As the tenth anniversary of the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA) approaches in October, there appears to be confusion about some of the provisions of the Act regarding the safety of dietary supplements and ingredients. A little-reported provision of DSHEA addresses the issue of determining the safety of new dietary ingredients. Congress inserted a provision in DSHEA that is intended to ensure that new ingredients with no prior history of food use in the United States are subjected to Food and Drug Administration (FDA) review regarding their relative safety before these ingredients can be marketed in dietary supplements. —Editor
Is it better to be old or new? Most people would usually say new. But if you asked any dietary supplement manufacturer who was about to begin marketing a new dietary ingredient, the answer would probably be old. The regulations for marketing old vs. new dietary supplement ingredients under the Dietary Supplement Health and Education Act of 1994 (DSHEA) establish very distinct mandatory requirements for both, but the requirements are far less arduous for old or “grandfathered” ingredients. (Note: Some people in the herbal community express a preference for the term “grandmothered” or even the gender neutral “grandparented.”) Up to this point, many manufacturers assume their ingredients are grandfathered because of a “long history of use” and then proceed directly to market. However, an incorrect classification of a newly marketed dietary ingredient can lead to many troublesome legal issues.
Under Section 8 (New Dietary Ingredient) of DSHEA, a new dietary ingredient (NDI) means “a dietary ingredient that was not marketed in the United States before October 15, 1994.”1 In contrast, an old dietary ingredient (ODI) is a dietary ingredient that was lawfully marketed2 in the United States before October 15, 1994. For NDIs, Section 413 (a)(2) of the federal Food, Drug and Cosmetic Act (FDC Act) requires that the manufacturer or marketer notify FDA 75 days prior to the introduction of the ingredient into the market with sufficient data to provide substantiation of the ingredient’s general safety. For ODIs, a 75-day safety notification is not required. The ingredient is presumed to be safe unless evidence suggests otherwise (i.e., the ingredient is grandfathered).
In order to understand the significance of the NDI determination, there are several terms that merit definition. The definition of the term “lawfully” is certainly one for roundtable discussion.
According to informal FDA guidance,3 a “lawfully” marketed dietary supplement requires the manufacturer or distributor to have written evidence that the ingredient in question is chemically identical to a dietary ingredient that was marketed in the U.S. before October 15, 1994. However, FDA has indicated that some written evidence upon which the dietary supplement industry has historically relied may not be sufficient. FDA stated in correspondence to a manufacturer in responding to a 75-day notification that “inclusion in a published list” is not sufficient to show an ingredient is old.4 Such lists include e.g., the American Herbal Products Association’s (AHPA) Herbs of Commerce (1992),5 the “Old Dietary Ingredient List” from the Utah Natural Product Alliance, and the “CRN List of Dietary Ingredients – ‘Grandfathered’ Under DSHEA.”6 According to FDA, to meet this legal requirement a seller must be able to demonstrate that the inclusion of the ODI in the above-referenced publications is based on accurate and reliable evidence sufficient to support a finding that the ingredient is old. FDA considers independent documentation that an ingredient is old to be a product invoice, bill of lading, product label or labeling, or a catalogue with evidence of a date to show evidence of marketing before October 15, 1994.7
The significance of the requirement for lawfully marketing a dietary ingredient takes on even more meaning. In one of the initial submissions of a 75 day-notice for the ingredient stevia leaf (used as a natural sweetener, derived from Stevia rebaudiana Bertoni Asteraceae), it was argued that stevia was included in a number of marketed herbal products before October 15, 1994. However, FDA took the position that because stevia was considered to be an unlawful food additive, any marketing of the ingredient before October 15, 1994 was unlawful and therefore did not meet the old dietary ingredient qualification of DSHEA.8
Legal Significance of the “Prior Market Clause” of DSHEA
In the case of Pharmanex v. Shalala, the government succeeded in convincing the court that “market as” is not the same as “sold as.”9 It is not enough that the ingredient sold is present in food. In this case the issue concerned the presence of the naturally-occurring compound mevinolin, which, according to the government’s successful argument, is chemically and therapeutically similar to the active ingredient lovastatin found in the prescription drug Mevacor® (Merck & Co., Whitehouse Station, NJ) in red yeast rice (Monascus purpureus Went., Monascaceae). FDA argued that there must be evidence that red yeast rice was actually marketed for its lovastatin content. In other words, the food must be marketed for the presence of the ingredient in question.
Based on this decision, FDA’s position on the DSHEA “prior market clause” is that for a food constituent to have been marketed as a food or dietary supplement, the manufacturer of the food containing the constituent must have marketed or promoted the food based on the properties of the food constituent at issue or increased or optimized the concentration at issue. For example, it is not sufficient to show the marketing of malted barley if one is trying to demonstrate the prior marketing of a malted barley extract ingredient. The marketing of the source ingredient is not sufficient to prove prior marketing of an extract of the source ingredient.3
If a seller has an ingredient that does not qualify as an ODI, then it is subject to Section 413 of the FDC Act. Section 413 states that a dietary supplement containing an NDI shall be deemed adulterated under Section 402 (f) of the FDC Act unless it meets one of the following requirements:
1. A dietary ingredient contains only dietary ingredients which 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.
2. There is a 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; and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides the FDA with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.
Exemptions to Preclude Filing the 75-day NDI Notice with FDA
The next consideration must be whether the ingredient in question meets the second exemption from NDI legal status. To meet this requirement the seller must demonstrate that the ingredient is consumed in food in a form that has not been chemically altered.10 The question that remains unanswered in the dietary supplement industry is—if one extracts an ingredient from its botanical source, how much can the ingredient be concentrated before it is chemically altered? FDA has further indicated that even if the dietary ingredient extract was present in the food supply, the seller must prove that the extract ingredient was present in the food supply as an article used or marketed as a food or as an ingredient of a food. FDA states that mere incidental presence of a substance (e.g., an extract) as an inherent component of articles used for food does not establish that the substance itself is “an article used for food.”
Therefore, if a dietary ingredient is not proven to be old as discussed above, it is by law an NDI and cannot be lawfully marketed without the required 75-day pre-market notice to FDA. For that reason FDA has issued a regulation—“new dietary ingredient notification.”11 According to this regulation, the following requirements are needed for an NDI submission to FDA:
Name and address of manufacturer or distributor of the new dietary ingredient.
Name of the NDI.
Description of the NDI including a full characterization of the ingredient.
Level of NDI in dietary supplements which would include the amount included in dosage form products and expected daily consumption.
Conditions of use recommended in product labeling which includes the labeled suggested population for the ingredient (i.e., marketed to adults only or to all age groups).
History of use of other evidence of safety establishing that when used at the level of use and under the conditions of use the NDI will reasonably be expected to be safe, including citations to published articles or other evidence that is the basis for the manufacturer or distributor concluding that the new dietary ingredient is safe.
Table 1. Summary of all New Dietary Ingredient (NDI) Submissions by industry to FDA since passage of DSHEA in 1994 through June 2003
|All NDI Submissions: 1994 (Oct) - 2003 (June)*||238†||% of Total|
|Reasons for Rejection|
|Not reasonably expected to be safe||96|
|Incomplete Filing/Lacking Data||29|
|Does not meet definition of dietary supplement (ingredient is a food, drug or medical device)||12|
|Existence of IND§ before filing of NDI||2|
|Not reasonably expected to be safe for children||2|
|* FDA receipt dates vary considerably from the date that NDI submissions are posted for public viewing. Theoretically, FDA must post NDI filings in the public docket 90 days after receipt. The actual length of time averages between 10–14 months. † Determining the total number of NDIs filed with FDA requires some interpretation of the filed reports. The authors of this paper found what they determined to be 238 reports based on the data available from the FDA as of June 2003. FDA classifies NDI submissions with a Report (“RPT”) number (except the first 2 submissions). Some submissions received only one RPT number, but included multiple ingredients that were evaluated individually by FDA. The authors classified each separate evaluation as a unique submission. As of August 2004 there were 200 RPTs accessible on the FDA website (www.fda.gov). The last RPT (# 200) was received by FDA on June 30, 2003 and, based on the 90-day publication rule, was supposed to have been posted on Sept 30, 2003. FDA did not post this notice until July 8, 2004. Thus, for the purposes of this article, the “receipt” date is used even though the NDI submissions aren’t posted until 10-14 months later. In the 200 RPTs posted, treating ingredient evaluated by FDA as a unique filing, the total becomes 238. Resubmissions are also considered unique NDI submissions because they are evaluated as such by FDA. Therefore, when a new ingredient is the subject of multiple NDI filings, each is considered a new entry as part of the total. ‡ Five NDI submissions did not include a response by FDA. § IND = Investigative New Drug.|
The Acceptance/Rejection Rate of NDI Submissions
Based on NDI information obtained from the FDA website (www.fda.gov), 59% of the NDI notifications were rejected and not accepted for filing by FDA, and 38% were accepted as of June 30, 2003. The rejection rate for botanicals was higher (70%) than for non-botanical ingredients* (see Tables 1, 2, and 3). Various reasons for not accepting the 75-day NDI submissions by FDA include the following:
Exposure studies done on the source of the ingredient were not conducted on the actual ingredient.
Ingredient represented for a therapeutic indication. Therefore, the ingredient is legally a drug that requires a new drug application filing and is not a dietary supplement subject to DSHEA.
Ingredient is represented for use in the NDI submission as a conventional food and therefore does not meet the legal definition of a dietary supplement.12
Data submitted in the NDI notification was for use of the ingredient for disease conditions. FDA states that such studies have limited use for chronic long-term use in a health population.
Clinical studies submitted utilized a non-oral dosage form; therefore, those studies are not comparable for oral use of a dietary supplement.
Dietary ingredient submitted in the NDI notification met the legal definition of a biological product according to FDA; therefore, it is not a dietary supplement.
NDI notification contained historical and foreign references wherein the ingredient was studied for use in disease conditions but not for consumption and use as a food.
Studies submitted show the pharmacological effects of the ingredient but were not designed to study toxicity or safety of the ingredient for food use.
Description of the ingredient is insufficient to show specific qualitative and quantitative characteristics of the ingredient. Studies submitted describe an ingredient that is not proven to be the same ingredient subject to the 75-day notification.
Submission does not discuss safety concerns that were mentioned in the clinical studies submitted.
Reference to Chinese herbal medicine as a basis to show safety is not sufficient to show a history of use that the ingredient is safe. These references show pharmacological, clinical, or toxicological information on the source ingredient but there are no studies on the ingredient per se or on the exact dose exposure submitted in the 75-day NDI notice.
* Note: Although the rejection rate is higher for botanicals than other ingredients, many NDI submissions were rejected on the grounds that they were procedurally incomplete. The complexity of botanical filings for manufacturers appears to be caused by multiple language documents, larger amount of historical data, confusion about proper Latin nomenclature, and type of safety data required by FDA. Given the lack of guidance from FDA on the NDI submission procedure, many ingredients were therefore rejected simply on the grounds that they failed to include certain components within the submissions.
FDA believes there will be minimal burden on the dietary supplement industry to generate data to meet the requirements of the pre-market notification program. FDA makes this assumption because they believe they are only requesting information that the manufacturer or distributor should have already compiled and have on file to qualify safety for a product. These data are required to support that the ingredient or product marketed is “reasonably expected to be safe under the conditions of use recommended or suggested in the labeling of the dietary supplement.”13 FDA believes the industry burden is approximately 20 hours of work per submission. Many individuals, including the authors of this article, believe that this estimate by FDA is unrealistic.
FDA also states that each NDI submission is applicable and specific to the submitter. Other companies intending to market the same ingredient would have to submit their own NDI submission. In other words, there are no generic submissions that will benefit all other companies using the same ingredient.14
Table 2. Summary of NDI submissions containing botanical ingredient
|Botanical NDI Submissions: 1994 (Oct) - 2003 (June)||113*||% of Total|
|Reasons for Rejection|
|* A complete listing of all 113 botanical NDI submissions and their status is available online at www.herbalgram.org|
Table 3. Summary of all NDI submissions (botanical and non-botanical) after FDA published the pre-market notification for NDI submission in September of 1997. Until this date, FDA had not established criteria in which to evaluate NDI submissions
|NDI Submissions: 1997 (Sept) - 2003 (June)||213||% of Total|
|* Five NDI submissions did not include a response by FDA.|
Among those who are aware of the legal requirements under DSHEA for filing an NDI notification, some companies choose to ignore this component of DSHEA either on the basis that there is no FDA enforcement or, if questioned, they are confident that they could justify their position that the ingredient is “grandfathered.” In the authors’ opinion, this gamble exposes a manufacturer to other legal problems. The first is the potential product liability issue. If a manufacturer is selling a product that is subject to a product liability lawsuit, it is possible that the lawyer for the plaintiff will hire an expert (i.e., an attorney who specializes in FDA matters) to review the products for compliance with DSHEA. If the expert can take the position the product contained an NDI legally subject to the 75-day NDI requirement, which was not submitted and accepted by FDA, the expert can argue to a jury that the product was adulterated as a matter of law. This testimony would be very persuasive in a product liability lawsuit.
Another liability involves the definition of a dietary supplement. DSHEA amended the FDC Act in providing a legal definition of a dietary supplement. This definition, as a matter of law, excludes a dietary ingredient approved as a new drug under Section 505 of the FDC Act or an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval or authorization, marketed as a dietary supplement or as a food.15 This definition is predicated on the ingredient’s being lawfully marketed according to FDA. Thus, according to this definition, if a marketed dietary ingredient is not proven to be old, and a pharmaceutical or other company receives approval for an investigational new drug (IND, not to be confused with NDI) for which the clinical studies were later published before the 75-day NDI notice was submitted, then the dietary ingredient is disqualified as a dietary supplement under DSHEA and further marketing is unlawful.
This is not a theoretical discussion. In the case of U.S. v. Synthrax Innovations, Inc. the government discovered an investigational new drug application had been in effect for tiratricol since 1990 (tiratricol, the dietary supplement involved in this case, was an over-the-counter thyroid preparation marketed as a metabolic accelerator and fat loss aid).16 The court held that this IND precluded tiratricol from being a dietary supplement as a matter of law. The court found the facts demonstrated substantial clinical investigations had been instituted for tiratricol, the existence of such investigations had been made public, and tiratricol was not marketed as a dietary supplement or a food prior to the authorization of the IND. For those reasons the defendants in the case conceded that their product could not be considered a dietary supplement. Additionally, FDA asserts the legal position that it is not relevant in this determination whether the IND is currently in force, just that it was filed and accepted by FDA at one time. That is, the IND may be abandoned with no additional intention by the pharmaceutical company to pursue drug status for the substance; yet because the IND was filed prior to a dietary supplement company’s attempt to obtain NDI status for the ingredient, dietary supplement status would not be allowed.
In comparing the safety requirements for foods to dietary supplements it is clear there are different legal standards. For foods, an added ingredient must be generally recognized as safe (GRAS) by qualified experts. If not, the ingredient must be approved by FDA as a food additive before it can be allowed on the market. In contrast for dietary supplements, a company must have a basis for concluding that a supplement containing a “new dietary ingredient” is reasonably expected to be safe under the condition of use recommended or suggested in the product labeling. The new ingredient is legally exempted from the requirement to be approved as a food additive (one of the basic premises of DSHEA is that dietary supplements are not food additives).17 Additionally, the company must notify FDA regarding the basis for concluding an NDI is safe for its intended use at least 75 days before marketing.
If a company is successful in obtaining an NDI for its product, there is no “seal of approval” from FDA that can be included on the product label. If accepted, the agency takes the position that because all research on the ingredient has not been reviewed, FDA will make no statement regarding the ingredient’s safety. The commonly misused statement “approved by the FDA” or other similar statements are unacceptable based on this position. In contrast, a food additive, once approved, is safe as a matter of law. A “successful” NDI submission establishes FDC Act compliance but no FDA affirmation that the ingredient is safe for its intended use.
Another notable difference in the legal requirements between a food additive petition and an NDI submission is in the scientific validation needed for the new food additive ingredient. A new food additive petition must include full reports of investigations made with respect to safety of the food additive, and those reports must include detailed data from animal and other toxicology tests. In contrast, an NDI submission must include a history of use of other evidence of safety that the ingredient will be reasonably expected to be safe, including citations to published articles. While seemingly less stringent for an NDI, it is in this area that FDA apparently is expecting more studies and clinical information to show a reasonable basis for safety of a dietary ingredient. This is not found in any published FDA guidance but is discernable from the comments made by FDA for NDI submissions in which “no reasonable basis of safety” was cited as the reason for rejection. It is an FDA bias that results from the agency’s understanding of acceptable science for other food ingredients found to be GRAS or subject to a food additive regulation.
FDA regulations for marketing new dietary ingredients have been present since the inception of DSHEA; however, they have not been actively enforced. Some companies have used FDA’s tepid enforcement policy as a rationale to rush new ingredients to market without sufficiently qualifying the ingredient with a complete safety profile or determining its proper legal status. Many responsible members of the herb and dietary supplement industry are slowly integrating a more thorough investigative scientific approach for new dietary ingredients, but the first-to-market mentality runs counter to this practice. Requiring new ingredient suppliers, rather than marketers, to establish whether the ingredient is “old” or “new” under FDA requirements would be a step in the right direction. This could possibly limit the entry of “unsubstantiated” ingredients into the market by forcing suppliers to qualify the legal status of their ingredients; in other words, require those with the best understanding of the science of an ingredient to qualify its safety. This would remove a time-consuming task for those attempting to rush a new product to market. Whatever the solution may be, it is advisable that all manufacturers and marketers of dietary supplements thoroughly understand the legal requirements for marketing new dietary ingredients before making a significant investment in a new product.
Chris Noonan is President of HealthGuidance, a consulting firm located in Santa Monica, CA, that specializes in new product development, marketing, and copywriting for the natural products industry. Chris can be reached at firstname.lastname@example.org. W. Patrick Noonan is an attorney who specializes in matters concerning products regulated by the FDA with an office in Woodland Hills, CA, and he has a website at www.wpnpc.com. Patrick can be reached at email@example.com.
1. See Section 413(a) & (c) of the Food, Drug, and Cosmetic Act (FDC Act).
2. The FDA requires that an old dietary ingredient be lawfully marketed. Warning letter from FDA Director Joseph R. Baca, Office of Compliance, Center for Food Safety and Applied Nutrition, directed to TwinLab, dated March 11, 2004 regarding the labeling and promotion of androstenedione as an ingredient.
3. Letter from Felicia B. Satchell, Office of Nutritional Products, Labeling and Dietary Supplements to Holly M. Bayne, Hyman, Phelps & McNamara, P.C., regarding new dietary ingredient notification for Glucose Metabolism Modulator, July 15, 2001.
4. See 68 Fed. Reg. 51693, 51696 (August 28, 2003) where FDA states “In addition, Herbs of Commerce, 2nd Edition (2000) does not represent an authoritative compilation of botanical dietary ingredients that are marketed before October 15, 1994 (i.e., botanicals that are new dietary ingredients) under Section 413(c) of the Act.”
5. Foster S. American Herbal Products Association’s Herbs of Commerce. Austin, TX: American Herbal Products Association, 1992.
6. Council for Responsible Nutrition list of dietary ingredients “grandfathered” under DSHEA. Washington, D.C.: Council for Responsible Nutrition. Sep., 1998.
7. U.S. Food and Drug Administration. New Dietary Ingredients in Dietary Supplements, February 2001. Rpt 84, letter 4 (New Dietary Ingredient Submission for Glucose Metabolism Modulator) available at <http://www.fda.gov/ohrms/dockets/dockets/95s0316/ rpt0084.pdf>
8. U.S. Food and Drug Administration Import Alert #45-06, Automatic detention of Stevia leaves, extract of Stevia leaves, extract of Stevia leaves and food containing Stevia. Revised Feb. 2, 1996, Attachment revised May 28, 2003. Available at <http://www.fda.gov/ora/fiars/ora_import_ia4506.html>.
9. Pharmanex Inc. v. Shalala, Case No. 2:97CV262K, CD. Utah, March 30, 2001.
10. “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.” See 140 Congressional Record S 14801, Congressional “Statement of Agreement” on DSHEA (October 7, 1994) point 5.
11. 21 CFR §190.6
12. See § 201(ff)(2)(B) of the FDC Act.
13. Premarket Notification for a New Dietary Ingredient 62 Fed. Reg. 49886, 49891 (September 23, 1997). Available at <http://www.cfsan.fda.gov/~lrd/fr97923e.html>.
14. U.S. Food and Drug Administration. New Dietary Ingredients in Dietary Supplements. Available at <http://www.cfsan.fda.gov/~dms/ds-ingrd.html>. 61 Fed. Reg. 50774, 50777 (September 27, 1996).
15. See § 201(ff)(3)(B) of the FDA Act.
16. U.S. v. Synthrax Innovat.on,149 F.Supp 2d 880 (2001).
17.See § 201(s)(6) of the FDC Act.