Analysis: Kingdomway β-NMN letter reveals FDA legal interpretations on drug preclusion

This month, FDA delivered a letter to Inner Mongolia Kingdomway Pharmaceutical Limited (Kingdomway) regarding β-NMN (beta-nicotinamide mononucleotide) that I found significant.

Below are four of my takeaways:

1. First and foremost, the letter reveals the agency’s stance—a relatively new one, as reported Nov. 10 in my previous news article—that β-NMN is excluded from the definition of a dietary supplement.

American consumers may find it increasingly difficult in the future to purchase this anti-aging ingredient from trusted brands if FDA’s position is not challenged through a regulatory mechanism or in the judiciary.

In a Nov. 4 letter, R. Philip Yeager, Ph.D., of FDA’s Office of Dietary Supplement Programs (ODSP), said FDA was reaffirming its “earlier conclusion that NMN is excluded from the dietary supplement definition under 21 U.S.C. § 321(ff)(3)(B)(ii) and may not be marketed as or in a dietary supplement.”

2. The Kingdomway letter also is significant, in my opinion, because it underscores FDA’s view that the date an “article” like β-NMN is “authorized for investigation” determines the race to market between drugs and dietary supplements.

If a drug is authorized for investigation before an ingredient is marketed as a dietary supplement—and certain other requirements are satisfied in section 321(ff)(3)(B)(ii)—the drug wins the race to market, according to FDA. The prohibition is permanent, absent congressional action or a notice-and-comment rulemaking.

Related:Trade groups react to FDA decision on β-NMN in supplements

Industry stakeholders are frustrated, in part, because FDA does not typically reveal the date of authorization. Yet, again, that’s the date the agency says determines whether an ingredient is excluded.

“FDA’s regulations prohibit us from disclosing the existence of an IND [investigational new drug application] unless it has previously been publicly disclosed or acknowledged,” Yeager wrote in the Kingdomway letter. “Accordingly, although we can state our conclusions as to when NMN was first marketed as a dietary supplement or as a food and whether that date was before or after the date NMN was authorized for investigation as a new drug, we cannot specify the date of authorization or identify its source.”

3. The Kingdomway letter highlights FDA’s interpretation of “food supply” as it relates to a well-known and often-used exemption to the new dietary ingredient (NDI) notification requirement in the law.

Per DSHEA (the Dietary Supplement Health and Education Act of 1994), a supplement containing an NDI—such as β-NMN—is not subject to the 75-day, premarket notification requirement if it “contains only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”

Related:FDA says ingredient studied as drug—β-NMN—is excluded from supplements

Kingdomway argued NMN met the “food supply” exemption above because NMN capsules were offered for sale in Japan as early as January 2016. This could help demonstrate NMN was marketed in dietary supplements before it was authorized for investigation as a drug. However, in analyzing the exemption to the NDI notification requirement, FDA interprets ingredients in the food supply as being used in “conventional foods,” not dietary supplements.

In other words, the Japan evidence is irrelevant to the NMN analysis, according to FDA.

“Because the meaning of ‘food supply’ derives from the FD&C [Federal Food, Drug & Cosmetic] Act’s definition of ‘food,’ it refers to conventional foods and their ingredients,” Yeager wrote in the Kingdomway letter. “Although dietary supplements are taken by mouth, they are not typically ‘used for food or drink by man’ or used as components of conventional foods. Accordingly, a dietary ingredient that has been ‘present in the food supply as an article used for food’ is one that has been used as a conventional food or conventional food ingredient.”

4. This brings me to my last observation. Another factor FDA considers in determining the race to market is whether an ingredient has been “lawfully” marketed in a dietary supplement before it was authorized for investigation as a drug.

Per FDA’s letter, Kingdomway argued in an October 2022 letter that “even unlawful marketing of an article as a dietary supplement or food before the article’s authorization for investigation as a new drug should defeat the exclusion from the dietary supplement definition.” The ingredient company referenced structure/function claim notifications submitted to FDA in September and December 2020 for NMN-containing dietary supplements. The notifications are evidence that NMN was being marketed in dietary supplements and being promoted for certain health conditions.

FDA, however, disagreed with Kingdomway’s analysis. For a few different reasons—all of which I don’t quote or recite here—FDA concluded evidence of unlawful marketing of NMN as a supplement is irrelevant to determining whether the ingredient is excluded as a supplement under section 201(ff)(3)(B)(ii) of the FD&C Act. One of the reasons for FDA’s conclusion is that Kingdomway’s interpretation of the law would undermine the safety provisions in DSHEA, including the safety-related NDI notification requirement. Yeager noted supplements are "adulterated" under the law if they are marketed without the required NDI notification.

“In light of Congress’s statement in one part of DSHEA that FDA should take swift action against dietary supplements that are adulterated, it seems highly unlikely that Congress would have provided in another part of the statute that a dietary supplement firm could prevent a product from being excluded from the dietary supplement definition by marketing it in defiance of the safety provisions of DSHEA,” Yeager wrote.

Excluding irrelevant evidence, Yeager pointed to two possible dates that NMN was first marketed:

- “February 16, 2021 – First date on which another notifier could have marketed its NMN-containing dietary supplement lawfully after submitting an NDI notification to FDA on December 3, 2020; however, it is unclear whether NMN was actually marketed on that date.”

- “September 2021 – Month during which Kingdomway first marketed Doctor’s Best Instant Whey Protein Concentrate Plus NMN as a conventional food.”

Those dates, however, aren’t helpful to brands at this time since FDA has determined NMN was previously authorized for investigation as a new drug—consequently barring its use in supplements.

The FDA Kingdomway letter—as well as FDA’s responses in the spring of 2022 to citizen petitions filed by the Council for Responsible Nutrition (CRN) and Natural Products Association (NPA) related to NAC-containing dietary supplements—shed significant light on FDA’s interpretations of the drug preclusion provision in the law.  

Kingdomway and others are certainly free to disagree with FDA. But absent legislation passed by Congress amending the law or a successful lawsuit against the agency, FDA and its legion of attorneys are likely to hold firm to their views on the nearly three-decade-old law governing the race to market between drugs and natural products.