Client Alert. FDA Draft Guidance Broadens New Dietary Ingredient Definition and Extends Notification Requirements 1

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1 Contact Attorney Regarding This Matter: Emalee G. Murphy direct fax emalee.murphy@agg.com Attorneys at Law th Street NW Suite 2100 Atlanta, GA Pennsylvania Avenue NW Suite 250 Washington DC Client Alert FDA Draft Guidance Broadens New Dietary Ingredient Definition and Extends Notification Requirements 1 The Food and Drug Administration (FDA) has recently published a draft guidance on New Dietary Ingredient Notifications and Related Issues (announced in the July 17, 2011, Federal Register and available for review by clicking here. 2 The FDA has extended the comment period to December 2, This guidance, reflecting the FDA s current views, illustrates how difficult it is to obtain the agency s agreement about the appropriateness and safety of new ingredients in dietary supplements and may affect the classification of supplement ingredients currently on the market. As background, the Dietary Supplement Health and Education Act (DSHEA), which amended the Federal Food, Drug and Cosmetic Act (FDC Act), defined a new dietary ingredient (NDI) as one not marketed in the United States before October 15, The DSHEA also provided that new dietary ingredients in food supplements must be notified to the FDA at least 75 days before they are offered or marketed in the U.S., 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. 4 The chief purpose of the notification is to provide the FDA with the basis for the marketer s belief that the NDI will be reasonably expected to be safe under the proposed conditions of use. Either the NDI manufacturer or distributor or the manufacturer or distributor of the dietary supplement that contains the NDI may submit the required notification. If the FDA is not notified at least 75 days before the NDI is offered or introduced into interstate commerce, the FDA considers both the NDI and the products in which it is used to be unlawfully on the market. 5 1 The information in this AGG Client Alert originally appeared in Ms. Murphy s Report from Washington for Explore magazine U.S.C. 350b(c) DEFINITION For purposes of this section, the term new dietary ingredient means a dietary ingredient that was not marketed in the United States before October 15, 1994, and does not include any dietary ingredient that was marketed in the United States before October 15, U.S.C. 350b(a)(1) 5 Adulteration standards at 21 U.S.C. 342(f )(1)(B) (section 402f(1)(B) of the FD&C Act state that A food shall be deemed to be adulterated if it is a dietary supplement or contains a dietary ingredient that is a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury (emphasis added). Page 1

2 The FDA regulations at 21 CFR implement the NDI provisions of the DSHEA but lack detail, requiring only that an NDI notification include the following: 1. an authorized submitter signature and proper nomenclature for the new ingredient; 2. the level of the NDI in the dietary supplement; 3. the conditions of use recommended or suggested in the labeling of the dietary supplement, or, if no such conditions of use appear in the supplement s labeling, then the ordinary conditions of use of the supplement; and 4. the history of use or other evidence of safety establishing that the dietary ingredient, when used under the conditions recommended in the labeling of the dietary supplement, will reasonably be expected to be safe. In the draft guidance, the FDA explains its current thinking 6 about the following questions: 1. What is an NDI? 2. When are some NDIs exempt from notification requirements? 3. What kinds of safety and other information does the FDA expect in a premarket notification for an NDI? What is an NDI? The Limits of Grandfathered Status Definition of Marketed Under the DSHEA, dietary ingredients in supplements are grandfathered under the Act and are not NDIs if they were marketed in the U.S. before the October 15, 1995, deadline. The FDA s draft guidance states that a dietary ingredient was marketed if it was sold or offered for sale in the U.S. (sale outside the U.S. does not count) at a retail store, in a catalogue or price list or by any other means that indicated the article was available for purchase as a dietary supplement. The product must have been marketed for dietary supplement use. Marketing can mean that the ingredient was sold for use in dietary supplements or that it was used in a marketed dietary supplement, either as the sole ingredient or with other dietary ingredients. As evidence of dietary ingredient marketing, the agency requests written business records, promotional materials, press reports, all dated before October 15, 1994, including sales or manufacturing records, commercial invoices, advertisements, catalogues, and sales brochures. The FDA has stated that affidavits alone are not enough to prove pre-october 15, 1994, marketing. Further, the FDA confirmed its earlier position that presence on an industry-created list of pre-1994 dietary ingredients (such as the Herbs of Commerce list assembled by the American Herbal Products Association) is not enough evidence to support a 6 The FDA stated in the scope of the guidance that there are an estimated 55,600 dietary supplement products on the U.S. market, and the FDA has received approximately 700 NDI notifications since it began reviewing NDI notifications approximately 16 years ago. The Institute of Medicine has estimated that 1,000 new dietary supplements are introduced to the market each year. The FDA further stated that these figures, coupled with recent concern about undeclared active ingredients in products marketed as dietary supplements, highlight the necessity for marketers of dietary supplements to submit NDI notifications as an important preventive control to ensure that the consumer is not exposed to potential unnecessary public health risks in the form of new ingredients with unknown safety profiles. Page 2

3 grandfathered status. In addition, evidence that the ingredient was used solely as conventional food, as a drug, or for other non-food use prior to the grandfathered date is insufficient proof that the product was marketed as a dietary ingredient. Definition of Dietary Ingredient The new dietary ingredient must first be a dietary ingredient for use in a dietary supplement. The FDC Act dietary ingredients as vitamins, minerals, traditional herbs or botanicals, amino acids or dietary ingredients taken by humans to increase their intake in a person s diet. Also, concentrates, metabolites, constituents, extracts and combinations of these substances are included in the statutory definition of dietary ingredient. 7 However, not all ingredients in dietary supplements are dietary ingredients. Some ingredients may be present for technical purposes only, such as various vehicles, preservatives, or capsule components. Other non-dietary ingredient substances in supplements may be approved food additives or ingredients generally recognized as safe (GRAS) for food use. Substances that were present in the pre-dshea dietary supplement as food additives rather than as dietary ingredients, but that nevertheless fit within one of the dietary ingredient categories listed above, are dietary ingredients, but they are not grandfathered and are therefore NDIs. Substances that were present in pre- DSHEA dietary supplements as food additives and that do not fall within one of the categories of dietary ingredients listed above, are not dietary ingredients at all. The FDA has also identified other ingredients that do not fit the dietary ingredient definition. These include the following: Contaminants Although contaminants may be present in food or dietary ingredients, are not themselves dietary ingredients. Synthetic versions of dietary ingredients The FDA states that a synthetic copy of a constituent of a botanical was never part of the botanical and thus cannot be a constituent of the botanical that qualifies as a dietary ingredient. Similarly, a synthetic version of a botanical extract is not an extract of a botanical because it was not actually extracted from the botanical. Bacterial substances that are not intentionally added to food A bacterial microorganism is only a dietary ingredient if it is an intentional constituent of food or otherwise falls within one of the statutory dietary ingredient categories. The FDA states that bacteria used to produce fermented foods that are eaten without a cooking or pasteurization step (e.g., lactic acid bacteria used to produce cheese or yogurt) could be dietary substances for use by man to supplement the diet by increasing the total dietary intake. This definition, however, may not include many probiotics products. 7 Dietary supplements are defined by the FDC Act at section 201(ff) (21 U.S.C. 321(ff )). Page 3

4 Client Alert Pathogens Although pathogens may be present in the food supply, they are not dietary ingredients. Amino acids that are not an alpha-amino carboxylic acid used as a constituent of proteins or peptides This definition of amino acids may eliminate some substances currently used in dietary supplements. When is Notification NOT Required for an NDI? New Dietary Ingredients that have been present in the world s food supply as articles used for food in a form in which the food is not chemically altered, do not require notification when used in a dietary supplement. Some substances that meet the NDI definition do not need to be notified to the FDA. For example, if the NDI was legally marketed anywhere in the world as an ingredient for use in conventional food, it would qualify as an NDI. However, it would be exempt from notification if it is used in a supplement in a form in which the original food has not been chemically altered. 8 The FDA s draft guidance would also exempt other NDIs from notification as long as they have not been chemically altered since they were approved or cleared by the FDA: 1. ingredients in dietary supplements that the FDA has approved by regulation as direct food additives; and 2. GRAS substances for use in the food supply. The FDA is likely to conclude that there is adequate information to provide reasonable assurance of safety for these substances. Nevertheless, if the intake level of the NDI in the dietary supplement is higher than that resulting from conventional food use, the NDI s safety may not be assumed and the dietary supplement in which it is used at that higher level may be considered adulterated and unlawful. What does chemical alteration mean? The FDA discusses in the draft guidance the kinds of alterations that in its view do and do not result in chemical alteration of the NDI. FDA explains that minor loss of volatile components, dehydration, lyophilization, milling and formation of a tincture or a solution in water, a slurry, a powder or a solid in suspension, do not chemically alter an ingredient. Thus, for example, if leaves or roots of a plant consumed as conventional food (e.g., broccoli or carrots) are dried and ground for sale in powder form, or a tincture is made by soaking pears in aqueous ethanol and the moisture is then milled and dried into a powder placed in a capsule, NDI notification is NOT required because the vegetable or fruit has not been chemically altered. However, if the manufacturing procedure for a grandfathered dietary ingredient has changed since October 15, 1994, and the change alters the chemical structure or function of the ingredient, it may be considered new and require notification. Any of the following examples provided in the FDA s draft guidance represent the kind of chemical alteration that the FDA has stated would require notification of an otherwise grandfathered ingredient: 8 Section 413(a)(1) of the FDC Act (21 U.S.C. 350b(a)(1)) Page 4

5 A process that makes or breaks chemical bonds such as hydrolysis or esterification, unless the bonds created by the process are reversed when the ingredient is dissolved in water (e.g., creation of a soluble salt) or during ingestion. Removal of some components of a tincture or solution in water (e.g., by chromatography, distillation or membrane filtration), which changes the chemical composition of the mixture. Use of solvents other than water or aqueous ethanol (tincture) to make an extract. Water and aqueous ethanol are specifically excluded from processes that chemically alter a food in the official legislative history of the DSHEA. Other solvents alter the composition of the extract in significantly different ways, usually by extracting different types of constituents than are extracted using water and aqueous ethanol. High temperature baking or cooking of an ingredient that has not previously been baked or cooked, unless the process causes only minor loss of volatile components with no other changes to the chemical composition of the ingredient. Changing the manufacturing method for an ingredient such that the chemical composition is significantly different (e.g., changes that alter the composition of materials used to make the ingredient, use of a different solvent, use of a chromatographic matrix instead of a passive filter). Application of nanotechnology that results in new or altered chemical properties of the ingredient. Changing agricultural or fermentation conditions to alter the chemical composition of the ingredient, such as by sprouting garlic or fermenting yeast using a medium containing large amounts of sodium selenite to create large amounts of organic selenium compounds. Fermentation using a fermentation medium different from the one used to make conventional foods in the food supply (e.g., use of a defined commercial growth medium to produce a microorganism previously made by fermenting milk into dairy products like yogurt or cheese). Use of a botanical ingredient that is at a different life stage than previously used (e.g., making an extract from unripe instead of ripe apples or using the mycelium instead of the fruiting body of a fungus.) NDI Notification Applies to Supplements, Not Just to NDIs The FDA has clarified that it considers NDI submissions applicable to supplements, not just to NDIs. Each NDI submission must contain information about the specific dietary supplement in which the ingredient will be used, including the other ingredients in the formulation, the dosage, and the intended use and target population for the supplement. Thus, if a company makes a new formulation using an NDI that the FDA has acknowledged without objection, it must submit a new notification for that and every other new formulation that contains the NDI unless the company can show that all the following conditions are met for the new formulation: 1. the daily intake of the NDI does not exceed what the FDA accepted in a previous NDI notification; 2. the formula contains no new added dietary ingredients; 3. the target populations are the same for the previously accepted and the new NDI submissions; 4. all other conditions of use are the same or narrower than the previously cleared NDA submission, 5. The FDA did not express safety or other concerns in response to your prior NDI notification. Page 5

6 Client Alert Furthermore, a different manufacturer that wants to use the NDI in its own dietary supplement formulation, even if it meets all of the above criteria, must still notify its use of the NDI to the FDA because, as the agency states: The original notifier conducted its safety evaluation based on the characteristics and intended use of the specific product under review, including the composition and labeling of the dietary supplement that the notifier was proposing to market. Any other manufacturer or distributor who wishes to market its own dietary supplement containing the same NDI should submit a NDI notification to FDA explaining its own basis for concluding that this new product containing the NDI will reasonably expected to be safe under the conditions recommended or suggested in the new product s labeling. Manufacturing processes and specifications needed to establish the identity of a NDI are usually trade secrets that are not available in the NDI docket. It should be noted that the original notifier is under no obligation to share with other manufacturers and distributors any trade secrets or confidential commercial information that were part of the basis for a safety conclusion for the original notifier s product. Finally, notification from ingredient manufacturers or distributors for their NDIs does not eliminate the requirement for a notification from the manufacturer or distributor of the dietary supplement in which the NDI will actually be used unless that information is included in the ingredient manufacturer/distributor s notification. Thus, the NDI notification process has with this draft guidance become a de facto clearance procedure for all new dietary supplements, which arguably is exactly what the DSHEA was intended to avoid. Safety and Other Information Expected in an NDI Notification The FDA has included with the guidance a form that may be used to notify the FDA of a dietary supplement containing an NDI. The form is not required but it is interesting because it identifies, as does the guidance, two new sections of an NDI submission. These sections, the NDI Safety Narrative and the NDI Comprehensive Safety Profile outline the information that the FDA expects to receive in order to establish a reasonable basis for the safety of the NDI and supplement. NDI Safety Narrative The NDI Safety Narrative is an objective evaluation of the history of use and other safety information related to the ingredient. If an ingredient has not been used in food or supplements for 25 years, the FDA is likely to require other additional evidence of safety. The Safety Narrative must include an explanation of how the evidence presented provides a basis to conclude that the dietary supplement containing the new dietary ingredient, when used under the conditions described in the notification, will reasonably be expected to be safe. The safety information should include, among other items, a margin of safety calculation for NDI intake and the method of calculation should be explained and justified in the notification, even if a history of safe use is the basis of the safety evaluation. When the notification relies on a history of safe use, a margin of safety should be calculated based upon the historical levels of the NDI that were safely consumed and the NDI intake levels that would result from the conditions of use proposed in the notification. Page 6

7 Comprehensive Safety Profile The NDI submission should also include a Comprehensive Safety Profile, which is an objective summary of all available human and animal toxicological information (both published and unpublished safety studies) and any other information relevant to the safety assessment of the NDI. The information in the NDI Comprehensive Safety Profile should substantiate the safe use of the NDI in humans under the proposed conditions of use described in the notification. If the NDI notification relies on safety studies, the NDI Comprehensive Safety Profile should qualitatively and quantitatively compare the ingredients tested in each of the studies cited with the NDI. The FDA has stated that in general, if there is no history of use, two species should be used for 90-day sub-chronic studies and a one-year chronic toxicity study or two-year carcinogenesis study should be done in two species, depending upon the amount and type of historical use data and the proposed length of use for the NDI supplement. For example, if the proposed use of the NDI is for 30 days or less, then a 28-day animal study might be sufficient under certain circumstances (e.g., for an NDI that includes live microbes). The FDA has also stated that it will evaluate the safety of the dietary supplement as a whole, including an evaluation of submitted information on the No-observed Adverse Effect Level (NOAEL) and Acceptable Daily Intake for each dietary ingredient in the dietary supplement. This includes the toxicological data and adverse event reports that form the basis of the NOAEL assessment, the basis for margin of safety for each dietary ingredient in the supplement, and an evaluation of whether the synergistic effects of the dietary ingredients could affect the supplement s safety. The function and regulatory status of each non-dietary ingredient in the supplement must also be described in the submission. While the FDA has been implementing parts of its views on NDI notifications before now, the draft guidance sets a standard that may not have been contemplated in this manner by proponents of the DSHEA. It will have a significant effect upon the introduction of new dietary ingredients in dietary supplements. The extended comment period provides an immediate opportunity for communication with the FDA about the draft guidance. The FDA is taking comments on the draft guidance until December 2, serves the business needs of growing public and private companies, helping clients turn legal challenges into business opportunities. We don t just tell you if something is possible, we show you how to make it happen. Please visit our website for more information, This alert provides a general summary of recent legal developments. It is not intended to be, and should not be relied upon as, legal advice. Page 7