By Mike Montemarano, Associate Editor04.21.22
The U.S. Food and Drug Administration (FDA) has issued draft guidance for dietary supplement manufacturers, distributors, and other stakeholders regarding its enforcement discretion over products containing N-acetyl-L-cysteine (NAC). FDA is accepting comments on the draft guidance by May 22.
On Mar. 31, FDA issued a joint response to two citizen petitions, from the Council for Responsible Nutrition (CRN) and the Natural Products Association (NPA), rejecting requests that the agency conclude NAC be considered a lawful dietary supplement under section 201(ff)(3)(B) of the Food, Drug, and Cosmetic Act (FD&C).
Rulemaking ‘Likely’ Pending Safety Review & ‘Other Considerations’
However, the agency said it would consider NPA’s request to initiate rulemaking to permit the use of NAC in or as a dietary supplement. The agency still holds NAC was first approved as a new drug before it was marketed as a dietary supplement or as a food. Specifically, NAC (i.e., acetylcysteine) was approved as a new drug under section 505 of the FD&C Act on Sep. 14, 1963. The product was then marketed as Mucomyst for inhalation use as a mucolytic.
Though its full safety review of NAC “remains ongoing,” the agency conceded its initial review yielded no safety concerns. “If, among other considerations, FDA does not identify safety related concerns as we continue our review of the available data and information, we are likely to propose a rule providing that NAC is not excluded from the definition of a dietary supplement,” the agency wrote.
In addition, the agency noted: “NAC-containing products represented as dietary supplements have been sold in the United States for more than 30 years, and consumers continue to seek access to such products.”
Enforcement Discretion
Consequently, the agency said it intends to exercise enforcement discretion with respect to the sale and distribution of products that contain NAC and are labeled as dietary supplements so long as those products are otherwise lawfully marketed and comply with the FD&C Act.
In other words, products that are adulterated, misbranded or marketed for the diagnosis, cure, mitigation, treatment, or prevention of disease will be considered unapproved new drugs and the agency will enforce existing statutes.
“Unless we identify safety-related concerns during our ongoing review, FDA intends to exercise enforcement discretion until either of the following occurs: we complete notice-and-comment rulemaking to allow the use of NAC in or as a dietary supplement (should we move forward with such proceedings) or we deny the NPA citizen petition’s request for rulemaking.”
NPA: ‘Good First Step’ But Dark Clouds Loom
While NPA viewed the enforcement discretion guidance as a critical first step following its 2021 lawsuit and citizen petition, Daniel Fabricant, PhD, president and CEO of NPA, made the case there’s reason to believe this retroactive application of the drug preclusion provision won’t be limited to just NAC. Further, NPA believes the mandatory product listing FDA proposed in its 2023 budget request will only serve to muddy the waters and cause potential economic harm, should it move forward.
“We’re glad we won this round, but we’re not glad we had to go to such great lengths to secure this for American consumers and a functioning regulatory regime. FDA could have and should have reached this decision years ago, but I credit NPA’s members for realizing what was at stake and being committed to this extraordinary effort,” said Fabricant.
“While this is a good first step, we still see dark clouds on the horizon,” he added. “Citizens petitions and lawsuits should be the exception and not the rule, but FDA’s inaction on CBD is very similar to the NAC discussion. We also see greater risk of this happening on a widespread scale if efforts to pass unnecessary and unwise product listing requirements throw more sand in the gears of timely agency proceedings.”
Companies have experienced “significant economic harm as a direct result to the agency’s actions on NAC,” Fabricant continued. “Had mandatory product listing been in place at the time of FDA’s action we are confident the economic harm would have been more significant than it already has been for industry stakeholders who provide millions of consumers with NAC. We have to find a remedy to other actions that have adversely impacted the NAC market, specifically the denial of export certificates and the delisting of NAC from certain e-commerce platforms.”
NPA will be hosting a webinar on this NAC regulatory update on April 26.
CRN: Still Evaluating Options to Clarify Intent of Drug Preclusion Provision
Upon denial of its citizen petition, CRN President and CEO Steve Mister characterized FDA’s handling of NAC as an “extralegal power grab” by applying DSHEA retroactively.
He said he’s hopeful the agency’s enforcement discretion guidance will provide retailers with assurance that they can continue or resume selling NAC-containing supplements.
“CRN appreciates FDA’s quick action following its March 31 response to our citizen petition with the announcement of this draft guidance today. We thank FDA for realizing that retailers and marketers of NAC need clarity and certainty in the market and assurance from the agency that there are no known safety concerns with these products,” Mister said.
“CRN looks forward to working with our retail partners and other stakeholders in continuing to assure consumers have access to otherwise lawful dietary supplements containing NAC,” he added. “But CRN also continues to express our disagreement with FDA’s reasoning that led to this announcement. We believe FDA’s overly expansive interpretation of the drug preclusion provision in the federal Food, Drug, & Cosmetic Act and retroactive application of the clause are misplaced and set a dangerous precedent for the agency to remove other lawful dietary ingredients from the market based on the assertions of pre-1994 drug approvals or clinical investigations.”
"Without consideration of routes of administration, dosage/serving levels, biological mechanisms of action, or the intended uses of the products, FDA would allow drug manufacturers to remove safe and beneficial dietary supplements from consumers using decades old research to get a monopoly for their pharmaceuticals," Mister said. "We continue to evaluate our options to revise the statute to clarify the original intent of the drug preclusion provision.”
On Mar. 31, FDA issued a joint response to two citizen petitions, from the Council for Responsible Nutrition (CRN) and the Natural Products Association (NPA), rejecting requests that the agency conclude NAC be considered a lawful dietary supplement under section 201(ff)(3)(B) of the Food, Drug, and Cosmetic Act (FD&C).
Rulemaking ‘Likely’ Pending Safety Review & ‘Other Considerations’
However, the agency said it would consider NPA’s request to initiate rulemaking to permit the use of NAC in or as a dietary supplement. The agency still holds NAC was first approved as a new drug before it was marketed as a dietary supplement or as a food. Specifically, NAC (i.e., acetylcysteine) was approved as a new drug under section 505 of the FD&C Act on Sep. 14, 1963. The product was then marketed as Mucomyst for inhalation use as a mucolytic.
Though its full safety review of NAC “remains ongoing,” the agency conceded its initial review yielded no safety concerns. “If, among other considerations, FDA does not identify safety related concerns as we continue our review of the available data and information, we are likely to propose a rule providing that NAC is not excluded from the definition of a dietary supplement,” the agency wrote.
In addition, the agency noted: “NAC-containing products represented as dietary supplements have been sold in the United States for more than 30 years, and consumers continue to seek access to such products.”
Enforcement Discretion
Consequently, the agency said it intends to exercise enforcement discretion with respect to the sale and distribution of products that contain NAC and are labeled as dietary supplements so long as those products are otherwise lawfully marketed and comply with the FD&C Act.
In other words, products that are adulterated, misbranded or marketed for the diagnosis, cure, mitigation, treatment, or prevention of disease will be considered unapproved new drugs and the agency will enforce existing statutes.
“Unless we identify safety-related concerns during our ongoing review, FDA intends to exercise enforcement discretion until either of the following occurs: we complete notice-and-comment rulemaking to allow the use of NAC in or as a dietary supplement (should we move forward with such proceedings) or we deny the NPA citizen petition’s request for rulemaking.”
NPA: ‘Good First Step’ But Dark Clouds Loom
While NPA viewed the enforcement discretion guidance as a critical first step following its 2021 lawsuit and citizen petition, Daniel Fabricant, PhD, president and CEO of NPA, made the case there’s reason to believe this retroactive application of the drug preclusion provision won’t be limited to just NAC. Further, NPA believes the mandatory product listing FDA proposed in its 2023 budget request will only serve to muddy the waters and cause potential economic harm, should it move forward.
“We’re glad we won this round, but we’re not glad we had to go to such great lengths to secure this for American consumers and a functioning regulatory regime. FDA could have and should have reached this decision years ago, but I credit NPA’s members for realizing what was at stake and being committed to this extraordinary effort,” said Fabricant.
“While this is a good first step, we still see dark clouds on the horizon,” he added. “Citizens petitions and lawsuits should be the exception and not the rule, but FDA’s inaction on CBD is very similar to the NAC discussion. We also see greater risk of this happening on a widespread scale if efforts to pass unnecessary and unwise product listing requirements throw more sand in the gears of timely agency proceedings.”
Companies have experienced “significant economic harm as a direct result to the agency’s actions on NAC,” Fabricant continued. “Had mandatory product listing been in place at the time of FDA’s action we are confident the economic harm would have been more significant than it already has been for industry stakeholders who provide millions of consumers with NAC. We have to find a remedy to other actions that have adversely impacted the NAC market, specifically the denial of export certificates and the delisting of NAC from certain e-commerce platforms.”
NPA will be hosting a webinar on this NAC regulatory update on April 26.
CRN: Still Evaluating Options to Clarify Intent of Drug Preclusion Provision
Upon denial of its citizen petition, CRN President and CEO Steve Mister characterized FDA’s handling of NAC as an “extralegal power grab” by applying DSHEA retroactively.
He said he’s hopeful the agency’s enforcement discretion guidance will provide retailers with assurance that they can continue or resume selling NAC-containing supplements.
“CRN appreciates FDA’s quick action following its March 31 response to our citizen petition with the announcement of this draft guidance today. We thank FDA for realizing that retailers and marketers of NAC need clarity and certainty in the market and assurance from the agency that there are no known safety concerns with these products,” Mister said.
“CRN looks forward to working with our retail partners and other stakeholders in continuing to assure consumers have access to otherwise lawful dietary supplements containing NAC,” he added. “But CRN also continues to express our disagreement with FDA’s reasoning that led to this announcement. We believe FDA’s overly expansive interpretation of the drug preclusion provision in the federal Food, Drug, & Cosmetic Act and retroactive application of the clause are misplaced and set a dangerous precedent for the agency to remove other lawful dietary ingredients from the market based on the assertions of pre-1994 drug approvals or clinical investigations.”
"Without consideration of routes of administration, dosage/serving levels, biological mechanisms of action, or the intended uses of the products, FDA would allow drug manufacturers to remove safe and beneficial dietary supplements from consumers using decades old research to get a monopoly for their pharmaceuticals," Mister said. "We continue to evaluate our options to revise the statute to clarify the original intent of the drug preclusion provision.”
