Last Friday, April 27, marked the first time that the U.S. Food & Drug Administration (FDA) has sent warning letters with NDI-related language since 2010, prompting industry to wonder: Has NDI enforcement arrived?
In 2010, the agency warned supplement maker Unlimited Nutrition that its products contained piracetam—a nootropic drug—that did not meet the definition of a dietary ingredient. Before that, in 2004, FDA sent warning letters to 12 marketers of products containing the steroid androstenedione and asserted that their products were adulterated. Androstenedione, however, was already on its way to become a controlled substance, said Steve Mister, president and CEO of the Council for Responsible Nutrition. “FDA was just piling on at that point.”
Before 2004, no other NDI-related warning letters had been issued. Only a handful of warning letters has been issued in nearly 18 years—since 1994 when the Dietary Supplement Health and Education Act (DSHEA) gave FDA the authority to require NDI notifications.
“You can’t fault the agency for enforcing what’s clear on the face of the statute,” said Mister of the DMAA warning letters. “If you have an NDI, you must file.”
What is curious, though, is that FDA has so rarely taken the initiative to enforce the statute. “Industry shouldn’t be surprised,” said Todd Harrison of law firm Venable, LLP. “There is no doubt that DMAA is a new dietary ingredient. But FDA has allowed this to go on and on and on. FDA has created this issue through non-enforcement.”
FDA insisted in last week's warning letters to 10 sellers of DMAA-containing workout products that their products were adulterated because DMAA—a synthetic stimulant linked to the geranium plant—does not have a New Dietary Ingredient (NDI) notification to its name.
Are synthetic botanicals dietary ingredients?
On top of a lack of enforcement, the new warnings address a contentious point from agency’s recent NDI guidance document—whether or not synthetically-produced forms of botanical extracts qualify as dietary ingredients.
“I reopened those warning letters [from 2004] and they’re remarkably similar to the new [DMAA] warning letters,” said Michael McGuffin, executive director of the American Herbal Products Association (AHPA), “save for the paragraph on synthetics.”
Specifically, the warning letters state that “synthetically produced dimethylamylamine is not a vitamin, mineral, amino acid, herb or other botanical.” Neither is it a commonly used in food or drink, nor is it a “concentrate, metabolite, constituent, extract or combination of a dietary ingredient.”
AHPA takes issue with this point. In an April 30 press release, McGuffin said, “In AHPA's view, if DMAA exists in geranium through the plant's own synthesis processes, human-synthesized DMAA is also a lawful dietary ingredient.” CRN takes a similar position—that synthetic botanicals are dietary ingredients—though none of its member companies sell DMAA.
Companies named in the letters may use this argument against FDA in their responses. The agency gave the companies 15 days to respond or cease distribution of the ingredient.
“Companies should take advantage of these 15 days,” said Mister. “They can use this opportunity to present to FDA their safety data and substantiation that it is derived from geranium.”
One controversial study (Ping, et al.) out of China substantiates that geranium (Pelargonium graveolens) contains DMAA at a level of 0.66 percent. USPlabs—one of the companies named in the letters—recently published several baseline safety studies on its Jack3d and OxyElite Pro products, and also hired scientific consultancy Cantox to better substantiate the Ping study. In a September 2011 press release, Cantox stated they had two studies pending peer review that prove that DMAA is in geranium.
Companies named may also choose to reformulate. According to McGuffin, two of the companies have decided to nix DMAA from their preworkout products.
DMAA warning letters to set precedent for NDIs
For the remaining companies, a challenge to FDA’s warning could be in the cards. (On the other hand, companies that fail to respond at all would likely prompt a raid.) And what follows may well set the standards by which NDI enforcement is measured.
“We are looking at this from a process standpoint,” said CRN’s Mister. “It is setting some precedent for what FDA does next time.” Specifically, trade associations will look to see whether FDA holds safety and toxicology requirements up to food additive standards, a point of great contention between industry and the regulator.
Litigation could be in the cards. “If this becomes a test case for synthetic botanicals,” said McGuffin, “I would be surprised if you don’t see amicus briefs filed from a broad array of manufacturers in this area.”
If industry had to make their stand on synthetic botanicals with one ingredient, though, they certainly could have picked a better one than DMAA. “It is a very interesting ingredient for FDA to go after,” said Mister, “because of the class action lawsuits and the Department of Defense examination.”
“These are slam dunk cases for FDA,” said Harrison. “I don’t know why they don’t do these more often.” Harrison pointed to synephrine as another likely candidate for future scrutiny.
McGuffin warned against blowing these warning letters out of proportion. “I don’t believe that we’ll start to see 10 new warning letters every week. I don’t believe that this is evidence that the floodgates have opened.”
But a question remains: Does DMAA have enough safety data and substantiation to submit an NDI notification and receive no objection? “If one of [the companies named] or several decide that they think the agency’s wrong, I don’t know how they couldn’t file,” said McGuffin. But it would seem that the deck is stacked against DMAA. “Are they [FDA] motivated to exonerate this ingredient?” he asked.
Said Harrison: “I imagine that within the next six months, DMAA will be off the market.”
Retailers' role in policing NDIs
Retailers have begun to take action as well. Amazon announced Tuesday that it would no longer sell DMAA-containing products. According to Harrison, Bodybuilding.com has suspended sale of the supplements as well.
At a larger level, retailers are starting to take a role in policing NDIs. “You’re starting to get pushback from the retailers,” said Venable’s Harrison. “They’re asking if this or that product contains NDIs. Some of the larger finished product manufacturers are starting to ask that question as well. There’s more of that self-regulation going on.”
Leery retailers and manufacturers make somewhat of a business case for NDI notifications. And some companies are taking prophylactic measures to make sure their ingredients pass muster. Embria, for example, successfully completed the NDI process for its Epicor immune health ingredient in November 2011. "This positions Embria as a more trusted source for our partners, and provides additional assurance to our existing and future clientele that we have exercised our due diligence,” said Embria president Paul Faganel in a statement.
But such cases are exceptions. “If an ingredient is doing well in the market,” Harrison said, “an interested company is going to sell it, whether or not there’s an NDI notification.”
What does the future hold for DMAA and NDIs? Share in the comments.