April 11, 2023
FDA is holding firm to its position expressed in the fall of 2022 that a healthy aging ingredient cannot be lawfully marketed in dietary supplement products.
In letters that were made public in late March on the government docket, FDA reiterated its view that β-NMN (beta-nicotinamide mononucleotide) is excluded from the definition of a dietary supplement.
FDA made the January 2023 pronouncement in response to a new dietary ingredient notification (NDIN) filed by Effepharm Ltd., whose CEO Qiang Shen, listed an address in Shanghai, China. The agency reached the same conclusion in a January response to an NDIN prepared by SyncoZymes (Shanghai) Co. Ltd. and its U.S. distribution partner, CellMark USA LLC.
These premarket notifications are filed with FDA to demonstrate the safety of an ingredient in dietary supplements, based on a requirement in the Dietary Supplement Health and Education Act of 1994 (DSHEA).
SyncoZymes previously secured a so-called acknowledgment letter from FDA in May 2022, in response to a new dietary ingredient notification for NMN. However, the letter was issued before FDA concluded that a clinical-stage pharma company was researching the ingredient as a new drug, consequently barring its use in supplements.
FDA first made its “drug exclusion” determination in an October 2022 letter issued to a company called Inner Mongolia Kingdomway Pharmaceutical Limited and in a supplemental letter the following month to SyncoZymes.
Citing clinical trials of “MIB-626” being developed by Metro International Biotech LLC, FDA has concluded NMN was authorized for investigation as a new drug and the subject of substantial clinical trials that have been instituted and made public.
“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,” FDA wrote in the Nov. 4 letter. “This means that NMN may not be marketed as or in a dietary supplement.”
Under DSHEA, the pharmaceutical industry—specifically Metro International Biotech—doesn’t win the “race to market” for NMN if the ingredient was first marketed as a supplement before it was authorized for investigation as a new drug. But FDA determined yet again in January that the above exception does not apply to NMN.
“FDA has carefully reviewed the information provided in your amended notification and other relevant sources, including our own records, 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,” R. Philip Yeager, Ph.D., an FDA official in the Office of Dietary Supplement Programs (ODSP), wrote in a Jan. 18 response to an NDIN prepared by SyncoZymes and CellMark USA.
CellMark USA and SyncoZymes did not immediately return emails seeking comment.
An Effepharm employee said its NDIN was submitted to FDA for “Uthever” NMN before FDA changed its position regarding the ingredient.
Trade associations, consumers weigh in on NMN
Council for Responsible Nutrition (CRN) President and CEO Steve Mister said FDA has failed to properly apply the race-to-market provision in DSHEA between supplements and drugs.
“FDA’s latest actions with respect to the treatment of drug preclusion continue to demonstrate the agency’s complete misapplication of the drug preclusion principle,” Mister told Natural Products Insider. “The FDA’s criteria for determining when drug preclusion applies is incorrect. The issue here goes beyond any one ingredient and should concern the entire industry about which ingredient the FDA will target next.”
CBD (cannabidiol) and NAC (N-acetyl-L-cysteine) are among the ingredients that FDA has concluded are excluded from dietary supplements due to their earlier approval or investigation as a new drug.
“Looking at the record FDA has developed on drug preclusion for NAC, NMN and other ingredients, CRN is increasingly troubled that FDA’s positions are inconsistent, out-of-line with congressional intent, and fail to properly balance the equities for both pharmaceutical manufacturers and dietary supplement marketers,” Mister added. “The efforts to protect drug interests fail to consider the impact on dietary supplement innovation and create an unpredictable, unstable market for supplements. CRN plans to file a citizen petition in the next few weeks to raise these broader issues.”
In March, the Alliance for Natural Health USA (ANH) and Natural Products Association (NPA) asked in a citizen petition that FDA reverse its position on NMN. Alternatively, NPA and ANH requested FDA find NMN is lawful in supplements by promulgating a regulation following notice and comment through the secretary of the U.S. Department of Health and Human Services (HHS).
Through a grassroots effort led by NPA, about 2,000 letters regarding NMN have been delivered to Capitol Hill, said Kyle Turk, the association’s director of government affairs. The campaign includes a standard message and the option to include a personal story.
“Unfortunately, there’s some apathy out there or a view from companies that aren’t in the business of NMN that this is just someone else’s problem,” NPA President and CEO Dan Fabricant, Ph.D., said in an email. “This recent filing by FDA is a wake-up call—this isn’t just about NMN. This is FDA undoing the NDI process, removing an AKL [acknowledgement letter] six months after the fact not because of adulteration or misbranding per the statute.”
Fabricant, who oversaw FDA’s Division of Dietary Supplement Programs from 2011 until 2014, has been critical of the agency’s implementation and enforcement of the NDIN review process.
“New ingredients are the lifeblood of the industry, and without a clear process with stabilization around the rules to bring new products to market, that’s not the future that anyone should be accepting of right now,” he said, pointing to FDA inaction on regulating CBD, for example. “All the talks about ‘DSHEA modernization’ by the talking heads need to be put away. This is the biggest issue the industry faces and will be until these [drug preclusion] issues are resolved satisfactorily. NMN is a battle that cannot be lost.”
Over a handful of commenters have written to FDA in response to the ANH/NPA citizen petition. In large part, they requested FDA keep NMN available as a dietary supplement. The comments were incorporated in a docket that FDA opened at Regulations.gov in response to the citizen petition.
“If NMN is classified as a pharmaceutical drug, it will become increasingly difficult for consumers to access,” Trevor Collins wrote to FDA. “The supplement would become more expensive and would require a prescription from a doctor. This could prevent many people from being able to use NMN to improve their health.”
In the most recent public comment available on the docket as of this story's publication date, Terry Lim proclaimed, “If you guys make NMN only allowed to buy through a prescription, you guys are going to lose more trust about being in bed with pharmaceutical companies. Not that you guys haven’t lost that already. Stop trying to destroy every good thing on the market and capitalizing on everything for pharmaceutical company lobbies. Have some self-respect and morals for once.”
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