Editor’s note: This is a follow-up story to a four-part series of articles in 2020. Read here Parts I, II, III and IV.
Fourteen months after requesting in writing that FDA stop the importation into the U.S. of “adulterated generic forms of beta-alanine,” nutritional supplements manufacturer Natural Alternatives International Inc. (NAI) received an answer met with disdain from former FDA officials.
Cara Welch, the acting director of FDA’s Office of Dietary Supplement Programs (ODSP), essentially denied the request in an April 28 letter to NAI’s outside counsel, Kevin Bell, a partner in the nation’s capital with Arnall Golden Gregory LLP (AGG).
“FDA needs to make the best use of agency resources, and we typically prioritize those issues for which there is a known safety risk for consumers,” Welch concluded in the letter to Bell. “At this time, we do not have concerns about beta-alanine that warrant the further investment of FDA’s limited resources.”
Bell and two former FDA officials with whom he is associated blasted the public health agency. Welch’s letter, the men proclaimed, highlights FDA’s unwillingness to enforce a provision of the Dietary Supplement Health and Education Act of 1994 (DSHEA) intended to protect consumers from potentially harmful ingredients.
“This fight is far from over,” Bell promised in an interview. “Now that they’ve given us this final agency action, [the] law permits the next things to happen.”
At the tiff’s core: a premarket notification requirement for new dietary ingredients (NDIs), which the law defines as a dietary ingredient not marketed in the U.S. before Oct. 15, 1994. Subject to an exemption, a manufacturer or distributor of an NDI must provide FDA evidence that a “supplement containing such dietary ingredient will reasonably be expected to be safe,” based on the conditions recommended or suggested in the product’s labeling.
The NDI notification (NDIN) provision is crucial, FDA officials have said, because it represents the agency’s only chance to review the safety of a novel dietary ingredient in a supplement before it reaches consumers. The requirement is perhaps more important than ever, considering the industry’s extraordinary growth since 1994, when Congress estimated annual sales of $4 billion. Nutrition Business Journal estimated sales of dietary supplements in the U.S. grew 14.5% to $55.75 billion in 2020.
NAI, a public company (NASDAQ: NAII) based in Carlsbad, California, followed the NDIN requirement for its ingredient, CarnoSyn beta-alanine.
It took NAI nearly a year to compile all the information for its beta-alanine notification to FDA—with hundreds of pages of documents describing such matters as testing, manufacturing methods and safety, according to the company’s founder, chairman and CEO, Mark LeDoux. NAI spent a minimum of around $1 million investing in the NDIN process, and the figure is more than twice that amount when including human clinical trials to support components of the submission, he said.
In 2019, FDA responded to the notification with an acknowledgement or “good day” letter. Other manufacturers of beta-alanine for use in supplements have not followed the same regulatory pathway.
Enter Bell, who requested FDA essentially block “generic forms” of beta-alanine from entering the U.S. from China via an import alert. In a Feb. 24, 2020 letter, he remarked these forms of beta-alanine had not been the subject of NDINs and posed potential hazards to consumers. The lawyer noted different manufacturing processes could, for instance, introduce a contaminant or impact a substance’s purity.
FDA's burden of proof
In the April 28 letter to Bell, Welch stated “FDA bears the burden of establishing that the requirement to submit an NDIN applies.”
She continued, “Importantly, to meet this burden, FDA would need to demonstrate that beta-alanine is not present in the food supply as an article used for food in a form in which the food has not been chemically altered.”
Welch suggested it’s possible other forms of beta-alanine are in the food supply in a form not chemically modified, which would make the ingredients exempt from the NDIN requirement under Section 413(a)(1) of the Federal Food, Drug & Cosmetic Act (FDCA). She noted, for instance, beta-alanine is present in energy drinks.
“The presence of beta-alanine in the food supply raises significant questions that would need to be answered before FDA would be in a position to demonstrate that certain imported beta-alanine appears to be adulterated,” Welch wrote to Bell.
While manufacturers of a food ingredient have a duty to ensure its safety, they may do so through a process known as GRAS (generally recognized as safe) self-affirmation, which several consultants said is subject to a rigorous and thorough analysis by experts. On the other hand, critics argue GRAS self-affirmation avoids public input and FDA review, while leaving room for conflicts of interest to undermine the integrity of the safety analysis.
Companies also have the option to voluntarily notify FDA of a conclusion that a substance is GRAS under the conditions of its intended use. Marianna Naum, an FDA spokeswoman, confirmed FDA has not received any GRAS notices for beta-alanine.
It’s unclear whether China-based manufacturers of beta-alanine targeted in Bell’s 2020 letter have taken steps to comply with FDA rules. In a four-part series of articles on this topic reported by Natural Products Insider, several manufacturers of beta-alanine—as well as sports nutrition brands marketing the ingredient in the U.S.—did not respond to requests for comment.
Some industry veterans have characterized the NDIN exemption in Section 413(a)(1) as a “GRAS loophole” that wasn’t the intent of Congress when it passed DSHEA.
“You hear about this GRAS loophole,” said Dan Fabricant, who leads the Natural Products Association (NPA), whose chairman of the board of directors is NAI’s LeDoux. FDA has “effectively created it here or double-downed on it.”
Public health risks
FDA, though, cited other reasons for denying NAI’s request. Welch advised Bell that FDA is unaware “of any evidence to support an assertion that beta-alanine manufactured by others presents a risk to the public health.”
“Your communication speculated as to potential reasons that beta-alanine manufactured by other entities could be adulterated, but it did not provide any specific evidence that other beta-alanine currently being imported into the United States is adulterated,” Welch stated. “While we acknowledge that differences in manufacturing could potentially change the safety and suitability of the ingredient for certain conditions of use, or even change the identity of the ingredient, FDA is not aware that such differences are at issue here.”
In a 2020 interview, ODSP's then-director Steven Tave acknowledged FDA was given “mountains and mountains of information" by Bell and his allies, but he suggested the information could not help achieve “the result that they are demanding” because it did not show violations of the law.
Bell suggested FDA’s recent letter to him would encourage “bad actors” and sends the following message to industry: “You haven’t shown enough people got hurt yet or died. Those are the things we [FDA officials] take an interest in.”
Welch denied Bell’s request for NDI enforcement through an import alert about a week after a member of Congress wrote to her about related issues.
“My concern pertains to the lack of consumer protection regarding the new dietary ingredient notification (NDIN) process, which appears to lend itself to knock-off ingredients that ‘piggy-back’ off a valid NDIN submitters’ information,” Rep. Jeff Van Drew, a Republican from New Jersey, wrote to Welch in an April 20 letter. “American companies invest significantly in research and development to maintain compliance and appropriately introduce new dietary ingredients.”
The congressman added, “Knockoff or ‘copycat’ ingredients not only undermine the scientific, financial and regulatory investment of companies that submit an NDIN, but also erode the integrity of the NDIN process, which the FDA publicly states is critical to the dietary supplement industry.”
Van Drew requested Welch explain every action taken by FDA “to conclude generic beta-alanine entering our country from China was expected to be safe—and how they will be in the future.”
Criticism by former FDA officials
Welch’s letter to Bell drew a strong rebuke from former FDA officials with whom he is aligned, including Robert Durkin, an AGG attorney who previously served as ODSP’s deputy director. It was Durkin who signed the acknowledgement letter to NAI in 2019.
Asked what message FDA’s letter conveys to the broader marketplace, Durkin responded he wouldn’t spend a “dime” on an NDIN, and he advised supplement firms protect their intellectual property.
“Spend the money you need to spend to make sure your ingredient’s safe under the conditions of use, but instead of taking the time to write an NDIN or any of that, get yourself a patent. Get yourself a trademark,” Durkin said in a conference call interview, where he was joined by Bell and another former FDA official, Fabricant.
He added, “[It’s] obvious that FDA has no intention to enforce the NDIN requirements.”
FDA had no immediate response for this article to some of the criticisms leveled by former FDA officials. And in a follow-up email after this article was published, an FDA spokesperson declined to comment "on the agency's enforcement deliberations" outside its April 28 response to Bell.
Durkin, who once held the same position as Welch—acting director of ODSP—argued FDA has taken inconsistent positions regarding its burden of proof. For example, while the agency has noted it bears the obligation to show an ingredient like beta-alanine is subject to an NDIN, Durkin said FDA has put the placed the burden of proof on industry to establish NAC (N-acetyl-L-cysteine) is not precluded from the definition of a dietary supplement.
In 2020 warning letters, FDA asserted NAC was first approved as a drug in 1963, and therefore cannot be lawfully marketed in a supplement. FDA, however, is open to receiving evidence from industry that could change its mind.
“It just seems like the agency sways back and forth when it determines what it’s going to do and not do and what burden it has to meet,” Durkin said. FDA is “horribly inconsistent, and it almost seems like, in this case [involving beta-alanine], it’s an excuse to not do something.”
FDA “might not have liked the idea of pursuing beta-alanine, but it doesn’t mean it was incorrect” or “outside the scope of the law,” according to Fabricant, who previously directed what was then called FDA’s Division of Dietary Supplement Programs.
He suggested FDA has spent a lot of taxpayer time and money “to just avoid doing the right thing versus doing it.”
“And here we are,” he added. “Has it made the industry and … FDA’s regulation of the industry better? I think it’s a resounding ‘no.’”