FDA NDI guidance: Five key takeaways

Last week, the Food and Drug Administration issued a “final” guidance on its interpretation of an ingredient notification requirement in the law that was enacted before humans were glued to the internet and Amazon was the retail king of dietary supplements.

The 16-page document is called “Dietary Supplements: New Dietary Ingredient Notification Procedures and Timeframes: Guidance for Industry.”

FDA published the guidance 30 years after then-President Bill Clinton signed into law the Dietary Supplement Health and Education Act of 1994 (DSHEA). Subject to an exemption some critics have described as the GRAS loophole, a manufacturer or distributor must demonstrate a new dietary ingredient (NDI) “will reasonably be expected to be safe” when used under the conditions recommended or suggested in the labeling of the dietary supplement.

This premarket notification requirement is perhaps more important than ever in the history of DSHEA, considering the supplement market has grown from roughly 4,000 products in 1994 to over 100,000 products today, according to FDA estimates.

These are my five takeaways on the significance of FDA’s guidance.

(1) A novella

The length and substance of the document isn’t reserved only for attorneys and regulatory geeks. Totaling 16 pages and focusing on the “forest” rather than the “trees” of NDIs, a C-level executive or rank-and-file employee should be able to digest the guidance, and fairly painlessly at that.

The guidance “provides clarification” on the NDI submission and review processes, Cara Welch, Ph.D., director of FDA’s Office of Dietary Supplement Programs (ODSP), told me in an interview. The guidance will “ideally” help notifiers prepare a notification that is “comprehensive” and “well laid-out,” she added.

Remember that FDA’s 2016 NDI guidance was more of a novel than a novella, spanning 102 pages — or the entire kit and caboodle — even including information on when a notification is not required for an NDI. For any die-hards that enjoy digging into the nitty gritty, that beast has also been updated with the new revisions.

(2) Dribs and drabs

FDA has decided to break up final guidance into smaller, more manageable documents than the 2016 NDI draft. “This final guidance is our first public step at issuing final guidance on NDINs (new dietary ingredient notifications) as a whole,” Welch explained.

FDA said it intends to “prioritize finalizing other parts of the 2016 revised draft guidance as the agency completes its review and analysis of those sections.”

On deck: A draft guidance for industry on NDIN master files that FDA intends to publish by December 2024, based on a list of food programs guidance under development.

Following the document’s release, there will be a comment period and a final master files guidance in the future, an FDA spokesperson said.

(3) A willingness to meet

One significant component of the 2024 guidance, Welch said, is a discussion of pre-NDI meetings with FDA.

FDA offers notifiers “opportunities to have meetings with our reviewers in advance of submitting an NDI notification and ideally can provide some helpful guidance on the process,” she said, adding perhaps ODSP staff will raise questions specific to an ingredient for notifiers to consider.

The 2016 NDI draft guidance raised the issue of firms meeting with FDA, but it was only a cursory mention and focused on a specific topic: showing that certain manufacturing processes do not result in a “chemical alteration” or affect an ingredient’s safety profile.

Former ODSP official Bob Durkin agreed the focus on pre-NDI meetings in the 2024 guidance is noteworthy, and he’s observed over the last year that FDA is more open in these meetings.

Durkin cautioned that FDA won’t be a consultant to notifiers, and firms shouldn’t meet with the agency until they have their draft NDI filing in order.

“They’re not going to really be a start-from-zero type consultant,” the Washington, D.C.-based lawyer with Arnall Golden Gregory LLP said in an interview. “They’ll tell you to go get a consultant. But once you reach a certain level of sophistication, at a certain point of your NDIN, the meetings become helpful and useful.”

(4) Cause for alarm?

At a glance, the March 2024 guidance is focused on timeframes and procedures, not the most controversial material imaginable. That doesn’t mean the document is without its critics.

Duffy MacKay, SVP of dietary supplements with the Consumer Healthcare Products Association (CHPA), is among industry veterans who suggested FDA is taking an approach to NDINs focused on products rather than ingredients.

“While we’re pleased to see positive strides being made on this issue under Dr. Welch’s leadership, specifically when it comes to addressing procedures and timeframes, CHPA remains concerned that the final guidance issued today unequivocally asserts that extensive scientific information will be required for every individual dietary supplement product on the market containing an NDI, even if the NDI has already met safety requirements established by the FDCA [Federal Food, Drug & Cosmetic Act],” MacKay said in a statement.

Durkin reads FDA’s position in the guidance as having the potential to chill innovation and product development and increase the cost of an NDIN.

The guidance suggests that if a notifier plans to market an NDI with vitamins C, D and E, FDA wants that formula to be reflected in the notification, “and then a year later, if you decide to remove the vitamin E or add vitamin K, you need to file a new NDIN,” Durkin said. “That’s pretty extreme.”

(5) Elephant in the room

No matter how many “final” documents are published on NDIs in the coming months and years, FDA critics are likely to insist the mountain of ink is all for nothing unless FDA holds firms accountable for circumventing the notification requirement.

“Too many companies are going to market without submitting an NDI notification for their ingredient because another firm has done the hard work, covered the costs and submitted a notification — of which a large portion is public,” Dan Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), said in a statement.

“This ‘piggybacking’ is unacceptable and does not allow the agency the opportunity to review their manufacturing processes or product specifications,” added Fabricant, who a decade ago oversaw FDA’s Division of Dietary Supplement Programs. “This should raise bright red safety flags.”

I respectfully disagree with NPA’s CEO that the 2024 guidance is a “giant nothingburger.” The document marks the beginning of finality with respect to FDA’s thinking on NDIs, and by encouraging meetings with FDA, perhaps more companies will abandon the GRAS loophole — or noncompliance altogether — in favor of an NDIN.

FY23 data showed a high success rate with NDINs, marking the third year in a row that over half of the notices received a so-called good day letter. The data demonstrates that firms marketing novel dietary ingredients can achieve a path to regulatory compliance by going through the front door with FDA.

That said, without rigorous FDA enforcement, I concur that NDI documents — final or not — will continue to carry little weight with scofflaws, also known as the ingredient manufacturers and distributors around the world who flout the notification requirement. These firms are endangering public health by depriving FDA premarket review of their ever-growing portfolio of NDIs.