FDA rules: too risky to ignore

Supplements manufacturers who don?t follow Food and Drug Administration rules for introducing new dietary ingredients are leaving themselves open to attack in the courts. W Patrick Noonan and Chris Noonan explain

Is it better to be old or new? Most would say ?new.? But if you asked any dietary supplements manufacturer who is about to begin marketing a new dietary ingredient, the answer will probably be ?old.?

The regulations for marketing old vs new ingredients under the Dietary Supplement Health and Education Act of 1994 establish distinct mandatory requirements for both, but the requirements are far less arduous for an old ingredient. Up to this point, most manufacturers assume their ingredients are grandfathered because of a ?long history of use? and proceed directly to market. But an incorrect assessment of a newly marketed ingredient, not in accord with the Food and Drug Administration regulations, can lead to troublesome legal issues.

Under Section 8 of DSHEA, a new dietary ingredient (NDI) means ?a dietary ingredient that was not marketed in the US before Oct 15, 1994.? In contrast, an old dietary ingredient (ODI) is one that was lawfully marketed before that date. For NDIs, companies must notify the FDA 75 days before the introduction of the ingredient with sufficient data to provide substantiation of its safety. For ODIs, no new safety notification is required. The ingredient is presumed to be safe unless evidence suggests otherwise.

Defining terms
In order to understand the significance of NDIs, there are several terms that merit definition. The term ?lawfully? is certainly one for discussion. According to informal FDA guidance, a lawfully marketed supplement requires written evidence showing that the ingredient is chemically identical to a dietary ingredient that was marketed in the US before Oct 15, 1994. However, the FDA has indicated some written evidence upon which the dietary supplements industry has historically relied may not be sufficient.

The FDA stated in correspondence to one manufacturer, when responding to a 75-day notification, that ?inclusion in a published list is not sufficient to show an ingredient is old.? Such lists include the American Herbal Products Association?s Herbs of Commerce (1992),1 the ?Old Dietary Ingredient List? from the Utah Natural Product Alliance, and the ?List of Dietary Ingredients Grandfathered Under DSHEA? from the Council for Responsible Nutrition.

According to the FDA, a seller must be able to demonstrate that the inclusion of the ODI in these publications is based on reliable evidence that the ingredient is old. The FDA considers independent documentation to show an ingredient is old to be a product invoice, bill of lading, product label or labelling, or catalogue with a date to show evidence of marketing before Oct 15, 1994.2

Widely consumed
Another way to gain exemption from NDI legal status is to demonstrate the ingredient is widely consumed in food in a form that has not been chemically altered. But what if one extracts an ingredient from its source? Is the ingredient chemically altered? The FDA says that if the extract is present in the food supply, the seller must prove it.

Incidental presence of an extract as an inherent component of articles used for food does not establish that the substance itself is ?an article used for food.? In essence, just because an ingredient may have been consumed as part of a food for centuries, it does not mean that substance is exempt under the NDI requirements.

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 notice. For that reason the FDA has issued a regulation: New Dietary Ingredient Notification.3 In this, the following requirements are needed for an NDI submission to the FDA:

  • name and address of manufacturer or distributor of the NDI
  • name of the NDI
  • description of the NDI, including a full characterisation 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 labelling, which includes the labelled suggested population for the ingredient (ie, 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 of published articles or other evidence.

The FDA believes there will be minimal burden on the industry to generate the data to meet these requirements. This is because the FDA is only requesting information that the manufacturer or distributor should have already compiled to support that the ingredient or product is ?reasonably expected to be safe under the conditions of use recommended or suggested in the labelling of the dietary supplement.? The FDA believes the industry burden is approximately 20 hours of work per submission.4

Each NDI submission is specific to the submitter. Other companies intending to market the same ingredient would have to prepare their own NDI submission.5

Legal minefield
Some companies have ignored DSHEA requirements either on the basis that there is no FDA enforcement, or, if questioned, they would argue that their ingredient is ?grandfathered.? But this logic exposes manufacturers to other legal problems.

The first is potential product liability. If a manufacturer is selling a product subject to a liability lawsuit, it is possible the lawyer for the plaintiff will hire an expert to review the product for compliance with DSHEA. If the product contained an NDI legally subject to the 75-day requirement, which was not accepted by the FDA, the expert can argue to a jury that the product was adulterated as a matter of law.

A second problem involves the definition of a dietary supplement. DSHEA amended the Food, Drug and Cosmetic Act by providing a legal definition of a dietary supplement. This definition, as a matter of law, excludes a dietary ingredient approved as a new drug. It also excludes an article authorised for investigation as a new drug, antibiotic or biological.6 According to this definition, if a marketed ingredient were investigated as a new drug and studies were published before the NDI notice was submitted, the ingredient is disqualified as a dietary supplement and further marketing is unlawful.

This is not a theoretical discussion. In the case of US v Synthrax Innovations, the government discovered an investigational new drug (IND) application had been in effect for tiratricol since 1990. (Tiratricol was an over-the-counter thyroid preparation marketed as a metabolic accelerator and fat loss aid.) The court held that this IND precluded tiratricol from being a dietary supplement.

Many companies use the FDA?s tepid enforcement policy as justification to rush new ingredients to market. Responsible members of the industry are slowly integrating a more thorough scientific approach for new dietary ingredients, but the first-to-market mentality runs counter to this practice. Requiring new ingredients suppliers to present significant scientific documentation to establish whether the ingredient is old or new under FDA requirements would be a step in the right direction.

California-based W Patrick Noonan is an attorney specialising in FDA product regulations. Chris Noonan is president of HealthGuidance, a consulting firm. They are founding partners of Mercura LLC, a product innovation, intellectual property creation team.

1. 68 Fed Reg 51696 (2003, Aug 28) where the 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 (ie, botanicals that are new dietary ingredients under Section 413 (c) of the Act).?
2. FDA Docket No. 95S-0316 ? Report 84. See letter 4 ? for New Dietary Ingredient submission for Glucose Metabolism Modulator p2.
3. 21 CFR ? 190.6.
4. Fed Reg 50774-50777 (1996, Sept 27).
5. FDA Web site, New Dietary Ingredients in Dietary Supplements, and 61 Fed Reg 50777 (1996, Sept 27).
6. Section 201 (ff)(3)(A) of the Food, Drug and Cosmetic Act

11 reasons the FDA turns down NDIs
1. Exposure studies on the source of the ingredient were not conducted on actual ingredient.
2. Ingredient was represented for a therapeutic indication. Therefore, the ingredient is legally a drug that requires a new drug application.
3. Ingredient is represented in the NDI submission as a conventional food, and therefore does not meet the definition of a supplement.
4. Data submitted in the NDI notification was for use of the ingredient for disease conditions. Such studies have limited use for long-term use in a healthy population.
5. Clinical studies submitted utilised a non-oral dosage form; therefore, those studies are not comparable for oral use.
6. Ingredient met the legal definition of a biological product according to the FDA; therefore, it is not a dietary supplement.
7. 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.
8. Studies submitted show pharmacological effects, but were not designed to study toxicity or safety for food use.
9. Description of the ingredient is insufficient to show specific qualitative and quantitative characteristics. Studies submitted describe an ingredient that is not proven to be the same ingredient subject to the 75-day notification.
10. Submission does not discuss safety concerns mentioned in the studies submitted.
11. Reference to Chinese herbal medicine as a basis to show safety is not sufficient. 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.

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