Regulatory Guidance for “Old vs. New” Dietary Ingredient Analysis and New Dietary Ingredient Pre-Market Notifications
Recognizing a need to address the increasing role that dietary supplements have taken in health promotion, the Dietary Supplement Health and Education Act (DSHEA) was signed into law in October 1994. This amended the Federal Food, Drug and Cosmetic Act, since prior to this enactment, dietary supplements were regulated by the Food and Drug Administration (FDA) as other foods.The legislation established a new regulatory framework to address the safety and labeling of dietary supplements.Unlike prescription and over-the-counter drugs, dietary supplements do not need pre-approval before market.However, if a dietary supplement contains an ingredient that has not been marketed in the United States prior to October 15, 1994, then it is considered a “new dietary ingredient” and requires pre-market notification (as distinguished from product approval for prescription drugs and some over-the-counter drugs).
The FDA does not provide a comprehensive list of “old” or “grand-fathered” dietary ingredients marketed in the U.S. prior to October 15, 1994.Instead, the FDA requires manufacturers and distributors to determine whether their dietary ingredient is a “new” dietary ingredient or “old” dietary ingredient that has been marketed in U.S. commerce prior to the cut-off date.
To start the “old vs. new” dietary ingredient analysis, it is necessary to establish that the ingredient is actually a dietary ingredient.A dietary ingredient is defined as a vitamin, mineral, herb or other botanical, amino acid, or a dietary substance for use by man to supplement the diet by increasing the total dietary intake (such as enzymes or tissues from organs or glands), or a concentrate, metabolite, constituent, extract, or combination of any of the above dietary ingredients.In tandem with this first step, the product containing the dietary ingredient must be a dietary supplement.A dietary supplement contains one or more dietary ingredients that are intended to supplement the diet and is limited to those products taken by mouth.A dietary supplement is a product intended for ingestion in tablet, capsule, powder, softgel, gelcap or liquid form.If the product is not intended for ingestion in such a form, it must not be represented as a dietary supplement.
Once the product is identified as a dietary supplement and the ingredient is found to be a dietary ingredient, a determination of the dietary ingredient’s status must be made.Under the FDA’s enforcement of DSHEA, the Federal Food, Drug, and Cosmetic Act provides that a dietary supplement that contains a dietary ingredient will be deemed adulterated unless it falls into one of the following two categories:1) Ingredients that 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; or 2)Ingredients that have a history of use or other evidence of safety establishing that the dietary ingredient when used under the recommended or labeling conditions will reasonably be expected to be safe (21 U.S.C. 342(f)).The first category includes those ingredients present in the food supply prior to October 15, 1994 that have not been chemically altered.Chemical alteration does not include a product that was subjected to minor loss of volatile components, dehydration, lyophilization, milling, tincture or solution in water, slurry, powder, or solid in suspension.As stated previously, the manufacturer or distributor must determine whether the dietary ingredient was in the food supply before this date and in an unaltered state.If the product falls into the first category, the manufacturer or distributor should obtain an opinion-of-counsel letter from its attorney stating that the dietary ingredient is “old”/ “grand-fathered” and not adulterated because it was present in the U.S. food supply, in a non-chemically altered form, prior to inclusion in the dietary supplement.If the product is in the second category, it is deemed a “new” dietary ingredient and a new dietary ingredient pre-market notification (NDI notification) focusing on safety data must be filed.
A NDI notification must be filed per 21 C.F.R. 190.6 at least 75 days prior to introducing or delivering into interstate commerce a dietary supplement containing a new dietary ingredient.The NDI notification requires the following information:
1.The name and complete address of the manufacturer or distributor of the dietary supplement that contains a new dietary ingredient, or of the new dietary ingredient itself;
2.The name of the new dietary ingredient that is the subject of the pre-market notification, including the Latin binomial name, including the name of the author, of any herb or other botanical;
3.A description of the dietary supplement or dietary supplements that contain the new dietary ingredient, including the level of the new dietary ingredient in the dietary supplement, the conditions of use recommended or suggested in the labeling of the dietary supplement and the ordinary conditions of use of the supplement;
4.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 expected to be safe; and
5.The signature of the person designated by the manufacture or distributor of the dietary supplement that contains a new dietary ingredient.
In the United States, the safety of the new dietary ingredient is determined on a reasonable expectation of safety basis.The FDA does not publish specific guidelines on what a “reasonable expectation of safety” is for dietary ingredients.However, there is no limitation on what evidence a manufacturer/distributor can use for this safety determination.The FDA will consider animal and human toxicology data and any citation to published articles or other evidence that is the basis on which the manufacturer or distributor has concluded that the new dietary supplement will provide this reasonable expectation of safety.Copies of any reference information supporting the notification needs to be included, as well as any English translations of foreign material, if necessary.In response to comments prior to the enactment of the NDI notification requirement, the FDA stated that it is not overly burdensome on the manufacturer or distributor to provide information that they should have already used in their own determination that the product and/or dietary ingredient is reasonably expected to be safe.Because the NDI notification focuses on the particular dietary ingredient’s safety profile, the more comprehensive and relevant safety data submitted will lessen the likelihood of FDA’s rejection.
Recommendations for submitting safety data include consideration of the chemistry, method of manufacture and specifications of a dietary supplement, and compliance with good manufacturing practices (GMPs) to ensure the quality of the product itself.Extrinsic evidence such as clinical studies, animal and human toxicology data, the product’s history of use, and the current use of the ingredient is key information that should be provided.Strong methodology is recommended for such clinical trials and toxicology studies. A thorough literature search is also recommended to obtain other sources of information that the manufacturer or distributor may not have available.Although there is no efficacy requirement for dietary supplements, as there is for clinical studies for drug products, the safety data may include this information which would be helpful to the FDA in evaluating the NDI notification.Another important consideration is to investigate the recommended dose of the ingredient.The recommended dose should represent a safe level of use and it is critical to determine the dose that results in an adverse effect.However, this does not mean that the recommended dose should include an upper limit of use as exceeding this would not comply with the intended conditions of use.
In determining what type of safety data to submit and how much information is needed, the FDA evaluates each NDI notification on a case-by-case basis.Examining past NDI notifications is helpful in this determination and a listing is found at http://www.cfsan.fda.gov/~smdds-ingrd.html.The FDA states that although a new dietary ingredient may be listed in this table, this is not a finding that a new dietary ingredient or dietary supplement that contains the new dietary ingredient is safe or unadulterated under the Federal Food, Drug and Cosmetic Act.Additionally, each manufacturer or distributor is responsible for ensuring its individual compliance and even if a new dietary ingredient is present in the table, another manufacturer or distributor who has this ingredient or product containing this ingredient cannot legally market the dietary ingredient or dietary supplement without filing its own NDI notification.
Once a new dietary ingredient notification has been submitted, the FDA will send a written receipt to the submitter, designating the receipt date as the filing date.Additional submissions are allowed during the 75 day period, but we suggest to provide as much information as possible in the original NDI notification since the FDA will review the submission to determine if it is a substantive amendment, in which case the 75 day period will be re-set.The FDA may contact the submitter if some of the information required to be submitted wasn’t provided or the information provided didn’t adequately provide reasonable assurance of the safety of the dietary ingredient or dietary supplement.The primary reason for rejection of NDI notifications is the failure to provide adequate evidence supporting safety of the product or ingredient.During the 75 day period, the manufacturer or distributor of a dietary supplement containing a new dietary ingredient cannot market the product.If the submitter has not heard from the FDA after the 75 day period is tolled, they are free to market the dietary supplement containing the new dietary ingredient as the FDA will not notify a submitter if it does not object to the new dietary ingredient.Nevertheless, it is sometimes preferable to contact the FDA to verify that no objections exist.Lastly, any information that needs to be kept confidential should be marked as such in the notification as the FDA will publish the NDI notification 90 days after the filing date.
For more information, please contact Rakesh Amin at 312-466-1033 or [email protected].