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Is FDA regulating NDIs like GRAS substances and food additives?
FDA recently issued its highly anticipated guidance regarding new dietary ingredient (NDI) notifications,1 and several aspects have prompted substantial industry objection and concern. Most would agree that the agency thinking, as captured in the guidance document, will impose an increased burden on supplement companies seeking to comply with applicable regulations.
FDA’s present position would expand the need for the filing of more NDI notifications because fewer materials would qualify for the grandfathering authorization associated with marketing of dietary ingredients within dietary supplements in the United States prior to October 15, 1994. Furthermore, FDA would require filing of NDI notifications for dietary ingredients to which only minor changes have been made from previously acceptable substances, as well as for identical substances that have been the subject of NDI filings by other manufacturers or distributors.2
New dietary ingredients introduced to the U.S. market after October 15, 1994, must meet the stated NDI safety standard as established by the Dietary Supplement Health and Education Act (DSHEA), demonstrating that there is reasonable expectation of safety for the subject ingredient when incorporated in dietary supplement products.3 In other words, for new dietary ingredients, the composite safety information must support the finding that there is reasonable assurance that the subject ingredient does not present a “significant or unreasonable risk of illness or injury” when used as directed on the label or under normal conditions of use.
How does one fulfill this safety requirement? How much safety documentation is sufficient? What is meant by “significant or unreasonable risk of illness or injury,” and how does this differ from the safety standard used by FDA for food additives and Generally Recognized as Safe (GRAS) substances, which calls for “reasonable certainty of no harm under the intended conditions of use”?4 Has the NDI safety standard been transformed over the past 17 years into the historically more familiar “reasonable certainty of no harm” GRAS standard? Has FDA provided sufficient clarification to industry on the distinction to enable applying the NDI safety standard with confidence?
Interestingly, there are many who maintain that FDA is, and has been, applying the higher safety standard-that is, the standard used for food additives and GRAS substances-in its review of NDIs. In fact, a casual review of NDI submission statistics is consistent with such an interpretation, as it has been reported that less than 25% of the 700 NDI notifications filed with FDA received “no objection” determinations.
In 1995, shortly after the passage of DSHEA, FDA received a NDI notification from Sunrider Corporation for stevia usage in dietary supplement products, and FDA issued a letter with its findings in favor of the use of stevia as a dietary ingredient in dietary supplements. Interestingly, FDA included in its letter the following:
…you should be aware of the agency’s continued concern over the safety of stevia. We note that there are several published scientific studies suggesting that the consumption of aqueous extracts of stevia reduces the fertility of female laboratory animals. Additionally, other published studies raise concern over the possible hypoglycemic (low blood sugar level) effect of stevia in human subjects. These concerns are currently unresolved.5
This early example of FDA’s review of the NDI illustrates how the agency interpreted the reasonable expectation of safety standard shortly after implementing the DSHEA requirements. FDA recognized that not all safety issues were fully resolved as would be needed for food additive or GRAS clearance in accordance with the “reasonable certainty” safety standard, but FDA concluded that reasonable expectation of safety was established based on the then-available information.
Taking this one step further, we can contrast FDA’s findings on the stevia NDI notification with the various GRAS notifications that have been submitted to FDA for rebaudioside A and steviol glycosides since 2008. In order to fulfill the “reasonable certainty of no harm” standard, GRAS notifiers were compelled to resolve all safety issues, including those that FDA highlighted in its 1995 NDI review. The numerous GRAS notifications that have received “no questions” letters from FDA have presented persuasive documentation that goes beyond what was needed for the stevia NDI in 1995.
As we fast-forward to 2011, this distinction between how the two safety standards are applied seems to have become blurred-and, according to some, has nearly disappeared. One wonders whether or not this seeming lack of distinction between the two safety standards reflects the agency’s intent on making the authorization for increased usage of dietary supplements more difficult by having a single, more-stringent safety standard, despite Congressional guidance to the contrary.
In Section IV.B.2 of FDA’s new NDI guidance document, the agency noted that substances that are approved food additives or dietary ingredients that are listed or affirmed as GRAS-including self-affirmed GRAS status for direct addition to food-do not need to undergo agency review through the NDI notification process. Such food substances incorporated in conventional foods have undergone (or, for self-affirmed GRAS determinations, have presumably undergone) a rigorous safety evaluation for specified food uses in accordance with the higher GRAS standard of safety, “reasonable certainty of no harm under the intended conditions of use,” than that which applies to NDIs as established by DSHEA.
If the scientific burden of proof of safety for a NDI notification that is presently in effect is essentially indistinguishable from that required for GRAS status, a manufacturer or distributor may be better-served by establishing GRAS status because the addition of the substance in question to conventional foods (assuming that such expanded food uses can be supported from the composite safety documentation) affords greater commercialization opportunities by virtue of the ingredient’s ability to be added to a broader variety of food categories, in addition to dietary supplements.
It is intriguing to contemplate why FDA might be intentionally or unintentionally encouraging the regulation of NDIs, in part by exempting from the NDI notification process those substances that have GRAS status or are approved food additives. Is it due to the greater consumer protection that is potentially available because of the presumed higher GRAS safety standard? Could it be primarily a manifestation of agency familiarity with interpreting the composite safety information in reference to the “reasonable certainty of no harm” GRAS standard that has been in place since 1958? Or, possibly, does FDA prefer to avoid utilizing its scientific judgment with the lesser safety standard that is clearly more amorphous at this point in time?
By encouraging-actively or passively-the regulation of dietary ingredients via the GRAS or food-additive route, the likelihood of consumers reaping benefits of enhanced FDA oversight is questionable, especially if the GRAS approach is one of self-affirmation, in which such determinations are not voluntarily shared with FDA. With most self-affirmed GRAS determinations, no agency safety oversight occurs. (However, GRAS notifications that are alternatively voluntarily submitted to FDA are subject to this safety oversight.)
The NDI guidance document, if implemented in its present form, will certainly diminish the availability of many existing dietary supplements that are formulated with new dietary ingredients, and it will diminish the incentive to innovate with new dietary ingredients incorporated in dietary supplements. Furthermore, compliance with the requirements, as stipulated in the NDI guidance document, will impose additional costs on those firms willing to pursue innovation in the form of dietary supplement products-and such costs are likely to be passed on to consumers. In effect, we should anticipate at least a twofold impact on consumers, with the probable marketplace reduction of availability of dietary supplement products, as well as higher costs for those supplements that remain in the marketplace or that are subsequently introduced.
An integral part of the increased compliance costs is the generation of the safety dossiers to support the new dietary ingredients, and the potential impact of the NDI guidance depends on obtaining a clearer understanding of how FDA interprets the new dietary ingredient safety standard. What are the differences that exist between the “reasonable expectation of safety” or “absence of significant or unreasonable risk of illness or injury” NDI safety standard compared with the higher “reasonable certainty of no harm” GRAS safety standard? As it stands, there appears to be a blurring of the identified safety standards, suggesting that we have a legal distinction without a practical difference.
1 See www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/Dietary-Supplements/ucm257563.htm
2 Not only does FDA’s guidance document advocate the filing of NDIs for truly new dietary ingredients but also for new combinations of ingredients that include dietary ingredients that have previously undergone successful NDI review by FDA
3 See 21 CFR 190.6(b)(4)
4 See 21 CFR 170.3(i)
5 See www.fda.gov/ohrms/dockets/dockets/95s0316/m000002.pdf
By Justin Prochnow, Greenberg Traurig LLP
While there has already been much debate as to what significance the NDI draft guidance (“the Guidance”) really will have on the future of NDI notifications, one thing is clear: for supplement companies, the Guidance supplanted the latest thriller or beach book as the “must read” of the summer.
While the Guidance certainly provides some telling insights into FDA’s thought process regarding this issue, it is important to remember a fundamental principle-the law has not changed. The Guidance does not represent a change to the existing laws or regulations governing dietary supplements and, more specifically, new dietary ingredients. Failure to comply with Guidance itself is not a violation of the law.
The Guidance consists of 35 pages, divided into eight sections. Essentially, the first three sections are introductory in nature, describing the background and scope of the document, while the last two sections comprise definitions and appendices. Sections V and VI are reflective of a typical FDA draft guidance for industry. Those sections essentially set forth a step-by-step analysis of the procedures and timing for submitting a NDI notification and what should be included in a NDI notification.
The real center of all of the commotion surrounding the Guidance is Section IV, entitled “Determining Whether a New Dietary Ingredient (NDI) Notification is Necessary.” Following are just a few of the topics that have generated great discussion.
While FDA’s intentions in a draft guidance document are generally to clarify its thinking in the particular area, the complaint of many people who have digested the NDI draft guidance is that it has only further muddied already murky waters. One area of the Guidance that has received a fair amount of criticism is the discussion of grandfathered ingredients.
The issue of grandfathered ingredients related directly to the definition of new dietary ingredient found in the Federal Food, Drug, and Cosmetic Act. Pursuant to 21 U.S.C. § 350b(c), a “new dietary ingredient” is a “dietary ingredient that was not marketed in the United States before October 15, 1994, and does not include any dietary ingredient which was marketed in the United States before October 15, 1994.” Thus, dietary ingredients marketed in the United States prior to October 15, 1994, are considered grandfathered ingredients.
However, FDA “clarified” in the recent Guidance that it interprets this to mean that the ingredient must have been marketed in or as a dietary supplement, or for use in a dietary supplement, in the United States before October 15, 1994. Thus, evidence of an ingredient marketed as a food prior to October 15, 1994, is insufficient; evidence must be related to the marketing of the ingredient as or in a dietary supplement. This statement is confusing to many because the category of dietary supplements wasn’t defined as a category until the passage of the Dietary Supplement Health and Education Act of 1994, making it difficult to show proof of use in a category of products that didn’t exist before the date used as the cutoff.
Making it more difficult is the statement by FDA in the Guidance that FDA does not consider grandfathered ingredient lists compiled by industry trade organizations to constitute proof that an ingredient is not, in fact, a new dietary ingredient. FDA reiterated that companies must maintain their own records to establish proof that an ingredient is grandfathered.
One of the areas of the Guidance that will certainly receive its share of comments is the clarification from FDA that a NDI notification must be filed for each product in which a NDI is included, and by each manufacturer or distributor. While many people think of a NDI notification as pertaining to a particular ingredient-it is, after all, called a new dietary ingredient notification-FDA notes in the Guidance that the statute places the obligation on each manufacturer or distributor to provide safety information based on the characteristics and intended use of the particular product in which the NDI is included. FDA asserts that other manufacturers or distributors looking to use the same NDI in a different product must provide their own evidence of safety based on their particular product and circumstances of use.
Thus, the inclusion of a NDI in the NDI database is of little relevance, other than to know that someone else filed a NDI. Subsequent companies still must file their own NDI notification based on the specific circumstances related to their product.
More than a few industry members have already argued that it is a huge waste of time and resources to require continuous submissions from companies, and that it makes more sense for NDI notifications to be submitted by the ingredient manufacturer, who could then market that ingredient accordingly.
So, is the Guidance “much ado about nothing”-or a matter of grave concern to the supplement industry? As with most things, the answer probably lies somewhere in between the two and is dependent, in large part, on the nature of the company and its products. For companies using traditional ingredients, the Guidance will probably not implicate any change. However, for companies using novel ingredients or ingredients procured through new methods, the positions reiterated by FDA in the Guidance are significant.
Rest assured, there will continue to be lively discussion and debate right up to the October 3, 2011, deadline for submitting comments to FDA. Judging from the initial attention surrounding this issue, FDA should be prepared for some heavy reading of its own.