Why one FDA import alert on higenamine could increase NDI compliance industry-wide for all dietary supplements

On March 12, FDA updated its website to show it had issued import alerts in February to two China-based companies regarding the ingredient higenamine, a stimulant-like substance banned by the World Anti-Doping Agency (WADA). While the target of this specific import alert was higenamine, the overall wording of the import alert points to a potential widespread impact on the entire dietary supplements industry. In the import alert, FDA signaled that the agency now intends to issue an import alert for any imported ingredient that has not filed a required New Dietary Ingredient (NDI) notification.

Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), any dietary ingredient that was not marketed in a dietary supplement in the U.S. prior to October 15, 1994, must file an NDI notification with FDA, providing information about why the manufacturer or distributor of the ingredient has concluded the ingredient is reasonably expected to be safe under the conditions of use. In the U.S., a vast number of companies could currently be selling dietary supplements containing ingredients for which requisite NDI notifications have not been filed—meaning there are a vast number of ingredients currently on the market that have not demonstrated to FDA reasonable safety (unless the firm has submitted such information through another legal route, such as Generally Recognized as Safe). FDA has sent warning letters to some companies citing NDI notification infractions, but overall many in industry believe the agency’s enforcement of the NDI requirement has been lax.

Back in May 2019 during a public FDA meeting titled “Responsible Innovation in Dietary Supplements,” Steven Tave, who at the time was director of the Office of Dietary Supplement Programs (ODSP) at FDA’s Center for Food Safety and Applied Nutrition, estimated that only 1,100 NDI notifications had been filed. Meanwhile, Tave estimated that there were between 50,000 and 80,000 dietary supplements in the U.S. market, a number vastly disproportionate to the number of NDIs that should have been filed. (Tave has since departed ODSP, having this February taken a new role as director of FDA’s Office of Strategic Planning and Operational Policy.)

The import alert FDA issued this February blocks the higenamine ingredients from two Chinese firms—Jingjiang Jiangyang Fine Chemicals Company, Ltd., and Suzhou Win Health International Company, Ltd.—from entering the U.S. FDA invokes an import alert when it has found evidence that a company or a product “appear to be in violation of FDA’s laws and regulations.” Shipments are then halted at the border, an action the agency refers to as Detention Without Physical Examination (DWPE). In order for a company to remove a product from FDA’s “Red List” and for the shipment to be released, the firm must first demonstrate that it has fixed the violation for which it was flagged.

Common reasons for issuing import alerts include finding that a food or supplement product has been contaminated with a microbial bacteria like E. coli or Salmonella, or discovering that a company has violated Good Manufacturing Practices (GMP) regulations or made unauthorized drug claims.

The February import alert (Import Alert 54-18) is notable in that, for the first time, FDA states that failure to file an NDI notification will warrant an import alert. Calling such ingredients adulterated under the Federal Food, Drug, and Cosmetic Act, the import alert reads: “Based on FDA’s review of the available information, the products listed in the Red List of this Import Alert are or contain one or more new dietary ingredients 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.”

At the time, it’s currently unclear what FDA’s procedure is in gathering evidence to determine that a violative ingredient has failed to meet the NDI notification requirement—for instance, it’s unknown whether the agency is cross-checking with its own list of NDI filings or whether it also has other tools at its disposal. Nutritional Outlook interviewed Daniel Fabricant, PhD, executive director and CEO of the Natural Products Association (NPA; Washington, DC). When asked what FDA’s procedure might be, Fabricant said, “We don’t know yet. We’re trying to find that out.”

Fabricant pointed out, however, that the import alert’s Detention Without Physical Examination (DWPE) is a powerful tool because it can “shut down the whole line of commerce” for a company whose violations may run deep. The ability to detain without inspection is especially significant considering that FDA is typically only able to physically inspect less than 1% of food imported from foreign countries.

The three primary complaints—of many—made by industry about FDA over its handling of the NDI process are: 1) FDA has not released a final NDI guidance document to solidify guidelines for companies on how to file notifications, 2) FDA does not have adequate knowledge of the scope of dietary supplement products in the market in order to regulate the market, and 3) FDA has not adequately enforced NDI notification compliance.

Conceivably, if FDA were to use import alerts more aggressively to catch companies who haven’t filed NDIs, it could motivate a lot more companies to finally do so.

That is the hope of Fabricant, who said that he and many supplement industry colleagues had been actively meeting with Tave and FDA for several years to push the agency to activate NDI-based import alerts. Fabricant credits the following parties, among others, with helping to provide FDA with current evidence of marketplace violations: NPA’s board of directors, beta-alanine ingredient supplier Natural Alternatives International (NAI; Carlsbad, CA) and its founder Mark LeDoux, attorneys such as Kevin M. Bell and Robert Durkin at the law firm Arnall Golden Gregory LLP (AGG; Washington, DC), and Vice President Shoji Matsukawa of Mitsubishi Gas Chemical America (New York City).

In speaking with Nutritional Outlook, AGG’s Bell especially praised his client NAI and its leader LeDoux in helping to finance a lot of AGG’s efforts during the past few years in gathering marketplace data that was ultimately turned over to FDA. NAI, which holds an NDI notification acknowledgment from FDA for its flagship CarnoSyn beta-alanine ingredient, has had a vested interest in identifying other “copycat” beta-alanine ingredients that have not filed NDI notifications but that might be trying to pass themselves off as an ingredient with an NDI notification, such as CarnoSyn, even though the ingredients are not the same. Fabricant pointed out that not only would those companies’ production processes differ from NAI’s patented process, but companies could be making ingredients “with recombinant technology or with bacteria or E. coli.” In short, copycat companies have not submitted NDI notification evidence that their ingredients are reasonably expected to be safe.

Said Fabricant: “It’s not cheap to get an NDI. You’ve got to do safety studies. You’re talking hundreds of thousands of dollars, if not a million dollars, out of the gate. And then literally two days after you get your ‘good day letter’”—from FDA, indicating the agency has positively acknowledged the NDI filing—“…somebody knocks you off for pennies on the dollar without doing any of the safety studies and without any way of people knowing that it’s not the same ingredient.”

Until now, said Fabricant, FDA had not effectively cracked down on NDI notification enforcement. Moving forward, however, if companies face the threat of an import alert at the border, it could make a difference in getting more companies to file NDI notifications and in keeping unsafe products out of the U.S. “Now, the equation changes,” said Fabricant, “Company B can go, ‘Well, I need to get my own NDI or I may need to spend money getting off the Red List. That’s certainly a lot better than the prior equation, which was: Company A spends all the money, and Company B just rides on their coattails and the FDA turns a blind eye. That’s really where the shift can happen.”

Bell added: “This might sound pious, but you know what? Not breaking the law might have a competitive edge over breaking the law,” because companies could now face substantial penalties at the border for breaking the law.

Import alerts could make a big difference in NDI enforcement—but only if FDA actively leverages them to catch violative products. Whether or not the agency will is currently a question without an answer. “It still remains to be seen whether or not they’re going to do it, and we hope they do,” said Fabricant. “We want to see a lot more things on that list” besides higenamine, he added. Higenamine was “low-hanging fruit” given existing reports and journal articles about its use in adulterated sports supplements, he added. (Nutritional Outlook previously covered the issue here.)

On higenamine, said Bell, “if that was just [FDA’s] way of getting the ball rolling, that’s fine,” but he said he hopes the Red List will one day be longer.

If FDA doesn’t step up efforts to leverage import alerts to catch NDI infractions, the promising new wording in the new import alert “is not going to mean much,” said Fabricant.

Fabricant said NPA will continue alerting FDA about ingredients and companies it believes could be in violation of NDI laws. Other industry companies could do the same, but Bell warned that those companies should deliver that information to the agency in an organized way. “Sending them a 50-page document with a bunch of names…and not really putting context around it” won’t help FDA much, he added.

But if the agency does follow through with bite, there could be a sizeable compliance ripple in the industry. “This is the import alert that should have always been in industry,” said Bell. “This is what makes NDI submissions go up. This is what FDA should want.”

Bell pointed out that another way the new import alert could reverberate through industry is by driving more companies to work exclusively with ingredient suppliers that have already filed NDI notifications—and to avoid working with ones that haven’t.

Will industry “make the mistake of underestimating the fact that FDA has issued an import alert that it now intends to enforce?” Fabricant and Bell said they hope not. According to Fabricant, this new import alert declaration by FDA “is the biggest stick that has been used in terms of imports and really levels that playing field.”