During one of several discussions held at The Big Natural, an event hosted by the Natural Products Association (NPA), dietary supplement executives discussed some of the pitfalls that come with the way the U.S. Food and Drug Administration currently enforces the New Dietary Ingredient (NDI) policy.
 
Since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994, a company introducing a novel dietary ingredient that wasn’t commonly used for human consumption prior to 1994 is required to file suitable documentation with the FDA which thoroughly covers safety information. Few new dietary ingredients have actually made it through this process, which DSHEA requires; and FDA, by and large, does not take enforcement actions against manufacturers and sellers who eschew the process.
 
“We want the agency to tell us, ‘here’s the law, here’s the punishment, and here’s how to avoid such a result.’ While people know the rules, they’re not acting on them,” said Vaughn DuBow, North American marketing manager, Lonza.
 
“A lot of [companies] have just decided that this process is time consuming, and they’re going ahead and releasing a product to market in the off chance that no one will ever care,” said Mark LeDoux, CEO of Natural Alternatives International and chairman of the board at NPA. “50,000 new products have entered the marketplace since the passage of DSHEA. This entails safety data, toxicology data, and more—it’s a very thorough submission which allows the agency to do a deep dive into the processes and the science.”
 
Especially in the botanicals category, eschewing the NDI process exacerbates the presence of bad actors who attempt to sell fraudulent ingredients or finished products which don’t contain the active compounds or nutrients they promise.

Adulteration
Travis Borchardt, vice president of regulatory affairs and QC/QA at Nature’s Way, described just how concerning this “regulatory gap,” as the FDA describes it, has been for elderberry, a botanical tied to immune support which has seen unprecedented spikes in demand since the onset of the COVID-19 pandemic.
 
Without the publication of an NDI notification to back claims that an elderberry product contains not only elderberry, but an efficacious amount of bioactive components, for example, the burden lies on ingredient buyers and those within the supply chain to test products to confirm they are in fact sourced from the materials they claim to be.
 
“Some of the raw materials offered to us had zero elderberry within them, simply a mimic,” Borchardt said. “The costs per kilo of elderberry, however, show that you get what you pay for, with a range of anywhere from $12 to $550 per kilo.”
 
“This is not just elderberry,” Borchardt continued. “It happens over the years with all sorts of botanicals that become very popular and observe a spike. Revenue opportunity means opportunities for cheating, and incentives to play around with the supply chain when there are shortages spurred by incredible demand […] it’s a very confusing space for the consumer in terms of determining the value of what they’re buying.”
 
With the new updates to FDA compliance guidance in the works, however, Borchardt said he remains optimistic regarding statements being made about the agency’s inspection priorities, and the agency’s acknowledgement of the challenges involved in identity and strength testing as part of its routine inspections.

The Knock-Offs
Beyond adulteration creating confusion for consumers, a lack of differentiation on nuanced products types such as extracts that comes with an absence of NDI enforcement seriously muddles categories such as collagen, DuBow, said.
 
“It entails spending millions of dollars developing a product, just so someone else can steal the idea,” he said. “It’s not fair, it’s not right, and the ‘regulatory gap’ is here to stay.” FDA has indicated that “it will persist no matter how many resources are made available,” he said.
 
With Lonza’s UC-II undenatured type II collagen ingredient, the company saw firsthand what happens when a competitor neglects to meet NDI requirements.
  
“We performed tons of studies on the efficacy and mechanism of action of UC-II, investing about $4 million on research and development alone,” DuBow said. “Very little money is being spent by the companies that don’t do this.”
 
Soon enough, a competing product was launched at a significantly lower cost, which led Lonza to suspect the competing product couldn’t be adhering to the same standards for the price. Internal testing of the competing product revealed that the competitor’s testing method of their collagen product actually denatured it, which is known to create bioavailability issues upfront.
 
Further, comparisons in solubility showed stark differences between the two competing products’ abilities to disperse in water, DuBow said. Lastly, standard testing methods revealed that while Lonza’s product exceeded label claims, the competitor’s product contained less than one-fourth of the claimed undenatured type II collagen.
 
Because the competing company did not go through the NDI process, which entails a deep analysis of the chemical composition surrounding its collagen, any issue the agency would take with purity, strength, or efficacy was put on the back-end, rather than dealt with upfront.
 
“Our competitor claimed that their ingredient was exempt from an NDI, without having proven that their collagen product was present in the food supply, and without having proven that it was not chemically altered, despite our tests which show that it was hydrolyzed,” DuBow said. “The definition of an NDI, according to DSHEA, is a vitamin, mineral, herb, botanical, amino acid, or other dietary substance for use by man to supplement the total dietary intake; and it’s been that way since 1994 for anything that wasn’t marketed in the U.S. as a supplement prior. It might sound like everything under the sun, and that the law is black and white, but it’s not.”

Untested Synthetics, Too?  
Marc Ullman, an attorney with Rivkin Radler specializing in FDA regulatory issues, described perhaps the most pressing of all issues pertaining to the NDI issue: adverse events among consumers.
 
He chronicled the advent of a supplement called BioPQQ, an organically-made version of an antioxidant called PQQ, found abundantly in a wide variety of foods, which went through 25 clinical trials prior to the company filing an NDI notification with FDA, with extensive safety and toxicology data to boot.
 
Shortly after BioPQQ hit the market, a number of synthetically-produced PQQ ingredients were launched—all of which are untested and potentially dangerous given adverse events recorded during in vitro clinical trials. Ullman said that test animals used in preclinical trials on synthetic PQQ were developing tumors, for example.
 
Due to several problems, competitors had their NDIs rejected—not only because of safety and toxicology concerns, but also because, as a synthetic ingredient, PQQ which is not manufactured organically is not a dietary ingredient, Ullman said.
 
“A synthetic copy of a dietary substance is not a dietary substance,” he said. “It’s also not reasonably safe for human consumption because there’s no explanation about why test animals are developing kidney tumors. After several NDIs were rejected, this competing company decided to submit a GRAS (Generally Recognized As Safe) notification to FDA. The FDA, operating in silos with people who weren’t informed that this ingredient had a history of rejected NDI notifications, took no action. This case is a poster child of the left hand not talking to the right hand, with neither hand even speaking to the brain,” Ullman continued.
 
“What does it take for FDA to act? Is everything short of liver failure and death okay? […] This is an apocryphal story and it’s the kind of thing that should concern everybody in the supplement trade. Knockoff, low-quality ingredients with impurities are hurting consumers.”

At least to start with, NPA has long supported the idea that FDA should issue import alerts on any new dietary ingredient that enters the U.S. without first receiving NDI approval. However, its advocacy efforts have been to no avail. Despite all this, until NDI enforcement does occur, the trade association anticipates the market will still see unapproved NDIs, leaving the burden of differentiating approved products upon companies, third-party testing facilities, and others.