NDI enforcement quandary rears its head—again

At a recent conference, the leader of a dietary supplement trade group suggested FDA has “a credibility gap.”

The Sept. 16 remarks by Steve Mister of the Council for Responsible Nutrition (CRN) followed a speech from earlier that day by Steven Tave, an FDA official who identified a “regulatory gap,” that he described as the chasm between requirements in the law and what can be “realistically” achieved through enforcement.

That “gap,” Mister suggested during the Dietary Supplements Regulatory Summit, “is way too broad and it’s created a bigger problem from FDA, not an enforcement gap but what I would call a credibility gap or even a threatability gap.”

FDA has not enforced the new dietary ingredient notification (NDIN) requirement of the Dietary Supplement Health and Education Act of 1994 (DSHEA) since its enactment, “and therefore, there’s no perceived threat from FDA for noncompliant companies,” according to Mister, president and CEO of CRN.

The referenced provision is a crucial one in the law: Subject to an exemption related to an ingredient previously in the conventional food supply in a form not chemically modified, before marketing an NDI, a manufacturer or distributor must first provide FDA evidence to establish its safety in a supplement. FDA has received less than 1,200 NDINs since the law was signed by former President Bill Clinton—leaving industry observers and FDA officials to conclude that many companies have failed to meet the statutory requirement.

“And the lack of [NDI] filings may very well be directly related to the fact that there are no incentives to comply and no threat of enforcement if you don’t,” Mister added during the virtual summit.

Setting the ‘record straight’

His comments caught the attention of Tave, who directs the Office of Dietary Supplement Programs (ODSP). In a Q&A during the event, Tave said he “respectfully” disagreed with Mister’s conclusions.

“We have used our NDI enforcement tools many times over the past 25 years, bringing charges against ingredients either for not complying with the notification requirement … or not complying with the safety requirement,” Tave said. “The fact that we are not enforcing exactly when and against whom everybody wants doesn’t mean that we’re not enforcing. That may be something to discuss, but I do want to set the record straight.”

Whether FDA has been willing to enforce the NDIN requirement was the subject of debate in a series of articles this summer reported by Natural Products Insider. The series focused on a California-based supplement maker, Natural Alternatives International Inc. (NAI).

NAI called for FDA to enforce against beta-alanine manufactured in China. NAI also markets beta-alanine, with at least one key difference from the Chinese manufacturers: FDA has reviewed the safety and manufacturing details of the company’s NDI, CarnoSyn beta-alanine.

Tave advised Mister he could provide “plenty of examples” of FDA’s use of its NDI enforcement tools. In response to a request from a reporter, FDA furnished links to warning letters regarding three ingredients known as DMBA (1,3-Dimethylbutylamine), DMHA (1,5-Dimethylhexylamine) and Acacia rigidula. FDA issued warning letters to supplement firms regarding DMBA in April 2015, A. rigidula in March 2016—the month Tave began acting as interim director of ODSP—and DMHA in April 2019.

Assuming all those substances qualify as dietary ingredients, FDA determined they are NDIs subject to notifications to the agency. Because the products targeted in the letters failed to submit an NDIN, they are “adulterated” or unlawful, the agency concluded.

Providing another example of NDI enforcement, FDA shared a link to an import alert on kratom published in June 2019. According to an article published by the Food and Drug Law Institute, FDA first issued an import alert on kratom in 2012; the oldest kratom import alert an FDA spokesperson could identify occurred in 2014. 

No ‘sea change’ in compliance

Dan Fabricant, president and CEO of the Natural Products Association (NPA), led FDA’s Division (now “Office”) of Dietary Supplement Programs from 2011 to 2014. In an interview, he acknowledged there has been some NDI enforcement. However, he argued FDA under Tave’s tenure has failed to produce a “sea change in compliance” with the notification requirement.

“Has he improved compliance?” asked Fabricant, whose association’s board of directors is chaired by Mark LeDoux, the founder, chairman and CEO of NAI. “And the answer on the NDI program is flat-out no.”

Tave has acknowledged industry’s frustration over a perceived lack of NDI enforcement. His agency held a public meeting in May 2019 to explore ways to encourage innovation in the dietary supplement sector.

“I’m 100% sympathetic to the plight of a responsible firm that goes through the time and expense of complying with the law and gets frustrated that others who don’t comply are not facing any consequences for that,” he said in an interview this summer. “It’s absolutely essential that we come together and figure out a way to make sure that the incentive structure is right, to make sure that everybody is compliant with the requirements—not just because it’s the law, not just because it’s the right thing to do, but because there will be consequences if they don’t.”

In a follow-up interview after the Dietary Supplements Regulatory Summit, Mister argued warning letters aren’t enough of a threat from FDA for noncompliance with the NDIN requirement. He also noted such letters don’t constitute final agency action.

Frank Jaksch Jr. is co-founder of ChromaDex, whose flagship ingredient, nicotinamide riboside, has been the subject of two NDINs without objection.

FDA is enforcing on NDIs, but the agency is targeting “low-hanging fruit,” or “obvious” cases involving potential health risks, according to Jaksch, who also serves as executive chairman of ChromaDex’s board. He acknowledged such cases are important, but explained why FDA should do more when it comes to NDI enforcement.

Responsible companies with NDIs that go through the notification process are not reaping any benefits from doing so, he argued. “Eventually, those companies are going to question the investment,” Jaksch said in an interview.

A ‘threatability’ gap

Mister sympathized with FDA’s possible reluctance to enforce against firms mostly—though not entirely— in compliance with regulations. However, he distinguished those firms from “companies that thumb their nose at the NDI requirement and bring an ingredient to market” without disclosing to FDA how it’s manufactured or whether it’s safe.

“That should not be part of the ‘regulatory gap,’ and if it is, then there is no threat of prosecution, and it’s a threatability gap,” he concluded in an interview.

FDA’s perceived failure to act aggressively on NDI enforcement, several sources suggested in interviews over the last few months, has given supplement companies little incentive to follow the rules.

“There’s no apparent penalty for not complying,” Stuart Pape, a lawyer who previously worked in FDA’s Office of Chief Counsel, said. “One company spends the money and does the research and puts together an NDI and submits it. FDA says, ‘Great. Thank you very much.’ Then, a whole bunch of other companies don’t bother. That’s a systematic problem.

“Secondly, even when you call it to FDA’s attention in great detail, getting FDA to do something about that noncompliance is almost impossible,” added Pape, a shareholder in Washington, D.C., with the law firm Polsinelli. “This is not necessarily unique to NDIs, but it certainly is a problem there.”

Companies that have invested in the NDI process have certain expectations of FDA that haven’t been met, suggested Loren Israelsen, president of the United Natural Products Alliance (UNPA).

For instance, he cited concerns about so-called copycat ingredients of successfully notified NDIs, but whose identity and safety information has not been reviewed by FDA. This issue has been flagged by NAI, ChromaDex and others.

“The deal is that there should be some help from the government—the regulator—to assure that the rights conferred by an NDI be respected,” Israelsen said. “At least, that is certainly how the industry has understood the statute and what the administrative policy should be. And it’s been well known for a long time that ‘copycatting’ is considered to be a significant drain on innovation resources.”

Israelsen agreed with many others interviewed over the summer that FDA has failed to act in response to companies that ignore the NDIN requirements.

“The critical player, the agency, for some reason hasn’t done anything,” said Israelsen, who concurred FDA has administrative tools at its disposal, including authority at the U.S. ports, to hold firms accountable for noncompliance. “We’re left with little recourse.”

Jaksch suggested FDA needs to start with a case to crack down on copycat NDIs. Based on meetings between ChromaDex and FDA, he said the agency is “struggling” to get a case “across the finish line.”

Hands ‘tied’

But in order to take enforcement actions, ODSP needs the cooperation of various officials within FDA.

“It seems like their hands are tied because they’re not getting any engagement from the other offices that are responsible for … the broader enforcement activity, which they can’t do on their own,” Jaksch said.

ODSP did not immediately respond to a request for comment regarding Jaksch’s observation, which he said even FDA shared with ChromaDex. “We’ve heard that specific to our matter, meaning nicotinamide riboside copycatting,” Jaksch added.

That may be little consolation to the industry. Many supplement companies are likely weighing whether the costs of innovation are commensurate with the benefits.

“What the pharma industry would say is, ‘Why would we invest in a new drug if we would be ripped off and the regulator does nothing about it?’” Israelsen commented. “Are we left to a private right of action only and spend the rest of our money chasing people around that we believe are unlawfully selling an ingredient?”