The extensive list of FDA warning letters that cite dietary supplement companies and manufacturers for selling products containing substances that do not comply with the Dietary Supplement Health and Education Act of 1994 (DSHEA)(Pub. L. 103-417) highlights the fact that some brand marketers may not understand how to comply with the law, especially when it comes to new dietary ingredients (NDIs). While non-binding, FDA’s revised August 2016 Draft Guidance, “Dietary Supplements: New Dietary Ingredient Notifications and Related Issues: Guidance for Industry,” provides instruction on the process of submitting an NDI notification (NDIN), including a decision tree. However, at 102 pages long, the document can seem overwhelming. A brief review of the key provisions and process of analysis can help manufacturers and distributors launch a new dietary supplement product without running afoul of FDA.
The first question to ask before launching a new product is whether it meets the definitional criteria of a dietary supplement. The term “dietary supplement” means a product (other than tobacco) intended to supplement the diet that contains one or more “dietary ingredients.” A dietary supplement is limited to products that: 1) are intended for ingestion in tablet, capsule, powder, softgel, gelcap, liquid or certain other forms; 2) are not represented as conventional food or as the sole item of a meal or of the diet; and 3) are labeled as dietary supplements. The “certain other forms” cannot include sublingual or topical/transdermal products intended to enter the body through the skin or mucosal tissues. Therefore, a nasal spray could never be lawfully marketed as a dietary supplement in the United States. Substances that were marketed or studied as drugs are also restricted. A product containing an approved new drug or licensed biologic cannot be a dietary supplement unless the article was marketed as a dietary supplement, or food, before its approval as a new drug or licensing as a biologic. Also, dietary supplements cannot include articles that are authorized for investigation as a new drug or biologic (and for which substantial clinical investigations have been instituted and made public), unless the article was marketed as a dietary supplement, or food, before it was authorized for investigation. If the product meets the criteria to be a dietary supplement, a marketer can move forward.
The next inquiry is whether the product contains one or more dietary ingredients. A dietary ingredient is defined by FDA as “a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing total dietary intake (i.e., a substance commonly used as human food or drink); or a concentrate, metabolite, constituent, extract, or combination of any of the above dietary ingredients.” Dietary supplements that do not contain dietary ingredients are deemed “adulterated” by FDA and therefore illegal to sell. For example, in 2004, FDA published final rules that declared supplements containing ephedrine alkaloids and those containing androstenedione to be adulterated. In 2010, FDA took actions with respect to Piracetam1,4,6-etioallocholan-dione(more commonly referred to as “ATD”). FDA sent a warning letter, which indicated the agency did not believe that either Piracetam or ATD were dietary ingredients, and when combined with claims that the products affect the structure or function of the body, these substances were “new drugs,” not dietary supplements. In 2012, FDA issued two warning letters,(1) (2),over an ingredient contained in a sports nutrition product—1,3-dimethylamylamine (DMAA, which was initially marketed as a “natural” stimulant derived from geranium; DMAA has been the subject of extensive and ongoing litigation). If the compound or compounds are dietary ingredients, a marketer can move forward.
The next question is whether the dietary ingredient was marketed in the United States for use in dietary supplements prior to Oct. 15, 1994, which was the year DSHEA was enacted. To be clear, the ingredient had to have been marketed as a dietary supplement, not as a conventional food, a drug or for any other non-food use. Currently, there is no official list of these “old dietary ingredients” (ODIs). However, the Council for Responsible Nutrition (CRN) and other trade organizations have prepared unofficial lists of dietary ingredients “grandfathered under DSHEA” in 1998 to assist supplement companies. In its revised draft guidance, FDA revealed it was prepared to develop an authoritative list of pre-DSHEA (old) ingredients. On Oct. 3, 2017, FDA held an all-day public meeting at which stakeholders were invited to help develop a process to create such a list. If the ingredient meets the definition of a dietary ingredient and it was marketed in dietary supplements prior to Oct. 15, 1994, it can generally be used in a dietary supplement product; there is an exception if there are changes to the manufacturing process for the ingredient that change the identity of the ingredient, and the revised form was not marketed as a dietary ingredient in the United States before Oct. 15, 1994.
If the ingredient was not marketed in the United States as a dietary supplement ingredient prior to Oct. 15, 1994, then it is considered an NDI. An NDI is deemed adulterated, unlawful to market and subject to FDA enforcement sanctions unless it falls within one of two categories: either 1) the supplement in question 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”; or 2) there is a “history of use or other evidence of safety” provided by the manufacturer or distributor to FDA at least 75 days before introducing the product into interstate commerce. An effective way of describing the two categories is NDIs requiring pre-market notification to FDA (“notification NDIs”) and NDIs that are exempted from the notification requirement (“exempt NDIs”).
Notification NDIs require submitting a notification to FDA at least 75 days before the product is introduced into commerce. The notification must include information that is the basis on which a product containing the NDI is “reasonably be expected to be safe.” That information would include: 1) the name of the NDI and, if it is an herb or botanical, the Latin binomial name; and 2) a description of the dietary supplement that contains the NDI, including a) the level of the NDI in the product; b) conditions of use of the product stated in the labeling, or if no conditions of use are stated, the ordinary conditions of use; and c) a history of use or other evidence of safety establishing that the NDI, when used under the conditions recommended or suggested in the labeling of the dietary supplement, is reasonably expected to be safe.
Each manufacturer or distributor of an NDI is required to submit a notification to FDA. In other words, just because one company has filed a notification regarding a product containing the same NDI does not mean that a different company has to file its own notification. In fact, even if a company files a notification for one of its own products containing the NDI, it may sometimes need to file a new notification if it brings another product containing the NDI to market if the new product is significantly different, such as its conditions of use, daily intake level or combination with other ingredients. Further, even if the notification is submitted as required, the dietary supplement containing the NDI is adulterated unless there is a history of use or other evidence of safety establishing that the NDI, when used under the conditions recommended or suggested in the labeling of the dietary supplement, will reasonably be expected to be safe. The revised draft guidance provides extensive content on what information to include in an NDIN.
Exempt NDIs are limited to ingredients that are present in the food supply as articles used for food without chemical alteration. There are a few elements to this alternative. One is that the ingredient must be present in the conventional food supply, either within the United States or outside it. FDA takes the position that food supply does not mean an ingredient that was eaten in the Australian bush by a small tribe. And by saying articles used for food, it does not mean that the ingredient is present in something that could be eaten but is not even for food, such as a plant that nobody has ever eaten. Chemical alteration refers to the idea that the ingredient can be tweaked into a different form that it exists in nature. FDA, in its draft guidance, noted the adulteration standard applies to all NDIs, unless there is adequate information to provide reasonable assurance that the ingredient does not present a significant or unreasonable risk of illness or injury. So, for example, an ingredient with an intake level in the conventional food supply may not necessarily be safe if used in a dietary supplement at a much higher level.
If an NDI is an herb or botanical, FDA has adopted the literal meaning of “constituent” and “extract” in stating that a synthetic copy of a concentrate, constituent or extract of a botanical is not a dietary ingredient since it was never actually part of the plant or extracted from the plant itself. So, a synthetic version of a plant ingredient that has been created in a laboratory or factory is not a dietary ingredient at all and would therefore fall into the category of an unapproved (and adulterated) new drug. Essentially, that is what the DMAA lawsuit is about; Hi-Tech argues that since DMAA has been found in geraniums, it is a dietary supplement. FDA has argued, and the courts thus far have found, that no company has physically extracted the DMAA from the geranium plant and placed it in a product. Therefore, up until this point, FDA believes DMAA is not a dietary ingredient because it is a synthetic version of a botanical, not a physical extract. Trade groups have expressed general opposition to FDA’s view as overly literal and needlessly restrictive if the natural and synthetic versions are identical in every way. Whether FDA will revise its position in the final draft NDI guidance is currently unknown.
By following a structured process of analysis in launching a new dietary supplement, manufacturers and distributors can avoid launching non-compliant products and save the costs and headaches associated with warning letters and recalls.
Rick Collins, Esq., is a principal in the law firm of Collins Gann McCloskey & Barry PLLC, practicing in the areas of dietary supplement law and criminal defense. He counsels numerous companies in the natural products industry, serves as legal counsel to the International Society of Sports Nutrition (ISSN), and has contributed chapters to two textbooks on sports nutrition. To learn more about Collins and his team, please go to supplementcounsel.com.