A large percentage of the U.S. population uses dietary supplements on a daily basis as a means to counter an essential nutrient deficiency, improve quality of life, achieve a medical/health benefit, or supplement the diet with a dietary ingredient. The foods Americans consume on a daily basis contain a complex array of substances with a wide range of chemical structures and physiological effects. The study and understanding of the human diet, its structural diversity, its ingredient composition, its complex interaction with other ingredients and its ability to enhance health present a great scientific interest to toxicologists, pharmacologists and regulators. The regulation of ingredients by the U.S. FDA is governed by the provisions set forth in the Federal Food Drug and Cosmetic Act (FD&C), and how FDA regulates conventional foods and dietary supplements is determined by their intended uses through statements made on the product label and in labeling.
Through the FD&C, FDA is the enforcement agency responsible for evaluating the safety of all food ingredients. The safety of conventional foods and dietary supplements is addressed in §402, including adulteration provisions applying to all foods and separate provisions unique to dietary supplements. While the FD&C has adulteration standards specific to supplements, including “significant and unreasonable risk of illness or injury," FDA bears the burden of proof in showing that a supplement is adulterated under this standard.
Among other things, the Dietary Supplement Health and Education Act of 1994 (DSHEA) amended the FD&C to require a pre-market safety notification for some ingredients, termed “new dietary ingredients" (NDIs). FDA views products containing NDIs as adulterated per §402(f)(1)(B) in the absence of a submitted notification to the agency, or if there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury. The statute further specifies that the notification must include a “history of use or other evidence of safety that the dietary ingredient, when used under the conditions of use suggested or recommended in the labeling of the dietary supplement, will reasonably be expected to be safe …" (§413). If a firm is unable to document the history of safe use at the level specified in the conditions of use of a product, then it must perform toxicology studies to support the basis for a reasonable expectation of safety.
The safety standard for NDIs is, by statute, less stringent than the safety standard for other ingredients, including food additives and GRAS (generally recognized as safe) ingredients, as DSHEA took dietary ingredients out of the food additive provisions (§201(s)(6)). The safety standard, “reasonable certainty of no harm," is the same for all substances added to food. The use of a food additive requires pre-market review and approval by FDA, a process that leads to a regulation and condition parameters surrounding its safe use in foods.
Exemptions to the pre-market review and approval system for food additives include the allowance for GRAS ingredients. GRAS means that the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use. GRAS status for a food ingredient can be achieved either based on a history of common use in foods before 1958, or through scientific procedures. An NDI introduced to the market may use the GRAS notification process to become an FDA-acknowledged NDI for use in a dietary supplement.
Food additives are also used in dietary supplements, a category of food, but must be listed separately in an ingredient listing below the listing of dietary ingredients.
Congress defined the term “dietary supplement" in DSHEA and the types of substances that could be “dietary ingredients." These include vitamins, minerals, herbs or other botanicals, amino acids, enzymes, organ tissues, glandulars and live microbial ingredients, as well as metabolites, extracts, concentrates and constituents of these substances.
FDA has received more than 900 NDI notifications (more than 500 unique ingredient or ingredient combinations) to date. Natural botanical ingredients represent the vast majority (approximately 60 percent) of NDI notifications in the portfolio. The statute created a notification system whereby FDA is required to respond to the NDI notification, acknowledging receipt, and after 90 days, post the notification on the public docket.
FDA reviews notifications and frequently comments on their adequacy on the basis of safety or identity concerns. The reason for FDA objecting to an NDI notification is split down the middle between safety and identity. Approximately 25 percent are objected to for safety concerns alone, another 25 percent for identity concerns alone, and 50 percent for the combination.
At SupplySide West, I will discuss the general framework for assessing the safety of NDIs, the advantages of submitting NDI notifications, how to avoid the threat of NDI enforcement, and issues the agency must address in the re-draft of the NDI guidance. I will also discuss alternative avenues to market for NDIs outside the NDI notification process.
For more tips to help understand laws regulating the supplement and functional foods market, visit INSIDER’s Regulatory Content Library. Also, hear more on this topic during the panel discussion, "Current Issues Regarding New Dietary Ingredient (NDI) Notifications," on Thursday, Oct. 8, at 9 a.m., during SupplySide West, Las Vegas.
Corey Hilmas, M.D., Ph.D., is senior vice president of scientific and regulatory affairs for the Natural Products Association (NPA).