The Agency made this determination after having been made aware of recent drug studies on the ingredient. This came while doing due diligence on a recent New Dietary Ingredient Notification.
NMN, or nicotinamide mononucleotide, is one of the forms of vitamin B3, or niacin, that has been shown to enhance the levels of the coenzyme nicotinamide adenine dinucleotide (NAD+) in the cells of the body. Boosting these levels has been shown to have some significant benefits in staving off cellular senescence.
Another well known ingredient along these lines is nicotinamide riboside, patented and marketed by ChromaDex under its brand Niagen, and its finished product brand, TruNiagen. The ingredient is also marketed by supplement manufacture Elysium, whose supplements feature the same ingredient from another source.
The anti aging supplement category has boomed of late, driven partly by high profile marketing conducted by Elysium as well as the extensive research collaborations developed by ChromaDex. NMN, which works on a slightly different mechanism, sidesteps some of the patent issues connected with the use of nicotinamide riboside.
FDA: No history of NMN being on market lawfully prior to drug
As a result, many players have sought to crowd into the space, with dozens of products in the market and a number of New Dietary Ingredient Notifications being filed on NMN. In responding to an NDI filed by Chinese firm Kingdomway, FDA noted that the commercial history of NMN includes supplements that have come to market without NDI Notifications on file. Some of these ingredients may have had self affirmed GRAS dossiers in place, which theoretically obviates the need for a NDIN, but it’s common knowledge in the industry that some new ingredients debut without either.
In the Kingdomway response, FDA said: “Under that [the drug exclusion] provision, if an article, in this case NMN, has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, the article may not be marketed as or in a dietary supplement unless the article was marketed as a dietary supplement or as a food before being authorized for investigation as a new drug. 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.”
Studies filed by MA-based drug developer
The investigations in question were conducted by Metro International Biotech, which is based in Cambridge, MA. The company is investigating a drug candidate designated as MIB-626, which it refers to as an ‘NAD Boosting Drug.’ Harvard anti aging researcher David Sinclair, PhD, is listed as the head of its Scientific Advisory Board.
On the company’s website under ‘Our Science’ the company refers to NAD+ research dating back as far as 2014. However, the FDA response to Kingdomway refers to three studies on COVID-19 outcomes for kidney disease patients, a study on Alzheimer’s disease and another on Friedrich’s Ataxia.
The first two of these were made public on Sept. 9 and 10, 2021, respectively. One of these was said to be nearing completion while the other has a completion date set for 2024. The third study is said to be ‘not actively recruiting.’
Metro International Biotech did not respond to a request for more information on the timing of its drug development in time for publication.
Questions of fairness, transparency
Sources said that this move could fuel the suspicions within the dietary supplement industry that the Agency seeks ways to favor drug makers. Whether that’s because those products are seen to be better supported by science or whether it’s because of a very narrow interpretation of the letter of law when it comes to the ‘drug exclusion clause’ of DSHEA is open to interpretation.
That part of the Dietary Supplement Health and Education Act states that if an ingredient was first investigated as a drug, a drug it must remain. Ingredients that were first marketed as dietary supplements can subsequently be developed into prescription medications and the two delivery formats can coexist in the market going forward.
This has created a situation characterized as the ‘race to market.’ Filing an Investigational New Drug application with the right date on it can have big implications for future market exclusivity.
Sources in the industry have been critical of the NDI procedure because of a belief that the scientific goal posts have moved over time, making it more difficult and risky than it needs to be. GRAS submissions, by contrast, are viewed as being more straightforward.
Question raised about FDA’s recent interpretations
This new development makes the decision to develop an NDI dossier even more complicated, said Ivan Wasserman, a partner in the firm Amin Talati Wasserman. It’s part of a recent course at FDA which has seen the Agency take an increasingly hard line on the drug exclusion question, with potentially grave implications for the marketers of some ingredients with significant market histories.
“First CBD, then NAC, and now NMN. What’s next? Is FDA’s 2022 interpretation of this and many provisions of DSHEA consistent with Congress’ intent in 1994? Without any legislative history to guide it is very difficult to know. Should companies go through the time and expense of submitting NDI notifications when there will always be a risk that some drug study will at some point be uncovered?” Wasserman told NutraIngredients-USA.
“The fact that FDA can’t even disclose the date on which the NMN IND was authorized, but relies on that date to invoke preclusion, raises fundamental questions of fairness. Congress needs to take a closer look at how FDA’s application and interpretation of various ambiguous provisions of DSHEA impact the dietary supplement industry and consumer access to safe and effective products,” he added.
Should an IND be the one ring to rule them all?
Consultant Mark Miller, PhD, of Kaiviti Consulting, concurred, saying, “It is more than disappointing for the FDA to scuttle a dietary ingredient that has been in commerce for some time, for the benefit of a late arriving pharmaceutical application. Within the context of drug development, IND submissions are the first step and is far from assured that it will result in a viable, approved drug.”
“This action has the appearance of favoritism to the pharmaceutical industry over dietary supplements. This is not the FDA’s finest hour and does not represent the best interest of consumers,” Miller added.
Attorney Marc Ullman, of counsel with the firm Rivkin Radler, said the current FDA interpretation sets up a situation in which a pharma company could file an IND, let the issue lie fallow, and then reinvigorate its drug development after a supplement company has developed new applications for the same substance.
“This interpretation will have a chilling effect on the developement of new preoucst to support public health,” Ullman said.
