Dietary supplements1are big business. A recent estimate pegs the U.S. market for dietary supplements at over $35 billion annually. The U.S. Food and Drug Administration (FDA) estimates the number of dietary supplements to be over 55,000 and notes that more than 5,500 dietary supplements come on the market each year. While the path to market is easier and more straightforward than for pharmaceuticals, dietary supplement manufacturers and distributors still must meet a number of legal requirements. One of these is the requirement to notify the FDA at least 75 days before marketing a dietary supplement that contains a new dietary ingredient (i.e., NDI notification).
Failure to timely provide the FDA with an NDI notification, or marketing the dietary supplement before the 75-day period ends, adulterates the dietary supplement. Thus, it is important to be able to determine when an NDI notification should be provided to the FDA. The FDA published draft guidance on this topic earlier this month.2We discuss important elements of this guidance below.
Dietary Ingredients (DIs)
Before determining whether an NDI notification is necessary, would-be supplement manufacturers and distributors must first determine whether an ingredient qualifies as a dietary ingredient (DI). This is important because formulating a dietary supplement around an ingredient that does not qualify as a DI adulterates the dietary supplement, even if premarket notification is timely provided.3
The Federal Food, Drug, and Cosmetic Act (FDCA) defines a DI 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; or a concentrate, metabolite, constituent, extract, or combination of any of these ingredients."4
The determination of whether an ingredient can legally be a DI is nuanced and can be confusing. For example, an amino acid is a DI. Synthetic amino acids are also DIs because an amino acid "is defined by its nutritional function... not by its state of matter like a botanical."5On the other hand, absent more, a "synthetic copy of an herb or other botanical does not qualify as a [DI]."6However, a synthetic copy of a botanical ingredient can be a DI if the synthetic copy "has been used as an ingredient in a conventional food supply."7Synthetic copies of botanical ingredients may also qualify as DIs if they can be shown to be "dietary substance[s] for use by man to supplement the diet by increasing the total dietary intake."8The NDI draft guidance contains a number of examples to aid in DI determination.
One area of growing interest is the possible use of bacteria in dietary supplements. Bacteria can qualify as DIs. The FDA notes that a "bacterial microorganism is a dietary ingredient if it is a dietary substance (an intentional constituent of food) or otherwise falls within one of the dietary ingredient categories..."9The NDI draft guidance cautions, however, that pathogenic species of bacteria "are not dietary ingredients even though they may have been inadvertently present in foods as contaminants."10The FDA regards all members of a species that contains human pathogens as potentially harmful to human health and therefore inappropriate for use as dietary ingredients. The NDI draft guidance specifically states that Escherichia coli, Enterococcus faecalis, Enterococcus faecium, and Salmonella should not be used in dietary supplements.11
New Dietary Ingredients (NDIs)
If an ingredient qualifies as a DI, a supplement manufacturer or distributor must then determine whether the DI is an NDI and therefore requires 75-day premarket notification. An NDI is a DI that was not marketed in the U.S. before October 15, 1994 (the "critical date").12Thus, if a DI was marketed in the U.S. before the critical date, then the DI is not an NDI and does not require 75-day NDI premarket notification.13
Determining whether a substance is a DI that was marketed in the U.S. before the critical date is also not a simple undertaking. For instance, marketing the DI in a country other than the U.S. before the critical date is not relevant to this determination because the statute requires the sale of the DI in the U.S.14Also, there is no authoritative list of DIs that were marketed prior to the critical date.15Thus, to show prior DI marketing in the U.S., the NDI draft notification guidance suggests that the manufacturer or distributor have documentation consisting of "written business records, promotional materials, or press reports with a contemporaneous date prior to [the critical date]."16The FDA also considers "GRAS [generally recognized as safe] and food additive regulations in the Code of Federal Regulations as documentation that an ingredient was marketed as a [DI] before [the critical date]."17
An NDI notification is not required when the "NDI and all other [DIs] in the dietary supplement have been present in the food supply, as articles used for food in a form in which the food has not been chemically altered (the "food exception")."18The FDA narrowly interprets the food exception. Further, even if the NDI meets this exception, if the dietary supplement contains more of the NDI than is used in a conventional food, the FDA recommends consulting with the agency and that it may be advisable to voluntarily submit an NDI notification.19Chemically altering an article of food can also put the DI outside of the food exception, and even render the chemically altered article ineligible to be a DI.20
NDI Premarket Notification
Assuming that a dietary supplement contains an NDI, and that an exception does not exist, the NDI draft notification guidance then addresses the notification itself. Various questions are addressed, including whether notifications can cover multiple dietary supplements (they can);21and whether the separate requirement to submit dietary supplement labeling to the FDA within 30 days of marketing can be met by pre-submitting the labeling in the NDI notification (it cannot).22
Importantly, NDI notifications are published 90 days after submission, so material that is confidential or constitutes trade secrets should be clearly marked so that the FDA can redact this material before publication. Failure to clearly identify material as confidential will result in the material being published.
Finally, the NDI draft notification guidance provides helpful tools, including a recommended template for organizing an NDI notification,23a list of definitions,24and a notification decision tree in an appendix.
Conclusion
The decision to provide the FDA with an NDI premarket notification is important and legally nuanced. Failure to timely provide required NDI premarket notification, or marketing the dietary supplement before the end of the 75-day period, adulterates the dietary supplement. Further, NDI premarket notification is only one of several requirements that must be met to legally market a dietary supplement in the U.S. Consulting with counsel through the dietary supplement premarket, launch, and post-marketing phases is thus highly recommended.
For questions about NDI premarket notification, or dietary supplements generally, please contact David Hoffmeister or any member of Wilson Sonsini's FDA regulatory practice.
