U.S. regulators have determined an ingredient marketed on Amazon for such health conditions as anti-aging and energy production cannot be sold in dietary supplements due to being investigated as a pharmaceutical drug.
Several companies were recently advised that β-NMN (beta-nicotinamide mononucleotide) is excluded from the definition of a dietary supplement.
A recent batch of FDA letters to Inner Mongolia Kingdomway Pharmaceutical Ltd. (Kingdomway) and others stand in contrast to the position previously taken by the agency in its review of β-NMN ingredient submissions made to FDA to establish the safety of the ingredient in supplements.
In publicized responses to five new dietary ingredient notifications (NDINs) filed with FDA between the summer of 2020 and the spring of 2022, FDA did not conclude NMN was precluded from use in dietary supplements due to it being investigated as a drug. The agency objected to four of the five notifications for reasons unrelated to its status as a new drug under investigation.
What's more, in a May 16, 2022, letter to SyncoZymes (Shanghai) Co. Ltd. made public in July, FDA acknowledged the company’s ingredient notification without an objection. Whether the ingredient is excluded in dietary supplements was the subject of a two-part series of articles published by Natural Products Insider in late September and early October.
The acknowledgment (AKL) letter to SyncoZymes paved the way for β-NMN to be lawfully marketed in dietary supplements in the U.S. Last week, however, an FDA official advised SyncoZymes that β-NMN is excluded from the definition of a dietary supplement.
“Based on new information that came to light when we were reviewing another notification, FDA initiated a review of past notification responses for NMN and concluded that NMN is excluded from the definition of a dietary supplement,” an FDA official, R. Philip Yeager, Ph.D., wrote in a Nov. 4 letter.
Yeager is director of the Division of Research and Evaluation with the Center for Food Safety and Applied Nutrition’s (CFSAN) Office of Dietary Supplement Programs (ODSP).
“FDA has carefully reviewed the information available to us and has determined that NMN was not marketed as a dietary supplement, except unlawfully without an NDI notification, or as a food before FDA authorized it for investigation as a new drug,” Yeager wrote in the letter to a representative of SyncoZymes, whose name and affiliation was redacted.
“Further, FDA has carefully considered the information available to us and has determined that NMN is an article for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public,” Yeager added. “Accordingly, we conclude 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.”
He said FDA was communicating its conclusion in letters to all firms that submitted NDINs to the agency for NMN.
After this story was first published, FDA provided a written statement in response to a request for comment on what specific new information “came to light.”
"While review of whether a particular ingredient is excluded from the definition of dietary supplement is not required as part of a new dietary ingredient (NDI) notification review, the FDA makes an effort to conduct a thorough review of the NDI that is the subject of an NDI notification, including the identity and safety information provided, as well as other regulatory issues that are applicable, during the review period," an FDA spokesperson said. "When the FDA initially reviewed NDI notifications relating to NMN, NMN was not clearly identified as an article that was authorized for investigation, i.e. MIB-626. Once the FDA was made aware of the connection between NMN and MIB-626, we concluded NMN is, in fact, excluded from the definition of a dietary supplement under section 201(ff)(3)(B)(ii) of the FD&C Act. The reasons for our conclusion are explained in the FDA’s supplemental response letter to NDIN 1259."
SyncoZymes CEO Wei Zhu, Ph.D., described the recent letter to his company as “very unfortunate news indeed.”
“Of course, when we received the acceptance of our registration, we never imagined that it could be withdrawn for any reason other than safety,” he said in an email to Natural Products Insider.
During several conversations with FDA, the issue of an investigational new drug (IND) application filing was never raised, Zhu said, calling the situation “very frustrating.”
“We invested a lot of time and money into pursuing the proper registration for NMN,” Zhu said, adding SyncoZymes was “regrouping” with its partner CellMark USA LLC and assessing its “next course of action.”
Publicly available documents suggest FDA first raised the drug preclusion issue in an Oct. 11 letter to Kingdomway. The letter, which Yeager signed, was in response to an NDIN submitted by the ingredient supplier.
FDA sent a supplemental letter to Kingdomway on Nov. 4, reaffirming its position that NMN is excluded from the definition of a dietary supplement, despite arguments to the contrary made by lawyers who represented Kingdomway.
Miriam Guggenheim, a Washington, D.C.-based attorney with Covington & Burling LLP, who—along with several of her colleagues—represented Kingdomway, did not immediately respond to a request for comment.
FDA’s position regarding the legality of NMN is likely to cause disruption to the marketplace and may culminate in a fight—perhaps litigation—between the dietary supplement and drug industries, with the public health agency at the center of the dispute.
Metro International Biotech LLC, developer of a proprietary form of β-NMN called MIB-626, has been devoted to pursuing a pharmaceutical development pathway since the company’s inception, its president and chief scientific officer, David Livingston, Ph.D., previously told Natural Products Insider.
Livingston didn’t immediately respond to a follow-up request for comment regarding FDA’s recent NMN letters.
In public comments filed in December with FDA, a representative of Metro International Biotech requested “FDA take the preclusion provision of section 201(ff) of the Federal Food, Drug and Cosmetic Act seriously.”
Michael A. Willis, Ph.D., corporate counsel to Metro International Biotech, asked FDA to “protect the right of companies that have spent significant time and research to develop drug products from competition from dietary supplements that are clearly new dietary ingredients that have never filed a new dietary ingredient notification prior to the institution of substantial clinical trials.”
The comments were submitted to an FDA docket in response to a citizen petition filed by the Natural Products Association (NPA) regarding NAC (N-acetyl-L-cysteine) products marketed as dietary supplements. Although NAC is a different ingredient than β-NMN, both substances have been investigated and/or approved as a drug.
FDA concluded in 2020 warning letters that NAC was excluded from the definition of a dietary supplement due to its earlier approval as a drug in 1963. That prompted industry trade associations to challenge the agency in citizen petitions and a lawsuit filed in U.S. District Court by NPA. In comprehensive responses to the citizen petitions, FDA reaffirmed its position that NAC is excluded from the definition of a dietary supplement.
However, FDA subsequently adopted a policy of enforcement discretion in a final guidance, which essentially grants dietary supplement marketers a legal avenue to market NAC in the U.S.
On Nov. 4, a federal judge dismissed NPA’s NAC lawsuit without prejudice after the Washington, D.C.-based trade association provided a notice of voluntary dismissal. That was the same day FDA issued letters regarding NMN to Kingdomway, SyncoZymes and others.
“There appear to be some items regarding [IND] trigger dates, an unprecedented NDI AKL reversal and possibly the active moiety that warrant further discussion,” NPA President and CEO Dan Fabricant, Ph.D., said in an email, commenting on NMN. “Most importantly, the discussion can and should advance swiftly to some form of relief without any red tape, moving more expeditiously than was the case on NAC.”
Fabricant, a former FDA official who oversaw the Division of Dietary Supplement Programs from 2011 until 2014, added, “There’s no reason why the agency couldn’t begin a policy of enforcement discretion here on NMN immediately, even if it is draft or interim.”
Such a proposal could keep NMN available as a dietary supplement in the U.S. but is likely to face resistance from the clinical-stage pharma company researching the ingredient as a drug: Metro International Biotech.