There’s more at stake than just one ingredient in the battle between the supplements industry and FDA over N-acetyl-L-cysteine (NAC).
N-acetyl-L-cysteine (NAC) may not be a familiar ingredient to some dietary supplement users, but within the supplements industry—and among those who regularly take NAC supplements for antioxidant, liver, and respiratory support1—NAC is now a red-hot topic thanks to recent regulatory actions taken by U.S. FDA. In 2022, expect further discussion about NAC and possible friction between FDA and the industry leaders confronting the agency to protect the supplement industry from what they say is FDA’s misapplication of the law.
First, some background: Within the Federal Food, Drug, and Cosmetic Act (FD&C Act) governing dietary supplements in the U.S. is an infamous “drug exclusion provision” (Section 201(ff)(3)(B)(i)). This provision was signed into law on October 15, 1994, as part of the Dietary Supplement Health and Education Act (DSHEA) that amended the FD&C Act with new regulations for dietary supplements.
The drug exclusion provision states that dietary supplements may not include “an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public.” In other words, if an ingredient was first approved as a drug, or studied as an investigational new drug (IND) and that research was made public, supplement companies thereafter could not begin selling the ingredient as a dietary supplement—in essence, protecting drug companies’ research investment from supplement companies turning around and selling that same ingredient in lower-cost supplements. If the ingredient was, however, sold as a dietary supplement before the ingredient was publicly investigated or approved as a new drug, supplement companies could legally continue selling the ingredient as a dietary supplement.
Several drug and supplement ingredients lawfully coexist in the market under the drug exclusion provision. Omega-3 fish oil is one. The Natural Products Association (NPA; Washington, DC) points to L-carnitine and caffeine as other examples.2
FDA has also used the drug exclusion provision to challenge the legal status of certain dietary supplement ingredients. In 2016, for instance, FDA declared that vinpocetine, already a longtime ingredient in the supplements market, was now on the wrong side of the drug exclusion provision.3
N-acetyl-L-cysteine is the latest ingredient in FDA’s crosshairs involving the drug exclusion provision. In July 2020, FDA sent warning letters to a handful of companies selling products as dietary supplements, some as hangover remedies. In those warning letters, FDA claimed that NAC was approved as a new drug in 1963 and that there are no records showing that NAC was marketed in supplements prior to then.
Supplement industry leaders rebutted FDA’s reasoning in citizen petitions filed by NPA2 and the Council for Responsible Nutrition (CRN; Washington, DC)4, plus comments on these petitions from the American Herbal Products Association (AHPA; Silver Spring, MD)5, here and here.
First, pointed out CRN and NPA in their petitions, as well as AHPA in its comments, the NAC article approved as a drug in 1963 is different from the article that’s sold as a supplement. The drug approved in 1963 was an inhaled drug and not a substance to be orally consumed. In fact, an oral NAC drug was not approved for use until 2016, long after NAC oral supplements entered the market, both CRN and AHPA stated4,5. In its citizen petition2, NPA said it remains “unclear” whether an ingredient can be excluded from the definition of a dietary supplement “when the article has been approved as a drug not intended to be administered by ingestion.”
Second, CRN and NPA wrote in their citizen petitions, evidence substantiating the 1963 drug approval or public records showing investigation as a new drug are shaky. NPA wrote2, “Usually, evidence from the period of time in question are handwritten notes and documents.” In a December 2020 letter6 on the matter to Steven Tave, then-director of FDA’s Office of Dietary Supplement Programs, CRN wrote, “This handwritten notation [indicating a drug approval date of 1963] raises a number of questions about the reliability of this record, not the least of which is whether the approval date was actually 1963 or sometime later, why was the approval date handwritten, when was the notation made, and who made it. This is not the type of document that should be regarded as authentic.”
CRN pointedly added: “The unreliability of a handwritten date is exactly the type of issue that FDA likely would raise for a dietary supplement company providing similar evidence that an ingredient was marketed as a supplement before being approved as a drug.”6
Third, the associations said, evidence—including documentation AHPA cited in its comments to FDA5—shows that NAC was on the market as a supplement before the drug exclusion provision became law when DSHEA passed in October 1994.
Michael McGuffin, AHPA’s president, explains to Nutritional Outlook, “AHPA submitted comments to FDA wherein we identified a number of dietary supplements being marketed with NAC as an ingredient prior to the enactment of DSHEA. Following our comments, FDA issued a formal request for information, stating their interest in receiving ‘data and information on the earliest date that NAC was marketed as a dietary supplement or as a food, the safe use of NAC in products marketed as a dietary supplement, and any safety concerns.’ Since submitting our initial comments, we have found documentation of NAC marketed as an ingredient in a food product, and intend to provide the information to FDA.”
Most critically, these industry leaders argue that the drug exclusion provision, which was enacted with DSHEA’s passage in October 1994, is not allowed to be applied in order to retroactively pull off the market ingredients that were already on the market prior to the provision’s passage. In CRN’s letter to FDA’s Tave, the association wrote6 that “the definitional exclusion established by section 201(ff)(3)(B)(i) should be read to have proactively prohibited products containing articles that were approved as new drugs after October 25, 1994, from being marketed as dietary substances, unless such articles were marketed in dietary supplements prior to approval. By contrast, section 201(ff)(3)(B)(i) should only be read to retroactively apply to products containing articles that were approved as new drugs before October 25, 1994, if Congress expressed a clear, unambiguous intent for this provision to have a retroactive effect.”
Clearly, Congress did not expressly intend for the drug exclusion provision to act retroactively, CRN extensively explained in its citizen petition based on its review of both DSHEA and the provision’s legislative history.4 “If these ingredients were on the market pre-DSHEA passage in 1994, FDA doesn’t have the authority to remove them,” Megan Olsen, CRN’s vice president and associate general counsel, tells Nutritional Outlook. “Congress never gave that intent, and there’s strong legal argument that when Congress does not give a clear, unambiguous intent that a statute is intended to be applied retroactively, then it cannot be applied retroactively.”
McGuffin says the same: “Congress did not intend for DSHEA to be retroactive. Rather, DSHEA was intended to incentivize drug research on ingredients first brought to market…—not in the past, but in the future. Any contrary interpretation is, at best, strained.”
Olsen adds that “the purpose of this provision, and this bears itself out in the legislative history, was to encourage drug development and protect drug investment. You’re encouraging development by protecting those investments and helping ensure to drug companies that they wouldn’t have to be concerned about putting investment in and then have a supplement come on the market.” In the case of NAC drugs and supplements, “those arguments aren’t available,” she says, because both coexisted in the market prior to the passage of DSHEA’s drug exclusion provision. “It’s concerning that you would apply it retroactively when drug companies would never have any assurances that there would be a protection,” she adds. “If a supplement is already on the market and a drug company also gets that ingredient approved in a drug, the supplement doesn’t come off the market. It’s not, ‘Okay, now that the drug is here, you no longer can sell the supplement.’”
“It’s important that the FDA is interpreting all of the provisions in a manner that is consistent with Congressional intent,” she says. “And I think here, we very much are concerned that the way that they’re using it does not match Congressional intent.”
Supplement leaders are adamant about defending the industry from FDA’s turn on NAC because FDA’s actions could set a dangerous precedent in the supplements industry for years to come.
McGuffin says, “If FDA bans NAC by retroactively applying the drug exclusion clause, there is concern that the agency could do the same with any vitamin, mineral, or herb that has ever been the subject of any formal drug investigation.”
Daniel Fabricant, PhD, NPA’s CEO and president, tells Nutritional Outlook, “It’s incredibly concerning if FDA can retroactively apply the drug exclusion clause. DSHEA was introduced to balance consumer access to nutritional supplements and strong federal oversight of the industry. However, what we are seeing with NAC is unnecessary federal intervention. NAC has been on the market for over three decades, and there are more than 800 NAC product labels in the [National Institutes of Health’s] Dietary Supplement Label Database. These products have been safely on the market, so what’s to say FDA wouldn’t respond this way for other ingredients? Vitamin C and other dietary supplements have been on the market as drugs. So, this action gives way to FDA arbitrarily using the drug exclusion clause as an administrative procedure disrupter to business.”
Imagine the unstable environment supplement companies face if, at any point, someone could introduce obscure evidence long buried to threaten the existence of a supplement decades later. Consider that documentation of clinical trials done long ago is often publicly unavailable or unreliable. “It becomes almost impossible when you’re looking back decades for a company to readily determine what types of drugs were included,” Olsen points out. And, she says, “I think there’s concern that FDA, which does have records, but you almost have to FOIA [Freedom of Information Act] those records, could turn around and say, ‘Hey, five years from now, well, this ingredient is precluded because there were drug trials in the 1980s.’”
How can a supplement company confidently move forward amidst that kind of uncertainty? It’s unfair to supplement companies for FDA to do a 360 on an ingredient like NAC, leaders say.
“Here, FDA has implemented a sudden policy change without providing a well-reasoned explanation, and has done so in a manner that will affect thousands of industry and consumer stakeholders…,” CRN’s letter to Tave6 pointed out. “As noted above, prior to July 2020, it was FDA’s longstanding policy to permit the marketing of dietary supplements containing NAC. FDA had reviewed over 100 30-day notifications of structure/function claims for NAC and never raised any issues with the drug preclusion clause. FDA also had reviewed a qualified health claim for NAC and failed to raise the drug preclusion clause. As part of the qualified health claim review process, FDA specifically assesses whether the substance that is the subject of the qualified health claim qualifies as a food or dietary ingredient in dietary supplements. In response to the qualified health claim petition involving NAC, FDA states that NAC is a dietary supplement.”
Olsen says, “There are other legal concerns or other legal doctrines that say that after so long of allowing companies to rely on FDA’s position, FDA can’t reverse that position without significant reason.”
Why is FDA going after NAC? After all, safety concerns about NAC aren’t popping up, to industry’s knowledge. Says NPA’s Fabricant, “Our members go to great lengths to provide consumers with safe products. We know NAC is safe, but if FDA has data points that suggest otherwise, they need to communicate those findings to us, which they haven’t.”
Olsen says, “When FDA has raised concerns about the legality of ingredients as dietary supplements in the past, we often see those concerns tied to safety issues. For example, with vinpocetine, FDA in 2019 raised safety concerns about the use of the ingredient by women of childbearing age. FDA, however, has not banned the use of vinpocetine as a dietary ingredient. FDA also maintains a Dietary Supplement Ingredient Advisory List regarding dietary ingredients the agency has indicated ‘do not appear to be lawful.’ For the ingredients on this list, FDA has generally flagged safety concerns about the ingredient. This list is not a final determination of legality or safety by FDA, but a common concern in FDA evaluation of a dietary ingredient’s legality is safety. What is so striking here for NAC—FDA has never, that we are aware of, questioned the safety of NAC in dietary supplements. The ingredient has a decades-long history of safe use, and its safety record has been acknowledged by other authoritative government bodies like the National Institutes of Health (NIH), which noted in a recent review of NAC that ‘[n]o safety concerns have been reported for products labeled as dietary supplements that contain NAC.’”
Industry leaders are demanding that FDA defend its reversal on NAC. They want answers. So far, they haven’t gotten them, leading associations to take more aggressive steps. This fight will persist in 2022.
On November 24, 2021, for instance, FDA sent CRN a “tentative response”7 to CRN’s citizen petition. Instead of addressing the petition’s legal questions, FDA’s letter simply asked for more proof of NAC’s market history as a supplement—which, Olsen says, “is information we think is irrelevant to answering the legal questions that CRN has posed.” CRN, she says, “asked the agency solely to review and defend legal arguments and legal concerns with the validity of their July 2020 position on NAC,” which she says thus far the agency has failed to do.
Frustrated with FDA’s lackluster reply, this January CRN sent another letter to FDA8 criticizing the agency, stating, “The agency’s nonresponsive November 24th response does not address the single legal issue first raised by CRN in December 2020 and restated in CRN’s June 1st citizen petition: whether the drug preclusion provision in section 201(ff)(3)(B)(i) properly precludes NAC from being marketed in dietary supplements.” And on January 25, 2022, CRN officially filed new comments with FDA, demanding the agency’s response to its legal question by February 24, 2022.9
AHPA, in its comments to FDA5, stated: “To AHPA’s knowledge, FDA has not expressly addressed the question of whether DSHEA, and the prior drug exclusion provision in particular, has retroactive effect.” On January 25, 2022, AHPA also filed new comments with FDA, this time even more extensively providing evidence to show that NAC was marketed as an ingredient in conventional food or dietary supplements prior to October 1994.10
Following lack of response to NPA’s citizen petition, in December 2021 NPA took the strong step of suing FDA, asking the court11 to “hold unlawful and set aside FDA’s final actions that are arbitrary, capricious, an abuse of discretion, and contrary to law.”
Fabricant tells Nutritional Outlook, “NPA will leave no stone unturned until FDA’s decision is reversed.”
How many NAC companies and products today are adversely impacted by FDA’s reversal? AHPA’s McGuffin points out, “At least 600 products with NAC as an ingredient can be found in the National Institutes of Health’s Dietary Supplement Label Database (DSLD), the public database for volunteer product listing of dietary supplements.”
“NAC supplement sales are very significant for the industry,” Fabricant tells Nutritional Outlook, adding that the ingredient is sold both domestically and internationally. He adds: “NAC has been safely on the market for decades, and the agency should know this because they have the data to back it up. Over 800 labels accompanied by product information, including claims, are available to them through the NIH Dietary Supplement Label Database.”
Nutritional Outlook asked market researcher SPINS (Chicago) to provide an estimate on NAC market sales in the supplement channels it tracks. Sales appear to be growing.
“N-acetyl-L-cysteine saw 61% growth in sales in 2021 compared to 2020,” says Haleigh Resetar, SPINS corporate communications specialist. “The fastest-growing categories include performance nutrition—specifically hydration and electrolyte—and condition-specific supplement formulas, including cognitive health supplements and organ support supplements.” Performance nutrition is definitely a key market, adds CRN, citing data from SPINS multioutlet (MULO) channel tracking, powered by IRI (Chicago), and SPINS natural enhanced channel tracking, showing NAC supplement sales for performance nutrition up 98% over a year ago.
Resetar’s colleague at SPINS, Senior Market Insights Analyst Scott Dicker, says, “We are seeing a lot of growth for NAC in the MULO plus convenience channel, the natural enhanced channel, as well as some in [the] regional [independent grocery channel] as well. The dollar volume isn’t high in it, but we’re definitely seeing a lot of consumers interested in it.”
FDA’s adverse opinion on NAC’s legal status—which, it’s key to note, is only mentioned in warning letters and is not an official policy change—has already negatively impacted NAC supplements on the market. NAC supplements are sold by respected brands including NOW Foods, Thorne, Pure Encapsulations, and Life Extension, to name a few. Natural Products Insider reported last year12 that Amazon.com had ceased allowing NAC products to be sold on its website.
Fabricant tells Nutritional Outlook, “We have heard of other e-commerce platforms prohibiting the sale of NAC on their platform, and financial service providers restricting transactions related to NAC.”
“We understand that some contract manufacturers have also indicated that they do not want to continue to manufacture NAC. So, there are real-world implications that are happening here,” Olsen adds. “And we’ve heard directly from consumers, we’ve heard from healthcare practitioners that sell these products to patients or work with patients to secure these products, that there’s a concern out there that consumers rely on these products as dietary supplements for their health, and they’re having trouble accessing the products because either Amazon or companies are deciding to limit or stop their inventory.”
SPINS’s Dicker says that while NAC might not be a flagship product for some brands, it’s likely still an important one given the rising consumer interest. During the pandemic, he says, while brands might have started cutting the “tail” off their product lines and discontinuing less-popular products, NAC probably remained a priority. “With something growing in popularity like NAC, it could become a more major role in their business, so that is definitely something to consider as well, those financial implications” of any FDA actions, Dicker says.
Unfortunately, because FDA’s opinions are still not official legal action and only mentioned in the warning letters, NAC companies have few options for recourse at this point, even as they see tanking sales, Olsen points out. “Warning letters are not final agency action, and that position has been well established by both FDA and the courts,” she says. “And so, it doesn’t give companies the opportunity, like they would where there’s actually legal consequences that have flowed out of an FDA action, to take that action to court.”
For now, she says, “Companies need to assess their own risk of selling NAC. CRN considers this still a very open matter. We have seen FDA reverse its position in warning letters in the past.” So perhaps there’s hope.
Will some in the industry end up calling on Congress to intervene? As McGuffin says, “AHPA and the industry are doing what we can to ensure safe and informed consumer access to NAC. We are evaluating every avenue. The actions taken so far—two citizen petitions, comments by AHPA, the lawsuit against FDA—may help, but we might have to seek a solution in the Congress.”
What’s more, he says, given FDA’s attempt to use the drug exclusion provision to remove a supplement from the market once again, it may be time to reexamine this provision altogether. “If the dietary supplement industry brings a new ingredient to market first, we share the market with the drug industry. However, if the drug industry initiates research on a new ingredient, the dietary supplement industry is shut out. It is time for Congress to reconsider the drug exclusion clause, a restrictive provision of DSHEA that impacts consumer access and choice, and apply congressional pressure to FDA accordingly.”
In August 2021, Natural Products Insider reported that U.S. Senator Michael Lee (R-UT) requested a FDA hearing on the NAC issue but was denied.13 Says Fabricant, “When you have not one, but two, members of Congress request more information about NAC, and the agency ignores their questions, it’s a sign of disrespect. Congress has oversight over agencies like the FDA. FDA’s actions have put them under a microscope, and Congress is exploring legislative measures to make them more transparent. It’s a strenuous time at the FDA for several reasons, and we understand that. However, when you become less and less transparent with the industry, it will rightfully raise concerns. I’m confident we will see more congressional action in the coming months that demand more accountability from the FDA.”
What could ultimately happen? “If FDA maintains its position that NAC isn’t a legal dietary ingredient, it would need to begin taking enforcement actions against companies selling,” Fabricant continues. “Given their posturing with [cannabidiol] CBD, and considering NAC’s safety record, I have a hard time believing FDA would begin seizing products or using other enforcement action.”
Dietary supplement associations will continue fighting FDA on the matter this year. Says Olsen, “CRN doesn’t consider this a settled battle while the agency continues to deliberate as to what their response will be.”
In the meantime, “We’ll probably see more actions taking place in the fight over NAC,” says Fabricant.
It’s a fight worth having, he and the others say. “This issue is more important than just NAC,” says Fabricant. “FDA’s action sets a dangerous precedent which presents a real and present danger for the dietary supplement industry.”
*Story updated on January 26, 2022, 12:15 PM PST, with mentions of Council for Responsible Nutrition and American Herbal Products Association comments to FDA filed January 25, 2022.