Regulatory Status And Safety Of Dietary Ingredients
Analyzing the legislation.
By Todd Harrison
There appears to be an ever-expanding number of dietary supplements available in the marketplace. Many of these products contain new combinations of “old” dietary ingredients, while others contain ingredients that have never appeared in dietary supplements, and possibly in the food supply, until just recently. Marketing these new combinations and ingredients involves a degree of risk, not only from a regulatory standpoint, but also a product liability standpoint. Indeed, the Federal Food, Drug and Cosmetic Act (FD&C Act), as amended by the Dietary Supplement Health and Education Act (DSHEA), places primary responsibility for ensuring the safety of supplement products on the manufacturers and distributors of the products. What follows is an overview of the FD&C Act’s provisions governing the safety of dietary supplements.
Rehashing DSHEA
One of the primary purposes of DSHEA is to promote the importance of nutrition and the benefits of dietary supplements in the maintenance of health and the prevention of disease in the U.S. and to restrict FDA’s ability to regulate dietary supplements as drugs or food additives, while ensuring the safety of dietary supplements for human consumption. DSHEA implements this intent in several ways, including:
• Under DSHEA, dietary supplements are considered foods, thereby exempting such products from the definition of a “drug.”
• DSHEA exempts dietary ingredients from the “food additive” provisions of the FD&C Act.
DSHEA, however, does not leave FDA powerless to regulate dietary supplements as the popular press would lead many of us to believe. Indeed, DSHEA specifically allows FDA to regulate dietary supplements as foods subject to specific adulteration and misbranding provisions of the FD&C Act. Dietary supplements, as foods, are also subject to the Nutrition Labeling and Education Act of 1990 (NLEA). This past year, FDA’s final rules applying NLEA to the labeling of dietary supplements were announced and they became effective on March 23, 1999.
Under DSHEA, a dietary supplement is a product intended to supplement the diet, that contains at least one dietary ingredient and is not represented for use as a conventional food (FD&C Act § 201(ff)). A “dietary ingredient” is defined as any vitamin, mineral, botanical, amino acid or any other dietary substance intended to supplement the diet by increasing the total dietary intake of that substance (FD&C Act § 201 (ff)(1)). The definition includes any concentrate, metabolite, constituent part, extract or any combination of vitamins, minerals, herbs, botanicals, amino acids or other dietary substances (FD&C Act § 201 (ff)(1)(F)).
A dietary supplement also includes any article approved as a new drug under § 505 of the FD&C Act; certified antibiotic under § 507 or a licensed biologic under § 351 of the Public Health Service Act if, prior to its approval, it was marketed as a dietary supplement or as a food. Articles that meet the definition of dietary ingredients, but that also are the subject of substantial clinical investigations as potential new drugs where such investigations have been made public, may be marketed in dietary supplements if the articles were marketed as dietary supplements or as food prior to the authorization of the clinical investigations (FD&C Act §201(ff)(3(B)(ii)). The converse is also true: an article approved as a drug or for which FDA has authorized substantial clinical investigations (which authorization has been publicly acknowledged) is excluded from the definition of a dietary supplement unless the article was marketed as a food or as a dietary supplement prior to such approval or authorization.
DSHEA permits the Secretary of Health and Human Services to restrict a dietary supplement that is also an FDA-approved drug or is undergoing substantial clinical trials, by issuing a final rule, after notice and comment, that the article, when used in a dietary supplement under the supplement’s labeled conditions of use and dosage level, is adulterated under § 402(f) of the Act. In other words, the Secretary would have to find that the supplement poses a significant or unreasonable risk of harm when consumed in accordance with the labeled directions. While this section may make it difficult for FDA to prohibit the use of an article in a dietary supplement, it does leave room for FDA to place reasonable restrictions on the dosage level of the article if the article presents a significant or unreasonable risk of harm at high levels, but not at lower levels. (In effect, this is what the FDA is attempting to do in its proposed rule to limit ephedrine alkaloids in dietary supplements to a dosage level of 8 mg per dose, 24 mg per day, while continuing to allow higher amounts in over-the-counter drug products and prescription drugs.)
Food Additive Provisions Of The FD&C Act
The food additive provisions of the FD&C Act are not applicable to dietary ingredients (FD&C Act § 201 (s)(6)). Thus, a dietary ingredient, such as St. John’s Wort, that is not generally recognized as safe (GRAS) for consumption may be marketed as part of a dietary supplement regardless of its food additive status. A dietary ingredient, however, cannot pose a significant or unreasonable risk of illness or injury under its intended conditions of use (FD&C Act § 402(f)(1)(A)). This standard—the absence of proof of significant or unreasonable risk of illness or injury—is clearly a lesser threshold of evidence than what is necessary for a substance to receive food additive approval or to be considered generally recognized as safe (GRAS) for human consumption. However, what represents a significant or unreasonable risk of harm is unclear under the present state of the law. Indeed, neither DSHEA nor FDA provides any guidelines as to what level of scientific information is necessary to establish the safety of a dietary supplement or ingredient.
The regulatory status of a dietary ingredient also depends on whether it is a “new” or “old” dietary ingredient. This determination depends on whether the ingredient was marketed as part of a dietary supplement prior to October 15, 1994. The significance of this date is that a dietary ingredient that was marketed prior to October 15, 1994, is considered an “old” dietary ingredient. A dietary ingredient not marketed as part of a dietary supplement prior to October 15, 1994, is considered a “new” dietary ingredient, which requires 75 days advance notice to FDA before it may be marketed (FD&C Act § 413(a)(2)). The new dietary ingredient notification must contain sufficient information regarding the ingredient’s history of use or other scientific evidence to establish that the product does not pose a significant or unreasonable risk of harm when consumed (FD&C Act §§ 402(f)(1)(B) and 413(a)(2)). Failure to provide FDA with prior notification causes the product to be deemed adulterated under the Act unless the dietary ingredient was present in the food supply as an article used for food in a chemically unaltered form (FD&C Act § 413(a)(1)). In such a case, the new dietary ingredient may be marketed in a dietary supplement without notifying FDA unless there is inadequate information to provide a reasonable assurance that the ingredient does not pose a significant or unreasonable risk of illness or injury (FD&C Act § 402(f)(1)(B)).
Although there appears to have been a significant increase in the number of new dietary ingredients in the marketplace, i.e., those that do not meet the definition of an “old” dietary ingredient, there has not been a significant increase in new dietary ingredient notifications to FDA. Failure to file a notification runs a significant risk that FDA will deem the new dietary ingredient adulterated under the FD&C Act, unless there is some evidence that the dietary ingredient is part of the food supply.
For example, many of the new herbal ingredients found in dietary supplements appear to have been used by other cultures as traditional medicines, rather than as food. Because the FD&C Act requires that FDA be notified of all new dietary ingredients that are not part of the food supply, a company runs the risk that FDA will consider a supplement containing a new medicinal herb to be adulterated under Section 413(a) of the Act because the herb was used as medicine rather than as food. Indeed, under FDA’s new dietary ingredient notification regulations, one of the factors that it considers when evaluating the safety of a new dietary ingredient is the ingredient’s traditional medicinal use. Accordingly, a company should have reliable evidence that a new dietary ingredient is part of the food supply prior to making a decision to forego filing a notification with FDA.
As stated above, however, Congress, in enacting DSHEA, did not prescribe criteria defining the particular level of scientific information required to establish that a dietary ingredient, old or new, is safe, i.e., does not present a significant or unreasonable risk of harm. Moreover, FDA has not attempted to define a minimal level of scientific data required for a finding that a dietary ingredient is safe. Indeed, FDA has stated that DSHEA’s new dietary ingredient notification provisions merely provide a mechanism by which manufacturers and distributors of new dietary ingredients are required to provide FDA with information regarding the safety of such an ingredient and that the agency cannot establish a minimum threshold level of information that is required to establish the safety of a particular ingredient. Rather, FDA takes the position that DSHEA places the responsibility of ensuring the safety of a dietary ingredient on the manufacturer or distributor of the finished dietary supplement. Thus far, then, FDA is “keeping its powder dry.”
Therefore, the decision to market a dietary ingredient and combinations thereof is largely dependent on professional judgment regarding the safety of the product. Thus, a company should take into consideration all relevant safety information available in determining whether to market a particular ingredient. While an ingredient that has a long history of food use would likely require less safety data to establish its safety, a new ingredient that is chemically synthesized from natural sources may require a 90-day rat feeding trial to establish its safety. Indeed, from a regulatory and product liability standpoint, if there is insufficient information available to determine the safety of a particular dietary ingredient, then it would behoove a company to forego marketing the ingredient until sufficient evidence is generated to establish its safety.
Additionally, if there are known interactions between the dietary ingredient and other dietary ingredients or drugs, the label should adequately inform the consumer of the potential interaction. Failure to provide adequate warnings could cause the supplement to be misbranded under the FD&C Act and subject to adverse regulatory action.
NW