FDA Backgrounder Printed June 15, 1993 Dietary Supplements Health professionals have long recognized that vitamin and mineral dietary supplements, particularly in moderate potencies, are often useful. This is true, for instance, for women who are pregnant or breast-feeding, people with very low calorie intakes, and patients with disorders that alter nutrient requirements. And, some consumers who tend to eat on the run report that using a multi-nutrient supplement daily gives them a level of comfort that they're getting adequate nutrition. More recently, attention has focused on the possible role of certain nutrients and other food components in reducing the risk of chronic diseases. U.S. Dietary Guidelines even advise changing dietary patterns to promote health and reduce disease risk. Growing scientific support for diet-disease relationships and increased consumer interest in improving health through diet were among the primary motivating factors for the provisions of the Nutrition Labeling and Education Act of 1990 (NLEA) that allow health claims on the labels of foods, including dietary supplements. (For more about NLEA requirements, see "The New Food Label," FDA Backgrounder 92-4. Dec. 10, 1992.) This new interest in dietary supplements, however, raises questions about how the Food and Drug Administration should regulate these products. Important Issues The Federal Food, Drug and Cosmetic (FD&C) Act, which authorizes FDA to regulate foods, is designed to ensure that foods are safe and that their labels are truthful and not misleading. As directed by Congress, FDA also is implementing the NLEA by proposing to extend nutrition labeling to supplements and to require that disease-related claims are scientifically valid. (See "Call for Public Comment.") Consumers have a right to truthful labeling of supplements so that their free choices are well-informed. Yet, FDA critics seek to restrict the agency's regulation of health information, including health claims, on supplements or to reduce health information, including health claims, on supplements or to reduce safety requirements for these products. Such restriction could affect the safety, well-being, and pocketbooks of consumers. Indeed, use of products that have misleading claims or that haven't undergone a safety review may waste health-care dollars and jeopardize the health and lives of people who pass by proven remedies. Fortunately, safety and labeling are not issues for the majority of supplements -- vitamins and minerals. Scientists know a great deal about most of these nutrients. Scientists know a great deal about most of these nutrients, and most are offered at potencies reasonably close to U.S. Recommended Daily Allowances. FDA's concerns are about other products marketed under the dietary supplement banner, such as amino acids, herbs, and glandular extracts. Many of these types of products contain substances about which little is known or which haven't been evaluated for safety. (See "Safety Concerns.") Some people share these concerns and say the agency doesn't do enough to get fraudulent and potentially unsafe products off the market. Others have different viewpoints, for different reasons. Some people may not realize the potential risks posed by certain types of supplements. Others want supplements for perceived health benefits and believe FDA is restricting product availability. Still others may not understand how drugs, by law, differ from foods, including dietary supplements, or how U.S. laws affect regulation of these products. A few promoters flout the laws for their own gain -- despite risks, sometimes serious risks, to consumers' health. Some promoters claim FDA is going to take supplements off the market. The agency has said in numerous public statements that it has no such plans for safe, properly labeled dietary supplement products. What Is A Dietary Supplement? Traditionally, FDA has considered a dietary supplement to be a product in capsule, tablet or liquid form that provides an essential nutrient -- such as a vitamin, an essential mineral, or a protein. The NLEA, however, expanded the category to include "herbs, or similar nutritional substances." So, in addition to vitamins and minerals, substances being marketed in dietary supplements include herbs and other botanicals such as ginseng and yohimbe; amino acids; extracts from animal glands; garlic extract; fish oils; oil of evening primrose; fibers such as psyllium and guar gum; compounds not generally recognized as foods or nutrients, such as boiflavonoids, enzymes, germanium, nucleic acids, para-amino-benzoic acid, and rutin; and mixtures of these ingredients. To regulate these varied products, FDA annually devotes less than 1 percent of its work force. When products are marketed for food use, FDA regulates them through its Center for Food Safety and Applied Nutrition. When they are marketed for drug use, FDA regulates them through its Center for Drug Evaluation and Research. The law defines "drugs" as products intended to diagnose, cure, mitigate, treat, or prevent disease, or non-food products intended to affect the structure or a function of the body. A Half-Century of Regulation Under the FD&C Act of 1938, dietary supplements were regulated as foods "for special dietary uses." Such a food was misbranded unless its label contained information about its vitamin, mineral, and other dietary properties "necessary in order to fully inform purchasers as to its value for such uses." To enforce this provision, in the Nov. 22, 1941, Federal Register, FDA specified the first minimum daily requirements for dietary supplements -- for vitamin A, vitamin C, vitamin D, thiamine, riboflavin, calcium, iron, iodine, and phosphorus. The FD&C Act's only safety provision concerning foods including supplements, was that a food was adulterated if it contained an injurious substance. Then, because of an increasing use of processed foods and functional ingredients added to these foods, Congress passed the 1958 Food Additives Amendment, requiring FDA to implement pre-market clearance of food additives. Such additives are substances (including compounds in packaging materials) that, because of their intended use, will become a component of food, but that are generally recognized as safe (GRAS) substances. Before 1958, the burden was FDA's to prove that a substance in a marketed food was harmful. With the 1958 amendment, vendors for the first time had to provide data to establish the safety of a food substance before marketing it. A compound considered to be GRAS, but not marketed before 1958, has to be recognized as safe by the scientific community on the basis of scientific procedures. FDA has used this amendment to remove supplements that contain unsafe or fraudulent ingredients from the market. The Drug Amendments of 1962 required firms wanting to market products with drug claims to prove, besides safety, effectiveness for intended use. Under this strengthened authority, FDA has taken many drug products sold as dietary supplements off the market because their manufacturers had not submitted data through the new drug approval process to establish safety and efficacy. On Aug. 2, 1973, FDA adopted final regulations that included definitions, labeling statements, and standards describing the composition of supplements and setting maximum potencies. Fifteen petitions challenged these rules and were consolidated for hearing by a U.S. appeals court. The court upheld FDA's mandate to regulate supplements, but it took issue with certain provisions of the rules and, thus, ordered FDA (among other things) to accept the petitions and reopen the hearing on which the rules were based -- which FDA did. In April 1976, Congress enacted a bill introduced by then Sen. William Proxmire, D-Wis. The Proxmire Amendment, as the law came to be known, restricted FDA's authority to limit the potency of vitamins and minerals and the composition of multinutrient products, except for safety reasons and except for products intended for certain people, such as children and women who are nursing. The law also prohibited FDA from classifying a vitamin or mineral as a drug solely because its potency exceeded the limit determined by FDA to be nutritionally rational. A final FDA rule on Oct. 19, 1976, stated that supplements with therapeutic or other false or misleading claims were misbranded and would be subject to seizure and injunction. Petitioners asked FDA to reconsider the propriety of issuing this final rule without having published it first as a proposal. The agency denied the petitions, saying a proposal was unnecessary as the rule merely recognized the will of Congress. The petitioners appealed, and the court sent the petitions back to FDA along with the final rule, which the court determined was invalid. The court made it clear a proposal was needed before a final rule. FDA therefore published a final order in the March 16, 1979, Federal Register revoking the 1976 final rule and reinstating the 1973 final rule. Since then, FDA has taken no further action on either rule and has basically not changed its approach to supplements, regulating these products on a case-by-case basis as foods, drugs, or both, depending on their purposes and claims. Generally, foods are not subject to pre-marketing approval. Safety protections for foods are mainly the FD&C Act's adulteration provisions, which say a food can't be contaminated, can't be held under conditions whereby it might become contaminated, and will be deemed to be adulterated if it contains an unapproved food additive. FDA also has voluntary food sanitation good manufacturing practices (GMPs), which if followed, will usually prevent a food from becoming contaminated. Foods, including supplements, don't have to be proven beneficial. In regulating drugs, FDA has more authority over prescription and new drugs than over-the-counter products. For example, while both prescription and OTC drugs are subject to stringent mandatory GMPs, FDA has greater access to records for prescription drugs. For products subject to new drug approval requirements, manufacturers must report adverse reactions. Before FDA will approve new drugs for marketing, they must be proven safe and effective for their intended use. Thus today, the agency may take food or drug products off the market for a number of reasons. Among them: if a product contains a harmful substance or an unapproved food additive; if a product has false or misleading labeling; if a drug product lacks adequate directions if a drug product is adulterated because the manufacturer didn't follow GMPs; or if a product is a new drug marketed without an approved new drug application. FDA also takes action against products under its health fraud program, but only when safety is an issue or products represent fraud. This program gives first priority to direct health hazards, usually from unapproved food additives or contaminated or unapproved drugs. It gives second priority to indirect hazards, as may result from delayed or discontinued proper treatment; these usually are misbranded or unapproved products with claims for unproven therapies. Lowest priority goes to economic fraud form unproven claims for harmless products. Also, the agency is reviewing its drug listing data base to identify dietary supplements of vitamins, minerals, or other substances that are labeled with a National Drug Code (NDC) number. The law requires firms to list all their drugs with FDA, and regulations permit firms to voluntarily label their drug products with an NDA number. But a non-drug product with an NDC number represents it to be a drug, or suggests that it is. Such labeling is false and misleading. FDA considers these non-drug products with NDC numbers to be misbranded and therefore illegal. Why would a firm label supplements with an NDC number? Because many states reimburse under Medicaid for products on the basis of NDC numbers, on the assumption the products are drugs. Thus, if a firm manufactures a product with an NDA number, the federal government reimburses for the product, even if it is not a "drug" under the FD&C Act definition. From 1989 through 1992, FDA took 40 actions against products the public may have perceived as dietary supplements -- mainly on grounds of unproven therapeutic claims or dubious safety. Most charges were made under the drug provisions of the FD&C Act. FDA continues to work with state and local authorities, the Department of Justice, Federal Trade Commission, and U.S. Customs Service to keep illegal products off the market. L-tryptophan In late 1989, adverse effects associated with L-trytophan, an amino acid, heightened FDA's concerns about the safety of these supplements. People were using L-tryptophan (listed for only limited use as a food additive) for problems such as sleep difficulties, depression, and premenstrual syndrome. FDA requested a recall of L-tryptophan after published reports associated ingestion of the substance with eosinophilia-mylagia syndrome (EMS), a connective tissue disease characterized by often debilitating muscle pain and skin and neuromuscular effects. More than 1,500 cases, including 38 Prevention's description of EMS symptoms; the true incidence is thought to be much higher. Because of safety issues associated with consumption of this amino acid, FDA in 1990 contracted with the Federation of American Societies for Experimental Biology (FASEB) to review the scientific literature on amino acid supplements and to provide data on the level of safety concern that these products present. FASEB reported in September 1992 that safety data were inadequate to determine safe upper levels of use for amino acids, and that consumers -- especially children, women of childbearing age, and older people -- should not take amino acid supplements without responsible medical supervision. Dietary Supplements Task Force In May 1991, prompted in part by the L-tryptophan epidemic, FDA began a comprehensive review of its regulation of supplements by convening the Dietary Supplements Task Force. At an open hearing the task force held, some consumers said they wanted as many facts as possible about supplements and assurances of safety, but they didn't want access to products limited. Others said controls should be put in place to ensure the safety of supplements. In its final report in May 1992, the task force made 20 recommendations for regulating supplements, including: regulate amino acids more strictly label supplements with accurate information about ingredients establish GMPs for supplements establish purity standards for ingredients in supplements establish disintegration and dissolution standards to ensure vitamins and minerals in supplements are available for use by the body (the U.S. Pharacopoeia already has set voluntary standards for some water-soluable nutrients) apply existing regulations about tamper-resistant packaging and child-proof caps to supplements strengthen the adverse reaction reporting system conduct an education campaign to give consumers accurate, scientifically objective information about the safety, use, benefits, and risks of supplements. (FDA issued the complete task force report on June 15, 1993 [see "Call for Public Comment"] and is soliciting comment on the recommendations and other approaches to ensure the safety of products sold as dietary supplements.) The NLEA During this same time, FDA began implementing the NLEA, which acknowledges the agency's authority to regulate health claims about diet-disease relationships on labels of foods, including dietary supplements. However, due in part to concerns that FDA would limit claims when it applied this law to supplements, some companies, through a consumer campaign, asked Congress to restrict FDA's authority. On October 29, 1992, the Dietary Supplement Act of 1992 became law, imposing a year's moratorium on NLEA implementation with respect to dietary supplements. Nevertheless, a supplement may bear an approved NLEA health claim if its manufacturer meets the claim's requirements. FDA issued final rules in response to the NLEA in the Jan. 6, 1993, Federal Register. While agreeing that emerging science on diet-disease links may offer a potential for improved public health. FDA believes potential risks as well as benefits of important diet changes require sound scientific evaluation. The NLEA requires pre-market review of new health claims to ensure their scientific validity. The standard for health claims is different than for drug claims. Unlike drug regulations, which call for proof of safety and effectiveness for intended uses, health claim regulations only require significant scientific agreement among qualified experts that the claim is supported by the "totality of publicly available scientific evidence," including data from well-designed studies conducted with "generally recognized scientific procedures and principles." The experts must be qualified by scientific training and experience to evaluate claims. FDA's Jan. 6 rules have specific requirements for the wording in health claims. For example, because many factors affect disease development, it would be misleading to overemphasize the role of the food substance in a claim, such as indicating it will "prevent" the disease. Claims that a substance will prevent a disease are drug claims. Thus, in discussing the diet-disease relationship, health claims may only say the substance "may" or "might" reduce the risk. Claims must state that the disease depends on many factors and may be required to mention other factors involved in the effect diet may have on the risk of developing disease -- such as regular exercise in the approved claim for the link between calcium and a reduced risk of osteoporosis, a bone disorder. (For more information about requirement, see "Starting This Month: Look for 'Legit' Health Claims on Food" in the May 1993 FDA Consumer.) FDA is working intensively, in conjunction with an outside expert advisory committee, to evaluate not only scientific issues concerning the recognized relationship between intake of folic acid by women of childbearing age and a reduced risk of neural tube birth defects, but also potential safety issues related to fortification of the U.S. food supply with folate. FDA intends to publish a proposed health claim regulation on this relationship and to amend its food additive rule for folic acid. Scientific evidence was insufficient to support claims for several other nutrients. Supplements that are also OTC drugs pose a complicated issue when they have a food claim and a drug claim. As an example, certain calcium antacid drug products also have labeling about their use as a calcium supplement. The required OTC drug labeling for these products includes instructions for short-term use at medical dosages, while the dietary information often includes instructions for long-term use at lower dosages that are consistent with daily dietary guidelines. This dual labeling may be confusing to some consumers, who as a result might use the product unsafely. Under the FD&C Act, a drug labeled with instructions that both limit and do not limit consumption is misbranded if the label doesn't contain a material fact -- that is, how to reconcile these conflicting instructions. Thus, FDA will tend to view dual claims as misbranding a product. Before marketing such products, firms should submit data to the agency's Center for Drug Evaluation and Research to show that the dual claims neither misbrand the products nor create a safety problem. So far, the center is not aware of any labeling that would reconcile this issue. Meanwhile, the Dietary Supplement Act of 1992 requires a report to Congress from the Department of Health and Human Services on FDA's enforcement activities for dietary supplements. This was sent to Congress May 12, 1993. The law also requires that FDA propose NLEA-based labeling rules for supplements on health claims, nutrient content, and nutrient claims. FDA announced these proposals on June 15, 1993. (See "Call for Public Comment.") In addition: Until Nov. 8, regulations must not use recommended daily nutrient intakes other than current values of U.S. Recommended Daily Allowances. Until Dec. 15, FDA must not take action against supplements for unapproved health claims. By Dec. 31, FDA must issue final NLEA-based labeling rules for supplements. Also, General Accounting Office must report on FDA's management of activities concerning supplements, and the Office of Technology Assessment must report on the relationship between supplement regulation and human health status in the United States compared with other countries. Safety Concerns New theories about possible benefits of dietary supplements in reducing the risk of disease have stimulated research and much public interest. The resulting potential for increase use and for development of new supplement products raises concern at FDA about safety for users. Therefore, in June 1993, FDA called for public comment (see "Call for Public Comment") on approaches to ensure the safety of products sold as dietary supplements. Without data, the agency has no way to ensure that a significant number of consumers who take supplements will not be placed at risk. In 1991, an estimated 40 percent of adults in the United States took vitamin supplements. Total retail sales for over-the-counter nutritional products was some $3.3 billion, 70 percent of which was spent for vitamins. FDA has no reason for concern about safety of moderate-potency, properly labeled vitamin and mineral products. But the agency has many concerns about products such as amino acids, herbs, glandular extracts, and other substances sold as dietary supplements. Although marketed as supplements, these products often have little or no known nutritional value and have not been evaluated for safety. Substances FDA recently warned against include: Amino Acids - FDA requested a recall of the amino acid L-tryptophan after published reports associated its ingestion with a connective tissue disease. Reported diagnosed cases of illness totaled more than 1,500, including 38 deaths. FDA contracted for a review of scientific literature on all amino acids. The findings: Data to evaluate safety are inadequate. Chapparal - After learning of five cases of chaparral-related acute toxic hepatitis, FDA warned against consuming this herb, and manufacturers removed it from the market. Chaparral is claimed to slow aging, "cleanse" the blood, and treat skin problems -- all unapproved claims. Guar gum - (a complex carbohydrate that swells when wet) - One brand resulted in hospitalization of 10 patients and one death from a blood clot after surgery to remove a throat blockage. Guar gum can cause diarrhea, vomiting, bloating, and intestinal blockages. It is used in weight-loss products. Germanium - Germanium used for a long time may cause serious, irreversibly kidney damage and has resulted in death. It's promoted as an "electronutrient" for uses such as neutralizing heavy metal toxicity. There is no evidence of effectiveness. Glandular extracts from adrenal, pancreas, thyroid, and other animal glands: In 1992, FDA had concerns that glandular extracts might derive from cattle with a fatal encephalopathy (brain degeneration) called "mad cow disease" in Britain. FDA wrote to all manufacturers of glandular extracts, telling them to be sure their products originate in animals free of the disease. It hasn't been established whether the cow encephalopathy can be transmitted to humans. Many supplements are available in forms and potencies similar to drugs, but without the safeguards of FDA-approved drugs. For instance, white willow bark is marketed for use in children. This herb contains an aspirin-like constituent, but its label has not warning -- as FDA requires on aspirin labeling -- that children shouldn't take it for chickenpox or flu symptoms because of an association with the serious illness Reye syndrome. In addition, levels of natural constituents sometimes vary greatly. An herb's concentration, for instance, varies with the part of the plant it comes from, growth stage at harvest, and processing and dilution during manufacture. Some ingredients in herbal products naturally contain chemicals -- such as certain alkaloids -- that are harmful at high doses. And, herbal products may have "active" ingredients that may not yet be definitively identified. Some herbs, such as comfrey, are known to be harmful. Even with vitamins and minerals, there may be toxic effects from a contaminant or an ingredient. At one time, for instance, FDA discovered that some calcium supplements contained lead, so they had be reformulated. Some calcium supplements had excess levels of vitamin D, which would have been toxic at continued high intake. And it's common knowledge that all minerals become toxic at some level. Other safety issues center on vitamins and minerals in potencies far higher than needed to prevent deficiencies. While many vitamins and minerals in supplements are on FDA's list of substances generally recognized as safe, their GRAS safety evaluations were often based on intakes much lower than those in supplements. Since these substances are not evaluated as GRAS for use in supplements, their safety at the higher doses remains unknown and unapproved. Also, substances natural to conventional foods often are concentrated in supplements, making it easy to greatly exceed normal intakes from conventional foods. Bulk and calorie content limit intakes or foods and, thus intakes of any one substance they contain. A single substance in excess may cause imbalances. Excess zinc, for instance, interferes with absorption of copper, an essential nutrient. Some risks of nutrients taken at excessive potencies are: Folic acid -- intakes higher than 1 milligram a day can mask symptoms of pernicious anemia while the disease progresses undetected. Iron -- As few a six high-potency iron tablets can kill a child weighing 22 pounds or less. Iron is the most common cause of U.S. child poisoning deaths, causing about 2,000 poisonings a year, mainly in young children taking their mothers' prenatal supplements. Niacin -- High doses can damage the liver. Vitamin A -- Continued excess amounts can cause headaches, liver damage (including cirrhosis), bone damage, diarrhea, and, during pregnancy, birth defects. Vitamin B6 -- High intakes can cause nerve disorders. Vitamin C6 -- Very high doses can cause diarrhea and kidney damage and may cause bladder problems. Vitamin D -- Continued excess amounts can cause kidney damage and bone deformity. Further, just because there are no reported adverse reactions concerning a supplement, this doesn't mean it is safe. A person taking a supplement may not connect it with an adverse effect. Indeed, many hospitalized patients do not report all substances they've been taking, and doctors or other health professionals may not think to ask. Or, a large number of users may be needed before reactions show up. A history of unreported reactions may be unrelated to currently marketed forms of products. A selenium product, for instance, may be formulated in a way that the body can't use it; so it's not toxic, but it's not effective as a nutrient either. Call for Public Comment FDA is seeking public comment about new regulations it has proposed on nutrition labeling, nutrient content claims, and health claims for dietary supplements. It also is asking for comment about an advance notice of proposed rule-making on how it should regulate supplements to ensure their safety. FDA announced these documents on June 15, 1993. The agency said it wants consumers to have access to supplements that are safe and to have assurance that claims made about the health and nutritional benefits of these products are truthful. The proposed rules would extend the Nutrition Labeling and Education Act of 1990 (NLEA) to dietary supplements. Under these rules, supplements labels would have to provide the same kinds of nutrition information as that required for processed foods. A label panel would have to include the level and percent of daily intake of nutrients in a serving. The rules would permit health claims on supplement labels if FDA finds significant agreement among qualified experts that these claims are scientifically valid. This is the same standard the NLEA requires for conventional foods. FDA intends to work with food and supplement manufacturers and the scientific community on additional health claims that should be permitted on labels. For example, in July, FDA intends to publish a proposal authorizing a health claim for folic acid in reducing the risk of neural tube birth defects. A potential claim for antioxidant vitamins in reducing the risk of cancer and other diseases will be the next area given priority. In the advance notice, FDA calls on manufacturers of amino acid supplements to submit information substantiating the safety of their products and explaining the basis upon which they believe their products could be lawfully marketed. The agency has special concern about these substances. Several years ago, the amino acid L-tryptophan, widely sold as a supplement, was associated with some 1,500 cases of a painful muscle disorder, including at least 38 deaths. The notice includes a summary of a report by the Federation of American Societies for Experimental Biology, commissioned by FDA in 1990 to examine scientific data on the safety of amino acids. According to the report, the fragmentary nature of the data precluded a definitive judgment on amino acid safety. FDA also seeks comment on how to establish the upper limits of safe use of vitamins and minerals. Much research is being conducted on health benefits of these substances, and FDA believes the public health will be served of questions about the safety of high-potency vitamins and minerals are resolved. In addition, FDA seeks comment on the final report of its Dietary Supplements Task Force, convened in 1991 to examine alternatives for regulating various types of supplement products. In its report, the task force recognized the interest of many consumers in having ready access to supplements. It is recommended that FDA consider specific changes designed to improve the safety and labeling of supplement products of questionable safety. The report doesn't represent FDA's official position. The agency will evaluate the comments before considering possible actions. Written comments should be submitted within 60 days to: Dockets Management Branch (HFA-305) FDA, Room 1-23 12420 Parklawn Drive Rockville, MD 20857 Reprinted from the International Food Information Council Foundation, 1993

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