A citizen petition filed this week asked FDA to reverse its position that N-acetyl-L-cysteine (NAC) cannot be lawfully marketed in a dietary supplement.
In the June 1 petition, the Council for Responsible Nutrition (CRN) requested the agency “reverse its recently adopted position that the Federal, Food, Drug and Cosmetic Act (FDCA) prohibits manufacturers from marketing” NAC-containing supplements.
CRN President and CEO Steve Mister signed the 10-page petition, along with his colleague, Megan Olsen, vice president and associate general counsel of CRN.
Substantively, the petition resembles a letter CRN sent in early December to Steven Tave, who at the time led FDA’s Office of Dietary Supplement Programs (ODSP). CRN makes the following arguments.
- FDA’s own records do not reliably show Section 201(f)(f)(3)(B)(i) applies to NAC. This section of law was incorporated into the FDCA as part of the Dietary Supplement Health and Education Act of 1994 (DSHEA). Section 201(f)(f)(3)(B)(i) prohibits manufacturers from marketing dietary supplements if they contain an “article” approved as a drug, unless the article was previously marketed in supplements or food before the drug approval.
- FDA has failed to acknowledge the article’s delivery form and route of administration must be considered in determining if the ingredient in supplements is the same article as the inhaled drug approved in 1963. Per CRN’s petition, “An inhaled substance should not be treated as the same article as an orally consumed substance. To do so would go against FDA’s own significant precedent and guidance.”
- FDA’s interpretation of Section 201(f)(f)(3)(B)(i) violates a presumption against statutory retroactivity. Even if FDA’s records show NAC was approved as a drug before the enactment of the above-referenced section, “[It] is a well-established canon of statutory interpretation that legislation shall not be read to have a retroactive effect on private rights unless Congress expresses a clear, unambiguous intent to the contrary,” CRN wrote in its petition. A comprehensive review of DSHEA’s text and legislative history suggests Congress expressed no clear intent for Section 201(f)(f)(3)(B)(i) to have a retroactive effect, the trade group said.
- FDA’s policy change regarding NAC is arbitrary and capricious and consequently invalid under the Administrative Procedure Act. FDA has suddenly implemented a change in policy “without providing a well-reasoned explanation and has done so in a manner that will affect thousands of industry and consumer stakeholders in whom the agency has ‘endangered serious reliance interests,’” according to CRN.
- An equitable defense known as laches prohibits FDA from enforcing its position on NAC because, in part, the delay in its new policy results from the agency’s failure to exercise diligence rather than an unawareness that NAC-containing supplements were on the market.
CRN shared its citizen petition with Amazon, which confirmed last month it was in the process of removing from its website dietary supplements containing NAC.
“Amazon’s actions severely limit manufacturers’ distribution channels and source of revenue for these products,” Olsen and Mister wrote in their petition. “This large-scale economic prejudice, coupled with FDA’s lack of diligence, will allow manufacturers to successfully invoke a laches defense in response to any attempt by FDA to take legal action against the marketing of dietary supplements containing NAC.”
Lindsay Haake, an FDA spokeswoman, said the agency is reviewing the citizen petition and will respond directly to CRN.
In the petition, Mister and Olsen said the courts could review FDA’s failure to timely respond to the petition within 180 days.
FDA stated in 2020 warning letters that NAC could not be lawfully marketed in dietary supplements because the ingredient was first approved as a drug in 1963. The agency’s move, trade groups argued, marked a sudden, unexpected pivot affecting an ingredient widely sold in supplements.
But industry could not challenge FDA’s position, based on the 2020 warning letters, because courts would hold the case is not ripe for judicial review since the letters do not constitute final agency action, several lawyers said.
“Filing a citizen petition is the logical step if your interest is in getting final agency action, which is subject to judicial review if not to your liking,” explained Stuart Pape, an attorney in Washington, D.C., who chairs the FDA practice of the law firm Polsinelli.
FDA has 180 days to respond to a citizen petition. However, it often doesn’t provide a substantive response within that deadline, lawyers said. According to FDA’s own regulations, one of its acceptable responses to a citizen petition within the 180-day time frame is the agency is unable to reach a decision due to such reasons as “the existence of other agency priorities, or a need for additional information.”
“If FDA failed to respond in 180 days, one could sue, but it would be challenging to prevail after just 180 days,” Pape said via email. “Typically when agencies lose suits related to failure to act, there is a much longer period of time of inaction.”
If CRN eventually sued FDA and won the case based on the agency’s failure to respond substantively to the petition, the best outcome would be a court order requiring FDA to act by a certain date. And such a court order wouldn’t bar FDA from eventually denying the petition on the merits.
“Unless FDA for its own reasons wants to decide the issue on the merits, I do not expect a ruling on the citizen petition soon,” Pape remarked.
Kevin Bell is outside counsel to the Natural Products Association (NPA) and a partner with Arnall Golden Gregory LLP. He called the filing of a citizen petition a “fool’s errand.”
“You’re going to get a letter about five months and thirty days in that says, ‘We’re still considering this and we’ll get back to you,’” the lawyer said in an interview. Citizen petitions “go into the abyss. This is very well known.”
Several citizen petitions filed by stakeholders in the dietary supplement industry have not elicited a substantive response within 180 days, including one filed in November 2019 by the Consumer Healthcare Products Association (CHPA). The petition urged FDA to issue regulations to allow manufacturers to lawfully market CBD in supplements. On June 16, 2020, FDA advised CHPA in a letter that the agency needed “additional time to issue its final response because of the complexity of issues raised in your petition.”
In an interview before the filing of CRN’s citizen petition, Mister recognized FDA’s delays in responding to citizen petitions. However, he noted filing a citizen petition related to NAC would start the 180-day clock for FDA to respond and demonstrate to retailers the issue hasn’t been resolved.
Mister said he didn’t disagree with Pape that citizen petitions frequently “languish at the agency for years and never get answered.”
“But at least on paper, [FDA officials] are supposed to respond in 180 days,” he said. “That would at least give retailers a little breathing room to say, ‘OK, for the next six months, the ball is back in FDA’s court.’”
According to Mister and other industry representatives, FDA’s position on NAC in late 2020 marked a sudden, inexplicable change given an absence of safety concerns related to the ingredient.
FDA acknowledged NAC’s existence in supplements “in multiple ways without any regulatory action, so we agree with CRN that the agency’s action now is inconsistent with its prior position,” said Loren Israelsen, president of the United Natural Products Alliance (UNPA), in an interview.
Mister said in a 2020 interview that CRN was aware of about 150 structure/function (S/F) claim notifications related to NAC that did not draw objections from FDA. Also, 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.
FDA’s review of S/F claim notifications “is generally limited to the text of the claim itself,” according to Haake, the FDA spokeswoman.
“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 2020, 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.”
Tave further noted in a 2020 interview that a different office than ODSP handles qualified health claims.
He also said FDA’s warning letters simply reiterated its previous conclusions that NAC is excluded from the definition of a supplement. FDA advised a company more than a decade ago that NAC couldn’t be lawfully marketed in a supplement because it was first approved as a new drug in 1985.
FDA expressed its position in a 2010 response letter to a new dietary ingredient notification (NDIN) filed by a company known as Tiara Pharmaceuticals.
FDA’s arguments haven’t won over industry. Bell plainly rejected the notion that a letter from federal regulators to one company—through a response to an NDIN—was sufficient to put an entire industry on notice that NAC couldn’t be lawfully marketed in supplements.
He also observed it wasn’t until more than a decade later that FDA took public action on NAC through its warning letters.
"I'm sorry, but the record-keeping at FDA sucks," Bell said.
NPA in 2020 provided FDA evidence that NAC was on the market as a supplement in the early 1990s before passage of DSHEA.
Dan Fabricant, Ph.D., president and CEO of NPA, said in an interview that FDA should recognize NAC was on the market as a supplement for more than a quarter century without interruption from regulators.
“The business community,” Fabricant said, has faced “enough disruption the past 15, 16 months—real disruption.”