In July, the US Food and Drug Administration (FDA) drafted a guidance document for industry on dietary supplements. Although the document is a draft with "non-binding" recommendations, the wording is very formal and appears ready to be implemented. The "guidance" calls for manufacturers of food supplements to report to the FDA the ingredients of all supplements marketed after 1994. The purpose of the report is to notify the FDA that food supplement ingredients are being manufactured by a specific company and to provide data to the FDA that the "new dietary ingredients" (NDIs) are safe. The guidance draft differentiates between a dietary ingredient that is wholly derived from a food and an ingredient that has undergone chemical processing. In the event that there has been enzymatic or chemical manipulation of the food or botanical ingredient, a statement is required explaining the exact manufacturing process. As a whole, the reporting process appears to be more than onerous and time-consuming – for those "new dietary ingredients" that lack safety documentation based on historical use, the FDA is requiring expensive, multistep, multiorganism, lengthy safety studies.

The US Congress enacted the Dietary Supplement Health and Education Act (DSHEA) on October 25, 1994. The legislation defined dietary supplements to distinguish them from drug agents. The purpose of the legislation was to protect dietary supplements from needing to undergo the rigorous testing required of pharmaceuticals. However, DSHEA apparently also defined a new term, "new dietary ingredient." An NDI is simply a dietary ingredient, a food supplement ingredient, that was not marketed in the U.S. before October 15, 1994. Hence all supplements marketed prior to this date are considered "grandfathered" from this FDA regulatory guidance NDI reporting. No reporting is required for these supplements. Unfortunately all supplement ingredients marketed after this date are subject to the NDI notification requirements. The FDA is proposing that an NDI notification for each ingredient in a supplement must be made 75 days before the marketing of that product. In the event that no NDI notification is made the supplement is considered to be "adulterated."

The FDA defines a food supplement ingredient that has not been chemically altered as one which has only been dehydrated, milled, lyophilized, or made into a tincture. However, if the food or botanical ingredient has been subject to a process of hydrolysis or esterification, mixed in solvents other than water or ethanol, subject to high-temperature baking, nanotechnology, or fermented to a different chemical composition, it would be considered a new NDI requiring notification. The notification process, once approved, would be published for public information. However, one manufacturer may not use the NDI notification of a second manufacturer for an identical dietary ingredient.

The FDA also defines a new dietary ingredient based on its derivation from a food or botanical source that has undergone chemical alteration. In the event that the food supplement contains a chemical or a synthetic copy of a botanical or food constituent, it would not be considered a dietary ingredient – instead, it would be considered "adulterated" as a food supplement. If a drug company has applied to the FDA to use a dietary ingredient as a drug agent, the FDA will disallow a food supplement manufacturer from using that ingredient as an NDI in a food supplement. Hence, drug applications will supersede NDI notifications.

The most onerous part of the NDI reporting process is establishing the safety of the dietary ingredient. In providing documentation for an NDI, the FDA recommends including "published data such as peer-reviewed scientific literature, reports from authoritative bodies, survey data on food or nutrient composition and consumption, advertisements or other published promotional material describing the composition of products and published agricultural or food production data." However, when the "use of the NDI differs substantially" from historical use of the ingredient "additional supportive data" would be required to prove the safety of the NDI. The major difficulty occurs when there is no historical information to substantiate the safety of an NDI. Then the FDA requires scientific testing to prove that the NDI is safe.

The FDA draft guidance proposes the following scientific studies to assess the safety of a dietary supplement's NDI(s):
         
1. A three-study genetic toxicity (genetox) battery (bacterial mutagenesis, in vitro cytogenetics, and in-vivo mammalian test) that includes a test for gene mutations in bacteria, either an in vitro mouse lymphoma thymidine kinase+/- gene mutation assay (preferred) or another suitable in vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells, and an in vivo test of chromosomal damage using mammalian hematopoietic cells;
2. a 14-day range-finding oral study to establish a maximum tolerated dose (MTD) in at least two appropriate species, at least one of which is non-rodent;
3. two 90-day sub-chronic oral studies (one for each species for which there is a range-finding study) to establish an MTD and a NOAEL (no observable adverse effect level) for use in calculating the margin of safety;
4. a one-year chronic toxicity study in an appropriate animal model or a two year carcinogenesis study in rodents;
5. a repeat-dose tolerability study in humans (30-90 days duration);
6. a multi-generation rodent reproductive study (minimum of two generations); and
7. a teratology study (rodent or non-rodent)¹

It is hard to imagine that food supplement manufacturers and/or distributors would be capable of organizing, financing, and carrying out the aforementioned safety studies. It is evident that the FDA's intent is to set up egregiously overwhelming NDI safety requirements. While these requirements may make sense for a new drug or biologic agent, clearly they make little sense for food supplements. The Centers for Disease Control's reporting of poisoning from the use of food supplementation has consistently shown that extremely few incidents have occurred. Toxicity data from use of food supplementation has historically shown minimal incidents of adverse effects. To apply the same standards to food supplements as to drug agents is ridiculous. If drug companies were obliged to sell new drugs in the $20 to $60 range with competition from a myriad of other manufacturers, there would be no business of new drug design. Drug companies manufacture drugs because they receive patent rights to their new drug agents and they can market the drugs for hundreds if not thousands of dollars each month. Such is not the case for food supplement manufacturers. While the intent of the FDA to regulate food supplements deserves some merit, this guidance draft has set the requirements for safety impossibly high to comply with. The FDA should limit safety requirements to documentation from historical use. Once the safety of a dietary ingredient has been established, that information should be sufficient for all supplement manufacturers to use; it is ridiculous that individual companies need to do their own safety studies on the same ingredient. Given that accomplishing these safety studies will require great expense, the FDA should be obligated to set up the testing facilities for these studies and provide financing to do them.

Jonathan Collin, MD

Notes
1. US Food and Drug Administration. Draft guidance for industry: dietary supplements: new dietary ingredient notifications and related issues [online document]. July, 2011. http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/
GuidanceDocuments/ucm257563.htm. (One link on two lines.) Accessed August 2, 2011.

"FDA Guidance for Industry Dietary Supplements: New Dietary Ingredients Notifications and Related Issues" posted in federal register on July 1, 2011 has a 90-day comment period. Read the information about the FDA "Guidance" Statement as titled. Action to prevent this guidance statement from taking effect is needed immediately.