After years of pressure from industry stakeholders, the U.S. Food and Drug Administration (FDA) has declared that Beta Nicotinamide Mononucleotide (NMN) is lawful for use in dietary supplements, in response to Citizen Petitions filed by the Natural Products Association (NPA) and Council for Responsible Nutrition (CRN). The agency stated that it was aware that NMN was marketed as a dietary supplement in the United States in 2017, years before the ingredient was authorized as the subject of an Investigational New Drug (IND) study.

While observers anticipated that FDA might exercise enforcement discretion for NMN products, as it did with N-acetyl-cysteine products after first declaring that ingredient subject to drug preclusion, the agency fully reversed course on its position that NMN was authorized as an investigational new drug (IND) prior to being marketed as a supplement.

In 2022, the agency declared that NMN was precluded from use in dietary supplements because it was investigated as a drug prior to being legally marketed in supplement products, per the “drug preclusion” rule found in the Dietary Supplement Health and Education Act (DSHEA). However, it did not provide the public with the details of the IND study that triggered this instance of drug preclusion.  

This led NPA and CRN to independently file Citizen Petitions, calling for a reversal of the decision and clarity in how the agency more broadly enforces drug preclusion, respectively. NPA also sued the agency, but the case was stayed to allow FDA time to respond to its initial Citizen Petition.

While industry stakeholders were pleased with the NMN decision, critics argued that the agency preserved the status quo; the core, structural issues with how it interprets drug preclusion will continue to impact future product development. FDA will continue to consider the date at which it confidentially authorizes an IND to be the trigger date for “drug preclusion,” giving the supplement industry zero notice that an ingredient is precluded from use in supplements or food.

NPA: We’ll Continue to Fight ‘Abuse’ of Drug Preclusion Rule

In its 26-page response to NPA’s Citizen Petition, FDA elaborated on how it interprets the “drug preclusion” clause of DSHEA.

The agency declared that the date on which it authorizes an IND study is the date that precludes a substance from being a dietary supplement. “The relevant date is not the date that substantial clinical investigations were instituted or the date that the existence of such investigations was made public,” the agency wrote.

The agency noted that, based on this interpretation, it is impossible for anyone other than an IND holder or someone at FDA with access to such records to know that an IND has become effective.

“While we are sympathetic to these concerns, the textual analysis disfavors an interpretation of the statute different [from what was described] … Congress may have decided to make the IND ‘authorization’ date the operative date because it is a clear, definitive date that FDA can easily determine, whereas it could be difficult to pinpoint the precise date substantial clinical investigations were made public.” For instance, multiple clinical trials can occur under a single IND authorization, which could muddy the waters, the agency noted.

FDA also acknowledged that the term “substantial clinical investigations” found within the drug preclusion clause is highly subjective. Rather than interpreting this as meaning clinical investigations as “quantitatively large in size,” the agency will interpret them as “of qualitative importance in the context of new drug development.”

FDA also stated that it would only consider marketing that occurs in the United States when determining whether an ingredient was marketed as a supplement prior to IND authorization.

Importantly, the agency reconsidered its position that pre-IND marketing of an ingredient must be “lawful” to be considered in drug preclusion. “It is not sufficiently clear that Congress intended FDA to assess any aspect of the lawfulness of a dietary supplement or a food when assessing when an article was first marketed … there is not always a clear and easily obtainable answer as to whether a dietary supplement or a food satisfied all applicable premarket requirements.”

“FDA’s decision today confirms NMN is lawful in supplements, and we now call on e-commerce platforms to immediately restore NMN products to the market,” said Daniel Fabricant, PhD, president and CEO of NPA. “We will continue pressing Congress, the courts, and the administration until FDA stops abusing the drug preclusion clause once and for all.”

CRN ‘Dismayed’ by FDA’s Interpretation

FDA also responded to a Citizen Petition filed by CRN, which was less specific to NMN. CRN called on the agency to change how it interprets and enforces the drug preclusion provision of DSHEA to provide the public with more transparency. According to CRN, FDA’s response resolves immediate questions for a single ingredient, but “fails to address the core structural problems” that created the issue to begin with.

CRN’s petition requested that FDA only consider an ingredient to be precluded when “substantial” clinical investigations have been made public. This would provide supplement product developers with some notice that an ingredient is the subject of an IND study and is precluded from use in supplements or food.

A soon as FDA authorizes an IND study, it will consider an ingredient to be precluded from legal use in food or dietary supplements, leaving “systemic barriers to innovation intact” for those developing dietary supplement ingredients.

With only FDA and IND holders knowing when an authorization occurs, the industry can continue to get blindsided if the agency suddenly declares an ingredient is precluded, as was the case with NMN, NAC, and other ingredients, CRN noted.

“FDA missed a pivotal opportunity to bring clarity and balance to the line between pharmaceuticals and dietary supplements,” said Steve Mister, president and CEO of CRN. “At every juncture where FDA had the opportunity to choose between two interpretations of the statute, it chose one that favors pharmaceutical development over supplements. Consumer access to affordable and accessible healthcare products will be stymied as a result.”

Additionally, CRN’s argues that the drug preclusion provision calls for the completion and publication of “substantial clinical investigations,” which should constitute large-scale trials. “Even early-phase or limited studies can confer drug companies with a monopoly for an ingredient if FDA deems them qualitatively important for drug development,” CRN stated. “CRN had sought clear delineation from FDA for what constitutes a ‘substantial’ investigation. Basically, FDA claims it will know it when it sees it.”

“The agency’s reliance on non-public IND dates and an expansive view of ‘substantial clinical investigations’ creates a moving target that businesses cannot reliably plan around,” said Megan Olsen, senior vice president and general counsel at CRN. “Yes, FDA now says that NMN is not a drug precluded. But the same unstable framework remains in place for the next ingredient, inviting repeat uncertainty.”   

FDA’s response allows it to avoid a legal battle over NMN’s status, “but FDA has aggressively declined to provide any real guidance to the supplement or pharmaceutical industries,” Mister continued. “Without transparent, publicly knowable triggers and workable guidance, companies will continue to face unnecessary conflict with drug development rather than a coherent policy that advances public health.”