Pharma company raises questions over race to market between drugs, supplements

Editor’s note: This is part one of a two-part series of articles examining the applicability of the so-called drug preclusion clause in DSHEA (Dietary Supplement Health and Education Act of 1994) to an ingredient marketed in dietary supplements called β-NMN. The second article will be published next week.

A race-to-market provision in U.S. law that pits natural products against drugs resurfaced again in December when a clinical-stage pharmaceutical company essentially raised a question for federal regulators charged with overseeing dietary supplement products.

Is β-NMN (beta-nicotinamide mononucleotide), an ingredient under investigation as a new drug, precluded from the definition of a dietary supplement? FDA suggested the answer is “no” in a response to a premarket ingredient notification, yet an analysis of β-NMN highlights the complexities of a race-to-market provision in the Dietary Supplement Health and Education Act of 1994 (DSHEA).

Metro International Biotech LLC in Worcester, Massachusetts, has developed MIB-626, a proprietary form of β-NMN. NMN also is marketed in dietary supplements sold on Amazon, in products promoting such health claims as anti-aging, brain function and energy production.

NMN is a precursor to nicotinamide adenine dinucleotide (NAD+), which Quicksilver Scientific CEO Christopher Shade, Ph.D., described as “a coenzyme present in all living cells” in an article published in Integrative Medicine: A Clinician’s Journal (IMCJ). NAD+ plays a crucial role in such biological processes of the body as aging, cell death, DNA repair, gene expression and neuroinflammation, academics from China and New Zealand wrote in the Journal of Advanced Research (2022;37:267-278).

NMN is naturally found in many fruits and vegetables, including avocado, broccoli, cabbage, cucumber, immature soybean pods, mushroom and tomato, as well as raw beef and shrimp, according to the article. 

"Though at first, NMN was only considered as a source of cellular energy and an intermediate in NAD+ biosynthesis, currently, the attention of the scientific community has been paid on anti-aging activity and a variety of health benefits and pharmacological activities of NMN, which are related to the restoring of NAD+," the researchers wrote.

SyncoZymes (Shanghai) Co. Ltd. is the first company in the world to receive an acknowledgment letter for β-NMN from FDA in response to a new dietary ingredient notification (NDIN). In a May 16 letter, an FDA official acknowledged SyncoZymes’ premarket ingredient notification without an objection. The two-page letter did not raise any issues about the ingredient’s status as a new drug under investigation.

The notification to FDA was submitted to establish the ingredient meets a safety standard in DSHEA, which nearly three decades ago amended the Federal Food, Drug and Cosmetic Act (FDCA). However, a separate provision in DSHEA precludes β-NMN in dietary supplements if the same “article” was first approved or studied as a drug.

Research of an article as a drug doesn’t knock out a supplement ingredient from the U.S. market unless three criteria are satisfied, said attorneys who specialize in regulatory matters. First, the article must be authorized for investigation as a new drug. Second, substantial clinical investigations must have been instituted. Third, the clinical investigations must have been publicized.

Meeting the three criteria does not trigger the drug exclusion clause if the article was previously marketed as a dietary supplement or as a food prior to its authorization for investigation as a new drug.

“In general, an article that was authorized for investigation as a new drug or as a biologic before being marketed as a food or as a dietary supplement cannot be marketed as a dietary supplement if substantial clinical investigations of the article have begun and the existence of such investigations has been made public, as described in section 201(ff)(3)(B) of the” FDCA, FDA spokeswoman Lindsay Haake said.

Metro International Biotech suggested to FDA that drug preclusion applies to its article under investigation. “As a company that has instituted publicly available clinical trials on β-NMN, we request that 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, wrote to FDA in Dec. 1, 2021 comments.

The public 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.

Willis requested FDA “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.”

FDA considered Metro International Biotech’s comment and other public comments during the agency’s review of NPA’s citizen petition, Haake said.

It’s unclear if Metro International Biotech has followed up with FDA and offered a deeper analysis of the legal issues. Natural Products Insider requested from FDA written correspondence between FDA and the pharma company that related to its public comments. In response to a Freedom of Information Act request, FDA could find no responsive records between Dec. 1, 2021, and the third week of August 2022.

FDA concerns over β-NMN ingredient notifications

FDA has received and responded to five dietary supplement ingredient notifications concerning β-NMN. FDA objected to four of the NDINs for various reasons, including due to concerns that the notifications did not provide sufficient evidence of safety. Subject to an exemption in DSHEA for NDIs present in the food supply in a form not chemically altered, supplements containing NDIs are considered “adulterated” unless evidence is provided to FDA to demonstrate the product containing the ingredient “will reasonably be expected to be safe.”

FDA received the first ingredient notification (NDIN #1174) for β-NMN in January 2021. In a response addressed to Weiyin Zhou of Willy Chemicals Inc. in Derwood, Maryland, FDA determined the company’s ingredient, which was intended to be “taken under the tongue or in the buccal area,” did not meet the definition of a dietary supplement.

Since “the term ‘ingestion’ means introduced into the gastrointestinal tract, a product that is intended to have its effect before it is ingested or that is a delivery system for ingredients absorbed prior to ingestion, is not subject to regulation as a dietary supplement because it is not ‘intended for ingestion’ and may be subject to regulation as a food or drug,” Ali Abdel-Rahman, Ph.D., an FDA official, wrote in response to the NDIN.

Abdel-Rahman is listed as FDA’s branch chief of the Safety and Evaluation Branch of the Division of Research and Evaluation of the Office of Dietary Supplement Programs (ODSP).

In responses to two additional notifications filed by Willy Chemicals (NDIN #1189) and Willy Nutra Inc. (NDIN #1234), which both listed the same address, Abdel-Rahman advised Weiyin Zhou that FDA was unable to establish the safety of its dietary ingredient.

For instance, in the letter to Willy Nutra, Abdel-Rahman suggested a clinical study provided was insufficient since it only included 10 men, failed to include a placebo control and was based on a single daily dose.

“Because your clinical study was not a dose response study, FDA was unable to determine the no observed adverse effect level (NOAEL) for the study,” Abdel-Rahman wrote. “Therefore, it is unclear how the history of use or other evidence of safety information will establish the basis of the safety of your dietary supplement containing the new dietary ingredient under the proposed conditions of use.”

Willy Nutra, which describes itself on its website as “a company focused on dietary supplements,” did not respond to an emailed request for comment regarding FDA’s response to its NDIN and the letter from Metro International Biotech.

Another notification submitted to FDA by SyncoZymes (NDIN #1240) was met with concerns from the agency, which was unable to establish the safety of the company’s ingredient based on the history of use presented in the notification.

While the notification noted β-NMN is naturally occurring in myriad food sources at different levels, Abdel-Rahman observed the exposure in food is several times lower compared to the company’s maximum proposed serving level of 300 milligrams a day.

SyncoZymes provided preclinical and clinical studies conducted on other forms of β-NMN, such as NMN or nicotinamide riboside (NR), but the notification to FDA failed to show “how the test articles used in these studies are quantitively and qualitatively related to your new dietary ingredient,” Abdel-Rahman wrote in response to the NDIN.

Acknowledgement letter for β-NMN

SyncoZymes likely addressed FDA’s concerns in a subsequently filed NDIN (#1247) since it received an acknowledgment letter signed by Abdel-Rahman. The letter did not raise any objections or concerns.

None of FDA’s responses to the notifications identified β-NMN as a new drug under investigation, although it doesn’t mean the issue wasn’t considered by agency staff. FDA reviews an NDIN to determine whether it complies with the relevant regulatory and statutory requirements, including whether the drug exclusion provision applies to a new dietary ingredient subject to a notification, according to Haake, the FDA spokeswoman.

“Following the review, the FDA’s practice is to send a response letter to the notifier to provide information about our review, and if we determine an NDI that is the subject of an NDI notification appears to be excluded from the definition of dietary supplement, we will explain this point,” she stated.

Haake said FDA had no further comment on β-NMN.

Wei Zhu, Ph.D., CEO of SyncoZymes, said his company’s plan to register with FDA began in 2017 when it was approached by a co-sponsor for the NDI, CellMark USA LLC (FDA does not “approve” an NDIN, and an ingredient subject to an acknowledged NDIN could be targeted for enforcement if FDA determines it is misbranded or adulterated).

“Together we developed a roadmap for how to become a leading supplier of NMN to the U.S. market,” Zhu said in an email to Natural Products Insider. “Number one on the roadmap for success was completing an NDI submission. We knew NMN would require this registration since it was not considered a pre-DSHEA ‘old dietary ingredient.’ It took countless hours of work from both the SyncoZymes and CellMark teams to get it done. We're very proud to have the distinct honor of becoming the first NMN manufacturer to have a successful NDI submission.”

Zhu said it was not clear why Metro International Biotech issued its β-NMN letter to FDA as part of a request for information on the past use of NAC.

Both ingredients, however, implicate the “race to market” between dietary supplements and drugs. FDA concluded in 2020 warning letters—and reaffirmed this year in response to two citizen petitions—that NAC is excluded from the definition of a supplement because it was first approved as a drug in 1963.

FDA has subsequently issued a final guidance announcing its plans to exercise a policy of enforcement discretion regarding NAC-containing supplements. Unlike NMN, however, NAC-containing supplements have been sold in the U.S. for decades.