The guidance, New Dietary Ingredient (NDI) Notifications and Related Issues; Identity and Safety Information About the NDI: Guidance for Industry, is intended to help firms demonstrate that an NDI can reasonably be expected to be safe under its intended conditions of use before marketing the product. It finalizes portions of prior FDA draft guidance concerning identity information, history of use, safety evidence and safety conclusions.
Ashish Talati, FDA and FTC regulatory attorney and founding member of the Talati Law Firm, said there were no major surprises in the guidance and that overall it is a positive development for the dietary supplement industry.
“My biggest takeaway is that FDA seems to be taking a more flexible, case-by-case approach to evaluating the safety of new dietary ingredients, rather than expecting companies to follow a standard checklist of safety studies,” he said. “The focus is more on the existing safety data, the ingredient’s history of use and whether additional studies are needed to address specific safety gaps. FDA has kept many of its longstanding recommendations on safety factors and animal testing, but there appears to be more flexibility in how companies can demonstrate safety.”
Talati noted that, for example, FDA has revised its safety testing table and removed certain long-term animal and reproductive toxicity studies that were included in the 2016 draft. The agency also recognizes alternative testing methods, including in vitro and computational approaches, which could help companies address specific safety concerns without necessarily conducting additional animal studies.
“Given this approach, I think it will be even more important for companies to engage with FDA early through pre-NDIN meetings. Getting feedback on the proposed safety studies and overall approach before spending significant time and money could help avoid unnecessary testing and potential issues down the road,” Talati said. “Of course, the real question is how FDA will apply this flexibility in practice, especially when reviewing novel ingredients that don’t have a long history of human consumption.”
NDI notifications
Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, a manufacturer of a New Dietary Ingredient—i.e., one that was not marketed as a dietary ingredient prior to Oct. 15, 1994—is required to file a notification with FDA 75 days before putting the ingredient on the market. The dossier is supposed to provide scientific backing to prove that the ingredient can be “reasonably expected to be safe” under the conditions of use.
Within that timeframe, FDA is supposed to respond with a letter, either concurring with the assertion of safety or raising objections. It is important to note that this is a notification process and that FDA does not ‘approve’ ingredients.
First issued in 2011, the initial NDI draft guidance was met with significant industry backlash, prompting the agency to revisit the document and release a revised document five years later. That revised version was described as “more positive than negative” by Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), at the time, but some stakeholders still voiced concerns that the agency’s approach would dampen innovation.
Since the, the FDA has adopted more of a piecemeal approach to the NDIN guidance, stating in 2022 that it was working “expeditiously” to finalize sections as and where it can.
To date, the agency has finalized two sections: Section V (“NDI Notification Procedures and Timeframes”) in 2024 and the new section released today.
Daniel Fabricant, PhD, president and CEO of the Natural Products Association (NPA), asked how the agency’s initiatives around reforming the self-GRAS (generally recognized as safe) for food ingredients could potentially impact the new dietary ingredient notification process.
“We need to have a conversation in light of the proposed self-GRAS changes,” he said. “How do all those pieces fit together?”
New guidance
Ingredient identity is a major focus of the latest guidance, with the agency recommending detailed information describing the NDI, including its composition, physical and chemical characteristics, manufacturing process, specifications, contaminants, impurities and supporting analytical methods.
Additional recommendations are provided for specific ingredient categories such as botanicals, extracts, metabolites, enzymes, fermentation-derived ingredients, salts, isomers and live microbial ingredients (probiotics). For botanical ingredients, for example, FDA expects scientific nomenclature, source information, cultivation and processing details, and controls for potential adulterants and toxins.
For live microbial ingredients (probiotics), the agency recommends the Latin binomial name and information about the origin of the strain, the methods used for its isolation and to establish the identity of the strain, the location of the reference strain and the relationship to other strains used to establish the history of use or safety.
Documented history of safe use
The guidance also places significant weight on documented history of safe use, with adequate history generally involving widespread consumption by large populations under conditions comparable to those proposed for the NDI. FDA also stated that if a notifier is relying on history of safe use data alone, then approximately 25 years of widespread use is recommended.
“There are plenty of other foods that went to market without 25 years of safe use,” Dr. Fabricant noted. “We’re going to push back on that.”
When history of use alone is insufficient, FDA recommends other evidence of safety, which may include genetic toxicity testing, in vitro or new in silico methodologies, animal studies and human clinical studies.
The Council for Responsible Nutrition (CRN) expressed disappointment with the recommended 25-year benchmark for establishing a history of safe use but noted that the agency clarified that shorter periods may be supported by additional evidence.
“The guidance also continues to recommend that notifications include safety information about other dietary and non-dietary ingredients in finished supplements, an approach CRN has previously urged FDA to reconsider,” the association shared in a statement.
What’s next?
Several notable sections remain to be addressed, including sections pertaining to when an NDIN is required and the issue of Master Files. During a fireside chat hosted at the Council for Responsible Nutrition’s Convergence conference recently, Dr. Cara Welch, director of the Office of Dietary Supplement Programs (ODSP), stated that the agency is hoping for some good progress on NDI guidance in the coming months.
Dr. Welch later discussed potential guidance on how FDA interprets “dietary substance” and how that applies to different ingredient types and production methods.
She said she hoped for “a distinct draft guidance” addressing the dietary-substance question and asked: “What is the best interpretation of dietary substance? How does this apply to certain ingredient types?”
