Premarket Notification for New Dietary Ingredients: A Leading Manufacturer's Perspective

New products are the lifeblood of most industries, and dietary supplements are no exception. Innovative new products often contain new ingredients, and as such, it’s essential to develop a workable system for introducing products that contain what are known as new dietary ingredients (NDIs). Currently, FDA (Rockville, MD) is focusing on a provision in the Dietary Supplement Health and Education Act (DSHEA) that outlines an NDI evaluation process. FDA posed several questions in the October 20, 2004, Federal Register and has asked industry and others to comment.

This article outlines three critical questions that need to be addressed when assessing NDIs; it also offers current perspectives about these topics.

Three critical questions to consider when developing a new product are:

• What is a dietary ingredient?

• What is a new dietary ingredient?

• Is notification to FDA required?

DIETARY INGREDIENTS

Before considering use of a new substance in a dietary supplement, dietary supplement manufacturers must first ensure that the proposed NDI is in fact a “dietary ingredient” as defined in DSHEA. In addition to ordinary nutrients (i.e., vitamins, minerals, herbs, botanicals, and amino acids), DSHEA also describes a permitted dietary ingredient as “a dietary substance for use by man to supplement the diet by increasing the total dietary intake.” It further provides for “a concentrate, metabolite, constituent, extract, or combination” of such substances.

Based on these criteria, what definable limits does DSHEA impose on the scope of what qualifies as a dietary ingredient?

Opinions on this question are quite diverse. Some argue that DSHEA allows any substance, including chemically synthesized ingredients that are unlike substances found in nature (except for new drugs and investigational new drugs, etc.) to be categorized as dietary ingredients as long as they are intended to supplement the diet. This is probably too extreme.

Others claim that a dietary ingredient (or its precursor) must be present in the human food supply or at least exist in nature. This position is confounded by the fact that some grandfathered dietary ingredients, such as calcium citrate, don’t exist in nature-in the exact form used in dietary supplements.

A reasonable interpretation may be that a dietary ingredient must either occur in nature or be a chemically modified version of a substance found in nature.

"NEW" DIETARY INGREDIENT (NDI)

Once a substance is determined to be a dietary ingredient, one must consider whether it is a “grandfathered” ingredient or an NDI. DSHEA defines a “new dietary ingredient” as “a dietary ingredient that was not marketed in the United States before October 15, 1994.” For truly unique ingredients this is a fairly straightforward analysis, but an issue arises when a new or innovative substance is chemically similar, but not identical to, an “old” ingredient.

It is Pharmavite’s view that any chemical modification to an old dietary ingredient produces a new dietary ingredient. As such, different salts, esters, chelates, complexes, and other modified versions of old dietary ingredients are in fact NDIs. So, too, are chemically synthesized ingredients that have a different stereochemistry from previously used ingredients. Further, ingredients derived from a plant part not previously used in supplements are NDIs. Technology also plays a role. For example, a process change that yields an extract which contains chemical compounds not found in an old extract should also be considered an NDI.

PREMARKET NOTIFICATION

If an ingredient is determined to be an NDI, the final consideration is whether a 75-day notice needs to be filed with FDA prior to market introduction. An exclusion from the 75-day-notice requirement is provided in DSHEA for NDIs 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.”

This language has yielded much discussion. A key question: Does this exclusion only apply to whole substances used as food (e.g., botanicals and glandular products), or do isolated compounds and/or extracts of foods also qualify? Some interpret the exclusion very broadly to include any component found in food. On the other hand, a strict, literal interpretation of the language may argue otherwise. What’s clear is that there is much confusion around what is meant by being “present in the food supply as an article used for food.”

A reasonable position is that the exclusion should apply equally to whole food ingredients, constituents, and compounds found at any detectable level in food, as well as chemically synthesized compounds that are identical to compounds found in the food supply. However, different salts, esters, chelates, complexes, or other chemically modified or stabilized forms of compounds otherwise identical to compounds found in the food supply should not be excluded from the notice requirements.

If conditions for the above exclusion are not met, DSHEA requires two things before the NDI is marketed. First, some “history of use or other evidence of safety” that the dietary ingredient, when used as recommended, will “reasonably be expected to be safe.” And second, at least 75 days before market introduction, the NDI manufacturer or distributor must provide FDA with information, including any citations of published articles, which is the basis for the conclusion that the NDI will “reasonably be expected to be safe.”

Many questions exist regarding the appropriate interpretation of what is “reasonably expected to be safe.” We believe that marketers should have latitude to determine the appropriate basis and it should not be as comprehensive and onerous as food additive and generally recognized as safe (GRAS) affirmation petitions. The rationale behind this position lies in DSHEA itself. DSHEA established a different legal standard for the safety of new dietary ingredients, compared with food additives and GRAS substances, which have a standard of a “reasonable certainty of no harm.” In addition, FDA must approve food additives and GRAS affirmation petitions, but does not formally approve NDIs. Under DSHEA, it is the manufacturer’s or marketer’s responsibility to provide to FDA the company’s basis for its conclusion that the ingredient is reasonably expected to be safe.

A final good rule of thumb is that even when a notice is not required, a marketer has an obligation to assess the safety of any NDI and should keep records on file to support such a conclusion. It would also be prudent for such information to be evaluated by a panel of independent, third-party experts.