After two attempts at a draft guidance on New Dietary Ingredient Notifications (NDINs), in 2011 and 2016, the U.S. Food and Drug Administration’s (FDA) Center for Food Safety and Applied Nutrition (CFSAN) is issuing the first of what will be several final guidance documents on discrete sections of the complicated and controversial premarket safety-notification process.
 
The guidance, set to pubilsh in the Federal Register on March 6, 2024, finalizes Section V of the 2016 revised draft guidance, “NDI Notification Procedures and Timeframes,” as well as several related questions from other sections.
 
The guidance is intended to help manufacturers and distributors of NDIs and dietary supplements prepare and submit notifications to FDA.
 
“We understand the importance of finalizing other parts of the 2016 revised draft guidance,” FDA said in its announcement, “and we plan to finalize other individual sections as we complete our review and analysis of those sections.”
 
For now, the “Procedures and Timeframes” guidance provides information in a question and answer format about the NDIN submission and review process. Topics include, among others:

• Who needs to submit an NDIN?
• How should the information be organized and presented?
• Where should an NDIN be submitted?
• What happens after an NDIN is submitted?

 
Changes since the revised draft guidance include the following:
 

• Additional clarity on the procedures for preparing and submitting an NDIN;
• Technical updates related to recent changes to FDA’s online submission portal for NDINs; and
• More information about communications with FDA during the NDIN review process.

 
The agency has also “made editorial changes to improve clarity.”

Who Needs to File an NDIN and When?

Under section 413(a)(2) of the FD&C Act, “the manufacturer or distributor of an NDI, or of the dietary supplement that contains the NDI, must submit a premarket notification to FDA at least 75 days before introducing the product into interstate commerce or delivering it for introduction into interstate commerce, unless the NDI and any other dietary ingredients in the dietary supplement ‘have been present in the food supply as an article used for food in a form in which the food has not been chemically altered’ (21 U.S.C. 350b(a)(1)).”
 
Exactly what “chemically altered” means has been a topic of intense debate.  
 
However, dietary ingredients have been defined by section 201(ff)(1) of the FD&C Act (21 U.S.C. 321(ff)(1)) as:
 

• A vitamin;
• A mineral;
• An herb or other botanical;
• An amino acid;
• A dietary substance for use by man to supplement the diet by increasing the total dietary intake; or
• A concentrate, metabolite, constituent, extract, or combination of any dietary ingredient from the preceding categories.

Any dietary ingredient not marketed in the U.S. before Oct. 15, 1994 would thus be considered an NDI and require premarket notification to FDA.

What to Include in an NDIN?

An NDIN must contain information, including citation to published articles, that provides the basis for a reasonable expectation of safety under the proposed conditions of use. Absent submission of premarket notification, the dietary supplement containing the NDI is considered adulterated.
 
Basic information a manufacturer or distributor must have in a premarket NDIN include:
 

• Name and complete address of the manufacturer or distributor submitting the notification.
• The name of the NDI that is the subject of the premarket notification. For botanicals, the Latin binomial name must be given, including the author citation (i.e., the name of the scientist who gave the botanical its Latin binomial name).
• A description of the dietary supplement (or dietary supplements) that contains the NDI, including: the level of the NDI in the dietary supplement; and the conditions of use recommended in the labeling of the supplement.
• The history of use or other evidence of safety establishing that the dietary ingredient, when used under the conditions recommended or suggested in the labeling of the dietary supplement, will reasonably be expected to be safe.
• The signature of a person authorized by the manufacturer or distributor to sign the notification on its behalf.

How to File?

FDA said it encourages electronic submission through FDA’s CFSAN Online Submission Module (COSM) “to help ensure that you submit a complete NDIN and to enhance FDA’s ability to process and review your NDIN efficiently.”
 
COSM’s data validation helps prevent incomplete notifications by ensuring that all required fields are completed before the NDIN is submitted.
 
The agency will accept paper filings and offered a recommended template for organizing a paper NDIN.

Other Procedures to Know

• Whether submitting electronically or on paper, all references to published information must be accompanied by reprints or photocopies of the full text of each reference. An abstract alone “is not sufficient for FDA to evaluate whether the study supports the assertions in your NDIN.”
• Material written in a foreign language may be used as part of the basis for concluding an NDI is safe, but material must be accompanied by “an accurate and complete English translation.”
• If including unpublished work, provide a complete description of the data and methods used.
• Although data summaries are often sufficient, raw data are sometimes necessary for a thorough review. “The more critical the data are to the overall safety evaluation, the more likely it is that more detail is needed.”
• During review, FDA may request raw data and will disclose if the data submission warrants a new filing date, at which time the 75-day period (before a product can go to market) resets.

Trade Secrets and Confidential Commercial Information

For the first 90 days after the filing date, FDA will not disclose the existence or content of the notification. After the 90th day, all information in the NDIN will be made public, except for any information that is trade secret or confidential commercial information (CCI).
 
FDA recommended clearly identifying any information considered a trade secret or CCI “either by marking the information where it appears in the notification or by identifying this information in a separate document that accompanies the notification.” Filers must also explain the basis for claiming trade secrets or CCI.

Examples of Incomplete NDINs

FDA offered examples of omissions that can cause an NDIN to be incomplete. These included:

• Material in a language other than English that is either not translated or is translated inaccurately or incompletely.
• Citations to published literature for which a full copy of the publication is not provided.
• An NDIN that is not signed, or contact information that is inaccurate and does not permit FDA to establish contact with the notifier.
• Failure to provide the Latin binomial name, including the author citation, for any ingredient that is a botanical or derived from a botanical.

FDA Communication

After receiving an NDIN, FDA sends an acknowledgement to the notifier stating the date of receipt and provides the NDIN number assigned to the notification.
 
“The date of the NDIN’s receipt is also the filing date on which the 75-day prohibition on introducing the NDI-containing dietary supplement into interstate commerce begins.”
 
“We may use electronic communication to send the acknowledgement of receipt. In this communication, we will also state that we intend to send a detailed response letter within 75 days of the filing date. After finishing our review, FDA will send the response letter to the notifier.”
 
Examples of response types that FDA commonly sends include:
 
• Letter of acknowledgement without objection;
• Letter listing deficiencies that make the NDIN incomplete under 21 CFR 190.6;
• Objection letter raising concerns with the adequacy of the identity information or safety information (e.g., identifying gaps in the history of use or that the safety information on the NDI does not support the conditions of use); and
• Letter raising other regulatory issues with the ingredient or product (e.g., the ingredient is not a dietary ingredient under 21 U.S.C. 321(ff)(1), or the product does not satisfy all parts of the dietary supplement definition under 21 U.S.C. 321(ff)). 

Meetings Between FDA and Notifiers

“Some firms request meetings with FDA to ask questions and get preliminary and non-binding feedback from FDA regarding planned or potential NDINs. For example, some notifiers find it useful to obtain information regarding identity, safety, or how to submit before submitting an NDIN.”
 
Others have questions on submitting a new NDIN that is related to a previously reviewed submission. For example, they may wish to obtain clarification about what information could be useful to address concerns raised in a prior related FDA response letter.
 
A request for a meeting may be denied, “although this is a rare occurrence,” FDA said. For example, the agency may deny a meeting request “if a previous meeting for the same purpose has already been held and no significantly new information has become available, or if the subject matter is not appropriate for a meeting with FDA.”