NMN and the case for litigation

Yesterday, as I read the 12-page letter from Metro International Biotech to the Food and Drug Administration concerning nicotinamide mononucleotide (NMN), it occurred to me that I was developing a headache from the legal mumbo jumbo.

The basic premise of the letter was simple: FDA is correct in its determination that NMN—a popular healthy aging ingredient—cannot be marketed in dietary supplements in the United States. The ingredient, according to FDA and Metro, is barred from being included in supplements under the so-called drug preclusion provision in the Federal Food, Drug & Cosmetic Act (FDCA).

The letter from Metro, a clinical-stage pharma company that is studying NMN to treat Alzheimer’s and other medical conditions, reads like a mini legal brief, and it raises a larger question than the legality of one ingredient.

Simply put, what does the drug exclusion language in the FDCA mean and how does FDA properly apply it to an ingredient like NMN? For better or worse, FDA—and its industry critics—can’t answer those questions without thoroughly analyzing section 201(ff) of the FDCA, which was amended by DSHEA (Dietary Supplement Health and Education Act of 1994).

The provision states in relevant part that the term “dietary supplement” excludes “(i) an article that is approved as a new drug under section 355 of this title ... or (ii) an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food unless the Secretary, in the Secretary’s discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this Act.”

(Sorry reader: Congress is no fan of brevity).

In November 2022, in a letter addressed to a company called Inner Mongolia Kingdomway Pharmaceutical Limited, FDA comprehensively evaluated the drug preclusion clause and applied it to NMN. A year later, in its letter to FDA that I reported on Wednesday, Metro offered its reasons concerning what it views as FDA’s proper interpretation of the law and correct conclusion that NMN is excluded from dietary supplements.

But in my opinion, these factual and legal questions are not the stuff of child’s play. To wit: Does the marketing of NMN several years ago in Japan, for example, influence whether the ingredient is excluded from supplements in the U.S.?

And does the date that FDA authorizes an article for investigation as a new drug—a secret date in most cases—determine the so-called race to market between the pharmaceutical and supplement industries? Or stated another way, is an ingredient potentially barred in dietary supplements if an IND (investigational new drug) application was authorized by FDA before an ingredient like NMN was lawfully marketed in supplements?

That’s essentially what FDA concludes. (See its Nov. 4, 2022, letter to Kingdomway).

Or is the race-to-market date tied to when the substantial clinical investigations of said “article” or ingredient have been publicized? (Some industry legal eagles would answer in the affirmative). I urge you to read the language above in Section 201(ff) and reach your own conclusions.

According to Metro’s letter, even if you interpret the drug exclusion provision differently than FDA, the supplement industry still has no right to market NMN. In other words, assume the key date in section 201(ff) is actually when the substantial clinical investigations have been publicized.

“As described in detail … both the effective date of Metro’s IND for MIB-626 and the publicization of clinical studies conducted thereunder clearly predate any lawful dietary supplement marketing,” Metro’s letter asserted.

These questions in the law, and facts related to NMN, are in desperate need of answers that all stakeholders can live with. That’s because, as we have observed with NMN, NAC (N-acetyl-L-cysteine) and other ingredients, the issue of drug preclusion is a growing source of confusion and controversy.

Ever since FDA made the connection between NMN and Metro’s MIB-626—in the words of an FDA official to me in a 2023 interview, the agency didn’t initially “connect those dots”—FDA has remained firm in its stance that NMN isn’t a lawful ingredient in supplements. Yet, to my knowledge, FDA hasn’t seized NMN-containing supplements or otherwise taken affirmative action to remove these products from U.S. commerce.

Without a proper fight in the judiciary, FDA and industry will continue to bicker about how the drug preclusion provision is being applied with no resolution in the foreseeable future. Sure, there are some relevant citizen petitions pending at FDA related to NMN and drug preclusion more generally, but if you believe the agency is going to be persuaded to reverse course, please send me what you’re smoking.

The current impasse doesn’t contribute to fostering innovation of ingredients that could promote health generally or alleviate the symptoms of diseases like Alzheimer’s. So, for 2024, I’ll be keeping a close eye on NMN and whether somebody—FDA or the supplement industry or even Metro—makes a bold move to get this controversy before a federal judge.

A lawsuit, in my opinion, is a more plausible path to a firm resolution than a congressional fix, which Big Pharma’s lobbyists will most certainly oppose. Sure, litigation is fraught with uncertainty and expense, but industry can always run to Capitol Hill if court challenges result in a nothing-burger.