26 years post-DSHEA, FDA still rejects most NDI notifications

Since the mid-1990s, FDA has objected to most new dietary ingredient notifications (NDINs) for one reason or another. This past fiscal year was no different.

In FY20, filed 27 objection letters to NDINs and acknowledged 16 notifications without objection, reflecting an acknowledgement rate of 37.2%, FDA data shows.

Steven Tave, director of FDA’s Office of Dietary Supplement Programs, reminded industry during a 2019 public meeting that “an effective NDI notification process represents FDA's only opportunity to evaluate the safety of a new dietary ingredient before it becomes available to consumers.”

But most firms that have gone through the 75-day, pre-market notification process—a requirement in the Dietary Supplement Health and Education Act of 1994 (DSHEA)—have met resistance from FDA for one or more reasons.

Of the agency’s 1,078 substantive responses to NDINs since 1995, the acknowledgment (AKL) rate has been, on average, 36.5%, according to an FDA spreadsheet, which Natural Products Insider obtained in November 2020 through a Freedom of Information Act request.

FDA’s objections have ranged from identity and safety concerns to assertions that a notification was incomplete or didn’t qualify as a dietary ingredient.

Considering FDA receives only 35 to 45 NDINs annually, it is hard to draw too many conclusions about the data, said an FDA spokesperson, who added “2020 was an unusual year in every respect.”

“Nevertheless, we are pleased that more than a third of the notifications once again received no objection this year,” the spokesperson added in an email. “We hope this trend will continue and even increase. NDI notifications are integral to a strong dietary supplement regulatory program, providing valuable information about the safety of dietary supplements and ingredients. We appreciate the efforts of the many responsible firms who continue to demonstrate that it is possible to successfully comply with the notification requirement, and we remain committed to working with firms to help them understand and navigate the process.”

Commenting on the FDA spreadsheet, American Herbal Products Association (AHPA) President Michael McGuffin concluded, “The broad data means very little.”

McGuffin pointed out that while FDA may object to a notification, a firm can eventually achieve success through the NDIN process. Case in point: FDA in 2016 rejected two NDINs filed by POM Wonderful for its pomegranate fruit polyphenol extract or pomegranate polyphenol extract powder. In both responses, FDA raised concerns over its ability to sufficiently identify the dietary ingredient. Later that year, however, the agency acknowledged a third NDIN filed by Pom Wonderful for its pomegranate fruit polyphenol extract.

“That’s a two-thirds failure by the simple arithmetic,” McGuffin observed. “It’s actually 100% success. One of the strengths of the system is that it does allow a revision process to occur, and the agency has historically been very specific in its commentary.”

Firms can obtain an AKL letter if they understand all the regulatory requirements and “take seriously” their duty to provide information that will persuade an “informed” and “stern” FDA reviewer that a finished product containing an NDI will be safe, McGuffin said.

But more often than not, FDA is convinced a firm has failed to meet such a burden. Over the last decade, the acknowledgement (AKL) rate has ranged from a low of 12.6% (FY17) to a high of 47.5% (FY19), FDA data shows.

“What the data demonstrates is that while there have been just under 1,100 submissions [eliciting] substantive responses from the agency, fewer than half meet the high bar for acknowledgement by the agency,” said Mark LeDoux, founder, chairman and CEO of Natural Alternatives International Inc. (NAI), a manufacturer and marketer of nutritional supplements, in an email. “Without some semblance of market protection or, at the very least, intellectual property protection of the supporting data that companies pay dearly for prior to completing their dossier for submission, one wonders why any company would go through the effort and expenditures other than to demonstrate their authentic leadership.”

In reviewing the FDA spreadsheet and reasons some firms’ NDINs have been met with objections in recent years, Douglas Kalman, Ph.D., of contract research organization Nutrasource suggested firms don’t understand the safety data that FDA expects to be incorporated in a notification. That presents an opportunity for the agency to remind or educate the nutrition industry about the safety packages that should be included in an NDIN or GRAS (generally recognized as safe) submission, he said in an interview.

Kalman, vice president of scientific affairs with Nutrasource, also suggested “part of the nutrition industry may lack some of the sophistication needed to understand all of the regulations that are in place, especially regarding either GRAS or new dietary ingredients.”

That was evident in FY17, when FDA’s unprecedented objection rate (87.3%) reflected many NDINs by Amazon merchants who did not understand the requirement, and in certain cases, weren’t even selling dietary supplements.

While FDA has received 1,166 NDINs since 1995, according to the FDA spreadsheet, it only responded to 1,078 notifications. That’s because, for example, a submission is sometimes withdrawn or FDA encounters a software upload problem.

Some FDA critics have blasted the agency for not aggressively targeting so-called copycat NDIs, ingredients that resemble novel ones in supplements, whose identity and safety have been reviewed by FDA. These copycats are not the only NDIs that haven’t been the subject of an NDIN. Many supplement firms have moved to demonstrate the safety of their NDIs through GRAS self-affirmations that aren’t reviewed by FDA. They are relying on an exemption to the notification requirement in DSHEA for ingredients present in the conventional food supply in a non-“chemically altered” form.

“Allowing copy-cat materials into the marketplace without scientific evidence to support such decisions or to allow self-affirmed GRAS notifications to be a substitute for NDI submissions has not yielded the intended effect, if said effect was to engender compliance with federal law,” proclaimed LeDoux, whose company was the subject of a four-part series of articles related to NDI enforcement. “I fear the loser here will ultimately be the consumer when something slips through that is poorly manufactured, or which is misbranded or mislabeled and therefore legally adulterated. At that point, the agency will no doubt act, but the damage will have already been done. This really is a shame, and did not have to be this way."

Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), said FDA hasn’t issued a final NDI guidance, making it challenging to judge what the data in the FDA spreadsheet really means. He cited, for example, the question of whether certain dietary ingredients can be synthesized.

“There’s no doubt that if you’re introducing a synthetic dietary ingredient … that’s ‘new,’” Mister said in an interview. “But we still don’t have clarity as to whether it’s a dietary ingredient or not. From time to time, [FDA officials] will throw out these objections saying … ‘That’s not a dietary ingredient,’ but you don’t have clarity. They’ve never finalized the guidance and given us a rational for really why it’s not.”

Citing another example, Mister observed there is lack of clarity on the concept of NDI master files.

“That’s why I don’t think you can make a lot of meaningful judgments about these data when you don’t have clear direction from the agency,” he concluded.

AHPA is in favor of FDA issuing a third NDI guidance on select areas that have presented obstacles to getting an AKL letter, such as a frequent comment by the agency in its response letters that a notifier has not clearly defined a dietary ingredient.

“How do you clearly identify your botanical extract so that the agency can tell that’s it’s your specific extract?" McGuffin asked. “That’s a big challenge, and we’ve asked for that.”

John Endres is a naturopathic doctor and chief scientific officer of AIBMR Life Sciences, a scientific and regulatory consulting firm. He also said FDA objections often have been tied to the agency’s view that the notifier did not adequately describe an ingredient, especially botanical ingredients.

Ricardo Carvajal, a director with the law firm Hyman, Phelps & McNamara P.C., suggested industry was not fond of FDA's approach to the NDIN process in the early years post-DSHEA.

“It was perceived as a process where it was not transparent," he said during an Oct. 14 virtual conference hosted by CRN. "You were uncertain of what the standards for evaluation were going to be, it felt like the bar was being set impossibly high, and so people started looking for an alternative. And that’s when we see the rise of interest in the GRAS self-determination process.”

In more recent years, industry representatives have commended FDA for holding pre-NDI meetings to help companies successfully navigate the notification process. 

"FDA wants the NDI notification process to be less of a black box for folks, so come on in to that pre-submission consultation," Carvajal said. 

That's not to say FDA is immune from criticism over its approach to NDINs, especially as relates to enforcement of the premarket notification requirement.

"FDA projects a dismissive attitude of NDINs through its written responses to good actors and refuses to engage in meaningful enforcement against bad actors," according to Kevin Bell, outside counsel to the Natural Products Association (NPA) and a partner with the law firm Arnall Golden Gregory LLP (AGG), in an email. "While FDA may not know how many NDINs should be submitted each year, the companies not filling them know FDA is on the record publicly stating [FDA officials] will look the other way." 

Lack of enforcement doesn't benefit responsible industry stakeholders and will eventually harm consumers, Bell said.

Tave, FDA's supplements chief, disagreed with the notion that FDA has failed to enforce the NDIN provision.

“We have used our NDI enforcement tools many times over the past 25 years, bringing charges against ingredients either for not complying with the notification requirement … or not complying with the safety requirement,” he said during the CRN conference in October. “The fact that we are not enforcing exactly when and against whom everybody wants doesn’t mean that we’re not enforcing. That may be something to discuss, but I do want to set the record straight.”

Aside from enforcement, FDA and industry continue to have disagreements on certain scientific matters related to NDINs.

For example, Dan Fabricant, Ph.D, president and CEO of NPA, said FDA is not reviewing certain probiotic NDINs due to the agency’s view they are not articles of the diet—a position he rejects.

“These [ingredients] aren’t being developed as drugs,” he said in an interview. “They’re being developed for food use because they originally came from food.”

Sophisticated companies are being pushed to demonstrate safety through GRAS rather than the NDIN process based on positions that aren’t in FDA regulations or the statute, according to Fabricant, who previously oversaw FDA's Division of Dietary Supplement Programs before it was elevated to an "Office." 

During the CRN conference, Miriam Guggenheim, a partner with the law firm Covington & Burling LLP, credited FDA for improving its process of reviewing NDINs. However, she said she’s “still hearing horror stories, where, for example, the [FDA] reviewers have no concerns about safety, but they’re nitpicking on the nuances of whether it’s really a dietary substance.”

The FDA data reflects the agency’s opposition to many NDINs, based on its view that a substance doesn’t meet the definition of a dietary ingredient, according to Amy Mozingo, director of Nutrasource’s U.S. regulatory business unit, GRAS Associates LLC.

“Many companies find themselves in an unfortunate dilemma when their ingredient can only meet the definition as ‘a dietary substance for use by man to supplement the diet by increasing the total dietary intake,’” Mozingo said in an email. “In this case, even if the intended use is in a dietary supplement and not conventional food, a company is forced to either utilize the … GRAS pathway or the Food Additive Petition (FAP) pathway and place the ingredient into the food supply in order to meet the definition.”

She cited, as an example, live microbials.

“Even if the genus and species of the microbe is found in the food supply, unless one can prove the specific strain is found in the food supply, the microbe does not qualify as a dietary ingredient,” Mozingo said. “This is a significant barrier to innovation as it often deters industry from developing new ingredients for use in dietary supplements.”

Stuart Pape, a shareholder with the law firm Polsinelli, expressed doubt during CRN’s conference that the regulatory system for “ensuring the safety of ingredients in dietary supplements” is working effectively.

“I mean something’s not working—whether it’s the GRAS part, or the NDI part, or a little bit of both, or the way FDA reacts to these things, the criteria it’s using,” he said. “This space strikes me as one that, if we can’t figure out how to fix it in the relatively near term, it’s at risk of Congress fixing it in ways we wouldn’t like.”