In late April, FDA sent 10 Warning Letters to firms that make or distribute dietary supplements containing the ingredient 1, 3-Dimethylamylamine, DMAA or Methylhexanamine. DMAA is a vasoconstrictor derived from Asian geranium. It has been touted to narrow blood vessels resulting in increased blood pressure, with the benefits of increased focus and energy. Over the last few years, DMAA has assisted athletes, most notably body-builders, in increasing their training intensity. While banned in professional sports, DMAA is still widely used in the off season for training purposes and contributes to large sales numbers for companies like GNC and Vitamin Shoppe. Many companies use DMAA in their pre-workout formulas, such as USP Labs Jack3d and Scivation Quake 10.0.
In its Warning Letters, FDA claims that products containing DMAA are technically “adulterated” for two reasons: (1) DMAA has not gone through the NDI notification process, and (2) DMAA is a synthetically produced botanical, which, by definition, is not an NDI. The FDA further asserts that even if the required NDI notification had been submitted, there is inadequate information to provide reasonable assurance that DMAA does not present a significant or unreasonable risk of illness or injury when used as a dietary ingredient. For example, the letters claim that DMAA is known to “narrow the blood vessels and arteries, which increases cardiovascular resistance and frequently leads to elevated blood pressure. This rise in blood pressure may increase the work of the heart such that it could precipitate a cardiovascular event, which could range from shortness of breath to tightening of the chest and/or a possible myocardial infarction (heart attack).”
It is not the fact that DMAA is a frequently used ingredient in dietary supplements or the allegation that DMAA is an NDI that failed to go through the pre-market notification process that have made the recent set of Warning Letters so noteworthy. Rather, it is FDA’s second argument—that DMAA produced synthetically is not a “dietary ingredient”—which could have devastating and far-reaching consequences for the entire dietary supplement community. After all, the notion that a synthetic botanical does not fall within the definition of a “dietary supplement” under the federal Food, Drug and Cosmetic Act (“FDCA”) was not introduced until FDA published its Draft Guidance on New Dietary Ingredients on July 1, 2011.
As many commentators on the Draft Guidance had feared, it appears FDA has decided to enforce the Draft Guidance provisions without engaging in notice and comment rulemaking to elicit industry input with regard to the standards to which industry will be held. In short, FDA is using the “draft” guidance to enforce a legal provision that should go through the administrative rulemaking process.
To make matters worse, from a legal standpoint FDA is wrong in its assertion that the dietary supplement definition does not include synthetic botanicals. The statute defines a “dietary ingredient” as a vitamin, mineral, herb or other botanical, amino acid, dietary substance for use by man to supplement the diet by increasing the total dietary intake, or concentrate, metabolite, constituent, extract, or combination of any such substance [FDCA § 201(f)]. The term “botanical” has a plain meaning that includes both natural substances and related synthetic substances. Dorland’s Medical Dictionary defines “botanic” as both “pertaining to botany” and “derived from plants.”
The distinction between substances “relating to plants” and substances “derived from plants” is clear. Substances “derived” from plants are natural botanicals and substances “related” to plants are botanicals that are artificial rather than natural. This, without question, includes synthesized substances that mimic substances derived from plants. Thus, under the plain meaning of the statute, synthetic substances that mimic natural botanicals are “botanicals.”
Furthermore, FDA generally draws no distinction between natural and synthetic molecules or substances in its regulation of foods, drugs, biologics and dietary supplements. The agency has consistently made it clear that there is no basis in science or policy for such a distinction. Synthetic versions of naturally occurring substances are no less likely to be safe and, where necessary, effective.
FDA has not sought to stifle the marketing of synthetic foods, vitamins, drugs and biologics. Indeed, synthetic products are often superior to their natural counterparts because they can be well-characterized, consistently produced and formulated without impurities. Synthetic botanicals, too, have the benefit of being produced in a controlled environment. This closed environment eliminates impurities that may occur naturally, e.g., are absorbed from the soil in which the botanicals are grown. Synthetic versions of botanicals are free from these impurities. This is as true of synthetic botanicals as it is for other substances, and there is no logical reason to treat dietary supplements differently from other categories of FDA-regulated products when it comes to use of synthetic substances.
Enforcement of the interpretation of a “dietary ingredient” suggested in the Draft Guidance and now stated in the Warning Letters will no doubt preclude the development of higher-quality botanical supplements. Furthermore, all 10 recipients of the FDA Warning Letters over supplements containing DMAA have now been targeted in a new wave of class action lawsuits in California that allege their products contain DMAA in a synthetic form that is “illegal and dangerous.” These cases illustrate the newest trend in class action litigation where plaintiff’s attorneys are building cases by hunting through FDA warning letters. However, these letters, like the NDI Draft Guidance, only reflect FDA’s current thinking. Most important, they are not legally binding.
While many industry members would like to see DMAA leave the market due to the negative press it is attracting to the entire dietary supplement community, if the industry does not protest FDA’s synthetic botanical argument many other products are at risk. In fact, if FDA fully enforces its NDI Draft Guidance, the dietary supplement community could suffer an economic loss of between $5.6 billion and $10.5 billion, as reported by the Alliance for Natural Heath-USA. So far, Nutrex has responded to its Warning Letter stating that it “vigorously disagrees with FDA’s allegations.” This battle has only just begun, and it remains to be seen whether FDA will actively begin pulling DMAA products off store shelves. Only time will tell.