wahoo Fish Burger,” where FDA characterized the product as “misbranded” because the package was totally lacking in the Nutrition Facts panel.26
The serving size must also be included. According to FDA's Guidance for Industry, “[m]anufacturers must use the information provided in the regulation to determine a specific serving size for their products.”27 The serving size is disclosed in 2 tables in the Reference Amount Customarily Consumed (RACC) (21 CFR §101.12). The RACC amounts are considered by FDA to be the “serving size.”
An example of a complaint about serving size is from a warning letter against a soybean cake product. The warning letter against “Fried Soy Bean Cake” complained that the declared serving size was 57 g, whereas, in contrast, the RACC established for soybean cake (tofu) was 85 g.28 In its warning letter, FDA provided this helpful guidance to the manufacturer regarding serving sizes. FDA complained that “[t]he serving size declaration for this product is not based on the reference amount customarily consumed (RACC) … your Fried Soy Bean Cake declares a serving size of “2 oz. (57 g),” however, the RACC established for bean cake (tofu) is 85 grams … [t]herefore, a serving size for bean cake must be based on the RACC of 85 grams. We calculate that 3 oz. of your product would weigh approximately 85 grams, which appears to be closer to the appropriate RACC for this product.” In other words, FDA's recommendation was to change the serving size to 3 ounces.
This concerns a different warning letter against a different soy product. For the product “Soybean Cake,” the serving size was disclosed as “1 piece (37 g).” In its warning letter, FDA pointed out that the RACC for a cupcake product is about twice this amount, that is, 80 g.29 Then, FDA suggested to change the serving size to “2 pieces (74 g),” writing that “[t]he label lists the serving size as “1 piece (37G).” The … RACC … for cupcakes is 80 g … [s]ince the weight of 1 piece of the Cup Cake product is less than 50 percent of the RACC, the serving size should be declared as “2 pieces (74 g).” This warning letter reveals that FDA sometimes spontaneously provides helpful advice. This letter also provides the take-home lesson that the disclosed serving size does not have to be precisely that stated by the RACC.
Other warning letters complaining about failure to disclose the serving size, or disclosure of an inaccurate serving size, are cited.30
Sources of guidance
Guidance for the labeling of dietary supplements and food products takes the form of FDA's Guidance for Industry publications, CFR, USC, and various “public letters” that are issued by the FDA. Warning letters that rely on these public letters are cited.31 Each public letter is identified by a docket number.32 Guidance also comes from a number of published opinions from federal courts, where examples are cited.33
The following outlines the regulatory basis for various types of claims on package labels.
- Structure/function claims are regulated by 21 USC §343(a)(1), which recites, “A food shall be deemed to be misbranded—(a) False or misleading label. If … its labeling is false or misleading in any particular.” Structure/function claims are also regulated by 21 USC §343(r)(6)(13). This section of the USC requires that if the label characterizes the mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function, then the label must also include a disclaimer that the product is not intended to treat any disease (21 USC §343(r)(6)). See also 21 CFR §101.93, which refers to 21 USC §343(r).34 Guidance for assessing structure/function claims comes from the cited references.35-37 The need for this disclaimer is illustrated by warning letters against dietary supplements that included structure/function claims, such as “builds muscle mass”38 and “to promote wellness and vitality.”39 The package labels failed to include the required disclaimer.
- Health claims are regulated by 21 CFR §101.70-§101.83. Guidance for drafting and assessing nutrient content claims comes from the cited publications.40-42
- Nutrient content claims are regulated by 21 CFR §101.54-§101.69. Guidance for assessing health claims comes from the cited publications.43-45
- Drugs are regulated, for example, by 21 USC §321(g). Relevant warning letters generally state that, “your products are drugs as defined by … 21 U.S.C. §§ 321(g)(1)(B) and (C) … because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body of man.” To view the big picture, where a food or a dietary supplement contains a disease claim, FDA reviews the product as though it was a drug.
- New drugs are regulated, for example, by 21 USC §321(p). Relevant warning letters usually include a statement that, “these products are ‘new drugs’, as defined by … 21 U.S.C. § 321(p) … because they are not GRAS and effective for their labeled uses. Under sections 301(d) and 505(a) of the Act, a new drug may not be introduced into interstate commerce unless an FDA-approved NDA is in effect for it.” As illustrated by examples shown below, this statement is made where the package label has a disease claim, or where the product takes the form of a combination of a drug and a dietary supplement.
The author printed and reviewed all of the warning letters from the Web site of the FDA from the years 2002 to 2015 (14 y) that concerned dietary supplements and foods. Where a warning letter only concerned sanitation, manufacturing, or record-keeping, the letter was not used as a source document. Also, this review does not concern creams, lotions, powders, and sprays. Regarding the citations of warning letters that occur throughout this review, the citations disclose the warning letter number and the date of the letter. Where the number was omitted from the warning letter, the citation instead discloses the name of the company.
Disease claims are the most common source of complaint in FDA's warning letters. Where a product is marketed as a food or dietary supplement, and where the package label or the company's Web site includes a disease claims, FDA responds with a warning letter that rejects the product and requests a timely response by the company. FDA reviews disease claims that are on the package label and Web site in exactly the same way. FDA's review and approval process for pharmaceuticals is always implicated when FDA reviews a food or dietary supplement that includes a disease claim. To provide an example, the most prevalent issue in warning letters from the year 2015 was disease claims, where these disease claims included claims about cancer,46 asthma,47 arthritis,48 and heart disease.49
Claims on package labels and on company Web sites may include disease claims, structure/function claims, health claims, and nutrient content claims. Disease claims are not permitted in products that are foods or dietary supplements, though the safe harbor of “health claims” does permit a select group of claims that concern risk for a disease in healthy populations. An understanding of disease claims requires an understanding of FDA's approval process for drugs, as outlined below. To repeat, to understand how FDA responds to a food or a dietary supplement that is labeled with a disease claim, it is necessary to understand FDA's approval process for drugs that are intended to treat diseases.
FDA's approval process for new drugs
Foods and dietary supplements often contain disease claims on the package label. Disease claims on the label compel the requirement that the product be evaluated by the FDA as a “new drug.” Warning letters against dietary supplements or foods with disease claims almost always refer to FDA's approval process for new drugs. This outlines FDA's approval process for new drugs. What is evaluated by FDA is the drug entity in combination with the excipient, the disease to be treated, and the dose and route of administration. In other words, what is approved by FDA is not merely the active drug component, but the combination of the active drug component and excipient, and the safety and efficacy for the relevant patient population.
The sponsor of a proposed drug, usually a pharmaceutical company, submits a document called an Investigational New Drug (IND) to the FDA. The IND includes data on safety and efficacy from animal studies and from the available clinical studies on human subjects. FDA reviews the IND. An IND provides background information on the mechanism of action of the drug, data from animal studies on efficacy and safety (toxicity), and data from clinical studies (studies on humans) on efficacy and safety.
Where FDA reviews and approves the IND, the sponsor writes and submits a Clinical Study Protocol, which is an instruction manual to physicians and nurses who conduct the clinical trials used for the drug-approval process, that is, the Phase I, Phase II, and Phase III clinical trials. FDA also reviews and approves the Clinical Study Protocol that is to be used for each of the Phase I, II, and III studies. Finally, based on data from the clinical trials, the sponsor submits an NDA. Regarding the NDA, an affirmative decision by the FDA permits the pharmaceutical company to market the drug for the approved indication. FDA then reviews the NDA, and decides whether or not to grant approval of the drug. More accurately stated, in granting approval for a drug, it is the case that FDA approves the package label of the drug.50-54 As demonstrated by hundreds of warning letters, a problem with marketed foods or dietary supplements that have disease claim on the package label, or with marketed foods or dietary supplements that actually contain a pharmaceutically active ingredient, is that the manufacturer had failed to engage in the drug-approval process involving submission of an NDA and IND.
FDA grants approval not for the drug itself, but for all information on the package label, that is, the entire formulation that contains the drug, the indication, and the dose. Once FDA approves of the package label, the company or manufacturer is free to market the drug in the United States. FDA has granted approval for pharmaceuticals where the active ingredient is omega-3 fatty acids.55 Please note that even though omega-3 fatty acids are nutrients, in the same way that folate is a nutrient, it is the case that a formulation called Vascepa® having omega-3 fatty acids as the active ingredient went through the FDA-review process. An FDA-approval letter dated July 26, 2012 concerned eicosapentaenoic acid ethyl ester (Vascepa®). FDA's letter approving the NDA stated that the approval was for use as recommended in the labeling text, that is, the package insert. The approval letter stated that marketing a product in a way that is “not identical to the approved labeling text may render the product misbranded and an unapproved new drug.”56 The package insert stated that the product, which was a soft gelatin capsule containing 1 g of eicosapentaenoic acid ethyl ester, where the capsule also contained tocopherol, gelatin, glycerin, maltitol, sorbitol, and water.57
A number of companies have attempted to market omega-3 fatty acid supplements with disease claims on the package label or on the Web site. FDA issued a warning letter against a product, “Omega 3 Salmon Oil Plus.”58 The product's Web site contained the disease claim, “in just over 2 mo my cholesterol dropped 49 points … and my triglycerides fell over 100 points.” FDA characterized the product as a “new drug” and stated that this “new drug” had not been approved on the basis of data submitted by the drug sponsor to demonstrate that the drug is safe and effective. A similar warning letter was issued against a product where the label read “studies indicate that the omega-3 fatty acids found in walnuts may help lower cholesterol.”59
The existence of warning letters against various omega-3 fatty acid products in FDA's is to be expected, because of failure of these products to conform to the conditions set forth in any FDA-approved package labels or package inserts, such as the package insert for Vascepa®. The cited publication provides a scientific background on omega-3 fatty acids for treating high triglycerides.60 Specific formulations of omega-3 fatty acids have been approved by FDA for treating very high triglyceride levels.61
Disease claims compel FDA to conclude that a product marketed as a food or a dietary supplement needs to be reviewed as a drug
The way a package label characterizes a product can influence FDA's response to the product. The most frequent issue to arise in reviewing package labels is disease claims. For example, if a product taking the form of a conventional food, such as concentrated cherry juice, has a package label that advocates use of the food for treating or preventing a disease, then FDA typically responds by characterizing the product as a “drug,” and by further characterizing the product as “new drug.” A product called “Cherry Juice Concentrate” had a label reading “[o]ngoing research shows that tart cherries are a rich source of antioxidants … which may help to relieve the pain of arthritis, gout and possibly fibromyalgia … [t]art cherries … can offer joint pain-relief and anti-inflammatory properties, fight cancer and heart disease, and prevent sleep disorders."62, 63 Unfortunately for the manufacturer, FDA responded with a warning letter stating that:
“These claims cause your products to be drugs … [b]ecause these products are not generally recognized as safe and effective when used as labeled, they are also new drugs … a new drug may not be legally marketed in the United States without an approved New Drug Application (NDA).”
Other warning letters against cherry products with disease claims are cited.64 For all of these products, FDA characterized the product as a drug, and concluded that the product could not be marketed in the United States. These warning letters provide the simplest-case scenario, that is, where FDA observed a disease claim, and rejected the product solely on that basis.
In several of the cherry products, the company's Web site represented the product as a “food.”65 Despite these representations as a “food,” FDA determined that the disease claims compelled the conclusion that all of these cherry products were drugs. Even where the package label or company's Web site contains a disclaimer stating that the product is not a drug, the disease claim will override this disclaimer and FDA will still conclude that the product is a drug.66, 67 As cited, soybean products have also been the source of complaint because of inappropriate disease claims, usually concerning cancer.68 Regarding these disease claims, many of these originated from published data from studies with animals or human subjects. However, data of this type cannot override FDA's requirement that an FDA-approved NDA exist in order to make the disease claim.
Disease claims for a food product that contained an added FDA-approved drug
As mentioned above, a product that contains a food substance such as omega-3 fatty acids, will be rejected by FDA where the package label contains a disease claim. This further develops this topic, where the product contains an added drug, and where the package label contains a disease claim. A warning letter sent to Swanson Health Products provides an example of the differences in rules that regulate drugs and dietary supplements.69 The product was a mixture of “red yeast rice” and added lovastatin. Red yeast rice is a fermented form of rice that may contain some lovastatin, that is, lovastatin that is naturally generated during fermentation.70 FDA complained that the label had “claims about lipid control and other cardiovascular benefits supplied by this ingredient [lovastatin].” The manufacturer had promoted the product as a “dietary supplement,” however, the warning letter stated that the claim about lipid control excludes the product from the definition of a dietary supplement (21 USC §355), unless the product had, at some previous time, been marketed as a dietary supplement and then was subsequently approved as a drug.71
The warning letter observed that lovastatin had earlier been approved as a drug, and concluded that this earlier approval as a drug excludes the product from being marketed as a dietary supplement. In a warning letter against a red yeast rice product marketed by Sunburst Biorganics and bearing a disease claim (powerful cholesterol fighting) FDA complained that “lovastatin's approval as a new drug preceded its marketing as a food or dietary supplement, and your lovastatin-enhanced product is excluded from the dietary supplement definition.”72 Thus, the problem with the red yeast products was 2-fold: (1) The presence of disease claims; and (2) The fact that the product had an added drug (lovastatin).
In most or all of FDA's warning letters against foods and dietary supplements bearing disease claims, FDA states that “[t]hese therapeutic claims … establish that the products are drugs … because they are intended for use in the cure, mitigation, treatment or prevention of disease,” and concludes that the product “could not be legally marketed in the U.S. without prior approval from FDA.”
Other warning letters against products with disease claims are cited.73 Where the warning letter failed to include a warning letter number, the name of the company is disclosed instead. In this review, the number of citations for any given issue reflects the frequency by which this issue arises in FDA's warning letters. Thus, the most frequent source of complaint, in FDA's review of foods and dietary supplements, is unauthorized disease claims.
Please also note that where a package label or the company's Web site cites one or more publications, these publications can become evidence of the product's intended use, and the citation itself can be considered to be a disease claim (21 CFR §101.93(g)(2)(iv)(C)).74Promotional materials, such as information distributed at a trade show, can be included in the warning letter's analysis of a product, and can be used to arrive at the conclusion that the product is a “new drug” and thus cannot be marketed in the United States.75
Where FDA rejects a product because of a disease claim, FDA may continue to analyze the label for other issues
FDA's most frequent complaint against food products and dietary supplement products is that a disease claim causes the product to be classified as a drug. FDA's review process has a redundancy. For a given product that has a disease claim on the label, and where FDA concludes that the product is a drug and cannot be marketed in the United States, it is often the case that FDA continues with its review of the label, as though the disease claim did not exist. This type of redundant review occurred in the cited warning letters.76 This redundant review is likely to be helpful to companies, because it enables the company to make most or all of the relevant corrections at the same time.
Guidance on evaluating structure/function claims is available from FDA's Guidance for Industry.77 This cited Guidance for Industry publication provides a number of examples of structure/function claims:
- “Promotes weight loss”
- “Improves blood circulation”
- “Reduces nervousness during stressful everyday situations, such as public speaking.”
- “The label of a dietary supplement containing “X” uses the claims: “The amino acid ‘X’ is the chemical precursor to nitric oxide. Blood vessel cells contain enzymes that produce nitric oxide. Nitric oxide is important in maintaining blood vessel tone.”
- “Corrects iron-deficiency anemia in the 10% of menstruating women with menorrhagia.”
Although iron-deficiency anemia is a disease, nutritional deficiency disease claims are permitted on dietary supplement labels for diseases that are “classical nutrient deficiency diseases.” Guidance for Industry states that “diseases resulting from essential nutrient deficiencies (for example, scurvy, pellagra) are not included in this definition.”78 Structure/function claims are defined in the USC by 21 USC §343(r)(6).
Standards of review
To justify a structure/function claim on a label, FDA will accept scientific evidence from the manufacturer or company, where this evidence takes the form79 of “tests, analyses, research, studies, or other evidence based on the expertise of professionals in the relevant area, that has been conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted in the profession to yield accurate and reliable results.”
This type of standard is familiar to scientists with training in the life sciences. This essay also describes other standards, that is, the standard for considering an ingredient as GRAS, the standard for FDA review of a NDA, and the standard of a New Dietary Ingredient (NDI). The GRAS standard is familiar to toxicologists, while the standard for reviewing NDAs is familiar to physicians involved in FDA-regulated clinical trials. American Dietetic Association has published a paper on structure/function claims.80
Examples of warning letters against products with structure/function claims
A dietary supplement called “Extreme Carb Blocker” had a package label with structure/function claims reading “blocks carb absorption” and “helps reduce sugar cravings.”81 FDA complained that “[w]e have reviewed these claims and have concluded that they are not supported by competent and reliable scientific evidence. Because these claims lack substantiation, they are false or misleading, and cause your product to be misbranded.” However, FDA provided helpful advice that “[i]f you have scientific evidence which you believe substantiates that your claims for … Extreme Carb Blocker are truthful and not misleading, please provide it to us within fifteen (15) working days.”
Table 2 provides a variety of structure/function claims for a number of dietary supplements. In the conclusion to all of the above warning letters, FDA characterized the product as “misbranded.” In some of these letters, FDA concluded with “[b]ased on the scientific data available to us, we do not believe that these claims are substantiated. If these claims do not have an adequate scientific basis, they are false or misleading and cause your products to be misbranded …[i]f you have data which you believe substantiates your claims, please share it with us within fifteen (15) working days.” It should be evident that the structure/function claims disclosed in Table 2 do not suggest or imply any particular disease, but instead relate to biochemical mechanisms or physiological mechanisms.
|Genesis Nutrition. March 26, 2004.||Super Chitosan||“dramatically reduce fat absorption in the body”|
|MuscleShoppe.com. Feb. 28, 2003.||Ripped Force||“for a ripped, well defined physique”|
|Natures Hand. Dec. 9, 2003.||Coral Calcium Supreme||“neutralize harmful acids”|
|W/L 31-04. March 4, 2004.||Coral Calcium||“when your pH is slightly alkaline, your body has the most ability to maintain good health. Only when you have enough calcium in the body will your pH be able to reach an alkaline state”|
|Natural Balance. Feb. 28, 2003.||Turbo Charge||“maximum sports performance”|
|SEA 05–14. Feb. 8, 2005.||Stabilized Vitamin O||“[i]n double blind clinical studies involving blood gas analysis, Vitamin O has been shown to significantly increase blood oxygen levels … those taking Vitamin O showed a 17% to 32% increase in arterial blood oxygen! In oral interviews conducted during this study, research participants reported greater youthfulness, improved mobility, better circulation, sharper mental clarity, enhanced lung and heart function, and increased physical energy”|
|Twinlab. Feb. 28, 2003.||Energy Fuel||“helps preserve lean muscle mass."|
Guidance from Federal Trade Commission (FTC) regarding structure/function claims
Regarding structure/function claims, although not requiring approval by FDA, it is the case that structure/function claims are frequently evaluated by the FTC. Evaluation by FTC is part of FTC's advertisement monitoring program, where FTC responds to complaints from consumer groups and from competitors.82 “Competitors” refers to manufacturers of competing food products and dietary supplement products.
FTC's role is illustrated by these examples.83 Where a nutrition supplement contains a structure/function claim, such as “promotes weight loss,” substantiating data should be provided by the manufacturer. Experts in the field of weight loss would generally require a randomized double-blind placebo controlled human clinical trial to substantiate a weight loss claim. Depending on the strength of the study, it may need to be replicated.
Where a nutrition supplement contains a structure/function claim, such as “promotes weight loss,” it is not acceptable to provide experimental weight loss data that is only from animal studies. Animal studies may provide information about safety and mechanism of action, but would not adequately support structure/function claims for efficacy in humans.
Where a nutrition supplement contains a structure/function claim, such as “promotes fat breakdown,” the question that arises with this claim is the nature of the substantiating data that must be possessed by the manufacturer. The problem with this claim is that consumers will interpret it as a physiological claim (and not merely a statement about a biochemical mechanism). For most consumers, they would not care about the breaking down of fat (a mere biochemical event) unless this breaking down of fat would lead to a physiological result. It is this physiological result that must be substantiated.84 Thus, where a nutrition supplement contains a structure/function claim, such as “promotes fat breakdown” it is not likely to be acceptable by the FTC to provide FTC with laboratory data on fat breakdown data that is only from animal studies.
Where a company includes a structure/function claim on the package label, such as “for weight loss” or “promotes fat breakdown,” there is not any requirement for notifying the FTC that the product that is being marketed under this label, and there is not any requirement for submitting a petition to the FTC of the product that is being marketed under this label.85
FTC and FDA work together under an agreement governing the division of responsibilities between the 2 agencies.86 As applied to dietary supplements, FDA has the responsibility for claims on product labeling and other promotional materials distributed at the point of sale. The FTC has the responsibility for claims in advertising, including print and broadcast ads, and catalogs. The FTC has taken action against supplement manufacturers, as well as against ad agencies, distributors, retailers, catalog companies, and others involved in deceptive promotions.
Health claims for foods and dietary supplements are voluntary statements that characterize a relation between a product and its ability to reduce the risk for a disease or disorder in healthy populations (21 CFR §101.14(b)).87-90 Health claims do not make claims for the treatment, cure, diagnosis, or mitigation of diseases. According to published comments from an FDA official, “[e]vidence to support a health claim should be based on studies in humans … randomized, placebo-controlled, double-blind intervention study provides the strongest evidence.”91 If there is a health claim, it must be in one place on the package label, and it must not be dispersed over different parts of the label.92
FDA provides guidance regarding eligibility for a proposed health claim and for petitioning to FDA for making this health claim. For a health claim for a food or dietary supplement that is not currently available among the options listed in Title 21, one can submit a petition to make such a claim concerning the nutrient (not the food or dietary supplement itself) for which the health claim is to be made.93 The petition needs to include research and evidence to demonstrate the claim that is being made. Petitions can be submitted on FDA's Web site.
What is described below are health claims that are permitted, health claims that are prohibited, and health claims for which the CFR is silent. The provisions in the CFR for “health claims” have been characterized as a “safe harbor” that permits package labels for dietary products to contain statements resembling disease claims. Regarding this safe harbor, the Nutrition Labeling and Education Act of 1990 (NLEA) created a “safe harbor” for foods and dietary supplements to bear FDA approved health claims. Prior to the NLEA, a health claim, which advertises a benefit for a disease or health-related condition, would render a food or a supplement an unapproved drug.94
Osteoporosis associated with calcium (21 CFR §101.72)
The CFR permits “health claims” that associate calcium, or calcium and vitamin D, with reduced risk for osteoporosis (21 CFR §101.72). The CFR provides a model health claim for calcium: “Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis” (21 CFR §101.72 (e)).
A gray area between what is “drug claim” and what is a “health claim” is disclosed by products that contain a drug and a nutrient. “BAYER'S WOMEN'S Low Dose Aspirin + CALCIUM,” included the claim, “helps strengthen bones to fight osteoporosis.”95 The issue was whether this was an FDA-authorized health claim, or if it was a disease claim. The warning letter stated that the language in question (“helps strengthen bones to fight osteoporosis”) is more assertive than the less assertive health claim language described by Section 101.72(e). FDA concluded that the claim was not authorized.
The next examples reveal that too little or too much of a particular ingredient can result in FDA's rejection of a product that has an authorized health claim. “Calcigenol Dietary Supplement,” had a label reading “calcium may be [sic] reduce the risk of osteoporosis.”96 FDA determined that this health claim was acceptable and that it was authorized. But FDA rejected this particular claim on other grounds, that is, the product did not contain enough calcium, citing 21 CFR §101.54(b), which concerns claims to “high in” and “rich in.” A related scenario, as cited, concerns a label with a health claim for osteoporosis but where the product's high levels of sodium prevented the use of the health claim for calcium.97
Cancer associated with fat (21 CFR §101.73)
“Health claims” that associate fat and cancer are permitted under Section §101.73. Relevant warning letters appeared not to exist on FDA's Web site.98
High blood pressure associated with sodium (21 CFR §101.74)
Health claims are permitted that associate sodium and high blood pressure (hypertension) (21 CFR §101.74). “HomeMaker Premium 100% Pure Florida Squeezed Orange Juice” had a label with a health claim concerning high blood pressure.99 This health claim associated the product content of folic acid, vitamin C, potassium, calcium, and sodium-free content, as all associated with reduced risk for high blood pressure. FDA complained that, although it is acceptable to state that the product's sodium-free content reduces risk for high blood pressure, it is not acceptable to state that the product's content folic acid and vitamin C also reduce risk for high blood pressure.
Coronary heart disease associated with saturated fat and cholesterol (21 CFR §101.75)
Health claims are permitted that associate “saturated fat and cholesterol” with risk for coronary heart disease. Section 101.75 provides model health claims, such as “While many factors affect heart disease, diets low in saturated fat and cholesterol may reduce the risk of this disease.” The cited information describes problems that arise when health claims relating to fat content of walnuts.100, 101
Cancer risk lowered with high fiber and low fat (21 CFR §101.76)
Health claims are permitted that associate diets low in fat and high in fiber-containing grain products, fruits, and vegetables, with reduced risk for cancer. The CFR provides model health claims, such as “Low fat diets rich in fiber-containing grain products, fruits, and vegetables may reduce the risk of some types of cancer, a disease associated with many factors.” The cited warning letter reveals a rejection of a product having a health claim for fiber, but where the product was an orange flavored beverage (not a grain, fruit, or vegetable).102 In another warning letter, FDA complained that “the claim on your Web site does not meet the requirements for the authorized claim … the claim must state that diets high in fiber-containing grain products, fruits, and vegetables may reduce the risk of some cancers. The claim on your website leaves out any reference to fruits, vegetables, and fiber content.”103
Coronary heart disease and high fiber and diets low in saturated fat and cholesterol (21 CFR §101.77)
Section 101.77 authorizes a health claim to high fiber foods that are low in saturated fat. This section states that “[t]he food shall meet the nutrient content requirements of 101.62 for a ‘low saturated fat,’ ‘low cholesterol,’ and ‘low fat’ food.” Section 101.77 also states that “In specifying the nutrients, the claim may include the term ‘total fat’ in addition to the terms ‘saturated fat’ and ‘cholesterol.’ Relevant warning letters include those against “Dippin Stix™ Fresh Apples Fruit Dip’104 and Cheerios.105
Diets low in fat and high in fruits and vegetables and cancer risk (21 CFR §101.78)
Warning letters against fruit and vegetable products that had cancer health claims are cited.106
Relationship between folate and neural tube defects (21 CFR §101.79)
FDA has authorized health claims for folate and neural tube defects, but only for dietary supplements that contain folic acid.107 A search of the warning letter database using the term “neural” or the term “101.79” did not reveal any warning letters.
Relationship between dietary carbohydrates and dental caries (21 CFR §101.80)
Searches of the warning letter database did not reveal the existence of any letters that concerned the relation between carbohydrates and dental caries.108
Relationship between diets that are low in saturated fat and cholesterol and that include soluble fiber from certain foods and the risk of coronary heart disease (21 CFR §101.81)
FDA has approved health claims for 2 types of dietary fibers for reducing risk for cardiovascular disease, namely, beta-glucan and psyllium (37 CFR §101.81). Federal Register provides additional information regarding claims to the dietary fibers, oat beta-glucan and psyllium.109, 110 Psyllium is a polysaccharide obtained from the husk of seeds of Plantago ovata.111 The cited warning letter reveals the failures of the package label, namely, failure to warn that the product should be consumed with fluids to avoid swallowing difficulties.112 In another warning letter, FDA complained that the health claim failed to specify the daily dietary intake of the soluble fiber source necessary to reduce the risk of coronary heart disease or the amount of soluble fiber in 1 serving.113
Relationship between diets that are low in saturated fat and cholesterol and that include soy protein and the risk of coronary heart disease (21 CFR §101.82)
Section 101.82 provides the example of an acceptable health claim, namely, “Diets low in saturated fat and cholesterol that include 25 g of soy protein a day may reduce the risk of heart disease. One serving of [name of food] provides ____ grams of soy protein." Soybean products that were characterized as having unauthorized health claims are cited.114
Relationship between diets that include plant sterol esters and the risk of coronary heart disease (21 CFR §101.83)
“EM Phytosterol” contained plant sterol esters and had a label with the health claim “excellent for lowering cholesterol.”115 In rejecting the product, FDA complained that the health claim “does not state that the plant sterol … should be consumed as part of a diet low in saturated fat and cholesterol,” that the label fails to state that the plant sterols “may” or “might” reduce risk for heart disease, and that the label fails to use the term “heart disease.” “Original Chocolate Bars,” had the health claim “promotes a healthy heart.”116 FDA rejected the product because it did not meet the requirement in Section 101.83 for being low in saturated fat.
Relationship between nuts and heart disease (Docket No. 02P-0505)
Additional allowable health claims are set forth by public letters that are identified by docket numbers, for example, Docket No. 02P-0505. Guidance for Industry refers to additional public letters.117 “Hot n’ Spicy Boiled Peanuts” had a label with the health claim “[s]tudies show 1 serving of peanuts a day can cut the risk of heart disease by ½ and diabetes by ¼.”118 The warning letter, illustrates the application of Docket No. 02P-0505, concluded that the product was misbranded.
Relationship between green tea and cancer (Docket Nos. FDA-2004-Q-0427; 2004Q-0083)
“Dragon Well Green Tea” had a package label with the health claim “green tea has been reported to contain … among teas, the highest concentration of catechins … to help prevent cancer.”119 FDA characterized the “health claim” as unauthorized, citing Docket No. FDA-2004-Q-0427. In this public letter, FDA stated that “FDA does not agree that green tea may reduce that risk because there is very little scientific evidence for the claim.” “Tea For Health,” which contained the same type of health claim, was rejected on the same basis.120
In this author's opinion, the unauthorized health claim on Dragon Well Green Tea was likely to have originated from publications, such as the following, which reported that, “[e]xperimental studies have consistently shown the inhibitory activities of tea extracts on tumorigenesis in multiple model systems.”121 However, it should be noted that health claims that seem to be supported by the scientific or medical literature, but are not authorized by FDA, are likely to result in FDA's rejection of the package label. This situation is in contrast to structure/function claims, where a company's own analysis can be used to justify a novel type of structure/function claim.
Silence of authorization for various health claims
In evaluating a number of products, FDA has characterized some of the claims as “health claims,” where FDA concluded that the health claim was not authorized and, as a consequence, rejected the package label. These include health claims to products with ingredients such as flax seed,122 phytoestrogens,123 and flavonoids.124, 125
Prohibited health claims
In evaluating a various products, FDA has characterized some of the claims as “health claims,” where FDA pointed out that the health claim was prohibited, as revealed below.
Zinc is one of the minerals required in the diet. Low zinc status and impaired immune function due to zinc deficiency have been documented in the elderly.126 However, FDA regulations prohibit health claims for “zinc and immune function in the elderly” (21 CFR §101.71(b)).