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Which provides the better regulatory pathway?
FDA regulatory compliance is always a key concern of ingredient suppliers and manufacturers of both foods and dietary supplements. In general, there are two key regulatory pathways for these types of products: Generally Recognized as Safe (GRAS) or New Dietary Ingredient (NDI).
First, GRAS: The Food Additives Amendment to the Federal Food, Drug and Cosmetic Act in 1958 established the need for premarket approval for food additives; at the same time, this legislation carved out an exception for premarket approval for substances that are Generally Recognized as Safe, or GRAS. Today, for food substances, we see the substantially increased use of GRAS status (either self-affirmed GRAS or GRAS as established through FDA GRAS notification procedures) as the preferred avenue for compliance with FDA requirements,1 with diminished reliance on the food additive petitioning process.
As for NDIs: The 1994 passage of the Dietary Supplement Health and Education Act similarly established that dietary supplement products and dietary ingredients must be safe before they are marketed, in order to comply with FDA requirements. New Dietary Ingredients, or NDIs-i.e., substances added to dietary supplement products that had not been incorporated into dietary supplement products in the United States prior to October 15, 1994-are subject to specific requirements as presently detailed in 21 CFR 190.6. In July 2011, FDA published its NDI draft guidance document to provide industry members with more clarity and details about the NDI requirements and process. As presently constituted, this guidance document would require NDI notifications (NDINs) to be submitted to FDA for a broad array of materials of interest unless, 1) they are documented as “old dietary ingredients” (those that have been used in dietary supplement products in the United States prior to the October 15, 1994 date), or 2) they are for other reasons exempt from the NDIN requirements.
The NDI draft guidance document2 addressed GRAS status directly when explaining which substances would be exempt from the NDIN process. In particular, according to the guidance, one need not submit a NDIN to FDA if the substance of interest already has GRAS status for direct addition to food-either by FDA or self-affirmation-or if a substance has been approved as a direct food additive in the United States. These NDIN exemptions apply as long as the substance in question has been used in the food supply and is to be used as a NDI without chemical alteration.
It thus appears that one can obtain GRAS status for a substance for use in conventional food and, after establishing such conventional food usage, this substance would be eligible for use in dietary supplements without the need for NDI notification.
This prompts a crucial question, then: Should a company go the NDI route or the GRAS route? We will explore the advantages and disadvantages of each approach, taking into consideration individual circumstances and marketing approaches.
In assessing the potential advantages and disadvantages of the NDI and GRAS regulatory pathways, one may raise the fundamental question: Why does it matter whether an ingredient manufacturer or supplier elects to pursue NDI or GRAS status? First and foremost, of course, companies do so to comply with FDA requirements to ensure that resulting conventional foods and/or dietary supplements are not adulterated. In addition to this, the manner in which a firm intends to market a product-as a conventional food, as a dietary supplement, or both-strongly dictates the regulatory pathway to be followed.
Table 1 (see figure image attached) further summarizes potential advantages and disadvantages of the respective NDI and GRAS regulatory pathways. Additionally, we discuss some key takeaways:
Both substances added to conventional foods, as well as dietary ingredients found in dietary supplements, must be established to be safe, but different safety standards apply. Going by the NDI draft guidance, dietary ingredients face a “lesser” safey standard whereby the new dietary ingredient does not present a significant or unreasonable risk of illness or injury. In contrast, GRAS substances (and food additives) must meet the “higher” safety standard of reasonable certainty of no harm under the intended use conditions.
In surveying Table 1, it would appear that the NDI approach would be more advantageous because it requires a lesser burden to establish safety. In actual practice, however, in FDA’s review of NDINs, the agency has deemed only approximately 30% of the submissions as favorable. Compared to this, the FDA favorable review for GRAS notifications is closer to 75%. With the “lesser” safety standard seemingly in place for new dietary ingredients, why this difference in favor of GRAS?
The magnitude of this difference may at least in part reflect FDA’s greater familiarity in applying the “reasonable certainty” safety standard to GRAS and food additives, which dates back to 1958. The fact that many FDA scientists may have greater familiarity and experience applying scientific judgment, over a much longer timeframe, in GRAS notification evaluations may contribute to this success ratio differential, to the detriment of new dietary ingredients.
How FDA interprets safety for NDINs compared to that for GRAS notifications and food additives is a critical issue to be considered prospectively, and this topic has been addressed more fully elsewhere.3
NDI evaluations do not require publicly available safety documentation, as opposed to the case with GRAS notifications submitted to FDA or self-affirmed GRAS assessments. Furthermore, confidential information can more easily be withheld or protected from public release in the case of NDINs than with GRAS notifications submitted to FDA. Bear in mind, however, that the information providing the basis for self-affirmed GRAS determinations can be maintained as confidential if the firm undertaking the self-affirmed GRAS evaluation takes appropriate efforts to preserve information confidentiality.
NDINs are reviewed within a shorter timeframe than FDA-submitted GRAS notifications. NDI evaluations are completed within 75 days, while FDA may take 180 days or more to complete the review of GRAS notifications, especially if substantive questions arise during the FDA review phase. Self-affirmed GRAS determinations, in contrast, are not subject to any additional time for completion since no filing occurs with FDA and no FDA oversight is undertaken which could lengthen the timeframe.
It is important to bear in mind that NDINs apply only to dietary supplement products and not to conventional foods. GRAS status, on the other hand, provides the advantage in that, as previously discussed, under the current version of the NDI draft guidance document, GRAS status may extend to dietary supplements if the substance in question has been used in foods (and has not undergone chemical alterations) prior to the addition to dietary supplements.
Thus, establishing GRAS status provides the potential advantage of having broader applications to both conventional foods and dietary supplements.
A further advantage of GRAS status is the requirement that production of finished food products must comply with the less onerous food Good Manufacturing Practices regulations found in 21 CFR 110, while dietary supplements must meet the more demanding dietary supplement Good Manufacturing Practices requirements detailed in 21 CFR 111.
In their marketing materials, numerous ingredient manufacturers and suppliers highlight the regulatory status of their substances. Many use a favorable FDA determination to enhance the marketing efforts for their substances; receiving a NDI authorization or a GRAS “no questions” letter from FDA is highly valued and can serve to favorably distinguish one’s substance from a competitor’s. However, self-affirmed GRAS determinations-which can still trigger the exemption from NDI filing if conventional food uses can be established-provide no FDA validation for use in marketing initiatives. However, the process may be faster and less burdensome without FDA’s administrative intervention.
It is most prudent to consider the specifics of each individual substance when choosing a regulatory strategy. For example, for the GRAS exemption to apply to a substance in dietary supplement products (by virtue of either FDA GRAS notification or self-affirmed GRAS), the substance in question must be used in the food supply-i.e., in conventional foods. Not only that, appropriate documentation of such usage must be available. And, to be sure, some substances may not lend themselves to use in conventional foods due to unfavorable organoleptic characteristics, so the use of such substances may be restricted to dietary supplement products.
At this point in time, firms should consider establishing regulatory compliance by means of NDI notifications or GRAS status depending on their unique circumstances, noting inherent advantages and disadvantages with either approach. Overall, however-and generally speaking-the advantages of establishing GRAS status appear to outweigh the advantages of gaining FDA authorization for NDIs.
There is still uncertainty regarding the content contained in FDA’s NDI draft guidance document. Changes and refinements are likely, and such adjustments very well may alter the circumstances, obligations, and benefits of gaining FDA’s favorable review of a submitted NDI notification. It is important to recognize that the regulatory landscape for new ingredients is dynamic and that some changes must be anticipated. This aspect should be given appropriate consideration in assessing which regulatory pathway will better advance a firm’s specific objectives.