While this Draft Guidance for Industry on NDIs has been long-awaited by those in the supplement industry and does provide some good insights into the FDA's thought process, it is important to remember, fundamentally, that the guidance does not represent any change in the law or regulations [emphasis added] governing new dietary ingredients. This guidance was prepared by the FDA to hopefully clarify the FDA's position with respect to many questions regarding the topic of NDIs (e-mail, July 5, 2011).

In my judgment, the combination of (A) the FDA's increased exercise of its enforcement authority, (B) its very narrow interpretation of Section 201 (ff)(1)(E) [of the Food, Drug and Cosmetics Act], and (C) this new Guidance, will clearly have a major stifling effect on the introduction of innovative products and on the creative talent of this industry” [emphasis added] (J Prochnow, e-mail to M. Blumenthal, July 5, 2011). (More commentary from Jim Prochnow is stated below in Sidebar 2.)

1. Many common manufacturing changes to existing NDIs or ODIs trigger a new NDI status.

2. Changing solvents will usually trigger NDI status.

3. When can existing GRAS [Generally Recognized As Safe] affirmation status create an NDI status?

4. Synthetic dietary ingredients are not dietary supplements at all. They have been kicked out of the DS category.

5. Changing agricultural or fermentation conditions may trigger NDI status.

6. The manufacturer or marketer must describe how the combination of all the ingredients in a DS formula relates to the history of safe use of the DS.

7. The bioavailability of the ingredients must be addressed as formulated.

8. Manufacturers must be able to explain how potential adulterants, e.g., non-food solvents, pesticides, heavy metals, and filth are excluded.

9. A manufacturer who provides an expiration date on its label should submit appropriate supporting stability data to FDA.

10. If fermentation is a part of the manufacturing process, the manufacturer must be prepared to explain precisely and in detail the fermentation process.

11. Many marketing companies will now need to file NDIs for their finished products—something they have never had to do before.

12. What documentation will be needed to definitively determine that an ODI is, in fact, old (i.e., marketed in the United States as a dietary supplement before October 15, 1994)?

13. Every dietary ingredient and dietary supplement manufacturer and marketer must now "audit" their ingredient portfolio to determine NDI/ODI status and activate an NDI compliance program.

I find the draft guidance document as potentially devastating if FDA actually decides to act on it and start enforcement actions based on it. I would estimate that at least 65% of the if not more of the herbal supplements being marketed today have ingredients that could be considered NDIs and, thus, adulterated as a matter of law rather than these products actually present any kind of safety risk. It is a very difficult situation for the industry. Moreover, FDA's position that it can actually reject a notification is without a legal basis. DSHEA simply states that a manufacturer must notify FDA prior to marketing the ingredient with its basis for establishing its safety; it does not state FDA has the right to reject the submission. Indeed, any other reading would make this provision a pre-approval provision not a notification provision. Unlike GRAS notifications, which was the creation of FDA, the notification provision for new dietary ingredients is not. Thus, FDA cannot redefine the rules as it has in this instance. (T. Harrison, e-mail to M. Blumenthal, July 5-6, 2011)

1.    The AHPA NDI Database—a searchable online database of the over 575 NDI notifications that have been submitted to FDA to date. It is the only up-to-date compilation of NDI notifications available. This subscriber-based database provides access to the actual filed documents and also gives a concise "outcome statement" for each NDI file that quickly summarizes how FDA has responded to every notification, and the problems—if any—that the agency identified for each. (More information and subscription information is available here.)

2.    Guidance for New Dietary Ingredient Notifications for Manufacturers and Distributors of New Dietary Ingredients, which was recently updated in June of 2011). It explains the NDI regulations, details what information to include—and exclude—in a notification, and provides 3 hands-on worksheets. This will be revised again to include any new and relevant information from the FDA guidance. (More information is available here.)

As FDA has reminded us, this draft guidance document describes the agency’s interpretation of the requirements for NDIs—it is not a new regulation and does not create new rights or responsibilities for the industry. Nevertheless, this draft guidance does represent an important step for the dietary supplement industry—and for the Agency—as it demonstrates further implementation of the requirements of the Dietary Supplement Health and Education Act (DSHEA) and will give companies clearer understanding of FDA’s expectations under the law….This guidance has potential for  short- and long-term implications for our industry and for our consumers’ ability to have access to in-demand products and we want to be sure the guidance is appropriate, reasonable and practical for industry and the more than 150 million consumers who use dietary supplements year after year (CRN, e-mail, July 1, 2011).

We believe the draft guidance does not match Congress’s clear intent that products made from ingredients on the market prior to DSHEA should remain on the market. The FDA is asking for far more from the industry to prove that an ingredient was on the market before 1994 than most makers can probably produce. That was not the intent of DSHEA. These requirements will reduce ingredients meeting the established grandfathered status to a regrettably small number.

[1] In our judgment, one effect of this Guidance will be to stifle, not eliminate, the development of new food ingredients and food products. The 14 pages that the FDA uses to describe the requirements for a NDI notification clearly sends a message to the industry that you must be a company with a large amount of cash in order to hire consultants, lawyers and an array of scientists in order to consider, seriously, developing a NDI or using a NDI in a dietary supplement product.  In my judgment, the combination of (A) the FDA's increased exercise of its enforcement authority, (B) its very narrow interpretation of Section 201 (ff) (1) (E) , and (C) this new Guidance, will clearly have a major stifling effect on the introduction of innovative products and on the creative talent of this industry.

[2] In our judgment, the Guidance is woefully lacking in its discussion of what constitutes a "dietary ingredient" in the context of the definition of "dietary supplement." The FDA informs the readers that this Guidance is only in the context of the NDI statute (see page 5, the fourth unnumbered paragraph of Part III of the Guidance) and that the FDA assumes the ingredient to be a "dietary ingredient" for the purposes of its discussion. We encourage the FDA to set out its position on the various substances that can be dietary ingredients.

The only place where the definition of "dietary ingredient" is directly addressed is in the FDA's answers to its Questions IV. D. 1-4.  There, the Guidance states that a synthetic version or edition of a botanical or of a substance derived from a botanical does not qualify as a "dietary ingredient," although no explanation is given for that position in this Guidance.  Significantly, the Guidance does not preclude the use of synthetic vitamins, minerals or amino acids.  The Guidance is silent on that issue.  In our opinion, that silence is important; in our opinion, if the FDA’s position is that all synthetic ingredients are precluded from use as dietary ingredients in dietary supplements, it would have declared that position.  In our opinion, the FDA’s current regulatory position can be summarized by the phrase “It is what it is.”  This means, that if a substance is a vitamin, for example, it is a dietary ingredient whether synthetic or whether derived from an orange.  Using that same logic, a synthetic could never be a mirror image of a botanical.  We encourage the FDA to discuss its position and confirm that “synthetics” position in the final edition of this Guidance document.

The FDA should discuss in the final Guidance the use of a synthetic substance that is not included in 201(ff)(1)(A, (B), (C), or (D). These special types of substances are new or novel substances created in laboratories and intended for use in food.

There is no reason why the FDA should not have seized the opportunity to explain the basis or rationale for its position, as expressed only in concluding fashion in several Warning Letters, that synthetic substances, which are not synthetic vitamins, minerals or amino acids, are not covered by the broad language of Clause (E), "...a dietary substance for use by man to supplement the diet by increasing the total dietary intake."  To date, the FDA’s position appears to be that Clause (E) applies only to substances (such as probiotics) that have been commonly used by man for food or drink.

Significantly, what the FDA did do in this Guidance document is to define "dietary substance" on page 24 of the Guidance, as "A substance commonly used as human food or drink."  Of course, "commonly used as human food or drink" does not appear in DSHEA. By the inclusion of this definition without discussion, it is not unreasonable to conclude that the FDA is unilaterally attempting to informally amend the FFDCA and DSHEA to conform to its position as the scope of Clause (E), without the specter of a robust industry discussion about the scope of that statutory provision.  

On July 1, 2011, the US Food and Drug Administration (“FDA”) published its long- awaited Draft Guidance on New Dietary Ingredient (“NDI”) notifications (“Draft Guidance”). The Draft Guidance can be found on FDA’s website at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm257563.htm. The notice of availability of the Draft Guidance was published in the Federal Register on July 5, 2011. While comments on the guidance may be submitted to the agency at any time, to ensure consideration by the agency, comments should be submitted by October 3, 2011.

The positions articulated by FDA in the Draft Guidance can be expected to have a significant impact on all those who manufacture or distribute dietary supplement products. The Draft Guidance must be evaluated very carefully to determine the effects it may have on your company. Even those companies that previously submitted NDI notifications that were filed without comment should evaluate whether the use of the NDI is consistent with the four corners of the notification, including the dietary supplement formulation as stated in the original submission.

Please note that the Draft Guidance is a fairly long document, and we did not rehash every issue in this client alert. Rather, the purpose of this client alert is to point out nuances that may have an impact on your company. However, we are happy to discuss with you other issues that are not explicitly discussed below.

    A.    Background

By way of background, the federal Food, Drug, and Cosmetic Act (“FDCA”) defines a “new dietary ingredient” as a dietary ingredient that was not marketed in the U.S. prior to October 15, 1994.1    The statute defines a “dietary ingredient” as a vitamin; mineral; herb or other botanical; amino acid; 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 of the above.2

Importantly, the FDCA requires manufacturers or distributors of an NDI or dietary supplement that contains an NDI to submit a premarket notification to FDA at least 75 days before introducing the supplement into interstate commerce, unless the NDI and any other dietary ingredients in the 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.”3

When an NDI notification is required, it must include a history of use or other evidence of safety for the ingredient. Based on that information, FDA determines whether it will file the notification with no questions asked, respond to the submitter with questions, or refuse to file the notification at all. However, until now, FDA has provided little guidance as to (1) what it considers “present in the food supply” to mean or (2) what type and quantity of evidence is sufficient to demonstrate safety such that the agency will permit the notification to be filed.

    B. Important Takeaways from the Draft Guidance

    The Draft Guidance contains the following important information:

•    Definition of “Marketing.” The Draft Guidance provides a definition of what the agency considers “marketing” for the purposes of establishing that a dietary ingredient was marketed in the U.S. prior to October 15, 1994 (i.e., is a “grandfathered dietary ingredient”). In particular, the agency defines “marketing” as “selling or offering the dietary ingredient for sale (1) as a dietary supplement, (2) in bulk as a dietary ingredient for use in dietary supplements, or (3) as an ingredient in a blend or formulation of dietary ingredients for use in dietary supplements.” The agency clarified that a dietary ingredient may be “marketed” by physically offering the article for sale at retail store, offering it for sale in a catalog or price list, or through advertising or other promotion, if the promotion makes it clear it is available for purchase. “Coming soon” advertisements do not qualify as marketing.

•    Evidence of Marketing. The Draft Guidance also clarifies what type of documentation the agency would expect in order to demonstrate that a dietary ingredient was marketed in the U.S. prior to October 15, 1994 (i.e., was a grandfathered dietary ingredient). Specifically, the agency indicates that it expects “written business records, promotional materials, or press reports with a contemporaneous date prior to October 15, 1994.” The agency lists the following as examples of adequate evidence of marketing: sales records, manufacturing records, commercial invoices, magazine advertisements, mail order catalogues, or sales brochures. Consistent with the agency’s response to the pyridoxamine citizen petition in 2009,4 the Draft Guidance states that affidavits that are
unsupported by contemporaneously-created written records are not adequate to show that an ingredient was marketed prior to October 15, 1994.

o    Industry Lists of “Grandfathered” Dietary Ingredients. Consistent with the agency’s previously-articulated position, the fact that an ingredient appears on one of the industry-complied lists of dietary ingredients that were marketed prior to October 15, 1994 (i.e., lists of “grandfathered” dietary ingredients) is insufficient evidence that an ingredient is not an NDI.

•    Changes in Manufacturing Processes. In the Draft Guidance, the agency states that even for a dietary ingredient that was marketed prior to October 15, 1994, if changes in the manufacturing process since that time have altered the chemical composition or structure of the ingredient, an NDI notification is likely required. The agency gives the following examples of changes to manufacturing processes that would necessitate an NDI notification: (1) an extract of a grandfathered dietary ingredient that is prepared using a solvent (because the final extract contains only a fractionated subset of the constituent substances in the original grandfathered dietary ingredient), (2) using a different part of the plant, or (3) a change producing nano-sized particles5.

•    Use in Food. An NDI notification need not be submitted for NDIs that have been present in the food supply as articles used for food, in a form in which the foods have not been chemically altered.

4. High-temperature baking or cooking of a previously uncooked ingredient;
                    5. Changing the manufacturing method such that the
                    chemical composition is significantly different (see above);
                    7. Fermentation using a different fermentation medium from
                    the one used to make conventional foods in the food supply;
                    or    
                    8. Use of a botanical ingredient that is at a different life
                    stage than previously used, such as making an extract from
                    unripe rather than ripe apples.

•    NDI Submission is Supplement-Specific, Not Ingredient Specific. Each NDI notification must contain information about the dietary supplement in which the new dietary ingredient will be used, including dosage and recommended uses, as well as other ingredients that will be included in the supplement. Because FDA relies on this supplement-specific information in making its determination about ingredient safety, the agency views each NDI submission as supplement-specific, rather than ingredient- specific. This is extremely important because the agency will require a new NDI notification for each specific formulation for which you use the NDI unless you meet all of the following requirements:

(1)    The daily intake level recommended or suggested in the labeling of the
new supplement will be equal to or less than that specified in your prior NDI notification;
(2)    The new supplement does not have other dietary ingredients that were not
 included in or original NDI notification;
(3)    The target populations are the same or a subset of the target populations
specified in your original notification;
(4)    All other conditions of use are the same as or more restrictive than the
 conditions of use described in your prior NDI notification; and
(5)    FDA did not express safety or other concerns in response to your prior
NDI notification.

O Evaluation of Dietary Ingredients Other Than the NDI. Because the agency will be evaluating the safety of the dietary supplement as a whole, FDA will require that the notification include the No-Observed-Adverse-Effect Level (“NOAEL”) and Acceptable Daily Intake (“ADI”) for each dietary ingredient, describe the toxicity data or adverse events that were the basis for determining the NOAEL, state the basis for the margin of safety for each ingredient, and discuss whether there is any possible synergy or interaction among any or all ingredients that could affect the safety of the dietary supplement. The notification must concisely evaluate known safety concerns and describe how the notifier concluded that the combination of ingredients can reasonably be expected to be safe.

o Evaluation of Non-Dietary Ingredients. Because the agency will be evaluating the safety of the dietary supplement as a whole, FDA will require that the notification include a description of the function of each ingredient that is not a dietary ingredient (i.e., each food additive, color additive, and substance that is Generally Recognized As Safe (“GRAS”)), including the technical effect and the quantity needed to achieve that technical effect. FDA also recommends inclusion of references to the applicable food additive, color additive, or GRAS determination.

•    Synthetic and Semi-Synthetic Versions of Extracts or Herbs are Not Dietary Ingredients. The Draft Guidance states that synthetic or semi-synthetic versions of substances that are found in botanicals do not qualify as a “botanical” (or extract or constituent thereof) within the definition of a dietary ingredient found in 21 U.S.C. § 321(ff)(1). According to FDA, for example, use of a large amount of a strong oxidizing acid like sulfuric acid to process a botanical mixture may create a new “semi-synthetic” mixture that is no longer a mixture of components that were present in the original plant, and the mixture is no longer a dietary ingredient. This position is consistent with the agency’s recent response to a citizen petition from OVOS Natural Health, Inc. requesting permission to use homotaurine as a dietary ingredient in dietary supplements.6    In that response, FDA indicated that, although homotaurine occurs naturally in some plants, OVOS’s homotaurine was not a botanical (or extract thereof) because it was made synthetically (i.e., it was not extracted from any botanical).

•    Definition of “Amino Acid.” The Draft Guidance defines an amino acid as “an alpha- amino carboxylic acid used as a constituent of proteins or peptides.” This is important for what it does not include. Importantly, based on this definition, if a substance is neither an alpha-amino carboxylic acid nor a constituent of proteins or peptides, then it is not an amino acid within the definition of a dietary ingredient and cannot be included in a dietary supplement unless it falls under one of the other categories of substances that qualify as dietary ingredients under 21 U.S.C. 321(ff)(1). This narrow interpretation of the definition of an “amino acid” likely excludes GABA (gamma- amino butyric acid), an ingredient that many dietary supplement companies use in their products. This position is also consistent with the FDA’s recent decision on the OVOS citizen petition.7

•    Probiotics. The Draft Guidance states that while certain microbial ingredients may be new dietary ingredients subject to the NDI notification requirement, others may not be dietary ingredients at all. Specifically, the agency is unlikely to view microorganisms that have never been consumed as food as dietary ingredients. This is because probiotics are generally not vitamins; minerals; herbs or other botanicals; amino acids;

6 FDA/CFSAN Response to OVOS Natural Health, Inc.- Petition Denial, Docket ID: FDA-2009-P-0298 (Feb. 23, 2011).
7 Id.

or concentrates, metabolites, constituents, extracts, or combinations thereof. Thus, the only way that a probiotic can meet the definition of a dietary ingredient is if it is a dietary substance for use by man to supplement the diet by increasing the total dietary intake.    
FDA has interpreted that to mean that the ingredient was an intentional constituent of food. Thus, bacteria that are used to produce fermented foods and are eaten without cooking or pasteurization may meet the definition of a dietary ingredient. However, others may not be dietary ingredients. The Draft Guidance also provides information on the content of notifications for ingredients produced using fermentation.

        o    Pathogens. FDA indicated that it does not view pathogenic species of bacteria as dietary ingredients--even though they may have been present in food as contaminants. In addition, the NDI notification for any microbial NDI should identify any human pathogens that are phylogenetically related to the microbial NDI at the species or genus level and should identify any toxins known to be present in the same species or in a phylogenetically related family or genus. The NDI notification should also document the absence (or the amount, if present) of such toxins in the NDI.

    o    Antimicrobial Resistance. The agency has indicated that if a microbial NDI is resistant to any clinically-relevant antibiotics, the NDI notification should also include an assessment of the ability of the antibiotic resistance genes to mobilize and transfer to human pathogens under the conditions of use of the dietary supplement.

        o    Pigs as Animal Model for Digestive Tract. If history of use data are inadequate to support the safety of a microbial NDI, studies in humans or animal models should be included. FDA states that it considers pigs to be the most appropriate animal model for the human digestive tract.

•    Ester Ingredients. The Draft Guidance indicates that the safety of an ester ingredient in an NDI notification can be inferred if you can provide data to demonstrate that the ingredient is rapidly hydrolyzed in the stomach or intestine into an acid and an alcohol, and that the acid and alcohol each have a long history of safe use in food.

•    Comprehensive Safety Profile and Safety Narrative. The Draft Guidance describes two new sections that should be included in every NDI notification: the Comprehensive Safety Profile and the Safety Narrative. The Comprehensive Safety Profile should provide objective summaries of all available human and animal toxicological information and should substantiate the safe use of the NDI in humans under the proposed conditions of use described in the notification. The Safety Narrative should include a concise summary of the scientific basis for your conclusion that the dietary supplement containing the NDI will reasonably be expected to be safe when used under the conditions recommended or suggested in the supplement’s labeling. It should explain how the various pieces of data and information fit together to form the basis for

your conclusions about the safety of the dietary supplement. The Draft Guidance provides detailed information as to what the agency expects in these two sections.

•    Thorough Description of Types of Evidence The Agency Will Likely Require. The Draft Guidance provides a thorough description of the types of evidence that the agency will likely expect depending on the intended frequency and duration of use of the supplement, the intended intake levels, and whether the NDI has a documented history of safe use. Table 2 sets out the information in chart form.

o Twenty-Five-Year Minimum for History of Safe Use. The agency specified that it considers 25 years of widespread use to be the minimum required to establish a history of safe use (without additional safety data).

o One-Year Or Two-Year Studies Likely Required If No History of Safe Use. If there is no history of safe use for an NDI, and if the proposed use is either intermittent or daily chronic, among many other requirements, the agency has indicated that it expects either a one-year chronic toxicity study or a two-year carcinogenesis study in at least two animal species.

o Human Studies May Be Required. The Draft Guidance acknowledges that human studies are not explicitly required by statute, but at the same time states that there may be circumstances in which it is required to conclude that an ingredient is reasonably expected to be safe under the proposed conditions of use.

o Highest Dose To Be Used in Animal and Human Safety Studies. Highest dose in animal studies should be the maximum tolerated dose (“MTD”), which is the dose that causes no more than a 10% reduction in body weight and does not produce mortality, clinical signs of toxicity, or pathologic lesions. Typically this is determined by a 14-day range-finding oral study in an appropriate animal model. The highest dose in human studies should be governed by safety considerations, but should be as high as feasible and at least as high as the total daily intake level of the NDI under conditions of use proposed in the notification—preferably higher. The Draft Guidance references several sources of testing protocols.

•    Flow Chart for Determining When to Submit an NDI Notification. The agency has provided a flow chart for companies to use in determining whether to submit an NDI notification. The flow chart can be found at Appendix A to the Draft Guidance.

•    New NDI Notification Form. The agency has provided a new NDI notification form that may be used but is not mandatory. The form can be found at Appendix B to the Draft Guidance.


C.    Next Steps
We urge all companies that manufacture or private label distribute dietary supplement products to engage in a thorough evaluation of each of their products to (1) confirm that all ingredients in the product qualify as dietary ingredients and (2) determine whether an NDI notification is necessary for that product. Even those companies that previously submitted NDI notifications that were filed without comment should evaluate whether the use of the NDI is consistent with the four corners of the notification, including the dietary supplement formulation as stated in the original submission.