Chapter III

Major Issues and Recommendations Related to
Labeling of Dietary Supplements

The Commission's charge to address major issues relative to the labeling of dietary supplements was reiterated in public testimony presented at meetings held throughout the country and in written submissions to the Commission. DSHEA mandated that the Commission review and make recommendations on label claims, substantiation of claims, and literature available to the public. In addition, the Commission identified issues related to label claims for botanical supplements. This chapter outlines the Commission's deliberations and findings on these issues and provides guidance and recommendations.

SAFETY OF DIETARY SUPPLEMENTS

Because of the concerns relative to safety issues expressed in the public submissions, the Commission included safety as a major topic in its deliberations.

1. DSHEA Provisions on Safety

In reflecting on issues associated with safety, during the creation and passage of DSHEA in 1994, Congress reached the following conclusions:

FDCA defines the conditions under which a food may be considered "adulterated" (i.e., unsafe) (Section 402(a)). DSHEA subjects dietary supplements to the original adulteration provisions governing food and adds additional conditions (Section 402(f)). Specifically, DSHEA indicates that a dietary supplement is adulterated:

If it is a dietary supplement or contains a dietary ingredient that—
A) presents a significant or unreasonable risk of illness or injury under—
(i) conditions of use recommended or suggested in labeling, or
(ii) if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use;
B) is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury;
C) the Secretary declares to pose an imminent hazard to public health or safety, except that the authority to make such declaration shall not be delegated and the Secretary shall promptly after such a declaration initiate a proceeding in accordance with Sections 554 and 556 of Title 5, United States Code, to affirm or withdraw the declaration; or
D) is or contains a dietary ingredient that renders it adulterated under paragraph (a)(1) under the conditions of use recommended or suggested in the labeling of such dietary supplement.

Under the authority created by DSHEA, FDA can bring enforcement action against an existing supplement if it presents an unreasonable or significant risk of harm. While not yet judicially interpreted, in many respects the test for safety under the new provisions of DSHEA is similar to the test enunciated by the Supreme Court in a landmark 1914 case concerning addition of poisonous and deleterious substances in food (138). Under this case, safety is to be related to the quantity of a substance and the risk when the facts are reasonably considered.

Under DSHEA, the safety of dietary supplements is determined based on the conditions of use recommended or suggested in the labeling (Appendix A). DSHEA exempts dietary supplement ingredients from the food additive provisions of FDCA and establishes conditions for the marketing of new dietary ingredients not marketed in the United States as dietary supplements prior to October 15, 1994. The new provisions have yet to be tested in court.

DSHEA stipulates that a dietary supplement that contains a new dietary ingredient:

. . . shall be deemed adulterated under Section 402(f) unless it meets one of the following requirements:
(1) The dietary supplement contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.
(2) There is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides the Secretary with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.

FDA approval is not required with regard to adequacy of substantiation. If FDA objects to marketing of the ingredient, the agency must initiate enforcement action. New uses of an existing supplement, or an increase in the recommended dose, does not make a supplement "new" for purposes of the substantiation requirement.

Under DSHEA, FDA must show affirmatively, in court, that an unreasonable risk is posed by consumption of a dietary supplement. The agency need not show that injury has occurred, only that a reasonable possibility of harm exists. Under provisions in DSHEA, before reporting a violation to the U.S. attorney for civil enforcement action, FDA must provide 10 days' notice to the affected party as well as an opportunity for the affected party to present views relative to the alleged violation, unless an imminent hazard to public health or safety exists.

2. Good Manufacturing Practices

Dietary supplements are considered foods and are subject to requirements of "Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Human Food" (108). These regulations provide guidelines with regard to maintenance of buildings and facilities, requirements for food handlers, and cleanliness of equipment, as well as procedural requirements for maintaining safety during the production and processing of foods.

DSHEA specifically authorizes FDA to establish dietary supplement GMPs. Recognizing this perceived need, major industry groups in 1995 jointly prepared extensive revisions to the food GMPs that address aspects of manufacturing practices used by the dietary supplement industry. These proposed GMPs for dietary supplements were submitted to FDA and subsequently published as an ANPR in the Federal Register (32). The Commission supports these efforts of FDA and the industry to develop appropriate GMPs for dietary supplements.

3. Safety of Botanicals

The Commission recognizes that most botanical products taken as dietary supplements in the United States are safe when used as directed on labels. There are relatively few reports in the scientific literature that indicate potential or actual toxicity following the use of these products. When such reports are found, they often are single-case reports involving an allergenic reaction or toxicity due to improper labeling, or adulteration, or an idiosyncratic reaction even though the product was taken under proper conditions of use and within reasonable dose limitations (23).

However, there are exceptions in which the use of botanical products has raised concerns about safety. Botanical products such as comfrey root (Symphytum officinale L.), which contains hepatotoxic pyrrolizidine alkaloids (86), pose a potential health hazard. There also has been consumer concern and State regulatory response over frequent or protracted use of foods or dietary supplements that contain senna (Cassia senna L.) (73). In countries other than the United States, some plants containing known carcinogens or tumor promoters are used medicinally (22,90), even though other well-known toxic plants usually are not consumed (18-20).

4. Federal Enforcement Issues

Section 301 of FDCA provides for broad enforcement powers in regard to adulteration and misbranding of foods, including dietary supplements. The Commission recognizes the importance of having adequate and timely enforcement procedures for products marketed as dietary supplements that are not safe or have a high potential for abuse while maintaining a regulatory climate that preserves the availability of safe products. The apparent safety of the majority of products now marketed as dietary supplements actually increases the importance of having adequate enforcement mechanisms, because consumers may then assume that a wide margin of safety automatically applies to any product classified as a dietary supplement.

Recent events associated with products containing ephedrine alkaloids illustrate these safety and enforcement concerns. During Commission hearings, some presenters expressed concern about the safety of products containing ephedrine alkaloids. Evidence that such products were implicated in numerous adverse reactions, including fatalities, throughout the country was presented. However, FDA has only recently proposed rules to define the conditions under which products containing ephedrine alkaloids would be considered a "significant or unreasonable" risk to health and safety (33). The Commission is aware of the problems of analytical methodology, identification of the products implicated, and the strength of evidence related to possible causation of several deaths associated with use of products containing ephedrine alkaloids. Despite the difficulty of making clear conclusions based on the reported effects of these products, the Commission questions whether the industry and FDA have responded as promptly to these incidents as would be in the best interest of the public.

Some Commission members hold that the delay in action by FDA has served to undermine public confidence in the agency's commitment to enforce DSHEA. The full Commission urges FDA to take a proactive stance in communicating its position to the public in such cases and in pursuing legal action where justified.

FDA's resources may limit its ability to take effective enforcement action, especially when extensive scientific analysis is required. For example, for many ingredients, there are no well-accepted analytical techniques for qualitative and quantitative analysis of products. Thus, should FDA have reason to initiate action against a product, the agency might have to develop and validate an appropriate analytical methodology to determine composition, presence of toxic substances, or adulteration. Similarly, FDA might need to establish the identity of plant parts in certain products. Such efforts are resource intensive and may be cost prohibitive for an agency with a broad range of regulatory responsibilities. These resource issues arise not only with regard to safety, but also with respect to the appropriateness of label claims.

The Commission observed that under Section 402(f)(2) of FDCA added by DSHEA, FDA must notify a manufacturer, distributor, or other person against whom civil action is pending at least 10 days in advance of the filing of the civil action on the supposed violation. This provision allows the company or individual an opportunity to respond to the alleged violation, both orally and in writing. The product may continue to be marketed during the 10-day period unless the Secretary declares it an "imminent hazard." DSHEA does not modify the definition of "imminent hazard" (96) but states that the authority to declare an imminent hazard cannot be delegated. Thus, in the case of action against a potentially hazardous dietary supplement ingredient, regulatory approval at several additional levels must be sought and obtained. That is, FDA staff must have sufficient information and data to convince not only the FDA General Counsel and Commissioner, but also the HHS General Counsel and Secretary. These additional requirements are appropriate but increase the time needed, the resources required, and the effort expended. Thus, to invoke this statutory provision may require decisions about administrative and regulatory priorities as well as public health and safety.

5. State Enforcement Issues

Representatives of several States who provided testimony to the Commission noted the absence of uniformity in regulations regarding dietary supplements among the States. They also commented on the demands on enforcement resources and indicated that, at the local level, staff expertise and time as well as fiscal resources for enforcement are limited. These representatives emphasized the need to provide FDA with sufficient resources to fulfill its responsibilities and noted that a cutback in the budget and efforts at the Federal level would increase the regulatory burden of the States. They also expressed concern about the wide and uncontrolled range of information available on the Internet. In discussing specific instances in which States had taken enforcement action, representatives of State health departments and public health organizations directed the Commission's attention to the plethora of locally prepared and marketed products that might not enter interstate commerce with which they had to contend as well as products in ethnic markets that were either not labeled in English or not labeled at all.

6. Postmarketing Surveillance

The safety of foods including dietary supplements is a concern of all responsible governing bodies worldwide. For example, the European Commission continues to work on integrating multinational concerns about the safety of dietary supplements into an acceptable directive that its member states could use to enact conforming laws reflecting their choice of the form and method of implementation (95). The European Commission has raised several issues regarding safety, including the potential excessive intake of dietary supplements and the presence of contaminants and natural toxins. Some countries have approached the safety of dietary supplements by planning or developing lists of ingredients that are permitted or not permitted (95).

In addition, many countries have a mechanism to document adverse health effects. For example, in Australia, the Adverse Drug Reactions Advisory Committee collects data and issues warnings, as necessary, about the side effects of various supplements (81,95). In the United Kingdom, the National Poisons Unit reviewed, retrospectively and prospectively, cases of suspected poisoning from exposure to traditional remedies and food supplements from 1983 until 1991 (120). In France, the Licensing Authority and Pharmacopoeial Authority maintains a pharmacovigilance system to gain an overview of the use and adverse effects of botanicals (70). In addition, the World Health Organization (WHO) maintains a Collaborating Center for International Drug Monitoring in Uppsala, Sweden, which may be expanded to cover botanical remedies (21).

In the United States, there are a number of voluntary systems for reporting adverse reactions to consumer products. The Association of Poison Control Centers maintains records on all adverse events reported to a national network of Poison Control Centers. The USP urges health care practitioners to report adverse effects through its Practitioners' Reporting Network. FDA maintains systems for postmarket reporting of adverse reactions to drugs, biologics, devices, and special nutritional products, including dietary supplements. For example, FDA requires reports of serious adverse reactions for new drugs (114). The Adverse Reaction Monitoring System is a passive surveillance reporting system for complaints of adverse reactions or events associated with foods and dietary supplements (48). MedWatch is an analogous passive surveillance system for notification of adverse events related to medications and devices (78,79). These and other FDA passive surveillance systems, such as the Drug Quality Reporting System and the Office of Regulatory Affairs Consumer Complaint System, are voluntary—there is no legal requirement for individuals, organizations, or facilities to report adverse reactions to these FDA systems. These systems provide a monitoring tool for identifying potentially serious public health issues that may be associated with the use of a particular product or type of product. The strengths of these systems include their large scale surveillance and their cost effectiveness.

However, as with all passive surveillance systems, these systems have certain weaknesses. Reports that are received need critical review to appropriately determine the likely cause. Otherwise, erroneous conclusions might be reached regarding a potential association between products and reported symptoms or conditions. Adverse events associated with product use are thought to be significantly underreported, because many consumers or health professionals may not recognize a link between a particular product use and an injury or illness, or they may not bother to register a complaint. A report may be fragmentary and of uneven quality. In addition, there may be a long lag time between the event and the receipt of the complaint. Difficulties in obtaining comprehensive information on the product used and on the health of the consumer are also often encountered. Despite these limitations, however, the systems serve to alert public health officials about potential problems.

Findings

The Commission considers it axiomatic that all marketed dietary supplements should be safe. The manufacturer bears the primary responsibility for assuring the safety of dietary supplements, both under the terms of FDCA and under the requirements of product liability (4,5). The Commission suggests that when health-related statements are made for dietary supplements in the form of statements of nutritional support or health claims, the manufacturer or vendor bears an added responsibility for assuring the safety of the product. The Commission concludes that while assurance of safety is primarily the responsibility of the dietary supplement industry, the Federal government shares the responsibility to ensure that there are adequate guidelines on GMPs, procedures for alerting the public when safety problems are detected, and procedures for recalls when necessary.

The Commission believes that existing postmarket surveillance systems could be improved. There is no requirement in the United States for mandatory reporting of adverse reactions to foods, including dietary supplements, and the Commission is not recommending such a requirement. However, better use could be made of the reports that are received under the voluntary systems. The Commission urges FDA, the industry the scientific community, and consumer groups to work together voluntarily to improve passive postmarketing surveillance systems, including adverse reaction reporting systems, to ensure that any safety problems that arise are identified and corrected promptly.

Some members of the Commission hold that FDA has sufficient authority to take action against supplements that are deemed unsafe but has failed to use this authority effectively in the case involving products containing ephedrine alkaloids. They hold that the enactment of DSHEA did not affect the agency's authority to protect the public from unsafe products. Other Commission members believe that FDA's enforcement efforts against dietary supplements are diminished by provisions of DSHEA that place the burden of proving the existence of a significant or unreasonable risk on the agency. One member believes that manufacturers should have a legal obligation, enforceable by FDA, to substantiate the safety not only of new dietary supplements, but also of existing products, particularly when there is a new statement of nutritional support or a new recommendation for increased dosage. This Commission member also believes dietary supplements that have not been adequately tested for safety should bear a warning such as that required for cosmetics (119).

DSHEA limits the determination of safety to the doses recommended on the label, even though harm may occur at higher levels and there may be a risk of use at higher levels. The Commission concludes that consumers should be provided with clear and adequate dosage recommendations on product labels, and labels should direct consumers to use products only as recommended. A label warning should also be utilized by the manufacturers, as specifically authorized by DSHEA, when the need for a warning is indicated for the safe and effective use of the product by consumers. For example, if there is a documented need for a warning relating to consumer abuse of a particular product, and no warning is being provided by the manufacturer, the Commission suggests that FDA use its authority to require warnings about exceeding label doses when there is possible risk of serious harm to consumers who inadvertently or intentionally exceed the recommended dose. Commission members recognize that safety hazards resulting from improper use of physiologically and/or pharmacologically active products at doses other than those recommended are not limited to dietary supplements. FDA has previously relied on warnings in dealing with issues of safety (102).

Guidance

LABEL INFORMATION

The Commission did not address specifically the basic format for ingredient labeling and nutrition labeling. DSHEA mandated some changes in FDA's existing regulations on these topics, and FDA proposed new regulations in December 1995 (40-43). At the time of the Commission's first meeting in February 1996, FDA was already in the process of receiving extensive comments on those proposals from the affected industry and from other members of the public. It was anticipated that these labeling regulations would be amended based on the public comments and would be finalized before the Commission's report was completed. Further, DSHEA's primary mandate to the Commission in regard to labeling concerned claims-related issues, which have been the focus of the Commission's efforts.

1. Label Format and Statement of Identity

Dietary supplements, like other foods, are subject to certain mandatory labeling requirements. Basic food labeling regulations, which apply equally to conventional foods and dietary supplements, are set forth in the Code of Federal Regulations (CFR) (97). These regulations define the principal display panel (PDP) of a product, which must bear the name of the product and a statement of contents or net weight. The information panel is defined generally as the panel to the right of the PDP. It bears other information required by regulation, such as the ingredient list and nutrition labeling. The name and address of the manufacturer, packer, or distributor of the product must also appear on the label. DSHEA imposed some special requirements for dietary supplement labeling, including the requirement that the term "dietary supplement" appear on the label.

2. Ingredient List

FDCA requires that food labels bear a list of all ingredients, and FDA regulations require that the ingredients be listed in descending order of predominance by weight (103). FDA exempted dietary supplements from this requirement in trade correspondence (66). As a result, dietary supplements historically have provided a table of nutrients, as required by special dietary food regulations, but did not always provide a separate list of all ingredients, including excipients.

DSHEA requires that all ingredients of a dietary supplement be listed on the label, but not necessarily as part of a consolidated ingredient list. Some ingredients may be named in the nutrition label and need not be repeated in a separate ingredient list.

DSHEA also requires that, when a product includes botanicals, the label indicate which part of the plant is used. FDA recently published a final rule on regulations that would require additional information about botanicals, including the Latin binomial and an identification of the scientific authority for the Latin name unless the botanical is listed in Herbs of Commerce (68).

3. Special Dietary Use Labeling and Nutrition Labeling

FDCA requires that the label of a food intended for special dietary uses include:

. . . such information concerning its vitamin, mineral, and other dietary properties as the Secretary determines to be, and by regulations prescribes as, necessary in order fully to inform purchasers as to its value for such uses (Section 403(j)).

To implement this requirement, FDA issued regulations in 1941 (66) regarding the format and content of vitamin and mineral labeling for nutritional supplements and fortified foods. Vitamins and minerals were to be listed in tabular form, with the name of the nutrient, the quantity in metric units, and a statement of the percentage of the MDR provided. The same regulations established MDRs for several vitamins and minerals. If substances were present in the product for which an MDR had not been established, an asterisk was to be used in the "Percent MDR" column, referring to a footnote that stated: "Requirement in human nutrition not established."

In 1973, after extensive proceedings, FDA revised the special dietary use regulations and initiated nutrition labeling (64). The agency also proposed a restrictive "standard of identity" for vitamin and mineral supplements, which was ultimately overturned by the courts, invalidated in part by legislation passed in 1976, and withdrawn by FDA in 1979. The history of the vitamin and mineral regulations is not discussed here, except to note that the only significant provision remaining was one replacing the MDR with the U.S. RDA as the label reference standard for vitamin and mineral content for conventional foods and dietary supplements.

Nutrition labeling was initiated by FDA as a voluntary program in 1973 (64). Nutrition labeling was not mandatory unless a nutritional claim was made. However, if a conventional food had nutrition labeling, then the label was required to follow the format established by FDA. Dietary supplements were exempt from nutrition labeling because they were intended to be covered by special dietary use regulations.

NLEA required nutrition labeling of all foods and supplements and required FDA to establish an appropriate format (67). NLEA also changed the general emphasis of nutrition labeling to increase the focus on macronutrients believed to have a major positive or negative impact on health. FDA took the opportunity to develop an entirely new and bolder format for nutrition labeling and replaced the U.S. RDA with a new label standard for vitamins and minerals, the RDI.

FDA recognized the need for somewhat different formats for nutrition labeling of conventional foods and nutritional supplements. Final regulations on nutrition labeling for conventional foods were promulgated in January 1993. Final regulations on nutrition labeling for vitamin and mineral supplements were issued in January 1994, prior to the passage of DSHEA. No special provision was made for botanical products, which would have been required to bear conventional nutrition labeling.

DSHEA was passed in October 1994 with provisions that require revision of FDA's regulations on nutrition labeling for dietary supplements. DSHEA specifies that nutrition labeling for dietary supplements be provided "in a manner which is appropriate for the product" and which is specified in FDA regulations. In addition, DSHEA specifically authorizes three departures in dietary supplement labeling from the nutrition labeling format applicable to conventional foods.

DSHEA requires implementation of its labeling provisions by December 31, 1996, but the procedures necessary for full implementation were not completed by that date. Final regulations were issued on September 23, 1997, and become effective on March 23, 1999 (26-28).

Finding

The Commission supports the informative label format mandated by DSHEA and urges orderly implementation of appropriate regulations.

NLEA CLAIMS IN DIETARY SUPPLEMENT LABELING

NLEA not only required mandatory nutrition labeling for all foods including dietary supplements but also defined "nutrient content claims" and established a process for approval of "health claims."

1. NLEA Nutrient Content Claims

NLEA requires that nutrient content claims not be used in food labeling unless the terms used have been defined by FDA and unless the terms are used in accordance with those definitions. This provision came about because terms such as "low fat," "high fiber," and "no cholesterol" were believed to be used in ways that were potentially misleading. FDA issued regulations implementing the requirement that nutrient content claims be defined (98). For the most part, the same nutrient content claims allowed for foods are also allowed for dietary supplements.

Nutrient content claim language allowed for both foods and dietary supplements includes the following:

FDA regulations permit nutrient content claims for substances for which a DV has been established. DSHEA specifically permits percentage nutrient content claims for dietary supplement ingredients for which a DV has not been established. This would allow a statement such as "twice the omega-3 fatty acids per capsule (80 mg) as in 100 mg of menhaden oil (40 mg)" on a dietary supplement label, even though no DV has been established for omega-3 fatty acids (27).

2. NLEA Health Claims

In enacting DSHEA, Congress intended the Commission to address whether changes should be made in the requirements for NLEA health claims for dietary supplements. Current FDA rules require the same type of scientific evidence and support and the same process for approval of NLEA health claims on dietary supplements as are required for conventional foods. DSHEA requires the Secretary to publish any recommendations the Commission makes with respect to changes in the existing FDA regulations concerning NLEA health claims on dietary supplements, along with a notice of proposed rulemaking on such recommendations. In the absence of timely action by the Secretary, dietary supplements will no longer be subject to the requirements applicable to health claims on conventional foods.

Historically, FDA had regarded health claims on foods as impermissible drug claims. In 1987, FDA changed its policy, recognized the appropriateness of health claims on foods, and proposed to develop guidelines or regulations regarding such claims (57). Under this rulemaking initiative, manufacturers would have needed to substantiate their health claims, but prior review by FDA would not have been required. What was sufficient for substantiation became a heated issue in the rulemaking process. As FDA developed its proposed policies, manufacturers were already making health claims for substances such as fiber, and some of these claims provoked public criticism and congressional debate, which led to the enactment of NLEA.

The Commission is aware that challenges have been brought on constitutional grounds to the provisions of NLEA concerning FDA approval of health claims (91,92). A time deadline for FDA action on final rules for health claims has been found necessary (92). The other provisions of NLEA have not been found to be invalid on constitutional grounds in the cases to date. The discussion of NLEA in this report is based on the provisions in their present form.

NLEA defines health claims as statements that characterize a relationship between a nutrient or food component and a specific disease or health-related condition (100). 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 (e.g., cardiovascular disease), or a state of health leading to such dysfunctioning (e.g., hypertension); except that diseases resulting from essential nutrient deficiencies (e.g., scurvy, pellagra) are not included in this definition (claims pertaining to such diseases are thereby not subject to . . . 101.14 or 101.70).

NLEA requires that the standard of evidence for health claims for conventional foods be significant scientific agreement among experts qualified by scientific training and experience to consider whether a claim is supportable. NLEA specified that health claims for dietary supplements would not be subject to that standard but instead would be "subject to a procedure and standard, respecting the validity of such claim, established by regulation of the Secretary" (FDCA 403(r)(5)(D). Numerous suggestions for alternative systems were made in comments on FDA's proposed health claims regulations. In promulgating regulations for health claims, FDA considered this issue and concluded that the same standard and procedure should apply to dietary supplements as to conventional foods (i.e., there should be a "level playing field" for health claims for all foods including supplements).

Significant scientific agreement is to be based on the totality of publicly available scientific evidence, including evidence from well-designed studies conducted in a manner consistent with generally recognized scientific procedures and principles (99,104,107). FDA regulations for NLEA health claims define the types of substances that are potentially eligible for specific health claims and identify additional requirements for making health claims.

Many of the diet-disease associations of potential relevance for health claims relate to chronic disease processes for which diet is one of many possible causes and which, for both ethical and practical reasons, are often not subject to direct experimentation. Thus, different types of evidence are usually considered in attempting to establish that a causal association actually exists and that dietary change would have preventive value. Where human experimentation is not appropriate, other approaches are useful. For example, an association may be inferred from a combination of epidemiological comparisons or long-term observations of populations exhibiting different dietary patterns, in vitro biochemical studies, and animal studies. Where feasible and appropriate, randomized controlled trials are conducted to establish the effects of dietary manipulations in human populations.

Commission members agree that a high standard of evidence is appropriate for health claims. A valid health claim may promote behaviors that have a beneficial effect on public health and, therefore, be associated with effects on health care costs, quality of life, and productivity.

Evaluating expert agreement is, by definition, a matter of judgment, and must rest on a body of evidence considered adequate to support such agreement (i.e., more than preliminary studies or a few emerging studies, even if the evidence seems convincing). Guidelines for selecting evidence for evaluating a body of scientific evidence are increasingly prominent in the scientific literature (11). The scientific literature also describes many processes for synthesizing and evaluating a body of literature (1,13).

Under NLEA, FDA was initially directed to review the evidence relating to 10 specific nutrient/disease relationships. In evaluating these initial candidates for health claims, FDA contracted with Life Sciences Research Office (LSRO), Federation of American Societies for Experimental Biology (FASEB), for expert literature reviews and recommendations and FDA also solicited data from the public. Subsequently FDA approved eight health claims (five of the original 10, plus three modifications of the original 10). Two, omega-3 fatty acids and coronary heart disease as well as zinc and immune function in the elderly, were not approved (Table 2).

Two of the original 10 claims (those relating to calcium and to folic acid) are approved for use in dietary supplement labeling as well as conventional food labeling. In evaluating the health claim for folic acid and neural tube birth defects, FDA convened an advisory committee and was also strongly influenced by the Public Health Service's adoption of a recommendation on this subject. The three modified claims relate to antioxidant vitamins and cancer, fiber and cancer, and fiber and coronary heart disease. FDA disapproved these claims for the substances per se but approved claims for food groups that are good sources of vitamin C, ß-carotene, or fiber.

For purposes of considering health claims other than the 10 mentioned in NLEA, FDA developed a petition process, as required by NLEA, whereby a petitioner may request the establishment of regulations authorizing a claim that characterizes the relationship of a nutrient to a disease or health-related condition (104). In considering such petitions, FDA indicated that manufacturers must demonstrate that a product is safe when used at the level needed to support a claim.

In response to petitions, three new health claims have been approved (Table 2), one for sugar alcohols and reduced risk of dental caries (36) and one each for soluble fiber from whole oats and from psyllium husks and reduced risk of coronary heart disease (34,35). FDA did not take action on a petition for a health claim for calcium-rich dairy products and reduced risk of hypertension (129). Health claims currently authorized in 21 CFR are listed in Table 2.

For each of the approved health claims, FDA regulations include "model claims" that may be used by manufacturers to assure that all criteria for a claim are met. However, manufacturers are free to develop their own claims language, provided it meets the criteria set forth by FDA.

Many food and dietary supplement manufacturers complained that the health claims requirements initially established by FDA were too cumbersome and that the model claims were not consumer friendly. In response to petitions filed by the National Food Processors Association and the American Bakers Association, FDA proposed in December 1995 to streamline specific requirements for health claims (44). These regulations are not yet final. The model calcium claims below illustrate the dramatic difference between FDA's original requirements and the streamlined proposal:

Original: "Regular exercise and a healthy diet with enough calcium helps teen and young adult white and Asian women maintain good bone health and may reduce their high risk of osteoporosis later in life. Adequate calcium intake is important, but daily intakes above about 2,000 mg are not likely to provide any additional benefit" (105).

New: "Especially for teen and young adult women, adequate calcium in a healthful diet may reduce the risk of osteoporosis later in life" (44).

When FDA proposed a health claim relating to folic acid in 1993 (58 Fed. Reg. 53254), the original language was:

Original: "Women who consume adequate amounts of folate, a B vitamin, daily throughout their childbearing years may reduce their risk of having a child with neural tube birth defect. Such birth defects, while not widespread, are very serious. They can have many causes. Adequate amounts of folate can be obtained from diets rich in fruits, dark green leafy vegetables and legumes, enriched grain products, fortified cereals, or a supplement. Folate consumption should be limited to 1,000 µg per day from all sources."

In March 1996, FDA finalized a regulation streamlining the model health claim relating to folic acid:

New: "Healthful diets with adequate folate may reduce a woman's risk of having a child with a brain or spinal cord birth defect" (37,106).

Findings

The Commission recognizes that appropriate NLEA health claims made for dietary supplements and foods may be an important method of public education about dietary practices that may have a positive influence on health. The power of advertising and marketing of products in connection with valid health claims provides a means for public education that is difficult to provide through other channels. For this reason, it is important that health claims be based on results of a body of research that demonstrates that public health benefits can be achieved through this mechanism. A useful consideration of how evidence should be evaluated relative to diet and health relationships has been published by the Committee on Diet and Health (13). Invalid health claims may increase costs to consumers or result in health behaviors that are not helpful or even have negative consequences to health and well-being.

The Commission supports the concept of fairness, in which the requirements for NLEA health claims are the same for foods and for dietary supplements. The Commission believes that different health claim standards for dietary supplements and conventional foods would be confusing to consumers and would be poor public policy. The Commission considered the standards for scientific evidence and the procedures required for health claim approval, including the question as to whether health claims for foods and dietary supplements should be regulated in the same way. The Commission concluded that both the scientific standards and the approval process for health claims for dietary supplements and for conventional foods should be the same. The Commission agrees with the key aspects of the rules that relate to the formal standard for decision making and believes these allow for flexibility in evaluating individual petitions for health claims.

Some Commissioners expressed concern about the current FDA review process for NLEA health claims. The Commission suggests that the process whereby FDA determines whether significant scientific agreement exists for support of a specific health claim could be improved. For example, there could be greater use of FDA-sponsored conferences or workshops on issues related to health claims of specific substances, such as those held on antioxidants, cancer, and cardiovascular disease (53). In particular, FDA should consider greater involvement of scientists outside of FDA, including scientists in other government agencies, in the review process. The agency should develop criteria for selecting review panels external to FDA that would be considered scientifically qualified, balanced, reliable, and independent. The LSRO/FASEB panels used by FDA provide one example of appropriate outside review.

Recommendations by such outside panels would not have presumptive weight in the approval process, but submission of evidence from such a review by petitioners should strengthen the petition and expedite the review process. The agency would be expected to provide an explanation of any disagreement with such a review panel, given the panel's expertise. Although the views of other governmental agencies should not substitute for the authority of FDA, they should be given serious consideration, and they are important in considering whether significant scientific support for a claim exists. FDA and other agencies need to be continually aware that the public may be confused by disparate recommendations of governmental public health agencies in relation to food or dietary supplements.

Guidance

SCOPE OF STATEMENTS OF NUTRITIONAL SUPPORT

DSHEA allows a dietary supplement label to bear a statement of nutritional support when the statement:

(1) Claims a benefit related to a classical nutrient deficiency disease;
(2) Describes the role of a nutrient or dietary ingredient intended to affect structure or function in humans;
(3) Characterizes the documented mechanism by which a nutrient or dietary ingredient acts to maintain structure or function; or
(4) Describes general well-being from consumption of a nutrient or dietary ingredient.

Statements of nutritional support relating to the structure and function of the body (2 and 3 above) are typically called "structure/function" statements of nutritional support. These are nearest in usage to the types of statements that otherwise might be considered to be health claims or drug claims.

Statements linking foods or nutrients with growth, health, and well-being (that is, with human structure or function but not with a specific disease or dysfunction) historically have been permitted on foods. The FDCA indirectly addresses structure/function statements by defining drugs as "articles (other than food) intended to affect the structure or any function in the body of man or other animals." The statement that "calcium builds strong bones and teeth" is a classic example of an allowable structure/function statement of nutritional support for foods.

DSHEA specifically creates a category of statements of nutritional support, including structure/function statements, to ensure that such information will be permitted for dietary supplements. Nutritional support statements, and especially structure/function statements, have become more visible since the passage of DSHEA and are subject to unique requirements for notification and for special labeling. DSHEA requires that the manufacturer notify FDA within 30 days after the first use of a nutritional support statement, that the manufacturer have substantiation for the statement, and that the label include the following disclaimer:

This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

What constitutes an allowable structure/function statement of nutritional support (i.e., a statement that is not a health claim and not a drug claim) has not been specifically outlined in either legislation or regulations. While some members believe statements of nutritional support may imply disease prevention, at least one member believes that statements of nutritional support may neither expressly nor implicitly claim such usage.

Commission members agree that claims for dietary supplements that meet the definition of health claims, as defined under NLEA, should continue to be regulated under the same NLEA provisions that apply to conventional foods. It can be difficult, however, to clearly distinguish an allowable structure/function statement of nutritional support from one that might be considered an unauthorized health or drug claim. The Commission reviewed approximately 1,000 statements of nutritional support referenced in notification letters submitted to FDA. Based on this review, the Commission concluded that the lack of definition of the clear boundaries of these statements leaves many uncertainties as to what actually constitutes a legitimate statement of nutritional support in the context of dietary supplements.

Commission members expressed concern that some statements of nutritional support being made are in fact more akin to drug claims. Commission members who were troubled about the wording of structure/function statements suggested that the most problematic wording is seen in statements ostensibly relating to "normal healthy function" that actually imply the need to remedy an underlying abnormal or unhealthy state and statements mentioning organs (e.g., heart, liver, and prostate) or systems (e.g., circulatory) associated with major clinical conditions.

The Commission was divided on the distinction between DSHEA-allowable structure/function statements and drug claims for claims referring to organs. Some Commission members believed that such statements were either drug claims or NLEA health claims. It was noted that, for health claims, FDA has defined a disease or health-related condition to include damage to an organ, part, or structure of the body so that it does not function properly (99). Some Commission members believe that the potential for allowing these types of statements for dietary supplements is a fundamental flaw of DSHEA, creating a loophole for quasi-drug claims. Others suggest that the ability to make such statements is implicit in DSHEA and that there is emerging scientific evidence for certain foods and other dietary ingredients having benefit for specific organs or functions of the body. These members of the Commission noted that these provisions of DSHEA were written with the explicit goal of making such information available to the public.

Statements of nutritional support relating to structure or function should not be used to imply effects that are currently considered prescription drug claims. For example, oral contraceptives alter physiological function, but a contraceptive effect is inappropriate as a statement of nutritional support.

Some Commission members noted that prior to DSHEA, FDA took the position that virtually any statement relating to cholesterol would be interpreted as a claim relating to the prevention of heart disease. These Commissioners believe that this position needs reconsideration in light of DSHEA and that it is possible to craft a statement of nutritional support regarding the maintenance of healthy blood cholesterol levels that is a statement of nutritional support and not a health claim or drug claim. In a similar manner, FDA historically has been sensitive to label statements relating to immune function on the grounds that they are implicit or explicit claims relating to acquired immune deficiency syndrome (AIDS). While a statement of nutritional support should not be such that it could be interpreted as a direct or indirect AIDS claim, some Commission members believe it should be possible to make legitimate statements of nutritional support about substantiated effects on immune function or disease resistance.

Statements of nutritional support that mention an acute effect on the structure or function of a major system (e.g., reduces heart rate) raise particular concern for some Commission members. In contrast, effects on stress, mental acuity, or bone or skin health within the normal range seemed to carry less serious connotations. However, some members still have concerns about stress and mental acuity claims and emphasize that these and all statements related to structure and function of the body need to be carefully evaluated on an individual basis. One important concern relates to safety, that is, the potential seriousness of any effect that might extend beyond the normal range. The consumer's ability to recognize the range of normality is also an issue. One member believes that to be an appropriate statement of nutritional support, a statement would need to identify a dietary relationship for the supplement.

Findings

The Commission has developed guidelines as to what constitutes an acceptable statement of nutritional support of the structure/function type. These guidelines are listed below as Commission policy guidance. The Commission considers that statements of nutritional support should provide information that can help consumers make informed choices about their health. In keeping with DSHEA, the statement should not be false or misleading and should provide scientifically valid information to the consumer. Also, the product should be safe under conditions of intended use.

Analysis by the Commission of FDA's responses to notification letters indicates that the agency has not objected specifically to statements that are consistent with the guidelines the Commission recommends, but FDA has also made it clear that the absence of an objection by the agency does not indicate acceptance of the appropriateness of the claim (128). The provision of early guidance by FDA to manufacturers making statements of nutritional support is appropriate and helpful in clarifying the appropriate scope of these statements.

Guidance

NOTIFICATION LETTERS FOR STATEMENTS OF NUTRITIONAL SUPPORT

DSHEA requires that the manufacturer of a dietary supplement bearing a statement of nutritional support notify the Secretary no later than 30 days after the first marketing of the dietary supplement that such a statement is being made. The law also states that the manufacturer must have substantiation that the statement is truthful and not misleading. The law does not provide that the evidence supporting a statement be reviewed by a regulatory agency prior to marketing of the product. Presumably the evidence substantiating a statement would be examined only if a challenge to the labeling or advertising were made.

Findings

The Commission believes that guidelines are needed for standardizing the format and content of the notification letters. In keeping with the intent of DSHEA, which is to provide consumers with truthful, not misleading, and scientifically valid information to make informed health care choices, the Commission suggests that the notification letters and the FDA responses continue to be made available in the public dockets at FDA (Docket Nos. 97S-0162 and 97S-0163).

The Commission considered whether there should be a requirement that a notification letter include a summary of the evidence supporting the statement of nutritional support and the safety of the product. This was an effort by the Commission to fulfill its mandate in DSHEA to "evaluate how best to provide truthful, scientifically valid, and not misleading information to consumers so that such consumers may make informed and appropriate health care choices for themselves and their families." Although DSHEA does not require that a summary of the data supporting statements of nutritional support be submitted to FDA with the notification letters, a majority of the Commission members favored such a requirement. Some members of the Commission saw major problems with such a recommendation because it would impose a requirement not specified in DSHEA. Further, some Commissioners were concerned that the summary might allow or require public display of information that makes or implies an unintended claim, thereby putting a company at risk of enforcement action for making an impermissible statement of nutritional support because of the nature of the evidence or publications cited. Also, there was some question whether FDA has legal authority to require a summary of the evidence in the notification letter.

The Commission recommended in its June 1997 draft report that the letter of notification include a summary of the evidence supporting both benefit and safety. There was considerable opposition to this recommendation in the public comments on the draft report. Industry representatives objected to a requirement that goes beyond the specific provisions of DSHEA, and some nutrition professionals, public health officials, and consumer groups objected to the public availability of a summary of the evidence because of the potential for confusion when that summary had not been approved by FDA. In response to the comments, the Commission has amended its recommendation to omit the requirement that a summary of evidence supporting both safety and benefit be submitted in the letter of notification.

However, the Commission urges that manufacturers voluntarily include an affirmation in the notification letter or in a separate public notice, indicating that the company has reviewed the evidence supporting the statement of nutritional support and has concluded that it is truthful, not misleading, and scientifically valid. DSHEA requires that manufacturers have evidence that a statement is truthful and not misleading. DSHEA charges the Commission to make recommendations for providing consumers with information that is scientifically valid. Therefore, all three of these criteria need to be reflected in the affirmation.

Also, the Commission suggests that manufacturers include an affirmation in the notification letter or other public notice that they have evaluated the available information relating to safety and have satisfied themselves that the product does not present a significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling. This language is consistent with the provisions of DSHEA that state that a product will be considered "adulterated" (unsafe) if it presents a significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling.

Based on the public comments on the draft report, the Commission deleted the recommendation that a consumer summary of the evidence for safety and benefit be submitted as part of the letter of notification. However, the Commission believes consumers need balanced, nonmisleading, and valid information regarding the evidence. These issues are addressed further in Chapter IV of this report.

The Commission recognizes that FDA recently published its final rule outlining the information that should be contained in a letter of notification (30) (see Endnote 1). The Commission prefers that the notification letter contain more information than FDA has required:

Statement of Purpose: An indication that the purpose of the letter is to provide notification of a statement of nutritional support, including the exact wording that appears on the label.

Vendor Information: The name, address, and telephone number of the manufacturer and, if available, the address and/or toll-free telephone number for consumer inquiries.

Product Identification: The name and description of the product should include the trade name and the common or usual name. A copy of the product label (or label copy, if labels are not yet printed) should be included.

Ingredient Statement: The specific individual ingredients or combination of ingredients for which the statement of nutritional support is made should be identified. For botanicals, ingredients should be identified by the common or usual name, the Latin binomial and its scientific authority, and the part(s) of the plant used. Some Commission members believe that many botanicals are adequately identified by common name, and that scientific nomenclature should be required only when confusion or misidentification might occur.

Intended Use: The statement of intended use should include the recommended dosage, and appropriate contraindications or warnings must be stated.

Statements of Affirmation: The Commission suggests that, in the notification letter or in a separate public notice, manufacturers should affirm that they have evaluated the evidence on safety and benefit. That is, the manufacturer should affirm that there is supporting evidence that the statement of nutritional support is truthful, not misleading, and scientifically valid. The manufacturer should also affirm that the product does not present a significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling. Manufacturers also need to comply with the FDA final rule on the contents of notification letters (30).

Guidance

SUBSTANTIATION FILES FOR STATEMENTS OF NUTRITIONAL SUPPORT

During its public hearings, the Commission was asked by several manufacturers to provide guidance regarding the type of information that a responsible vendor should have to substantiate a statement of nutritional support.

The law does not define "substantiation," and the Commission has considered guidelines as to what constitutes appropriate documentation for a statement of nutritional support. Following appropriate guidelines for substantiation could allow manufacturers to have more confidence that a statement will be sustained if challenged by regulatory agencies. Following the guidelines would increase the likelihood that statements will be appropriately supported and would provide consumers with some basis for judging the soundness of the statements that are made.

Statements of nutritional support as allowed under DSHEA must be substantiated by evidence that the statements are "truthful and not misleading." The evidence needed to substantiate statements of nutritional support will vary depending on the statement made. For example, statements about the relation of a vitamin or mineral to a classic nutrient deficiency disease are generally supported by a significant body of research. DSHEA requires that statements claiming a benefit related to a classic nutrient deficiency disease disclose the prevalence of the disease in the United States. The Commission concurs that the data on prevalence in the U.S. population should come from recognized sources, such as the several surveys that are components of the National Nutrition Monitoring and Related Research Program, the publications derived from this program, or publications in peer-reviewed journals.

Other types of statements of nutritional support may be substantiated by various types of evidence, including historical usage, animal testing, in vitro studies, epidemiologic data, and human studies. Controlled clinical studies represent important evidence to support a claim, provided the studies have been well designed. While proprietary studies can be important, studies published in peer-reviewed scientific journals have added credibility. Substantiation files should include key data, including evidence from studies showing no benefit or adverse effects. The weight of evidence should substantiate the statement of nutritional support.

The Commission recognizes that the content of the substantiation file may be developed by parties other than the manufacturer or vendor of the finished product, such as an ingredient supplier, a private label manufacturer, a trade association, or an external consultant.

The Commission considered the criteria that FTC has established regarding support of food advertising claims (24). In determining whether a reasonable basis exists for an advertising claim, such as an unqualified health claim, FTC evaluates the competency and the reliability of the scientific evidence and the level of support among scientists that experts would find necessary. Under general principles for substantiation of claims (25), consideration is also given to factors such as the type of claim, the product, the consequences of a false claim, the benefits of a truthful claim, the cost of developing substantiation for the claim, and the amount of substantiation experts in the field believe is reasonable. In addition, expert testimony and consumer surveys are useful in determining what level of substantiation consumers expect to support a particular product claim and the adequacy of the evidence an advertiser possesses. The Commission finds that substantiation for statements of nutritional support will likewise vary depending on the nature of the statement being made, the health importance of the statement, and the difficulty of conducting experimental studies.

The Commission discussed how a statement of nutritional support can be adequately substantiated when it is based solely on historical use without supporting experimental or clinical data. At a minimum, such a statement of nutritional support would have to be carefully qualified to prevent misleading consumers. Some Commission members believe that, in some circumstances, qualified statements based solely on historical use would be recognized by experts as being adequately substantiated. Other Commissioners believe that experts would want more scientific support for substantiation and especially so in the case of statements that have particular health importance. One Commissioner believes that scientific support for substantiation is needed for all statements with health importance.

DSHEA does not require that substantiation files be made available to FDA, and the majority of the Commission members are not recommending a change in legislation regarding the availability of these files. However, one member believes that FDA needs to be able to obtain access to the relevant files of a manufacturer to enforce effectively the manufacturer's obligation to substantiate statements of nutritional support and the obligation to substantiate safety. That member believes the authority to obtain access to substantiation files should be provided either through a rule similar to that proposed by FDA on nutrient content claims based on new technology for food ingredients (38) or through legislative action.

In the Commission's public hearings, a number of witnesses indicated that guidance regarding the content of the substantiation file is needed. The Commission has developed the following guidelines on the content of substantiation files.

Notification Letter: A copy of the notification letter should be included.

Identification of Dietary Supplement Ingredients: The identity and quantity of the dietary supplement ingredient(s) that is (are) the subject of the statement of nutritional support should be included. If possible, the active component and mechanism of action should also be indicated. In the case of individual chemical compounds, such as vitamins and minerals, the specific components are readily identified; in the case of botanicals or animal products, the active principle(s) in the product responsible for the effect should be identified, where known.

Evidence to Substantiate Statements of Nutritional Support: Such evidence should include copies of key references to experimental or clinical data and/or findings of authoritative bodies and other evidence, where appropriate. References should include relevant information, positive or negative. Research or monographs from appropriate foreign sources may be cited, along with evidence that specific uses or claims are approved in other countries. An interpretive synopsis by an individual(s) or group qualified by training and experience to evaluate the evidence should accompany the literature citations and should assess clearly the evidence supporting the statement. Evidence for efficacy should include the dosage at which effects are observed. Where historical use is cited as the evidence for a statement, the composition of the product should correspond with the material for which such claims of historical use may be made. The complexity of a product may affect the substantiation required.

Evidence to Substantiate Safety: The Commission believes safety is of primary concern in marketing dietary supplements, and the file should indicate the basis of the manufacturer's conclusion that the product can reasonably be expected to be safe at levels of intended use.

Good Manufacturing Practices: Assurance that GMPs were followed in the manufacture of the product should be indicated.

Qualifications of Reviewers: The qualifications of those who reviewed the evidence should be included. Substantiation should be assembled by an individual(s) or group qualified by training and experience to assess the evidence, and the file should list the qualifications of those who reviewed the data on safety and efficacy. If an external advisory body was consulted, it should be identified.

The Commission provides the following guidance regarding the information a responsible manufacturer should have in a substantiation file for a statement of nutritional support and product safety. While the Commission's guidance on substantiation files is directed to statements of nutritional support and safety, other types of label statements may be made for dietary supplements. The Commission's guidance on substantiation file content may be helpful in identifying what a responsible manufacturer would do for substantiation of other types of label statements.

Guidance

PUBLICATIONS EXEMPT FROM CLASSIFICATION AS LABELING WHEN USED IN CONNECTION WITH SALES

Historically, FDA has considered literature used directly in connection with the sale of a product to be "labeling" for the product. Section 5 of DSHEA exempts certain publications used in connection with the sale of dietary supplements from being defined as "labeling." The exemption applies to "a publication, including an article, a chapter in a book, or an official abstract of a peer-reviewed scientific publication that appears in an article and was prepared by the author or the editors of the publication, which is reprinted in its entirety . . . ."

DSHEA directs the Commission to study and make recommendations for the regulation and evaluation of label claims and statements for dietary supplements, specifically "including the use of literature in connection with the sale of dietary supplements."

DSHEA has only a brief official legislative history, and one of the few points it covers reiterates that the labeling exemption "does not apply to a summary of a publication other than an official abstract of a peer-reviewed scientific publication" (see Endnote 2). DSHEA exempts a publication from "labeling" only if it:

(1) is not false or misleading;
(2) does not promote a particular manufacturer or brand of a dietary supplement;
(3) is displayed or presented, or is displayed or presented with other such items on the same subject matter, so as to present a balanced view of the available scientific information on a dietary supplement;
(4) if displayed in an establishment, is physically separate from the dietary supplements; and
(5) does not have appended to it any information by sticker or any other method.

DSHEA specifies that this provision "shall not apply to or restrict a retailer or wholesaler of dietary supplements in any way whatsoever in the sale of books or other publications as a part of the business of such retailer or wholesaler." Further, DSHEA provides that in any proceeding brought under this provision, the government shall bear the burden of proof "to establish that an article or other such matter is false or misleading."

The Commission finds that some of these requirements of Section 5 of DSHEA are difficult to apply. The emphasis on the need to reprint the publication "in its entirety," the care given to describing an official abstract of a scientific publication, and the prohibition against the use of any summary other than the official abstract of a peer-reviewed scientific publication all suggest that Congress was referring primarily to scientific publications in drafting this labeling exemption. However, the term "publication" as used in this section is not restricted to a scientific publication and thus would appear to apply to almost any publication about the available scientific information on a dietary supplement, provided that the five additional requirements noted above are met. This matter also raises a concern about violation of copyright laws applicable to published articles.

The Commission believes the most important of the five requirements outlined in Section 5 of DSHEA is the requirement that the publication itself be balanced or else be displayed with other publications that taken together provide a balanced view of the available information. Determining when a balance exists may be difficult, but the concept itself is straightforward and includes a need to acknowledge negative as well as positive data and to indicate which position is supported by the weight of the evidence.

Well-written scientific review articles generally are balanced, in that they acknowledge both the positive and negative findings on a given topic, but scientific review articles are unlikely to be consumer friendly. The same applies to scientific articles reporting on original research. The introduction or the discussion section generally will note previous articles that reported findings consistent with or contrary to the new findings. However, scientific articles and perhaps especially the official abstracts of such articles may be difficult for the consumer to understand. Therefore, it appears likely that the bulk of the literature used in accordance with this provision may be in the form of publications specifically prepared for this purpose and written for the consumer. Some Commissioners believe that providing a balanced view of scientific information provided by positive and negative publications used in connection with sales presents particular difficulties. Further study is needed to determine whether there are adequate and reliable means to ensure that a balanced view is provided.

Several organizations are currently publishing materials specifically intended as "third-party literature," the term often used within the industry to refer to literature covered by this section of DSHEA. This literature can provide useful information for consumers, provided it meets all of the requirements of DSHEA, including the requirements that the information be truthful, not misleading, and balanced. The Commission encourages manufacturers, distributors, and others to provide reliable information to help consumers use dietary supplements appropriately, whether that information is in the form of "third-party literature" or in the form of labeling provided by the manufacturer for inclusion on or with the product. One member believes that the publications exempted from labeling should be independent and should not be written, developed, or funded by the manufacturers or sellers of dietary supplements, apart from any support they provide for the underlying scientific research.

There is uncertainty regarding the scope of the circumstances under which literature may be provided to consumers under the labeling exemption. It is clear from DSHEA that such literature may be provided in the retail setting, provided it is displayed in a location separate from the dietary supplement. Apparently it may also be provided in other instances, including direct sales (person-to-person sales), and some suggest it may even apply to mail order sales (7).

DSHEA requires that the literature "not promote a particular manufacturer or brand of a dietary supplement." The Commission has considered what constitutes promotion for purposes of this section. For example, in the case of a scientific article, the "methods" section of the article may identify a product that was used in the study and donated by the manufacturer (69). In the view of the Commission, the practice of donating products for research studies or directly supporting research on dietary supplements should be encouraged, and the mere mention of the identity of a product in a scientific article should not be viewed as "promotion" of that product. If mention of the product in this context were viewed as promotion, then all manufacturers other than the one that provided the material would be free to use the article as "third-party literature." This would not appear to be a reasonable outcome. However, this may be a moot point because, as mentioned above, the full text of a scientific article seems unlikely to be used directly for consumer information.

Finding

The Commission supports the provision of balanced, truthful information to consumers regarding the uses of dietary supplements. The literature provision of DSHEA should be used with care, strictly observing the five requirements pertaining to such literature.

Guidance

BOTANICAL PRODUCTS

Botanical products represent a major category of permissible ingredients of dietary supplements, but they also are used as conventional foods, culinary adjuvants, and drugs. In the United States, the highest-volume use of botanicals is undoubtedly as foods. This includes such staples of the U.S. diet as potatoes, tomatoes, corn, wheat, oats, rice, leafy greens, carrots, onions, and garlic. Many plants are also used as spices and flavorings. FDA regulations list approximately 250 botanical ingredients (and their essential oils and extracts) that are generally recognized as safe (GRAS) for use in foods as spices and flavorings, essential oils, and natural extractives (110-113). In addition, more than 100 are listed as approved flavoring agents for use as natural flavorings in foods and beverages (109).

In many countries, botanical remedies are a major component of the pharmacopeia of available medicinals. The Commission is aware that 80 percent of the world's population relies mainly on health care systems that include the use of plant extracts or their active ingredients (2). Further, many developed and developing countries have established regulatory systems covering the recognized preventive and therapeutic uses of botanical remedies (70). The United States is a notable exception.

1. Statements of Nutritional Support

When marketed as dietary supplements, botanical products are permitted to bear statements of nutritional support in the same manner as all dietary supplements. After reviewing letters of notification submitted to FDA, the Commission concluded that in many cases, a statement of nutritional support may be adequate to inform consumers of the appropriate use of a specific botanical product. However, the Commission also concluded that many botanicals now are being labeled with statements of nutritional support that suggest only indirectly the type of therapeutic use that is traditional for the product. In such cases, the Commission questions whether the statement of nutritional support is adequate to convey to consumers the intended use of the product.

For example, Figures 2 and 3 compare statements related to the uses of echinacea and ginger, respectively, in draft WHO model monographs (140) with statements of nutritional support from notification letters received by FDA. Most Commissioners believe that there are instances when statements concerning treatment such as those found in the WHO model monographs may be more informative to consumers than the less specific language used in some of the statements of nutritional support.

2. NLEA Health Claims

Botanical products, as dietary supplements, are theoretically eligible for the FDA-approved NLEA health claims, provided all of the requirements for health claims can be met. The Commission is not aware that any petition has been filed with FDA to request approval of an NLEA health claim for any botanical, except those used primarily as foods. For example, a health claim for soluble fiber from whole oats was approved in January 1997 and amended in May 1997 to include psyllium husks containing sufficient levels of naturally occurring ß-glucan to help lower cholesterol and thus reduce the risk of coronary heart disease (34,35).

In practice, some botanical products may have difficulty meeting the requirements for eligibility as NLEA health claims as set forth in the statute and 21 CFR 101.14 (99). For example:

1. The product may not meet the requirement of providing aroma, taste, or nutritive value.
2. The ingredient(s) may not meet other requirements established in regulations implementing NLEA, including the requirement that use of the ingredient(s) "at the levels necessary to justify a claim has been demonstrated by the proponent of the claim, to FDA's satisfaction, to be safe and lawful . . ." (101).
3. The product claim may not relate to a "risk of disease or health-related condition that is diet related, taking into account the significance of the food in the total daily diet . . ." (FDCA Section 403(r)(3)(A)(ii)).
4. The evidence supporting the health claim may be based on historical use rather than current scientific studies and thus may not meet the test of "significant scientific agreement."

The Commission suggests that NLEA health claims be permitted for botanical products where appropriate but recognizes that NLEA health claims will not cover all uses of such products, especially when the use is not diet related or relates to an acute condition or to treatment.

3. Regulation of Botanical Products in Other Countries

Several references regarding the regulation in other countries of botanical products for multiple uses were submitted to and reviewed by the Commission (8,70,137). Botanical pharmacopeias have been established by a number of countries, including Germany, France, the United Kingdom, and Japan. Systems of regulation applicable to therapeutic uses of botanical remedies have been established by the aforementioned countries as well as by Canada and other nations. Twelve of eighteen industrialized countries for which information was available have formal mechanisms allowing therapeutic claims for botanical products based on a combination of historical and scientific information. In some countries, clinical evidence is required to support recommended uses. In other countries, traditional use is sufficient to provide the basis for a limited therapeutic claim, but a disclaimer may be required (Table 3). Some countries have established lists of ingredients that are permitted or not permitted and/or lists of permitted claims for botanical products used for therapeutic purposes. WHO has published guidelines for the regulation of traditional medicines, including botanical remedies (141), and is finalizing a series of model monographs on specific botanicals (140).

Japan, China, and other Asian countries all have long histories of use of botanicals and other natural products. It should be recognized that products defined in the United States as dietary supplements (botanicals, vitamins, minerals, amino acids, hormones, enzymes) are generally regulated as drugs in Japan, China, and other Asian countries (70,121,133). Direct comparison of the Japanese and Chinese regulatory systems with that of the United States is further complicated because of differences in nomenclature and classifications.

In China, traditional Chinese medicine uses more than 6000 natural products. About 500 are most commonly used and of these about 82 percent are derived from plants, 12 percent from animals, and 6 percent are minerals. Most of these are regulated as drugs (70). With regard to foods purported to have special health benefits, recent legislation in The People's Republic of China bans the marketing of unregistered "health foods" and institutes an inspection process for manufacturers of such products (144).

The Commission concluded that a comprehensive evaluation of regulatory systems used in other countries for botanical remedies is needed. Such an evaluation should consider the scope of products covered, the means of assuring safety and preventing deception, the effect of such systems on overall medical care, the issue of defining appropriate OTC uses of products, and the appropriateness and applicability of the different types of disclaimers.

The Commission studied these issues in detail and concluded that although such a study is needed a comprehensive evaluation exceeds the mandate of the Commission. A comprehensive evaluation of the U.S. drug regulatory system and approaches used in other countries to the regulation of drugs, alternative medicines, and traditional botanical remedies is long overdue.

If the study were to suggest the use of botanical remedies under a lower standard of efficacy and a different approval process than that presently required by law for drugs, one member strongly recommends, in such a case, that the review also consider the need for a disclaimer that states: "This product is not generally recognized by experts and has not been approved by FDA as effective based on adequate and well-controlled studies." A change in the drug approval process or the standards for drug efficacy would require legislative action.

Some witnesses at Commission hearings suggested that the regulatory system in the United States should accommodate therapeutic claims for products currently marketed as dietary supplements. However, as defined in DSHEA and FDCA, products promoted for the treatment, prevention, mitigation, or cure of disease fall outside of the definition of dietary supplements. To the extent that botanical preparations are marketed for use as dietary supplements, their usage and all aspects of their labeling should comply with the requirements of DSHEA.

4. OTC Drug Uses of Botanical Products

Public testimony before the Commission indicated that many of the recognized traditional uses of botanical products are similar to those classified in the United States as OTC drug uses. Based on the testimony presented, the Commission believes that the history of use and the scientific evidence available for some botanical remedies may be sufficient to justify OTC approval within the U.S. drug regulatory system as it currently exists.

For the past 25 years, FDA has been reviewing the safety and efficacy of OTC drugs. Some botanical ingredients have been reviewed. Of these, six were listed as safe and effective for their intended uses and more than 150 were eliminated from consideration. However, the Commission believes many botanical manufacturers may not have participated in the OTC review, reportedly out of a concern that FDA would not consider approving botanical ingredients.

The Commission understands that petitions for OTC approval of two botanical products (valerian as a sleep aid and ginger as an antiemetic or for relief of symptoms of motion sickness) were submitted in 1992 to FDA by the European-American Phytomedicines Coalition but have not yet been approved.

In light of the increased public interest in botanical remedies, the Commission believes that FDA needs to give special attention to the feasibility of approving botanical remedies for OTC uses in cases in which sufficient evidence is available. The Commission recommends that FDA convene a botanical products review panel to review petitions concerning such products. Such a panel should include experts with an appropriate scientific background in pharmacognosy as well as experts in other applicable disciplines. In its deliberations, this panel should give priority to botanical remedies having the strongest supporting evidence. Initial candidates might include, for example, the botanical products for which the U.S. Pharmacopeial Convention, Inc., is currently establishing standards (132) and/or botanicals for which WHO has prepared draft model monographs (140).

The Commission urges FDA to put a high priority on expediting such a review panel. FDA should also explore whether it would be helpful to convene a scientific conference or workshop on a given product or set of products. The Commission also urges manufacturers of botanical products to prepare and submit scientific data as well as information on the "material time and extent" of use of the ingredient for the relevant purposes to facilitate review when FDA requests such data (39).

To be approved as OTC drugs, products must be generally recognized as safe and effective (116). Proof of safety includes adequate testing by methods reasonably applicable to show that an OTC drug is safe under the prescribed, recommended, or suggested conditions of use. General recognition of safety is ordinarily based on published studies, which may be corroborated by unpublished studies and other data (117). If these standards for safety are not met, submission of a new drug application is required. The U.S. Supreme Court has stated that it "may, of course, be true that in some cases general recognition that a drug is efficacious may be made" without this kind of testing, but "the reach of scientific inquiry" is the same (139).

Proof of effectiveness requires controlled clinical investigations that meet the regulatory criteria for adequate and well-controlled studies (115), unless the requirement is waived because it is not reasonably applicable or essential to the validity of the study and alternative methods of investigation are available (118). Proof of efficacy may also take into account partially controlled or uncontrolled studies, clinical studies by qualified experts, and experiential reports; isolated case reports and random experience are not considered.

FDA has waived requirements for well-controlled clinical studies for some OTC products. For example, in the case of certain OTC drugs used for earwax removal, an FDA advisory panel reviewed studies and clinical data showing that carbamide peroxide in anhydrous glycerin is effective in removing earwax. However, the panel noted that these studies were neither double blinded nor placebo controlled (59). FDA subsequently acknowledged that it agreed with the panel's conclusions and waived the requirement for double-blinded or placebo-controlled studies. FDA stated that the methods of investigation, along with the results of the studies, and human experience justified the waiver. Further, the study subjects were "examined professionally" and the earwax removal product achieved its intended effect by means of "mechanical action" (59). FDA promulgated a final rule based on the panel's conclusions and the agency's concurrence (58).

Some members of the Commission expressed concern that the existing FDA requirements for adequate and well-controlled clinical studies would preclude approval of some botanical remedies as OTC drugs because these types of studies have not been done. However, they also noted that over the past several years, OTC drug review panels and FDA reviewers have occasionally applied standards to some products that differ from those specified in the CFR (116).

For example, in a review of slippery elm bark as an antitussive OTC drug, an FDA panel in 1976 observed that there was a long history of safe use but that there were no well-controlled studies of effectiveness (63). It noted that data to support efficacy were needed. In 1982, another FDA advisory panel, citing the 1976 advisory panel report, recommended that slippery elm bark be approved as a safe and effective oral demulcent (60). The second advisory panel reviewed no new data. Based on the findings of this second panel, FDA proposed that elm bark be recognized as a safe and effective oral demulcent (56).

Similarly, in approving witch hazel as an OTC skin protectant drug, FDA relied on an advisory panel review of data submitted by manufacturers, absence of reports of adverse effects, and long history of use (61). The advisory panel referenced one animal study and one in vitro study of blood clotting efficiency. FDA's approval was based on the advisory panel's review and information published by the U.S. Pharmacopeial Convention, Inc., as sufficient to establish safety and effectiveness (54).

The Commission recommends that the amount of evidence required to support an OTC claim for a botanical product be determined specifically for each type of use being considered. The type of evidence that was required for OTC drugs already approved for certain uses should be the benchmark for determining what is generally recognized as sufficient evidence for botanical products intended for the same uses now. If a higher standard is deemed to be required today than was required historically, justification should be provided by FDA to show that such a higher standard is in the best interest of consumers who are currently using OTC drugs approved under a different standard. The Commission's recommendation regarding creation of an OTC review panel for botanical remedies is based on the assumption that there would be equity in the OTC review process and that it would apply equally to currently approved OTC drugs and to any botanical product covered by a new review.

Findings

The Commission recognizes that DSHEA includes botanicals under the definition of dietary supplements and does not intend to recommend any change in legislation to alter the status of these products as dietary supplements. They should continue to be available as dietary supplements when labeled as dietary supplements in accordance with DSHEA. Manufacturers should make every effort to inform consumers and health professionals of the basis for any statements of nutritional support that are made in the labeling of these products as dietary supplements.

The Commission observed that many botanical products are used traditionally for prevention and treatment purposes. The scientists on the Commission noted that in some cases, current scientific evidence supports such uses. Most Commissioners concluded that consumers would be better served by clear information regarding such uses than by the limited statements of nutritional support permitted by DSHEA. Current efforts to use statements of nutritional support to suggest such uses without overtly stating them may not provide sufficient information to consumers and may also create a climate of deception that serves neither the industry nor consumers.

The Commission believes its recommendation to encourage manufacturers wishing to make claims that go beyond those allowed by NLEA or DSHEA to submit them for OTC review would be in the public interest. Botanicals have always been included as potential candidates for OTC status. The Commission is not recommending a new category of OTC drugs, but believes that a dedicated OTC panel on botanicals would facilitate the review of appropriate OTC claims. In the judgment of the Commission, the extension of the existing OTC process to botanical remedies that are most likely to meet the existing requirements would not require new legislation but could be accomplished within the current legal and regulatory framework for OTC drugs. This concept is consistent with the OTC drug guidelines where there is general recognition of safety and efficacy and adequate current scientific evidence comparable to the evidence that was considered in approving similar OTC uses in the past.

In many other industrialized countries, specific claims for botanical remedies and medicines are permitted, generally in a separate category of nonprescription products within the drug regulatory system. Some Commissioners believe there should be a comprehensive evaluation of the potential applicability of such a system in the United States.

Guidance

Recommendations

ENDNOTES

1. On September 23, 1997, FDA published a final rule that provides guidelines for the content of notification letters. Specifically, the final rule calls for the notification to contain the following information:
2. See Chapter I Endnote.

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Commission on Dietary Supplement Labels