In line with suggestions from industry, FDA intends to finalize parts of a 2016 draft guidance on new dietary ingredients (NDI) before publishing a separate document that would grant manufacturers of dietary supplements a period of enforcement discretion for submitting delinquent pre-market ingredient notifications to the government.

On May 20, FDA published a draft guidance pertaining to NDIs. Once the guidance is finalized, distributors and manufacturers of NDIs would have 180 days to submit identity and safety data to FDA without fear of reprisal for failing to timely meet a premarket notification requirement in the Dietary Supplement Health and Education Act of 1994 (DSHEA).

“The goal of this policy, when finalized, is to encourage manufacturers and distributors to correct any past failures to submit a required NDI notification,” FDA stated in a May 19 constituent update announcing the draft guidance. “Notifications submitted under the enforcement discretion policy will help increase the amount of safety information the FDA has about NDI-containing dietary supplements in the marketplace.”

The notifications are a critical component of FDA’s oversight since they represent the agency’s only opportunity to review the safety of novel ingredients in dietary supplements before they are marketed to consumers.

The 102-page NDI draft guidance issued in 2016 describes such issues as what qualifies as an NDI, when an NDI notification (NDIN) is required, the procedures for submitting a notification, and the types of data and information FDA recommends considering when evaluating the safety of NDIs.

“FDA has expressed our desire to finalize those parts of the 2016 NDI draft guidance we can before publishing a final guidance on NDI enforcement discretion,” an FDA spokeswoman said Thursday in an email to Natural Products Insider. “We understand the importance of providing clarity for notifiers in general and we are working on this expeditiously. Further, should the enforcement discretion policy move forward, we hope this will facilitate manufacturers submitting late filed notifications.”

In comments filed recently with FDA, industry trade associations suggested that finalizing the 2016 NDI draft guidance—or parts of the document— should be completed before FDA publishes a final guidance on NDI enforcement discretion.

In a document called “Foods Program Guidance Under Development,” FDA disclosed its plans to issue further guidance by the end of December 2022 regarding “NDI notification procedures and timeframes.”

The American Herbal Products Association (AHPA) “looks forward to the issuance of such guidance and notes that guidance addressing outstanding questions about the NDIN process may increase the number and quality of required NDIN filings that the agency receives,” three AHPA representatives stated in comments filed with FDA. “In the event that FDA issues such guidance prior to the finalization of the May 20 draft guidance, the number and quality of late NDINs submitted during the period of enforcement discretion may likewise increase.”

Duffy MacKay, senior vice president of dietary supplements with the Consumer Healthcare Products Association (CHPA), said it would be appropriate for FDA to announce a period of enforcement discretion when the 2016 draft guidance is finalized.

“Manufacturers and distributors will then have clarity on FDA’s expectations and on the dietary ingredients that should have been the subject of an NDI notification prior to marketing,” MacKay explained in written comments to FDA. “A period of 180-day enforcement discretion at that time will allow those manufacturers and distributors to assemble the requisite information and file a comprehensive NDI notification that will add to FDA’s insight into the safety of the ingredient, as intended by the statute.”

Lack of filings tied to guidance?

FDA has received about 1,200 NDINs since 1994, but the agency has estimated it should have received more than 4,600. Some industry trade groups challenged FDA’s estimate since it was based on many assumptions, including the number of products in the market.

Nonetheless, industry stakeholders generally agree that an undetermined number of NDIs subject to the notification requirement have not been filed with FDA over the last three decades. In comments filed with FDA, United Natural Products Alliance (UNPA) President Loren Israelsen expressed the “view that the most significant reason for unfiled NDINs is FDA’s failure to engage with industry and complete the 2016 NDIN draft guidance.”

UNPA and other trade groups expressed many concerns with the 2016 draft guidance after the document was published.

“Frankly, it is difficult to understand why, after six years, this could not have been completed with the necessary and robust discussion with industry to achieve a final draft guidance that is both consistent with DSHEA and affordable to the majority of the dietary supplement industry, coupled with an active enforcement practice by FDA to pursue dietary ingredients and supplements with known safety risks,” Israelsen wrote to FDA.

Representatives with the Council for Responsible Nutrition (CRN) are among stakeholders who anticipate only a modest number of NDINs will be submitted during a period of enforcement discretion if industry’s concerns in response to the 2016 draft guidance haven’t been addressed.

“CRN expects only a small number of notifications will be submitted under FDA’s proposed enforcement discretion period while these concerns remain, and the August 2016 draft guidance still represents FDA’s current thinking on the NDI notification requirement and related issues,” the trade association wrote to FDA.

FDA enforcement, 'confusion'

But even if portions of the 2016 NDI draft guidance are finalized before FDA adopts a period of enforcement discretion, not everyone is convinced it will make a meaningful difference in incentivizing the filing of NDINs.

FDA officials should “enforce the law against the very entities they have allowed (and at times encouraged) to break the law,” Arnall Golden Gregory LLP (AGG) Partner Kevin Bell, a Washington, D.C.-based attorney who advises the Natural Products Association (NPA), said in an email to Natural Products Insider. “Enforcement will continue to be the best path forward regarding NDIs. Unfortunately, I’m just as confident that it will remain the last thing FDA is willing to meaningfully address.”

Robert (“Bob”) Durkin is of counsel in AGG’s FDA and healthcare practices and a former FDA official in the Office of Dietary Supplement Programs (ODSP). During his tenure at ODSP, he served as acting director and deputy director.

“It seems unreasonable that FDA [officials] would go to final with portions of the 2016 draft guidance when they have created so much confusion about very fundamental aspects of it over the last few years,” Durkin said in an email.

FDA, for instance, has issued “conflicting messaging about when a manufacturing change would require a new notification, and even if a notification is unique to the party that submitted it or if anyone can rely on it,” Durkin explained. “They’ve also said they have no way of determining if a dietary ingredient is in commerce by way of the 'GRAS loophole' and how to deal with products that claim to satisfy it but really don’t.”

Durkin was referencing an exemption in the law to the notification requirement for NDIs present in the food supply as an article used for food in a non-chemically-altered form. FDA has cited challenges in determining if NDIs meet this exemption in Section 413(a)(1) of DSHEA. Some critics have dubbed the exemption the GRAS loophole, reflecting skepticism that the exemption really applies to unnotified NDIs and that firms marketing NDIs in conventional food and dietary supplements have legitimately established their ingredients are generally recognized as safe (GRAS).

Durkin described FDA’s positions on the issues he identified as “absolutely foundational to [the] NDIN process,” and he concluded “the only reasonable thing for the agency to do is to reopen the comment period and allow regulated industry the opportunity to weigh in.”