On October 19, the U.S. Food and Drug Administration (FDA) finalized guidance addressing the identity and safety information manufacturers and distributors should include in new dietary ingredient (NDI) notifications. The guidance finalizes Section VI of FDA's broader draft guidance, originally issued in 2016, while leaving other portions in draft.
By way of brief background, the Federal Food, Drug, and Cosmetic Act (FDCA) defines an NDI as a dietary ingredient that was not marketed in the United States before October 15, 1994. See FDCA § 413(d) (21 U.S.C. § 350b(d)). Unless the NDI and the other dietary ingredients in the supplement qualify for the statutory food-supply exception, the manufacturer or distributor must submit an NDI notification (NDIN) to FDA at least 75 days before introducing the supplement into interstate commerce. The notification must provide the basis for concluding that the dietary supplement containing the NDI will reasonably be expected to be safe under its proposed conditions of use. See FDCA § 413(a) (21 U.S.C. § 350b(a)). FDA's final guidance addresses the evidence companies should provide to support that conclusion.
The most significant changes to the draft guidance offer companies more flexibility to develop targeted safety submissions, potentially avoiding unnecessary studies. FDA is reducing its standard testing recommendations, expressly supporting alternatives to animal testing, and permitting greater flexibility in relying on historical evidence of safe consumption of the ingredient. At the same time, the agency is expanding its recommendations for documenting ingredient identity and manufacturing controls. The guidance remains nonbinding but describes the evidence and explanations FDA recommends including in an NDIN.
A More Targeted Testing Framework
The draft recommends extensive testing for certain ingredients and uses, including reproductive studies following multiple generations, teratology studies evaluating birth defects, and either a one-year study of long-term toxicity or a two-year study of cancer risk. The final guidance materially narrows FDA's standard testing table and no longer lists multi-generation reproductive, teratology, or chronic-toxicity/carcinogenicity studies as standard studies for any of the scenarios it addresses.
The table still identifies other studies that may be appropriate, depending on the available history of use and proposed conditions of use, including genetic-toxicity testing, single-dose or 14-day animal studies, 90-day subchronic studies, one-generation reproductive studies, and certain human studies. But FDA emphasizes that the appropriate studies depend on the specific gaps between the available evidence and the proposed use. For example, FDA recognizes that published information on acute toxicity or tolerated doses may make a new single-dose or 14-day animal study unnecessary. Companies should explain why they selected particular studies and why others were unnecessary.
On the other hand, FDA changed its recommendations for how repeat-dose animal studies should be conducted. The final guidance expressly prefers oral gavage—administering the test substance through a tube into the stomach—because FDA considers it most comparable to human ingestion and believes it reduces uncertainty regarding the administered dose. Feeding and drinking-water studies remain acceptable, but FDA recommends documentation establishing actual intake or waste. Companies commissioning new animal studies should therefore consider FDA's stated preference, while companies relying on existing feeding or drinking-water studies should evaluate whether those studies adequately document exposure.
Express Support for Alternatives to Animal Testing
The final guidance adds substantial discussion of "new approach methods" (NAMs): testing strategies that reduce, refine, or replace animal testing. Examples include laboratory tests using cells, known as in vitro studies, and computer modeling, known as in silico analysis. These methods may help answer specific questions about an ingredient, such as whether it damages cells or how it is absorbed. FDA supports their use when they generate reliable scientific evidence suited to the ingredient and safety question being evaluated.
FDA cautions that these methods are unlikely to establish safety alone, although they may fill gaps or support conclusions drawn from historical use or other studies. The final guidance also recommends documenting how the method works, its limitations, and the information needed to verify its results. Companies should therefore consider NAMs when designing a safety program, but explain precisely what each method establishes rather than treating favorable laboratory or modeling results as a substitute for the entire safety assessment.
More Room to Rely on a History of Safe Use
The draft stated that FDA considered 25 years of widespread use the minimum needed to establish a history of safe use. The final guidance retains 25 years as a general recommendation when relying on historical evidence alone but expressly contemplates fewer years if additional information demonstrates that the shorter period provides sufficient, reliable evidence.
FDA is also softening its treatment of traditional-medicine evidence. Rather than stating that additional safety information is "almost always needed," the final guidance recommends evidence addressing gaps between traditional use and the proposed supplement use. FDA gives the example of a traditional one-week limit on use, which should be addressed when explaining why the proposed use is safe.
A More Streamlined Safety Narrative
The draft recommends both a comprehensive safety profile for the NDI and a separate safety narrative for the finished supplement. The final guidance instead calls for a single comprehensive safety narrative explaining how the evidence supports the conclusion that the product is reasonably expected to be safe under its proposed conditions of use. For products containing multiple NDIs, the narrative may rely on safety data for the combination or data for the individual NDIs, provided the submission adequately addresses the safety of the combination.
FDA is also streamlining the safety calculations presented across studies. If multiple studies report a no-observed-adverse-effect level (NOAEL), the final guidance recommends selecting a NOAEL, explaining that selection, and using it for subsequent safety calculations. The submission should still summarize the safety findings from all relevant studies, and FDA may conduct its own additional calculations.
More Detailed Support for Identity and Manufacturing
FDA is expanding its recommendations for evidence verifying the identity of the NDI and demonstrating compliance with specifications. The final guidance expressly recommends supporting identity with analytical methods, data, and calculations and providing data demonstrating that established identity specifications are met. For extracts and concentrates, FDA also recommends describing the original starting materials, their amounts, expressed as percentages or ranges, and applicable specifications.
The final guidance likewise requests more detail about manufacturing controls relevant to identity and safety, including monitoring critical process parameters, conducting analytical testing at key stages, and verifying that reactions, extractions, separations, and other processing steps have proceeded correctly. These recommendations reinforce the importance of obtaining sufficient analytical and manufacturing information from ingredient suppliers before preparing an NDIN.
On the other hand, the final guidance provides additional flexibility regarding degradants. Instead of recommending evidence that no new degradants form during shelf life, FDA now expressly allows companies to identify expected degradants and their levels and provide supporting safety data.
What Companies Should Do Now
Companies considering or preparing an NDIN should carefully review FDA's final guidance before commissioning additional studies. The final guidance may provide opportunities to rely on existing literature, history-of-use evidence, NAMs, or a more targeted testing program rather than automatically undertaking the broader battery of studies contemplated by the draft guidance.
Companies should also carefully define the product's proposed conditions of use—including maximum daily intake, frequency and duration of use, and the intended consumer population—because those conditions drive the safety evidence FDA expects. Unless an NDIN specifies restrictions, FDA assumes daily lifetime use by all populations at the highest recommended serving size. The notification, supporting evidence, and proposed labeling should therefore be aligned.
Companies should also take this opportunity to reevaluate whether the dietary supplements they market contain NDIs for which a required NDIN has not been submitted. The additional flexibility FDA provides for demonstrating safety does not change the statutory obligation to submit an NDIN when one is required. And now that FDA has finalized its guidance on NDIN identity and safety information, we may see an increase in FDA enforcement for failure to submit a required NDIN.
If you have any questions or would like assistance evaluating whether an NDIN is required, developing an appropriate safety strategy, or preparing an NDIN, Venable's FDA team is here to help.