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Recipients of FDA warning letters still marketing NAC supplements

FDA buildings 2020
FDA advised four companies in July 2020 warning letters their products did not meet the definition of a dietary supplement—even if they didn’t make therapeutic claims—due to the presence of an ingredient first approved as a new drug in 1963: NAC. But many of the firms—and the broader supplements industry—continue to sell the ingredient amid a two-year-old disagreement with FDA over its legality.

Some of the companies targeted in July 2020 warning letters by FDA for making claims of treating hangovers and selling NAC (N-acetyl-L-cysteine) in dietary supplements are continuing to market the ingredient in their products. That’s according to their “Supplement Facts” panels and other information published on their websites as of this week.

NAC is included in a proprietary blend in Happy Hour Vitamins’ multivitamin, listed as an ingredient in Hangover Heaven’s “liver support pills," and identified as an ingredient in LES Labs’ “liver support” dietary supplement.

FDA advised Happy Hour Vitamins, Hangover Heaven and LES Labs in July 2020 warning letters that NAC is not a lawful ingredient in dietary supplements because it was first approved as a drug in 1963. Two trade associations have challenged FDA’s position in citizen petitions and a lawsuit filed in U.S. District Court in Maryland.

Another company targeted in the batch of warning letters and selling NAC at the time—Purple Biosciences LLC—does not identify the ingredient in its multivitamin, based on a recent review of the Supplement Facts panel available on its website.

None of the firms mentioned above responded to requests for comment from Natural Products Insider.

While some of the companies targeted in the 2020 warning letters appear to continue to be selling products containing NAC, industry stakeholders have cited obstacles to the marketing of the ingredient since FDA publicized its letters—including a decision by Amazon in 2021 to remove NAC products from its platform.

FDA continues to suggest it has “not made a final determination on NAC,” yet is aware “companies like Amazon are taking concrete actions based on FDA’s statements to remove NAC from the marketplace,” said Megan Olsen, senior vice president and general counsel of the Council for Responsible Nutrition (CRN). The agency’s stance, she said in an interview, also places “companies in uneven positions as far as competition goes.”

FDA’s 2020 warning letters have caused genuine “damage” and “harm,” according to Dan Fabricant, president and CEO of the Natural Products Association (NPA), which sued FDA in December in an ongoing attempt to overturn FDA’s position regarding NAC. Fabricant said he wasn’t surprised some companies targeted in the warning letters are continuing to sell NAC, explaining, “We’ve told members—and we’ll continue to tell members—to keep selling NAC.”

He referenced a 2021 letter from an Office of Dietary Supplement Programs (ODSP) official regarding a separate matter (involving manufacturers of generic forms of beta-alanine) that FDA generally prioritizes its enforcement based on known safety concerns.

“It’s pretty clear there’s no public health concern with NAC,” Fabricant said. “It’s ridiculous … Enforce the laws on the books and quit monkeying around with stuff like this.”

FDA warning letters  

The warning letters, which concerned product claims of curing, treating, mitigating or preventing hangovers, were sent to seven companies, including four marketers of NAC-containing supplements. FDA advised the four companies their products did not meet the definition of a dietary supplement—even if they didn’t make therapeutic claims—due to the presence of an ingredient first approved as a new drug in 1963: NAC.

FDA cautioned in the letters that failure to correct the violations could result in such legal action as an injunction or seizure. The agency has not taken further action against NAC products beyond the warning letters, an FDA spokesperson told Natural Products Insider.

FDA has not officially closed the files on the majority of the warning letter actions. The agency has issued a “close-out letter” to one of the seven companies, Mind, Body & Coal, according to the FDA spokesperson. FDA issues such a document after determining a firm has taken corrective actions to address violations identified in a warning letter.

FDA did not mention NAC in the warning letter to Mind, Body & Coal.

Industry stakeholders have criticized FDA for taking what they claim are inconsistent or contradictory positions regarding NAC’s legal status. For instance, CRN in its June 1, 2021, citizen petition said FDA had considered and not objected to the presence of NAC for over 100 structure/function claim notifications and one qualified health claim petition.

FDA, however, has objected to several structure/function claim notifications since publicizing its 2020 warning letters. For example, in a Nov. 13, 2020, letter to Nestlé Health Science, the agency stated one of the company’s nutritional products did not meet the definition of a dietary supplement because it contained NAC.

“NAC was approved as a new drug … on September 14, 1963,” Haijing Hu, an FDA ODSP official, wrote to Nestlé. “FDA is not aware of any evidence that NAC was marketed as a dietary supplement or as a food prior to that date.”

Asked for comment, a spokesperson for Nestlé Health Science said, “NAC has been widely used as a dietary supplement for over 25 years, in hundreds of products from a variety of retailers and companies. Our NAC-containing products will remain available to consumers at this time while FDA continues to consider this matter.”

Many consumers have asked FDA to keep NAC on the market in the U.S. as a dietary supplement, citing its health benefits including the ability to help with breathing problems. NAC helps the body replenish its stores of glutathione, an antioxidant, and features several other health benefits, according to WebMD. A 2019 article in the journal Antioxidants described NAC as “a precursor to the amino acid L-cysteine and consequently the antioxidant glutathione” that is found in onion.

Nestlé Health Science continues “to monitor FDA activity relating to NAC” and submitted comments in support of CRN’s citizen petition, the company spokesperson said. Pure Encapsulations, a Nestlé Health Science business, disclosed in the comments that very few adverse events were associated with NAC supplements, perhaps strengthening industry’s argument that the ingredient has a history of safe use.

Nestlé is not the only company to receive an FDA letter regarding NAC in response to a structure/function claim notification. FDA has “received at least 49 structure/function claim notifications for NAC products and has raised objections in at least 17 of the notification responses,” according to a Nov. 24, 2021, letter to Rep. Jeff Duncan (R-S.C.) from Andrew Tantillo, FDA’s acting associate commissioner for legislative affairs. 

FDA in 2010 also objected to a new dietary ingredient notification (NDIN) from Tiara Pharmaceuticals, citing NAC’s exclusion from the definition of a dietary supplement, Tantillo said. He advised Duncan that FDA did not take enforcement action against the company, adding in the letter, “FDA cannot presuppose what, if any, potential enforcement action we would take on products containing NAC.”

“FDA prioritizes our limited compliance and enforcement resources based on risk and the agency’s public health priorities,” Tantillo wrote.

CRN’s ‘evolving playbook’

In January, CRN requested FDA consider its citizen petition separately from one filed by NPA, and substantively respond to its legal questions by late February. FDA has provided no such response.

Unlike NPA, CRN has not requested relief in the courts. After discussing the NAC matter in December with CRN’s board of directors, a decision was made not to bring a lawsuit, Olsen said. She said her organization is scheduled to meet again in late March with its board.

CRN doesn’t currently plan to sue FDA, Olsen said, explaining her organization doesn’t believe “FDA has taken final agency action.” However, she cautioned the situation was “very fluid,” and CRN would continue to consult with its members and board of directors regarding NAC.

Amid continuing developments pertaining to NAC, CRN’s “playbook continues to evolve,” she added.

CRN’s petition has raised a number of legal arguments that it wants FDA to address, such as whether the drug preclusion clause in the Dietary Supplement Health and Education Act of 1994 (DSHEA) applies to “articles”—or drugs studied or approved by FDA—before or only after the law’s enactment.

A narrow solution?

It’s unclear when or how FDA will respond to the citizen petitions filed by CRN and NPA. In tentative responses last year to both organizations, FDA explained it “needs additional time to carefully and thoroughly review the complex questions posed in these petitions.”

Among its options, FDA could directly address the “complex” issues raised by industry stakeholders. Or the agency could resolve the disagreement through a specific action that avoids having to answer contentious legal questions with potentially broad ramifications for FDA-regulated supplements and drugs.

For example, FDA could publish a formal policy of enforcement discretion that would permit NAC to be marketed in dietary supplements, despite the agency’s initial determination that NAC was first approved as a drug. When asked whether the agency is entertaining issuing such a policy, an FDA spokesperson responded, “The FDA is currently looking into this issue and will discuss this issue further when we respond to the pending citizen petitions.”

Olsen reiterated she wants FDA to address the broader legal issues that were incorporated in CRN’s citizen petition “because we think that it’s important to the industry as a whole, not just companies that sell NAC.”

She said CRN is supportive of a path that would permit the sale of NAC in supplements because it would benefit her organization’s members. She stopped short of saying whether CRN would fully support a pathway that would resolve the matter while giving FDA the latitude to avoid addressing the myriad legal issues raised by CRN in its citizen petition.

“Again, it’s a conversation that CRN would have among our membership and the board,” she said.

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