The legal and regulatory status of creatine forms other than CM in the USA, the largest market worldwide for dietary supplements, is somewhat ambiguous. According to US law, a “dietary supplement” is defined as “…a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: 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 the total dietary intake; or a concentrate, metabolite, constituent, extract…” (Federal Food, Drug and Cosmetic Act 1938a). Creatine, an amino acid derivative, would appear to satisfy this requirement. A “new dietary ingredient” (NDI) is defined as “…a dietary ingredient that was not marketed in the United States before October 15, 1994…” The law considers a dietary supplement that contains a new dietary ingredient adulterated, unless the ingredient has 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 there is a history of safe use of the ingredient and that the ingredient is the subject of a 75-day premarket notification to the Food and Drug Administration (FDA) (Federal Food, Drug and Cosmetic Act 1938b). The requirement for the notification to FDA prior to entering the market is to demonstrate to the agency that the ingredient, as intended to be used, is reasonably expected to be safe.
The legal and regulatory status of CM is unequivocal. CM first appeared on the US market in 1993 (EAS 1993) and therefore is not an NDI and instead is considered “Grandfathered” (i.e., a dietary ingredient marketed in the USA prior to 15 October 1994). Furthermore, it satisfies the statutory requirement of having been present in the food supply in a form that has not been chemically altered. Since 1994, many new alternate forms of creatine have entered the US marketplace, and only several of these have been subjected to the requisite 75-day new dietary ingredient notification (NDIN) to FDA. These alternate forms of creatine include, but may not be limited to, CC, CEE, COP, CPY, creatine malate (CML), creatine phosphate (CP), creatine-l-carnitinate (CLC), and tricreatine orotate (TCO). Of these, only CEE, CPY, CLC and TCO have been the subject of an NDI to the FDA, submitted to the agency between 1998 and 2004 (FDA 1995). The FDA has objected to each notification (with the exception of CPY where no decision has yet been posted) citing one or more of the following reasons as the basis for their objection:
1.
the form(s) of creatine may not be legal dietary ingredients as defined by the FD&C Act §201(ff);
2.
inadequate information to conclude that the form(s) of creatine is reasonably expected to be safe due to insufficient safety data and/or failure to establish a history of safe use; and/or,
3.
inadequate information about the chemical identity of the creatine form(s)
In each of its letters of objection, FDA includes the following text: “Therefore, your product may be adulterated under 21 U.S.C 342(f)(1)(B) as a dietary supplement that contains a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury. Introduction of such a product into interstate commerce is prohibited under 21 U.S.C. 331(a) and (v)…”
Due to the nature of the notification process in the USA, a non-response from FDA could, in theory, be considered a “non-objection” from the agency. Thus, the agency’s view on the regulatory status of CPY remains unclear.
However, with the notification process, FDA maintains the right to object at any time, whether it has previously responded or not. Thus, with the exception of CM and perhaps CPY, other forms of creatine appear to be on the US market without the proper sanction from FDA or without notification to FDA altogether.
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