Natural Products Association: NMN Lawsuit may Set Tone for Drug Preclusion Policy

In an ongoing legal battle, the U.S. Food and Drug Administration (FDA) delayed its determination on whether nicotinamide mononucleotide (NMN) a form of vitamin B3, is precluded from use in supplements because it was first investigated as a new drug. The agency committed to providing a final determination on the matter by Sept. 30. 

At a recent meeting, the Natural Products Association provided updates on the case, and expectations for what may happen next.

The NMN Saga

NMN is one of several dietary ingredients that have been targeted in warning letters issued by FDA, in which the agency expressed it was precluded from use in dietary supplements due to first being investigated as a new drug, in accordance with the Dietary Supplement Health and Education Act of 1994 (DSHEA).

The “drug preclusion” rule in DSHEA prohibits the use of an ingredient in supplements if it was first “approved as a drug or authorized for investigation as a new drug with substantial clinical investigations,” before being marketed as a dietary supplement. Both GRAS (generally recognized as safe) and NDI (new dietary ingredient) notifications have been submitted to the agency for NMN.

Trade groups like NPA have challenged this instance of drug preclusion, citing a lack of transparency and other issues. The agency has not provided the public with details about the IND study by a company called Metro Biotech which triggered preclusion, such as the date the study was published, or whether the study is “substantial” in accordance with the drug preclusion rule.

Similar disputes have occurred with other ingredients, such as N-acetyl-cysteine (NAC); in that case, the agency used its enforcement discretion powers to permit use of NAC in supplements despite holding the position that it was first investigated as a drug.

After first submitting a Citizen Petition, the Natural Products Association sued FDA for “unlawful retroactive application” of drug preclusion against NMN, but the case was stayed to allow FDA to respond to the Citizen Petition. After delaying its response, which was expected in July, FDA said it would respond to this Citizen Petition on Sept. 30. 

Will NAC Serve as Precedent in Similar Drug Preclusion Disputes?

Daniel Fabricant, PhD, president and CEO of NPA, said the association hopes FDA exercises enforcement discretion as it did with NAC.

“There’s a real desire to resolve this in a way that makes sense,” he said. “It’s a form of vitamin B3 that [FDA is] precluding from the market because of research which was initially filed as a dietary supplement trial but was changed mid-way through the process to an IND study.”

While enforcement discretion is a win, it leaves many important questions unanswered, and some retailers still won’t permit the sale of NMN.

FDA hasn’t determined whether it considers an ingredient to be precluded on the date the relevant IND study is completed, or on the date the study is published. But since the study precluding NMN supplements was originally a dietary supplement study, NPA contends the date at which the study was filed isn’t relevant to drug preclusion.

Further, absent any guidance, it’s unclear how FDA might use its enforcement discretion authority in future cases.

One thing is clear, Fabricant said: the NMN case is not about safety.

The fact that FDA has delayed its response to a Citizen Petition for this long, and has opted to exercise enforcement discretion on NMN for the duration of the lawsuit, “cuts against any arguments that this instance of drug preclusion has anything to do with safety,” he said.

What Might Happen After Sept. 30?

FDA’s final guidance on enforcement discretion for NAC products serves as a “treatise on what they believe,” about drug preclusion, but the agency maintains that it can’t be extrapolated to other ingredients, said Kevin Bell, partner at Arnall Golden Gregory LLP, which represents NPA. Whether FDA plans to maintain a status quo and handle issues on an ingredient-by-ingredient basis as it did with NAC remains to be seen. “As they did with CBD, they might push things toward Congress,” said Bell.  

“I’d be somewhat surprised if they completely back off their position on drug preclusion, because of their concerns about the impact it would have on the pharmaceuticals industry,” he added. “I also think that during this discussion between the supplement and pharmaceutical industries they don’t want Metro Biotech speaking on behalf of the whole pharmaceuticals industry.”

Upon receiving a response from FDA on Sept. 30, NPA will have a 14-day window to decide whether to resume litigation with possible amendments to the initial complaint, or if a settlement can be reached. Metro Biotech has filed a motion to intervene in the case between NPA and FDA, which, if granted, also presents many unknowns. And even if that motion is denied, Metro Biotech may still sue FDA separately depending on the decision reached in NPA’s lawsuit in September, noted Bell.

What Should NMN Brands Do in the Meantime?

Sept. 30 could bring a “quick end” to the years-long dispute over NMN, and could potentially bring more clarity to how FDA will enforce the drug preclusion provision of DSHEA more broadly.

However, “if legal and administrative matters don’t go our way, we won’t be done by a long shot,” said Fabricant. He urged industry stakeholders not to watch drug preclusion disputes silently from the sidelines. “This fight is way too important, and cuts across everything we do and how we innovate.”

If FDA’s response to NMN is similar to NAC, the battle for more consistency and transparency in how FDA determines when an ingredient is subject to drug preclusion is no closer to ending, said Bell. “It’ll most likely just raise questions about which ingredient is next.”

If FDA’s response on broader drug preclusion is lacking, it presents a stronger case for a legislative solution, “because we have a glaring problem to present to Congress, rather than a debate over hyper-technical issues,” Fabricant said. “When things are completely tilted one way or another, Congress is more likely to get involved. It’s not the outcome we want, necessarily, but it’s a possibility. The current administration seems willing to lend us an ear and might work with us, rather than just tilting the table toward pharma.”

The NAC matter set a precedent, but doesn’t resolve all issues, he added, noting that peptides, as a class of compounds, are of significant intrigue to the pharmaceutical industry.

“We shouldn’t have to litigate every time we need to get enforcement discretion. There’s too much uncertainty, which allows for gamesmanship,” Bell said, such as re-filing an already-published supplement study for an IND application.

“This isn’t a time to sit out and let someone else take all the fire for you. This really is a time to get involved, and participate,” said Fabricant.