Forty-five.

That’s the total number of notifications submitted last fiscal year to FDA to establish the safety of new dietary ingredients in supplements—a category of regulated products that has proliferated over the last 25 years.

Required by law, the 75-day premarket ingredient notifications are critical because they represent FDA’s only opportunity to assess the safety of dietary supplements before they are available to consumers. Only “new dietary ingredients” (NDIs) are subject to the notification requirement, which Congress defined as those that were not marketed in the United States before Oct. 15, 1994.

‘NDIs aren’t being submitted to the FDA’

FDA issued its NDI regulation in 1997, three years after passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA). Since then, FDA has received 1,104 premarket ingredient notifications based on the agency's most recent count, an FDA spokeswoman said. By comparison, an estimated 50,000 to 80,000 supplement products are on the U.S. market, according to FDA.

Industry lawyers and others have suspected many NDIs are marketed to consumers without first notifying FDA and supplying history of use or other evidence to fulfill the statutory requirement that “the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe.”

“We all know there are just hundreds, probably thousands, of new dietary ingredients being introduced to the market to consumers, and the NDIs aren’t being submitted to the FDA,” said Pieter Cohen, an associate professor of medicine at Harvard Medical School who studies the safety of products marketed as dietary supplements. “That’s an open secret.”

Cohen said an outbreak of hepatitis linked to dietary supplements in Hawaii and the continental United States highlights the potentially adverse consequences of bringing a new ingredient to market without first notifying FDA. The 2013 outbreak was connected to Texas-based USPlabs LLC, which distributed supplements containing an ingredient known as aegeline, according to FDA and the Centers for Disease Control and Prevention (CDC).

FDA advised USPlabs in a warning letter that aegeline was an NDI subject to a notification. USPlabs denied its products caused the liver injuries and disagreed with FDA’s position, asserting its ingredient was a constituent of a botanical (bael tree) and didn’t require a notification due to an exception in the law. However, the company agreed to reformulate its OxyElite Pro supplement and discontinue use of aegeline.

USPlabs, which was indicted in 2015, recently agreed to discontinue its business activities and liquidate its inventory after pleading guilty to a criminal count of conspiracy to introduce misbranded food into interstate commerce with intent to defraud and mislead.

“That’s a crystal-clear example of where at least the CDC believes people are harmed, and if you take a deep look at what’s in the products, it’s exactly what’s on the label,” Cohen said in a phone interview, commenting on OxyElite Pro. “But there wasn’t an NDI.”

Steven Tave is director of FDA’s Office of Dietary Supplement Programs (ODSP). He addressed conjecture that supplement companies are introducing NDIs to the market without notifying his agency.

“Number one, I don’t think that all of the … products that have been introduced to the market since 1994 are necessarily products that require a notification,” Tave said in a phone interview.

Dietary ingredients marketed in the United States before Oct. 15, 1994 are exempt from the notification requirement. The law also exempted dietary ingredients that have been present in the conventional food supply in a form not chemically altered. 

Some products introduced since 1994 "are going to be new versions of products that have been on the market,” Tave said. “Everybody acknowledges that. You go into the store, and there are dozens, if not hundreds, of vitamins, of minerals, of things that nobody in their right mind would ever claim are new. We certainly don’t expect notifications for those products.”

On the other hand, Tave acknowledged it seems somewhat “unreasonable” to conclude none of the supplements on the market since 1994 have failed to notify FDA before marketing a new dietary ingredient.

“The question is, which ones and how many?” Tave asked.

Answering that question is tricky.

DSHEA does not require registration of dietary supplement products with FDA or any other entity. FDA has acknowledged it isn’t aware of all the products on a market that has grown more than tenfold over the last quarter century.

In the 1994 law, Congress found annual supplement sales totaled at least US$4 billion, with an estimated 600 dietary supplement manufacturers producing 4,000 products. In 2018, U.S. sales of supplements generated an estimated $45.8 billion, reflecting 5.7 percent growth over the previous year, according to Nutrition Business Journal (NBJ). (Disclaimer: Informa plc owns both NBJ and INSIDER.) There are more than 50,000 products on the supplement market, and perhaps as many as 80,000 or more, according to FDA.

Tave outlined the challenges in determining the number of supplement products in one year alone—2018—that contained new ingredients and should have notified FDA.

“I don’t know how many new products were introduced to the market in 2018, and I don’t know what those products were,” the FDA official remarked, “so I don’t know if those were just multivitamins with different combinations or adding new minerals; or I don’t know if those are completely novel ingredients that everybody would say, ‘Sure, we absolutely needed a notification for that.’”

FDA has scheduled a public meeting on May 16 in College Park, Maryland to discuss innovation in the dietary supplement industry—including NDIs—after FDA’s outgoing Commissioner Scott Gottlieb, M.D., announced plans to strengthen regulation of dietary supplements.

“An effective NDI notification process represents the FDA’s only opportunity to evaluate the safety of a new ingredient before it becomes available to consumers and helps promote transparency and risk-based allocation of resources,” Gottlieb, who is expected to depart the agency next week, said in a Feb. 11 statement.

Providing incentives through ‘master files’

Not all products are subject to an NDI notification (NDIN), a message that has been conveyed to FDA, said Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN). For example, when an NDIN is submitted to FDA covering products within a range of doses in specific dosage forms, manufacturers of finished products should be allowed to rely on that notification, he said in a phone interview.

Industry sources have envisioned a concept in which an ingredient manufacturer grants its customers—manufacturers of finished brands, for example—permission to rely on an NDIN in a “master file” accessible to FDA. An anticipated caveat: Distributors and manufacturers listed in a master file would be required to follow the manufacturing processes, identity specifications, dosage limits and other criteria spelled out in the original notification to FDA that was acknowledged in a letter without an objection. (Industry sometimes described such FDA acknowledgments as “good day letters”).

Eventually, FDA could enact guidelines related to master files in a formal document. FDA released a second draft NDI guidance in August 2016, replacing a document published in July 2011 in an effort to improve the rate of compliance with the notification requirement and ameliorate the quality of submissions.

If FDA is going to address master files in a final guidance, it must also release “an enforcement plan of how [it] will address the companies that ignore the law,” Mister said. “You’ve got to back that up with real enforcement.”

Mark LeDoux is chief executive officer of Natural Alternatives International Inc. (NAI), a formulator, manufacturer and marketer of nutritional supplements. In a phone interview, he said his company invested more than $1 million in an NDIN for its patented CarnoSyn beta-alanine ingredient. FDA later acknowledged the submission without an objection—the best outcome for a notifier under the law and FDA regulations.

LeDoux said FDA field agents could enforce against products containing NDIs that purport to be listed in a master file but are not.

“If an agent finds a product in commerce that is improperly labeled because it claims to be part of the master file but is it not, then they have all kinds of recourse to get that product off the marketplace,” he said.

Inadequate enforcement

FDA must “ensure that our regulatory framework is flexible enough to adequately evaluate product safety while promoting innovation,” Gottlieb said in his statement. “The key to this effort will be important steps to foster the submission of new dietary ingredient … notifications.”

Cohen questioned why FDA is pondering ways to encourage the submission of NDIs. If FDA was doing its job, he commented, the agency would have already identified the dietary ingredients subject to a notification and sent warning letters to companies that haven’t complied with the requirement.

“This is a great example of the FDA not doing its job for 20 years and now saying ..., ‘We’re going to encourage people to submit NDIs,’” the physician said. “That’s not the point. The law is if you’re going to put a new ingredient [in a dietary supplement], you submit an NDI. Period.”

Why should FDA provide incentives to comply with a requirement in a 25-year-old law?

“Because the FDA currently is not providing adequate enforcement to give companies an incentive to file,” Mister reasoned. “Rogue companies will look at this, evaluate the business risk and decide to go to market without filing because they don’t perceive there to be a serious consequence if they don’t file.”

“I’m definitely sympathetic to the perspective that you shouldn’t need an incentive to comply with the law,” Tave said. “That seems fundamental. I think where it becomes a complicated translation is when there [are] questions and controversy about what it is precisely that the law requires and how we [need] to enforce that.”

Kevin Bell, an attorney based in Washington, concurred with Mister that FDA enforcement has been lacking.

“Everyone knows that there’s a lack of enforcement by the FDA on NDIs,” said Bell, a principal of Porzio, Bromberg & Newman P.C. and a member of the firm’s intellectual property and litigation departments. “I think [Dr.] Gottlieb’s statements … seemed to indicate that they were going to try to put more resources and effort into that.”

Knockoff ingredients

A recurring frustration for industry: so-called knockoff or copycat ingredients that purport to be identical to NDIs that have invested in the notification process but don't have a relationship with the notifier.

Daniel Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), said companies that receive a “good day” letter from FDA after submitting an NDIN could share with the agency a list of customers who are using the ingredient. If a copycat ingredient isn’t on such a list, FDA could place it on an import alert or bulletin, added Fabricant, who previously led what was then known as FDA’s Division of Dietary Supplement Programs. (In December 2015, the division was elevated to the status of an “office”).

“You’re never going to get an uptick [in ingredient notifications] if people don’t think their investment is going to be protected,” Fabricant said in a phone interview.

One of Bell’s clients—NAI—is developing a multi-pronged strategy to protect its NDI investment and hold others accountable for non-compliance with the law. Bell suggested the strategy includes working with federal agencies like FDA and U.S. Customs and Border Protection.

“We’re working on a pretty broad strategy on how to assist in enforcement of that [NDI], and compliance is what we’re really looking for,” the lawyer said.

Knockoff ingredients not only threaten to undermine the investments of companies that submitted an NDIN, they pose possible safety concerns. Although the knockoff ingredients may purport to be the same material as an ingredient subject to an NDIN, “we don’t know that they’re equivalent,” Fabricant observed. “We don’t have peace of mind with them.”

Failure of those ingredients to notify FDA, he added, “just disincentivizes everybody in the whole process.”

‘A disconnect’

In his February statement, Gottlieb raised concerns that “changes in the supplement market may have outpaced the evolution of our own policies and our capacity to manage emerging risks."

In the context of NDIs, Tave followed up on the commissioner’s latter point.

“Regardless of what we want to think as a matter of philosophy, the reality is there is a disconnect between the way firms are filing NDI notifications and our ability to comprehensively police the market,” he said.

ODSP has a staff of just two dozen full-time employees to oversee and police an industry with tens of billions of dollars in annual revenues.

The disconnect, Tave said, extends to FDA’s ability to police the market “in a way that is both resource-efficient and consistent with the goals of protecting the public health.”

Though it’s proven challenging to attain, FDA’s objective is straightforward.

“We want to be able to have an opportunity to review the safety profile of new ingredients before they get to reach consumers,” Tave said. “That means we don’t need to review notifications for products where they’re not required, but we do need to review them for products where they are required. The magic is in getting to a common understanding of when [a notification is] required and getting everybody to buy into that.”