Americans could lose access to dietary supplements containing N-acetyl cysteine (NAC) in 2022, unless the industry can convince the Food and Drug Administration (FDA) that this glutathione precursor was widely used as a supplement or a food ingredient prior to the mid-1990s.
FDA contends that because NAC was approved in 1963 as an inhaled drug for obstructive lung disease (Mucomyst), and then again in 1985 as an oral agent to treat acetaminophen toxicity (Acetadote), it is by definition excluded from the dietary supplement category. That’s despite the fact that NAC supplements have been on the market for more than 30 years.
[Update:FDA Issues Final Guidance on NAC Supplements]
In a concerted effort to protect NAC supplements, individual companies as well as industry trade groups and some practitioner organizations have put considerable effort into making a case that this compound should be grandfathered as an “old” (i.e., pre-DSHEA [Dietary Supplement Health and Education Act] dietary ingredient.
The industry’s position, expressed via comments on an FDA docket, is that NAC is extremely safe, that it has been used in supplements well before DSHEA was passed, and that a retroactive application of a drug exclusion provision based on obsolete patents constitutes an unfairrestriction of trade.
If you haven’t been following the NAC saga, here’s a quick recap:
In July 2020, the FDA issued a flurry of warning letters to several companies marketing NAC as a hangover remedy, stating that these companies were making unlawful claims and illegally selling a pharmaceutical ingredient mislabeled asa supplement.
The warning letters contained language stating that: “FDA has concluded that NAC products are excluded from the dietary supplement definition under section 201(ff)(3)(B)(i) of the Act [21 U.S.C. § 321(ff)(3)(B)(i)]. Under this provision, if an article (such as NAC) has been approved as a new drug under section 505 of the Act [21 U.S.C. § 355], then products containing that article are outside the definition of a dietary supplement, unless before such approval that article was marketed as a dietary supplement or as a food. NAC was approved as a new drug under section 505 of the Act [21 U.S.C. § 355] on September 14, 1963. FDA is not aware of any evidence that NAC was marketed as a dietary supplement or as a food prior to that date.”
In other words, the agency reverted to a position that NAC is a pharmaceutical ingredient based on a 60-year-old approval for an inhaled drug that was discontinued long ago.
In these warning letters, the FDA invoked the Drug Exclusion Provision within the Food, Drug, and Cosmetic Act, which states that a dietary supplement cannot contain:
- an article approved as a new drug; or
- 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, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food, unless the Secretary, in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this chapter.
This was despite the fact that FDA has tacitly permitted the sale of NAC supplements for many years. There are well over 1,100 non-Rx NAC products on the market, typically sold for liver health, detoxification, antioxidant activity, and immune system support. The ingredient is very safe, and until the June 2020 warning letters, the FDA had no issues with it.
Ripple Effects
On their own, these warnings would have had little impact; the companies targeted are not major players, and the claims that NAC can prevent or cure hangovers are indeed questionable. The agency did not issue letters to companies selling NAC for other health purposes, and it has not taken any further action to ban all NAC supplements. Not yet, anyway.
But in May 2021, Amazon announced that it was eliminating all NAC-containing supplements from its digital shelves, citing the FDA’s new position that these are basically unlawful drugs. Amazon’s move greatly amplified the impact of the FDA’s move, given that the e-commerce titan accounts for between 40% and 60% of total sales for manysupplement brands.
Though the FDA has not officially banned NAC supplements, the new position—and especially Amazon’s response to it—has definitely blunted sales.
According to Larisa Pavlick, vice president of global regulatory and compliance at the United Natural Products Alliance (UNPA), there were 718 NAC-containing products available on Amazon at the end of 2020; one year later, at the end of 2021, all of them were gone. For all intents and purposes, it is no longer possible to buy NAC on Amazon anymore.
All Hands On Deck
In November 2021, just before Thanksgiving, FDA issued a request for information on the past use of NAC in supplements, including any and all relevant safety data. Specifically, FDA called for: “information on the earliest date that NAC was marketed as a dietary supplement or a food, the safe use of NAC in products marketed in dietary supplements, and anysafety concerns.”
If the industry is able to prove NAC was broadly used in supplements prior to DSHEA in 1994, the substance would qualify as an “old dietary ingredient,” and be exempted from the priordrug exclusion.
Calling it an “all-hands-on-deck situation,” Pavlick and UNPA quickly coordinated with the Council for Responsible Nutrition, the American Herbal Products Association, and a long list of concerned stakeholders to gather information to support the exemption.
Because DSHEA became law in 1994, in the pre-internet era, much of the needed documentation is in paper form—old nutrition catalogs, manufacturing spec sheets, lab testing data, ancient freight bills indicating interstate commerce, product labels (if they have expiration dates).
UNPA assembled an NAC working group that dug up and sorted through “warehouses, boxes, and basem*nts for old paper records, and through antiquated software systems to provide a significant collection of pre-DSHEA records,” said UNPA President Loren Israelsen.
The UNPA team also audited back issues of the Townsend Letter, a print magazine that has covered the field of “alternative” medicine since the 1980s. The audit turned up 13 ads for non-prescription products containing NAC from the pre-DSHEA era. Companies producing NAC supplements prior to 1994 include: Allergy Research Group, Pure Encapsulations, NF Formulations, Tyler Encapsulations, and Thorne Research.
The American Association of Naturopathic Physicians (AANP), representing the nation’s NDs and NMDs, joined the effort to rescue NAC from regulatory exile. Naturopaths and other holistic physicians routinely recommend NAC for their patients who need antioxidant and detox support. Many are also using it in their “Long COVID” support protocols.
In its comments to the FDA, AANP noted that safety studies of oral NAC and citations about it in the naturopathic literature date back to the early 1970s. Based on 126 responses to a member survey, the organization holds that naturopaths have been routinely using NAC in practice since at least 1990. AANP provided the FDA with many verbatim comments from practitioners describing the utility and safety of the ingredient, and their own lengthy clinical experience with it.
“Until recently, FDA has consistently and affirmatively permitted manufacturers to market products with NAC. The impact of the FDA’s Warning Letters has been to restrict patient access to NAC—a critical nutritional supplement—which negatively affects the health of patients,” AANP contended in its docket comments. “We urgently request that the FDA exercise its authority to reverse this policy change and again allow manufacturers to market dietary supplements containing NAC as has been safely done for over40 years.”
According to Israelsen, “Our new evidence for pre-DSHEA dietary supplement usage is substantial. We have provided solid documentation for NAC as a pre-DSHEA ingredient and for finished dietary supplement products on the market prior to October 15, 1994.”
Whether FDA agrees with this assessment remains to be seen.
Petitions and Lawsuits
Many of the stakeholders who commented on the docket provided evidence of NAC’s safety. Indeed, there are many studies of NAC supplementation for diverse clinical problems in a wide range of patient subgroups showing very few adverse events.
FDA did ask for safety data, and it is important to formally establish the ingredient’s sterling track-record on thesafety front.
But the safety of NAC was never really in question. Neither the 2020 warning letters nor Amazon’s purge policy cite adverse events as a reason for action. The real issue is whether the 1963 approval of inhaled NAC as a drug can be retroactively applied in 2022 to block further sale of NAC in oral supplement forms.
Last June, the Council for Responsible Nutrition filed a Citizen Petition urging the FDA to reverse its stance, and to “revert to its longstanding policy of allowing manufacturers to market products containing NAC as dietary supplements” without obstruction.
CRN’s leaders had several meetings with the FDA since the 2020 warning letters, and claimed that the agency “is considering CRN’s position.” But the regulators have given no deadline for resolution of the issue.
The Natural Products Association (NPA) followed suit with a similar Citizen Petition in August; and last December it went a step further and filed a lawsuit against the FDA in the U.S. District Court in Maryland, seeking a permanent injunction against the FDA’s retroactive exclusion of NAC from the definition ofdietary supplements.
NPA claims FDA acted unlawfully in its application of the Prior Drug Exclusion standard, calling it, “a reckless misuse of government resources” and “a regulatory sneak-attack.”
The complaint states that, “NPA’s members have suffered harm as a direct and proximate result of FDA’s recent final agency actions concluding that the drug exclusion provision of DSHEA applies retroactively to NAC.
NPA members who have been selling NAC for years, if not decades, have seen their sales dry up as result of having to preemptively pull products from the shelves by virtue of FDA’s unlawful decisions.”
It also points out that FDA has been denying export certificates for NAC supplements, precluding U.S. distributors from marketing these products overseas.
If NPA wins its case, the injunction would block FDA from taking regulatory action against manufacturers, distributors, or retailers of NAC-based supplements solely on the ground that the ingredient is a pharmaceutical. But that’s a big “If.”
There’s a note of irony in the suit, given that NPA’s CEO, Daniel Fabricant, PhD, was Director of the FDA’s Division of Dietary Supplement Programs from 2011to 2014.
Fabricant contends that his former employer is way out of line on this issue. “This is government regulation run amok,” he said in a press release.
Though it is a rare occurrence, this is not the first time FDA has invoked the prior drug exclusion provision to retroactively regulate supplement ingredients. Over the years, it took similar action—to varying degrees of success—against vinpocetine, red yeast rice, vitamin B6 (pyridoxamine), and CBD.
Industry leaders are concerned that FDA’s position on NAC sets the stage for a wave of actions to eliminate other supplement ingredients such as L-carnitine, niacin, and CBD, which are currently available in supplement as well as prescription pharmaceutical form. Several herbs currently sold as supplements are also the sources of prescription drugs. They’re at risk too.
The contention over NAC clearly has implications that extend far beyond this one isolated compound.
NPA’s lawsuit also says the matter is exacerbating labor shortages and employee conflicts at a time when many companies are already struggling.
In addition to the NAC lawsuit, NPA filed two petitions with the U.S. Court of Appeals onNov. 11, 2021andDec. 7, 2021arguing the Biden Administration’s vaccine and testing mandate for businesses was unconstitutional, preempted state laws, and would negatively impact the ability of businesses to meet demand for natural products by slowing delivery times and driving-up costs. The issue subsequently went to the Supreme Court, which blocked the vaccine mandate for businesses in January.
People familiar with the subject say it is likely the District Court will dismiss the NAC complaint on the grounds that FDA has not taken any definitive action—such as a ban—against NAC, but merely issued warning letters to a handful of companies. These letters do not constitute “final actions.”
But the NAC issue has drawn the attention of some legislators. In October, Rep. Jeff Duncan (R-SC) sent a letter to the FDA demanding that regulators clarify their position on NAC, and cite any adverse events or other safety concerns that would warrant action to restrict sales. Earlier, Sen. Mike Lee (R-UT) had called on the FDA to hold a public hearing on the NAC issue, a request that so far, the FDA has denied.
Possible Motives and Outcomes
The reasons for FDA’s action against NAC are unclear. If the concern was merely about fringe players marketing bogus hangover cures, then warning letters about false claims should have been sufficient chastisem*nt.
Why invoke the prior drug exclusion?
Some within the natural products industry believe that in targeting NAC supplements, the agency is doing the bidding of pharmaceutical companies.
There are now 19 clinical studies of NAC for COVID-19 care in the government’s Clinical Trials registry, including several looking at NAC-based drugs. This includes a high-profile study now underway at Memorial Sloan Kettering Cancer Center involving 84 high-risk patients with COVID-19, treated with inhaled or intravenous pharmaceutical forms of NAC. This trial is slated for completion in May 2023.
Last year, a company called Orpheris—a division of Ashvattha Therapeutics—ran a phase 1 open-label clinical study of subcutaneous injections of “OP-101,” a Dendrimer N-acetyl cysteine. The company’s long-term vision for OP-101 is to develop it as a drug for childhood cerebral adrenoleukodystrophy (ccALD). Further, the company plans to “investigate the potential of OP-101 in other neurological diseases,” particularly Parkinson’s and amyotrophic lateral sclerosis (ALS).
One comment filed with the FDA on the NAC docket does indicate that pharma players see prior drug exclusion as a viable strategy for clearing the field of supplement competition.
John Gold, PhD, vice president of Emmeria, a privately-held drug company, writes that his company is “the sole sources of EMM-737, EMM-738, EMM-739 and EMM-740,” Emmeria’s proprietary form of trimethylglycine, astragaloside, ellagic acid and berberine, which have been studied as new drugs and for which substantial clinical investigations have been instituted. “As a company that has instituted clinical studies on trimethylglycine, astragaloside, ellagic acid, and berberine, we request that FDA take the preclusion provision of Section 201(ff) of the Federal, Food, Drug, and Cosmetic Act seriously to protect the right of companies that have spent significant time and research to develop drugs products from competition from dietary supplements that are clearly new dietary ingredients that have never filed a new dietary ingredient notification prior to the institution of substantial clinical trials.”
The supplement industry trade groups, along with the AANP, have amassed convincing evidence that NAC was widely used in supplement form well before 1994, and therefore prior to the formal definition of the term “dietary supplement” and to the prior drug exclusion provision.
But this forces the FDA into a difficult decision: either formally designate NAC as a drug, and ban its use in supplements outright, or fall back to the prior status quo and permit unrestricted sale of NAC products so long as marketing claims are valid and stay within the language of structure/function rather than disease treatmentor prevention.
If the agency takes the hardline stance, it will be rightly criticized for unnecessarily banning a harmless, effective, and accessible self-care modality in the middle of a raging pandemic, for no discernable reason and in the absence of any evidence of harm.
If FDA backtracks and reverts to permitting the unrestricted sale of NAC in oral supplements despite previously stating that NAC is a drug, it risks looking weak and indecisive. It also dissipates the future power of the “prior drug exclusion” clause.
After more than a year without a leader, FDA now has a new commissioner following the Feb. 15 confirmation of Robert Califf, MD. Over the course of his career, Califf has said surprisingly little about dietary supplements, so his overall attitude toward them is not yet known.
Whether Califf’s presence at FDA will shift the agency’s position on NAC—and if so, in what direction—also remains to be seen.
Holistic medical professionals, their patients, and the nutraceutical companies that serve them have much to lose—or to gain—in the outcome of thiscontentious situation.
Erik Goldman is co-founder and editor of Holistic Primary Care: News for Health & Healing, a quarterly medical publication reaching about 60,000 physicians and other healthcare professionals nationwide. He is also co-producer of the Practitioner Channel Forum, the nation’s leading conference focused on opportunities and challenges in the practitioner segment of the dietary supplement industry.
