Quantity & Quality of Evidence
The first, “Regulatory Framework,” brings up some interesting issues, if not in a slightly overbearing manner ─ more like warnings than counseling by an elder. For example, in the Introduction section there were several (sharp) bullet points reminding the reader of his/her responsibilities, including statements that FDA is releasing this guidance to:
“Remind you that a GRAS conclusion based upon scientific procedures requires the same quantity and quality of scientific evidence as is required to obtain approval of a food additive…”
Usually, this passage is followed by references to several citations of court cases, but these always reference disputes over the Generally Recognized As Safe and Effective status of a drug for what would become the category of OTC drugs. Further, the disputes tended to focus on recognition of the efficacy of the drug, not the safety. To the author’s knowledge, there has been no case dealing directly with what is required to establish the safety of a food ingredient. The FDA’s only exception to the “quality and quantity of evidence” rule is for those substances in common use in food prior to January 1, 1958. However, the requirements for documentation of “common use” are given extra dimensions (see below).
Possible Cyclic Review of Older GRAS Conclusions
The Introduction of “Regulatory Framework” continues with the following reason for the guidance:
“Remind you that all GRAS conclusions must be considered in context based on the knowledge and information available at a point in time…and scientific knowledge and information…can evolve and sometimes changes over time[.]”
This statement is a relatively new one from the agency and may be a harbinger of a mandate for a review of substances previously GRASed (i.e., a European REACH-type review). For example, those substances for which contradictory safety data may have been generated since the original GRAS and/or those substances for which consumption has significantly changed over time. The use of some substances have dramatically increased over time such as rosemary (once only used as a food flavor, is now used as a preservative in food and an antioxidant dietary supplement). It is entirely possible that the statement above presages a future requirement to confirm previous GRAS conclusions, via a voluntary confirmation by industry or possibly mandated by FDA on the basis of new findings and/or changes in consumption.
A Review of Actions FDA May Take
More warnings appear in the body of the document, including the list of actions the FDA may take if your ingredient is found not to be GRAS after all and would be regarded as an unapproved food additive. The FDA warns that “As appropriate, we can issue a declaratory order determining that the substance is not GRAS under the conditions of its intended use and is a food additive…” Actions the FDA may take under §409 for unapproved food additives include: “…issuing a warning letter (which we make public on our Web site) to companies that manufacture or distribute the food additive and/or food containing the food additive; issuing a public alert; and taking enforcement action to stop distribution of the food substance and foods containing it on the grounds that such foods are or contain an unlawful food additive.” Because the warning letter is not a final action by the FDA, it does not provide the force of law, but the implementation of public shaming by posting the warning letter on the FDA website or issuing a “public alert”, are actions for which only your worst enemy could hope and, taking an enforcement action to stop distribution of the food substance could have devastating consequences.
This warning about actions that could be taken should be especially meaningful to the manufacturers of 500 or so animal feed ingredients listed in the Association of American Feed Control Officials, “Official Publication” that are not federally compliant.
Use of Foreign History of Consumption – the Non-Concession Concession
In another passage of the “Regulatory Framework” document, the agency implies its generosity in its statement: “In 1988, we clarified that the criteria for eligibility for classification as GRAS through experience based on common use in food for a substance intended for use in human food could be based on common use in food outside, as well as in, the United States (53 FR 16544; May 10, 1988),” and, the fact that it was incorporated into the GRAS final rule of August, 2016 (81 FR 54869, August 17, 2016). However, this was hardly a concession, but a response to a mandate from the court in Fmali Herb, Inc. v. Margaret M. Heckler et al.3The court determined that the demand in 21CFR§170.3(f) that common use in food must be limited to the United States was “not a permissible interpretation of 21USC§321(s)” i.e., (21CFR§201(s)). There might be a possible interpretation of a concession by FDA; however, regarding the fact that incorporation of this court mandate into the final rule also included recognition of the common use in foreign countries by the Center for Veterinary Medicine, which had hitherto ignored the court finding.
The Conundrum of Unpublished Data
The agency also commented on the use of unpublished data to support a finding of GRAS i.e., “…may be corroborated by the application of unpublished scientific data, information, or methods.” The FDA elaborated further into the document that the GRAS criteria cannot be satisfied unless the substance could be found to meet the standard of safety for food (i.e., not harmful under the conditions of intended use) in the absence of the unpublished information. That is, the substance can only be GRAS on the basis of publicly available information i.e., there can be no unpublished information that supplements GRAS panel knowledge for a determination of safety. Such knowledge could, however, be empirical conformational information of an otherwise acceptable theory of safety established by the GRAS panel, such as metabolic disposal of an ingredient or a manufacturing process empirically shown to be without theoretical possible low-levels of contaminants. This refusal to allow the use of any unpublished information seems to imply that FDA is trying to re-interpret 21CFR§170.30(a) Eligibility for classification as…GRAS. “…may be corroborated by the application of unpublished scientific data, information, or methods.” Re-interpretation of the regulation by narrowing a definition is likely a violation of Administrative Law, which would otherwise require notice and comment period for what amounts to a change in a regulation. A possible remedy for use of unpublished information would be for FDA to liberalize use of the master file for food ingredients, allowing some non-public and often valuable proprietary information (such as manufacturing information) to remain under wraps – naturally, the sequestered information could not be pivotal to a decision of safety.
The Burden of Proving Common Use in Food
“Common use in food” is the provision inserted in 201(s) by Congress to allow for experience to substitute for scientific procedures, the latter of which often means costly animal testing must be carried out. The criteria for “common use” has long been absent, especially for use outside the United States. In the Framework document, common use outside the United States must be established by two methods (1) that the information on common use be corroborated by a second, independent source and (2) the source (the information) must be generally available in the country of origin. Neither of these are unreasonable at first glance, but establishing a second source for verification could be difficult as record keeping in some countries (especially in developing countries) from which most “new” foods would be “discovered,” is likely to be poor or non-existent in the pre-computer days of prior to 1958. Further, because the reliability of these declarations of use could be challenged, it makes the job of confirmation through a second source all that more difficult.
When a GRAS Panel Not Required
One curious passage included in this guideline was, “A GRAS panel is not required to demonstrate that a substance is GRAS under the conditions of its intended use, but is one mechanism that the regulated industry has used to demonstrate that the safety of a substance under the conditions of its intended use is generally recognized by qualified experts (81 FR 54960 at 54975).” At first glance, this passage appears to advise that a GRAS Panel is not needed to establish GRAS status, seemingly disregarding FFDCA4 §201(s). This passage, relating to the use of a GRAS Panel, cites [81 FR 54975], which, unfortunately, was written in such stilted language as to be difficult to understand. However, after several readings, it becomes apparent the passage in [81 FR 54975] is actually a response to a question proposing the findings of GRAS panels as being equivalent to determinations by authoritative bodies and peer reviewed published articles. The FDA responds that if there appears to be no dispute over the safety of a substance either by authoritative bodies or peer reviewed publications, essentially that the finding is “settled science” and a GRAS Panel is not be needed.
However, while not stating that GRAS Panels are never needed, the regulation in the General Provisions of Substances that are generally recognized as safe (21CFR§182.1(a)) states: “It is impracticable to list all substances that are generally recognized as safe for their intended use….the Commissioner regards such common food ingredients as salt, pepper, vinegar, baking powder, and monosodium glutamate as safe for their intended use.” At least one interpretation of this passage is that obviously GRAS substances are all around us and we do not need a GRAS Panel to tell us that substances such as salt, pepper and vinegar meet the GRAS standard.
Nonetheless, GRAS Panels are needed, as it would appear from [81 FR 54975], when there are any unresolved issues of safety, conflicts in the literature or presumably, when large amounts of a substance would be used and/or particularly vulnerable groups have been identified. However, one striking ironic statement in [81 FR 54975] seems to lessen the evidentiary standard for published data with the statement “…technical literature from JECFA can provide evidence that generally available safety data and information are generally accepted.” The ironic nature of this statement is that, in the past, GRAS Notifications which cited JECFA conclusions as a source were summarily dismissed, as JECFA conclusions were not always based on publicly available literature.
An Alternative to Notification Without Foregoing Public Disclosure
Without a doubt, the best idea presented in the Regulatory Framework document is the suggestion that the basis of the GRAS should be made public:
Make the basis for your independent GRAS conclusion publicly available (e.g., by placing a publicly accessible document analogous to the narrative of a GRAS notice, a report of any GRAS panel (if you convene a GRAS panel), or both a narrative and a report of a GRAS panel on your Web site), because we make information about GRAS notices readily accessible to the public.
If FDA or consumers are concerned about the legitimate use of the GRAS process and an abolition of the so-called “secret GRAS[es]”, this possibility is cured with the public posting of a GRAS conclusion – sunlight is a powerful disinfectant.
What Does All This Mean?
As often as not, a guideline such as the “Regulatory Framework” document can provoke considerable head-scratching à la “so, what does all this mean”? There are some obvious warnings about what a GRAS must include, but then again, the concept of what is GRAS is something about which “experts qualified by scientific training and experience”5 agree is safe when used as intended. A strict reading of the statute (i.e., 201(s) et seq.) makes no reference to criteria that may be set by FDA, only that experts agree on safety in use. True, there have been some unqualified individuals signing off on the safety of a substance whose scientific training or experience was inapplicable to food ingredient safety, but no mention of FDA applying any sort of test criteria as to who should sign off on a GRAS – maybe this lack of attention to validity of the experts is purposeful, to set up FDA as having the only “true” experts on food ingredient safety or having the final decision on “relevant expertise.”
In any event, it would appear that because of the reports critical of GRAS, FDA is attempting to square the circle concerning what a GRAS determination is supposed to be and make it workable for everyone. Nonetheless, the source of the criticisms should be understood. Reaching back a few years, the publication by the Government Accountability Office6 was something to which FDA was compelled to respond, despite the fact the report was obviously written by a layperson who understood little about the process. A few years later (2013), the perceptibly biased Pew report7 was released by opportunists with their own agenda, which became apparent when they joined the staff of the anti-industry Center for Science in the Public Interest. Both reports were followed by sensationalized reports in the mainstream media and the internet, all with a conspiratorial overtones of industry bamboozling an impotent FDA. Under this barrage of negative media and looming Congressional response, FDA was urged to “grow some spine” and put the screws to a reckless industry. Although beating up an industry might produce some good sound bites, imposing difficult constraints on a system that has proven so useful is not the way to rectify any past wrongs. After all, can anyone identify a food ingredient that was deemed GRAS by an independent panel that resulted in severe adverse reactions, deaths or a recall?
FDA is in the midst of a tight-wire act, trying to balance criticism of the GRAS process without hamstringing the process with unreasonable constraints. The GRAS process has provided incredible relief to an over-burdened FDA and allowed it to focus on other issues. For example, FDA has approved approximately 15 new food additive petitions (FAPs) in the last 20 years; this is a rate of less than one FAP per year. On the other hand, the GRAS notification program has administratively adjudicated approximately 685 Notifications since 1998 to November of 2017, a rate of about 36 Notifications per year. If FDA was required to review these Notifications as petitions, it would require over 900 years to dispose of these Notifications as FAPs under the current FDA time frame for FAPs. This does not even include the 30 – 100 flavor ingredients concluded as GRAS by FEMA each year. It is clear that the greatest beneficiary of the GRAS program is FDA itself. FDA should not throw the baby out with the bathwater, by making the GRAS process so narrowly constrained, that the process of GRAS becomes a rarity and FDA loses the benefit it gains from GRAS.
Regulatory Framework for Substances Intended for Use in Human Food or Animal Food on the Basis of the Generally Recognized as Safe (GRAS) Provision of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry.
Best Practices for Convening a GRAS Panel: Guidance for Industry will be discussed in a subsequent newsletter article.
US Court of Appeals for the Ninth Circuit – 715 F.2d 1385 (9th Cir. 1983)
FFDCA= (current) Federal Food Drug Cosmetic Act
FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS) GAO-10-246: Published: Feb 3, 2010. Publicly Released: Mar 5, 2010. Site visited November 19, 2017.