On April 21, 2022, FDA announced via a constituent update that it plans to exercise enforcement discretion on the use of NAC. It also said that it is ‘likely’ to make a rule that would formalize the legal use of the compound in finished dietary supplements.
The major caveat for the use of NAC (n-acetyl-L-cysteine) in supplements is that such products are ‘legal,’ i.e. that they are not making noncompliant disease claims.
FDA said the move was in response to two citizen’s petitions, one filed by the Council for Responsible Nutrition and the other by the Natural Products Association. Both petitions asked that FDA rule that NAC was a legal dietary ingredient because it was clearly on the market as a supplement prior to the DSHEA grandfather date of Oct. 15, 1994. The NPA petition also included an option for a formal rule that would grant an exception for NAC. FDA rejected the grandfather date approach but said it intends to move in the rule-making direction suggested in the NPA petition.
Enforcement discretion unlikely to evaporate
Legal experts contacted by NutraIngredients-USA said the new policy is about as a firm a footing as FDA is likely to provide in such cases. It is far more certain than the uneasy truce that currently rules the CBD market, for example.
Marc Ullman, of counsel with the law firm Rivkin Radler, said the enforcement discretion is unlikely to be rescinded, so companies currently marketing NAC or thinking of doing so could continue with their plans without fear of interruption.
“FDA enforcement discretion on matters like NAC should be fairly reliable in the absence of any data emerging indicating a potential public health risk. While enforcement discretions are subject to change without notice, it would be extraordinarily unusual for FDA to turn on a dime -- especially where there is a potentially serious economic impact to a reversal,” Ullman said.
Ullman said there is precedence for the reliability of FDA enforcement discretion policies.
“Most recently, FDA issued a spate of enforcement discretions related to products like hand sanitizers it believes to be important for combatting COVID. Most prominently for the Supplement Industry are the series of enforcement discretions issued in connection with qualified health claims. Many of these have been long standing and companies have been able to rely on them for marketing purposes with confidence,” he said.
Rend Al-Mondhiry, a partner with the firm Amin Talati Wasserman, emphasized, as did Ullman, that the FDA’s pledge not to enforce rests upon the apparent safety of the ingredient.
“The guidance also leaves open this possibility (of FDA changing its mind) by stating that, if FDA determines the enforcement discretion policy is no longer appropriate, due to safety concerns or other reasons, it will notify stakeholders. However, I see this policy being in place for the near term future, at least until FDA makes a decision about moving forward with a rulemaking,” Al-Mondhiry said.
As far as safety is concerned, the industry should consider itself to be on solid ground. Few if any adverse event reports have come in on NAC products. And Rick Kingston, PharmD, who is head of scientific and regulatory affairs with the firm SafetyCall International, said the one current therapeutic use for NAC is in emergency rooms to combat liver damage when patients come in with severe acetaminophen poisoning. NAC is used in a high dose (far greater than what is used in any supplement) with an excellent history of safety, he said. (Kingston is also a professor at teh University of Minnesota School of Pharmacy.)
Succor to plaintiffs law firms
Al-Mondhiry said one concern that could still cloud the horizon for NAC is that while the ingredient has now found a safe harbor as far as FDA is concerned, that might not be enough to placate the plaintiffs’ bar. The fact that FDA is still on record as saying that NAC is not a legal dietary ingredient because of the drug exclusionary clause (with documents showing clincal trials from the early 1960s) might give those kinds of firms a tool to put teeth into demand letters.
“FDA could potentially keep this policy in place indefinitely. However, we’ve heard of some recent class action demand letters against NAC supplements, based on the fact that FDA has stated NAC is excluded from the definition of dietary supplement and therefore illegal. We’ll see whether a suit is actually filed, and whether a primary jurisdiction defense could be successful in these cases, since arguably FDA is still deliberating next steps on NAC, and FDA is best suited to ultimately determine whether NAD is indeed a lawful dietary supplement ingredient (rather than a court making this determination),” Al-Mondhiry said.
Does purview of exclusionary clause extend back in time?
And what of that exclusionary clause? Should it apply to ingredients that have been researched as drugs at any time in history? Or should that aspect of DSHEA, like the law’s other provisions, only apply to market conditions starting from the law’s grandfather date? A legal expert contacted by NutraIngredients-USA said the powers granted to regulatory agencies under the Administrative Procedure Act can be broad, and in some cases might extend to making rulings on conditions or practices in regulated markets that extend back in time.
The citing of drug trials that were done and dusted years before DSHEA was even first thought of was greeted as something of a shot out of left field by the industry. A new criminal law, for example, couldn’t be used to prosecute actions that happened before the law became effective, right?
“I do think the criminal law context is very different given personal liberty is at stake, and thus ‘retroactive application’ is different in the administrative law context. This issue now seems moot since we have the enforcement discretion policy in place, so unclear if it will be revisited,” Al-Mondhiry said.
Ullman, for his part, said the history of DSHEA makes it clear in his mind that its framers did not intend for it to be used for historical fishing expeditions. ‘Legislative intent,’ however, can be a slender reed when it comes to dealing with the more recent policies of regulatory agencies, so he said it might be something that will have to adjudicated in the future.
“The primacy of the exclusionary clause or the grandfather date is an interesting one. Given that DSHEA's intent was to expand access to dietary supplements and the legislative history showing that the exclusionary clause was a late addition to the statute, I would argue that the grandfather clause should prevail. FDA, which is always interested in expanding its powers and has never liked DSHEA (also two reasons why I am opposed to a mandatory product listing) is taking the opposite position. This presents an interesting legal question that may have to be settled in court one of these days,” Ullman said.