U.S. REGULATORY FRAMEWORK FOR FUNCTIONAL FOODS

17.4 U.S. REGULATORY FRAMEWORK FOR FUNCTIONAL FOODS

Although there is no legal definition for a functional food, nor are there specific regulations to govern functional foods in the U.S., the Food and Drug Administration

(FDA) overlooks a number of regulatory policies that can be used as venues to approve functional foods and nutraceuticals for the American market. The FDA does not distinguish functional foods from conventional foods, since both categories, if qualified, may carry a health claim on their label. Any approval of functional foods and nutraceuticals has to be on a case-by-case basis under existing food regulations (Food, Drug, and Cosmetic Act) or the newly introduced regulation for dietary supplements (Dietary Supplement Health and Education Act (DSHEA)).

17.4.1 F OOD S AFETY :G ENERALLY R ECOGNIZED AS S AFE (GRAS)

Manufacturers of functional foods have to obtain premarket approval and demon- strate that all food additives, including functional ingredients, are generally recog- nized as safe (GRAS). If functional foods contain any non-GRAS ingredients, the potentially unsafe ingredient must undergo the FDA’s approval process for new food ingredients. This requires manufacturers to conduct studies in food safety and submit the results of these experiments to the FDA for review before the ingredient can be used in marketed products. Based on a review of results, the FDA either authorizes or rejects the food’s ingredients. Historically, to obtain a GRAS status for a food additive, the manufacturer must apply for approval under the Direct Food Additive Petition (21 CFR 171.1–171.8, 171.100–171.130, and 184.1). 17,18 This process is rather cumbersome, taking between 2 and 6 years for the GRAS status to be granted. In April 1997, however, the GRAS notification process was introduced to help speed

up approval for food ingredients. 19 This is the most suitable system for approval of functional foods in the U.S. This approval process requires submission of a document (dossier) that contains safety and efficacy data, which is prepared by the GRAS panel. All pivotal data must be published prior to the application. The GRAS panel should be composed of at least two experts qualified by scientific training and experience to evaluate the safety of food and food ingredients using scientific procedures. The panel must be recognized by the FDA and should be independent of the company seeking approval. The FDA reserves 90 days to review submission and respond to the applying company by sending a letter of no objection or rejection. The functional ingredient in question has to be presented in context of the final food product. If needed, subsequent applications for other food products containing an ingredient under review may be prepared under the GRAS self-affirmation system. The latter approach is a policy of the FDA but not part of the Code of Federal Regulations (CFR). Health claims are not permitted unless a submission is made to the FDA under the Nutritional Labeling and Education Act (NLEA). Table 17.3 provides the information required for the GRAS notification approval process (21 CFR 170.35). 20

Food Regulations

TABLE 17.3

Requirements for the GRAS Notification Approval Process (21 CFR 170.35) 20

Requirements of the Proposed Rule

1. Detailed information about the identity of the notified substance, composition, method of manufacture, characteristic properties, and specifications 2. Information on any self-limiting levels of use 3. Comprehensive discussion of, and citations to, generally available and accepted scientific data

and information, including consideration of probable consumption 4. The basis for concluding that there is a consensus of qualified experts that there is reasonable certainty that the substance is not harmful under the intended conditions of use

17.4.2 H EALTH C LAIMS

Prior to the introduction of functional foods in the American market, the U.S. was the first country to institute a law allowing health claims for constituents present in

foods. The link between diet and health was a major topic of the White House Conference on Food, Nutrition, and Health in 1969. 21 Since then, consumers’ interest in this area has grown. The issues of health, food safety, and nutrition labeling were the focus of attention for both the FDA and the U.S. Department of Agriculture (USDA) in the 1980s. Health messages on food labels were the subject of national debate, leading to mandatory nutrition labeling.

17.4.2.1 Nutrition Labeling and Education Act (NLEA)

In 1990, the American Congress passed the Nutrition Labeling and Education Act (NLEA) to ensure that food labels provide consumers accurate and reliable infor-

mation regarding the nutritional and health values of foods. 22 The act states:

The Secretary shall promulgate regulations authorizing claims characterizing the rela- tionship of a nutrient to a disease or health-related condition which is diet-related only if the Secretary determines, based on the totality of publicly available scientific evidence (including evidence from well-designed studies conducted in a manner which is con- sistent 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.

The NLEA clarified and strengthened the authority of the Food and Drug Admin- istration to require nutrition labeling on foods, as well as the establishment of

circumstances under which claims may be made about nutrients pertaining to foods. The legislation also provided a process for the orderly regulation of disease claims. This act describes the relationship between the food constituent and the disease or health-related condition. The health claim can be used only if it meets the require- ments of the act (21 CFR 101.14): 23

Functional Food Carbohydrates

TABLE 17.4

Disqualifying Nutrient Levels 23

Disqualifying Nutrients

Foods

Main Dishes

Meal Products

Fat

26 g Saturated fat

13 g

19.5 g

4g 6g 8g Cholesterol

120 mg Sodium

Note : Food must contain less than the specified levels to make a health claim (21 CFR 101.14).

1. The health claim must be about the link between diet and certain serious chronic disease conditions.

2. The statement must be specific to describing the health benefit the com- pound, upon ingestion, has on the risk reduction and prevention of a

particular chronic disease condition.

3. The health message must be made in the context of the total diet.

4. The health claim must be based on scientific evidence that is reviewed and accepted by the FDA.

In addition, food products that contain a specific health compound may carry a health claim on a label only if they do not contain excess amounts of undesirable

components as specified by regulation (disclosure/disqualifier levels), i.e., they fulfill the “jelly bean rule” (21 CFR 101.14). 23 The undesirable components are total fat,

saturated fat, cholesterol, and sodium. Food must contain less than the specified disqualifying levels of these four nutrients (Table 17.4). The disqualifying levels are

the amount in the reference serving size, the label serving size, or (for foods with

a reference size of 30 g or less or 2 tablespoons or less) the amount per 50 g. To qualify for a health claim, a food product must provide nutritional value to consum- ers. Therefore, it must contain, without fortification, at least 10% of the daily value for one of six nutrients, such as vitamin A, vitamin C, iron, calcium, protein, or fiber, per reference amount (Table 17.5). This rule is known as the jelly bean rule because jelly beans are free of disqualifying nutrients and, in theory, may carry a health claim. However, jelly beans are not nutritious and do not qualify as an appropriate food for the risk reduction of diseases.

There are currently 12 health claims approved under the NLEA rules (21 CFR 101.72–101.83). 24 It is worthwhile to note that 11 of these claims are in the form of final rulings, while the last claim, which links consumption of plant sterols to risk reduction of coronary heart disease (CHD), is still in purgatory and waits for the final version (Table 17.6). Four of the NLEA health claims are associated with the consumption of carbohydrates and the risk reduction of hearth disease and some types of cancers.

Fiber-containing foods have captured the interest of researchers for a long time. For almost 100 years, indigestible carbohydrates (equivalent to dietary fiber) were

Food Regulations

TABLE 17.5 Jelly Bean Rule

DV

Nutrient

DV Nutrient

Vitamin A

100 mg Vitamin C

500 IU

Calcium

5g Iron

Note : Food must contain, without fortification, 10% or more of the daily value (DV) for one of six nutrients, as specified in the table (dietary supplements excepted).

recognized to have positive effects on bodily functions. However, over the last 30 years, researchers proposed that this compound could be protective against many chronic diseases, such as cardiovascular disease, diabetes, and disorders of the gastrointestinal tract, including cancer of the colon. The FDA found this evidence nonconclusive, and petitions for approval of the dietary fiber and cancer claim, as well as the cardiovascular disease claim, have not been authorized and remain on a

list of unauthorized claims (21 CFR 101.71). 24 However, the FDA recognized a health importance of fiber as a part of the diet, “fiber food,” and approved two health

claims that link fiber as a part of food products with the risk reduction of cancer and coronary heart disease: 24

1. Fiber-containing grain products, fruits, and vegetables and cancer (21 CFR 101.76)

2. Fruits, vegetables, and grain products that contain fiber, particularly sol- uble fiber, and risk of coronary disease (21 CFR 101.77)

Both claims may be used only on grain, fruits, and vegetables that contain fiber without fortification. The type of fiber is not specified, but

food must contain enough fiber to qualify as a good source of fiber (10 to 19% of the Daily Reference Values (DRVs) or 2.5 to 4.9 g of fiber per reference serving size) for the cancer claim to pertain, and at least 0.6 g of soluble fiber per reference amount (RA) for the coronary heart claim to pertain. The food itself must comply with the requirements discussed above, such as those regarding fat and cholesterol.

Dietary fiber is also the subject of the third claim, which links fruits and vegetables with the risk reduction of some types of cancer: 24

3. Fruits and vegetables and cancer (21 CFR 101.78) In this claim, fiber is one of the food constituents that, along with antioxidants

such as vitamin A and vitamin C, may play an important role in the prevention of cancer.

In 1997, the FDA allowed for another health claim linking “soluble fiber from whole oats and risk of coronary health disease” (21 CFR 101.81). 24 In allowing this

538 TABLE 17.6

Generic Health Claims Approved under the NLEA Regulation in the U.S. 24

Approved Claims

Model Claim

21 CFR

Calcium and osteoporosis

Regular exercise and a healthy diet with enough calcium help teens and young adult white and Asian women

maintain good bone health and may reduce their high risk of osteoporosis later in life

Dietary lipids and cancer Development of cancer depends on many factors; a diet low in total fat may reduce the risk of some cancers §101.73 Sodium and hypertension

§101.74 Dietary saturated fat and

Diets low in sodium may reduce the risk of high blood pressure, a disease associated with many factors

§101.75 cholesterol and risk of

While many factors affect heart disease, diets low in saturated fat and cholesterol may reduce the risk of this

disease

coronary heart disease Fiber-containing grain

§101.76 products, fruits, and

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

vegetables and cancer Fruits, vegetables, and grain

§101.77 products that contain fiber,

Diets low in saturated fat and cholesterol and rich in fruits, vegetables, and grain products that contain some

types of dietary fiber, particularly soluble fiber, may reduce the risk of heart disease, a disease associated

particularly soluble fiber, and

with many factors

risk of coronary heart disease Fruits and vegetables and

§101.78 Functional F

Low-fat diets rich in fruits and vegetables (foods that are low in fat and may contain dietary fiber, Vitamin A,

cancer

or Vitamin C) may reduce the risk of some types of cancer, a disease associated with many factors; broccoli is high in vitamin A and C, and it is a good source of dietary fiber

Folate and neural tube defects

Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or spinal cord

ood Carboh Dietary sugar alcohols and

defect

§101.80 dental caries

Full claim : Frequent between-meal consumption of foods high in sugars and starches promotes tooth decay;

the sugar alcohols in [name of food] do not promote tooth decay Shortened claim (on small packages only): Does not promote tooth decay

ydrates

§101.81 Food Regulations

Soluble fiber from certain

Soluble fiber from foods such as [name of soluble fiber source and, if desired, name of food product], as part

foods and risk of coronary

of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease; a serving of [name of food

heart disease

product ] supplies __ grams of the [necessary daily dietary intake for the benefit] soluble fiber from [name of soluble fiber source ] necessary per day to have this effect

Soy protein and risk of

§101.82 coronary heart disease

(1) 25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk

of heart disease; a serving of [name of food] supplies __ grams of soy protein (2) Diets low in saturated fat and cholesterol that include 25 grams of soy protein a day may reduce the risk of heart disease; one serving of [name of food] provides __ grams of soy protein

Plant sterol/stanol esters and

§101.83 risk of coronary heart disease

(1) Foods containing at least 0.65 gram per serving of vegetable oil sterol esters, eaten twice a day with meals

for a daily total intake of at least 1.3 grams, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease; a serving of [name of food] supplies __ grams of vegetable oil sterol esters

(2) Diets low in saturated fat and cholesterol that include two servings of foods that provide a daily total of at least 3.4 grams of plant stanol esters in two meals may reduce the risk of heart disease; a serving of [name of food ] supplies __ grams of plant stanol esters

Functional Food Carbohydrates

claim, the FDA concluded that there is enough scientific evidence to support the relationship between soluble fiber from whole oats and the risk reduction of CHD.

Oats are an excellent source of beta-glucan soluble fiber, which upon con- sumption forms a gel in the intestines. Subsequently, fiber gel interferes with the absorption of cholesterol in the intestine and helps to lower blood cholesterol levels. In allowing the whole oats–CHD health claim, the FDA assumed that soluble fiber from sources other than whole oats could positively modify blood lipids and consequently lower the risk of heart disease. However, since soluble dietary fibers are a family of heterogeneous substances that vary greatly in their effect on risk of CHD, a case-by-case approach was necessary to evaluate petitions for this health claim. Nevertheless, this health claim was amended in 1998 to “soluble fiber from certain foods and risk of coronary health disease.” The autho- rization of the amendment was a response to a petition submitted by the Kellogg Company involving soluble fiber from psyllium seed husk. Psyllium, known also as blood or Indian psyllium, was introduced by Kellogg in a cereal product called Heartwise and in Kellogg’s Bran Buds, as well as in a number of dietary supple- ments, such Metamucil and Fiberall. Once again, the FDA’s decision was based on strong scientific evidence submitted by Kellogg with a petition. The FDA evaluated placebo-controlled clinical studies that tested an intake of over 10 g of psyllium (about 7 g of soluble fiber) per day as part of a diet low in saturated fat and cholesterol. These studies showed consistently significant blood total and LDL cholesterol-lowering effects. Foods carrying the health claim must provide at least

1.7 g of soluble fiber from psyllium per reference amount customarily consumed in the product. This single-serving size, multiplied by four eating occasions per

day, totals the 7 g/day intake of the controlled studies. On April 21, 2001, Pepsico’s Quaker Oats Co. and the Cranbury, NJ-based Rhodia, Inc., petitioned the FDA to amend the 1998 modified health claim again, reporting that the subject of the fiber health claim was broader than what available evidence supported. They asked that this amendment be made with specific reference to Oatrim, known under the Quaker/Rhodia brand name Betatrim, which is processed either by alpha-amylase enzymes or by acid–base hydrolysis and has a beta-glucan soluble fiber content between 4 and 25%. Once again, the FDA amended the soluble fiber health claim linking fiber to a reduced risk of coronary heart disease (CHD). The amended claim included, in addition to the broad term soluble fiber, “soluble fraction of alpha-amylase hydrolyzed oat bran or whole oat flour with a beta-glucan content of up to 10 percent.” The final rule of this health claim, “soluble dietary fiber from certain foods and coronary heart disease,” was published on July 28, 2003, in the Federal Register. 25

The above discussion about the soluble fiber claim indicates the interactive nature of the NLEA regulatory system. With proper scientific support, including clinical studies, some companies use this as a mechanism to gain approval for health claims in support of functional foods. The latest example of this interaction between the FDA and the food industry was an FDA-approved petition for a health claim linking consumption of sterols and stanols with the risk reduction of coronary heart disease. Although this claim is still an interim health claim, the ruling allows it to be used

Food Regulations

TABLE 17.7 Health Claims Authorized Based on Authoritative Statements by Federal

Scientific Bodies 26

Approved Claims

Claim Requirements

Docket No.

Whole grain foods and risk Diets rich in whole grain foods and other plant 99P-2209 of heart disease and

foods and low in total fat, saturated fat, and certain cancers

cholesterol may reduce the risk of heart disease and some cancers

Potassium and the risk of Diets containing foods that are a good source of 00Q-1582 high blood pressure and

potassium and that are low in sodium may stroke

reduce the risk of high blood pressure and stroke

on products produced by McNeal/Raiso Oy. Unilever, Cargill, ADM, and Forbes Medi-Tech, Inc.

17.4.2.2 U.S. FDA Modernization Act

Further opportunity for food manufacturers to use health claims on functional foods came with the introduction of the FDA Modernization Act in 1997. Accord- ingly, health claims can be used based on authoritative statements published by a scientific institution of the U.S. government, such as the National Institutes of Health, the Centers for Disease Control and Prevention, and the National Academy

of Sciences and its divisions. 26 These types of claims do not require approval by the FDA; however, the agency must be notified at least 120 days in advance of

marketing a product that carries a potential health claim. During this period, the FDA may authorize a claim or object to it by issuing an interim final regulation

prohibiting the claim. These claims must be solidly based on significant scientific evidence, similar to the NLEA claims. So far, the FDA has authorized two claims

based on authoritative statements by federal scientific bodies (Table 17.7). One of these claims is associated with dietary fiber and links “whole grain foods and risk of heart disease and certain cancers.” A food product may be illegible to carry a health claim on a label if it contains 51% or more of whole grain ingredients by weight per RA, and contains at least 3.0 g/RA of 55 g, 2.8 g/RA of 50 g, 2.5 g/RA of 45 g, or 1.7 g/RA of 35 g of dietary fiber. To qualify for such a claim, a food product must comply with the jelly bean and disclosure/disqualifier rules specified under NLEA regulations.

17.4.2.3 Dietary Supplement Health and Education Act (DSHEA)

In 1994, the U.S. Congress passed the Dietary Supplement Health and Education Act (DSHEA), which set up a new framework for FDA regulations concerning dietary

supplements. 27 Traditionally, dietary supplements referred to a narrow group of nutri- ents such as vitamins and minerals. The act broadens the definition to include, with

Functional Food Carbohydrates

some exceptions, any product intended for ingestion as a supplement to the diet. This includes, in addition to vitamins and minerals, herbs, botanicals, plant-derived com- pounds, proteins, peptides, amino acids, fatty acids, carbohydrates, and other nutrients and constituents. Typically, dietary supplements are sold in medicinal forms, including tablets, capsules, soft gels, gel caps, powders, and liquids. However, this act allows a dietary supplement to be introduced into conventional food forms. A dietary supple- ment may be a product with physical attributes (e.g., product size, shape, taste, pack- aging) that are essentially the same as conventional food, so long as it is not represented for use as a conventional food. Thus, whether a product is a dietary supplement or a conventional food all depends on how it is labeled. For example, a product in the form of a bar that is labeled a dietary supplement, but also bears a label statement with reference to a snack food or cereal bar, would be subject to regulation as a conventional food. However, a cereal bar that bears a label referring to a dietary supplement and does not represent itself as a breakfast food or use the term cereal as a statement of identity would be classified as a dietary supplement.

17.4.2.3.1 Structure and Function Claims DSHEA allows for the use of structure and function claims, which describe the role

of a nutrient or dietary ingredient intended to affect the structure or function in humans. 28 Under this legislation, structure and function claims for dietary supple- ments require postmarket notification, with manufacturers obliged to substantiate their claims. The label must also bear an FDA disclaimer such as: “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent disease.” Other information, such as directions for use and supplement facts (serving size, amount, list of ingredients including active ingredient), is also required on the label. 28

Unlike the new food additives that have to undergo the FDA GRAS approval process, FDA review and approval of supplement ingredients are not required prior to marketing. To market a dietary supplement, manufacturers must notify the FDA at least 75 days before putting the product on the market, as well as provide

information supporting the safety of the ingredient. 29 Safety means that a new ingredient does not present a significant risk of illness or injury under conditions of

use recommended in the product’s labeling. If the FDA feels a product may be harmful, it bears the onus of proving the danger.

The most important characteristic of DSHEA is that it allows the use of label structure–function claims for dietary supplements, including the use of publications or advertisements in connection with the sale of dietary supplements. 28 These claims link the relationship between nutrient and disease or any such related condition. They should not refer to the diagnosis, mitigation, cure, treatment, or prevention of disease. The following are examples of structure–function claims:

1. Fiber maintains bowel regularity

2. Maintains healthy cholesterol level

3. Use as a part of your diet to help maintain healthy blood sugar level

4. Calcium builds strong bones

Food Regulations

Although the structure–function claims may be used without FDA authorization, manufacturers of dietary supplements that bear a label claim must inform the FDA no later than 30 days after the product is marketed.

17.4.2.3.2 Qualified Health Claims Furthermore, dietary supplements are allowed to use qualified health claims. The use

of this type of claim resulted from the U.S. Appeals Court of the D.C. Circuit 1999 decision in the case of Pearson v. Shalala. 30 The court decision ruled that the First Amendment of the U.S. Constitution (free speech amendment) does not permit the FDA to reject dietary supplement health claims that the agency determines fail to meet the significant scientific agreement validity standard unless the agency also reasonably determines that a disclaimer added to the claim would not eliminate the potentially misleading character of the claim. The qualified claims are based on the weight of the scientific evidence; i.e., there is more evidence for, than against, the relationship, but it falls short of the validity standard required for foods under the NLEA. In other words, this system applies to dietary supplement health claims that do not meet the “significant scientific agreement” standard of evidence under the NLEA approval system. Currently, there are four qualified health claims that are approved:

1. B vitamins and vascular disease

2. 0.8 mg of folate in dietary supplement form is more effective in reducing the risk of neural tube defects

3. Omega-3 fatty acids (from fish oils) and coronary heart disease

4. Olive oil and coronary heart disease Dietary supplements of omega-3 fatty acids may bear the following label claim,

approved by the FDA in 2002: “Consumption of omega-3 fatty acids may reduce the risk of coronary heart disease. The FDA evaluated the data and determined that, although there is scientific evidence supporting the claim, the evidence is not con- clusive.” By the end of 2004, the FDA approved the next qualified health claim that links consumption of olive oil to coronary disease. “Limited and not conclusive scientific evidence suggests that eating about 2 tablespoons (23 grams) of olive oil daily may reduce the risk of coronary heart disease due to the monounsaturated fat in olive oil. To achieve this possible benefit, olive oil is to replace a similar amount of saturated fat and not increase the total number of calories you eat in a day. One serving of this product contains [x] grams of olive oil.”