August 11, 2020
The Memorial Sloan Kettering Cancer Center in New York is sponsoring research to determine if a medication known as N-acetyl-L-cysteine (NAC) can help fight COVID-19. The research is one of several studies registered on ClinicalTrials.gov to explore the potential of NAC in treating or preventing a disease that has ravaged people’s health and the global economy.
NAC has been approved by FDA to treat liver side effects from an overdose of Tylenol (acetaminophen), and it’s “also used to loosen the thick mucus in the lungs of people with cystic fibrosis or chronic obstructive pulmonary disease,” according to a summary of the study sponsored by the Memorial Sloan Kettering Cancer Center.
The ingredient also happens to be widely marketed in another category of products overseen by FDA—dietary supplements. But for at least the second time since 2010, FDA challenged the legality of NAC in dietary supplements.
In recent warning letters to several marketers of supplements for “hangovers,” FDA stated NAC is excluded from the definition of a dietary supplement because, in part, it was first approved as a drug in 1963. None of the companies flagged in the letters responded to requests for comment, including those selling NAC.
This is not the first time FDA has publicly asserted NAC can’t be marketed as, or in, a dietary supplement.
Responding to a new dietary ingredient notification (NDIN), FDA stated in an Oct. 21, 2010 letter that NAC was first approved as a new drug in 1985. To FDA’s knowledge, NAC hadn’t been previously marketed as a food or supplement prior to FDA’s approval—or its authorization for investigation—of a new drug, according to the letter to Tiara Pharmaceuticals. Based on these determinations, FDA concluded NAC couldn’t be marketed as a supplement.
The reality in the marketplace is far different. As of Monday, 1,170 products containing NAC were listed in the Dietary Supplement Label Database, which is maintained by the National Institutes of Health (NIH). A Google search reveals several prominent brands market NAC.
“This is not a fringe ingredient,” said Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), in an interview.
Since the warning letters were published, several members of CRN have reached out to the trade association, asking whether they should be concerned and if FDA is going to start targeting products containing NAC, he said.
Steven Tave, director of FDA’s Office of Dietary Supplement Programs (ODSP), said FDA’s warning letters simply reiterate its previous conclusions that NAC is excluded from the definition of a supplement.
“To the extent that any stakeholders and anyone in industry or anyone else has facts that they think would cause us to rethink our conclusion, then we would welcome that evidence,” Tave said in an interview. “We’re happy to review it, and we would invite them to submit it to us.”
CRN is aware of about 150 structure/function (S/F) claim notifications related to NAC that did not draw objections from FDA, according to Mister. Under the law, manufacturers of a supplement must submit such notifications to FDA when they are describing a dietary ingredient’s role intended to affect the structure or function in humans.
Lindsay Haake, an FDA spokeswoman, said the agency’s review of S/F claim notifications “is generally limited to the text of the claim itself.”
“Although we occasionally note obvious issues in courtesy letters responding to S/F notifications, it is not our normal process to evaluate issues such as ingredient qualification,” she said in an email, in response to a question about the NAC-related notifications. “The absence of a response to a S/F notification does not mean anything more than that we have not objected to the specific S/F claim about which we are being notified.”
Robert Durkin, formerly deputy director of ODSP, also said the agency is really concerned with the claim itself in reviewing notifications for S/F claims. “Usually, the firm making the notification will only get a ‘courtesy letter’ if they make disease claims,” added Durkin, a partner in Washington, D.C., with the law firm Arnall Golden Gregory LLP (AGG).
In a 2018 response to a petition for a qualified health claim, FDA determined six individual substances in the petitioner’s dietary supplement were either components of food, or a dietary supplement, including NAC—contradicting the agency’s view in the recent warning letters that NAC doesn’t belong in supplements.
“FDA has not been consistent over the years,” Mister concluded.
FDA’s response to the qualified health claim was issued by an office other than ODSP—the Office of Nutrition and Food Labeling, which, according to FDA, does not have authority over what is or is not a permissible dietary ingredient.
“Qualified health claims are reviewed under a different process by a different office,” Tave said. “Absolutely, people should expect FDA to be internally consistent, but it’s also possible that the people who were reviewing the evidence and whether or not it supported the claim weren’t aware of this issue.”
The drug exclusionary provision in the law, which FDA cited in the warning letters, “was intended to create a race to market so that you didn’t take away the incentives for drug companies to study products for potential disease uses,” Mister explained. “But it was never meant to be a shield to just go out and start removing products from the market. FDA has demonstrated over many … years a bias in favor of drug products, which makes sense because FDA has a lot more control over bringing a drug to market than they do foods or cosmetics or supplements.”
Asked to respond to such criticism, Tave said, “We don’t favor anybody. We read the law. We look at the facts. We see what the implication of the facts is in the context of the law, and we make our determination.”
He added, “Nobody’s accusing us of favoring dietary supplements in all the cases where we don’t make an exclusion determination because that’s not public. The statute is what it is, and all we do is apply it.”
In the clinical trials for NAC, at least one of the sponsors is a drug company, Orpheris Inc., a subsidiary of Ashvattha Therapeutics. Beginning July 1, Orpheris planned to study the efficacy and safety of OP-101 (Dendrimer N-acetyl-cysteine) in patients with severe COVID-19. Ashvattha Therapeutics did not immediately respond to a request for comment for this article.
FDA has created a “shadow” over NAC “as a dietary supplement, which would encourage the drug companies to go forward under the thought that they could get a monopoly on the ingredient if it [clinical research] pans out,” Mister said.
This isn’t the first time FDA has been critiqued for declaring an ingredient can’t be marketed in a supplement due to the drug exclusionary clause in section 201(ff)(3)(B)(i) of the Federal Food, Drug and Cosmetic Act (FD&C).
For instance, in a 2016 Federal Register notice, FDA noted vinpocetine was authorized as an investigational new drug (IND) in 1981. The agency tentatively concluded vinpocetine was excluded from the definition of a dietary supplement and separately did not qualify as a dietary ingredient.
Industry reps suggested FDA’s move was a surprising and unfair one since vinpocetine had five acknowledgements from FDA in the agency’s NDI database. The first notification was submitted to FDA in 1997.
“This means that vinpocetine has already gone under intense scrutiny five times over by the leading authority on food safety in the United States," the Natural Products Association (NPA) stated in 2016. “Each time, FDA responded with a letter that they had no concerns over the ingredient or the data provided in their safety dossiers."
Hundreds of consumers in 2016 urged FDA to keep on the market vinpocetine dietary supplements used by Americans to support brain health. Removing vinpocetine from supplements would raise costs for consumers who seek an alternative to prescription medications and would endanger the public health, some commenters argued.
In the recent interview, Tave confirmed FDA intends to make a final determination regarding vinpocetine, although he did not provide a timetable for doing so.
Asked about the prospect of litigation to resolve issues such as the legality of vinpocetine and NAC in dietary supplements, Mister responded, “There’s not a lot of options to the industry unless a company who is negatively affected wanted to try to bring a declaratory judgment against the agency to get clarity. But that’s really rolling the dice and spending an awful lot of money trying to force FDA to be clear, so companies are reluctant to do that.”
FDA supplement chief defends ‘hangover’ warning letters
by Josh Long
FDA delivered two distinct messages in a recent batch of warning letters to marketers of supplements.
First, supplements should not be marketed to cure, treat, mitigate or prevent hangovers, which can occur after a person becomes intoxicated with alcohol. Second, N-acetylcysteine (NAC)—an ingredient sold by many of the companies targeted in the letters (see story above)—was first approved as a drug and is excluded from the definition of a dietary supplement.
“Alcohol intoxication, like all poisonings, causes dose-related dysfunction and damage, ranging from mild impairments to death,” FDA stated in a July 29 constituent update. “Alcohol intoxication causes temporary damage to brain function, causing impairments of judgment, attention, reflexes and coordination.”
Some sources in the supplement sector questioned why FDA was devoting resources writing warning letters over “hangover” supplements, while the nation continues to struggle with a disease that has infected more than 5 million Americans.
“This does not seem to be a public health issue that warrants that kind of attention in the middle of a pandemic,” said Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), in an interview. “Many in the industry have disagreed with FDA for years about the characterization of hangover claims as a disease claim. It is not like you are saying ‘alcoholism’ and it’s hard to … argue that a hangover is a disease.”
Steven Tave, director of FDA’s Office of Dietary Supplement Programs (ODSP), addressed the agency’s use of its resources during the pandemic, including the recent warning letters.
“We do a lot of different things at the same time,” he said in an interview. “Some things move more quickly than others. Some don’t. This is something that’s been in the works for a while.”
“The agency is laser-focused on pandemic response,” Tave added. “We’ve done a lot of warning letters and enforcement related to fraudulent COVID treatments, but that’s not the only public health concern. If we thought this [issue over hangover supplements] was a public health concern before the pandemic, then it remains one during the pandemic.”
Mister acknowledged FDA may be concerned over suggestions that a product could cure a hangover, leading young people to drink excessively.
“That is not a question of whether or not the claim is a disease,” he said. Instead, it raises the question “whether the product presents a significant or unreasonable risk of injury or illness in the marketplace.”
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