What makes for a successful Generally Recognized as Safe (GRAS) determination? In the recent past many questions have been posed about the GRAS process, the transparency of the GRAS process, and the information necessary to determine that a substance is GRAS for its intended use. Over the next few issues of the newsletter, we will work to address these questions. Estimates vary on how many GRAS determinations are made, but only a fraction are made public. GRAS determinations made publicly available are found on Food and Drug Administration’s (FDA) GRAS Notification website. There is no premarket notification requirement for substances determined GRAS; FDA initially formalized a process whereby companies could voluntarily request FDA agreement to a GRAS determination through the GRAS Affirmation process (21 CFR 170.35 for human food and 21 CFR 570.35 for animal feed). However, this process became too arduous for both FDA and industry, and so a more streamlined notification process was initiated. Included on the GRAS Notification website are the FDA responses to the notifiers of the GRAS determination; the responses either state that the FDA agency “has no questions at this time” about the GRAS determination, that the notifier requested that FDA cease to evaluate the GRAS notice, or that FDA believes that the “notice does not provide a basis for a GRAS determination”.
To date (2016AUG05), of the 655 GRAS Notifications (GRNs) submitted to FDA under the GRAS Notification program and added to the FDA GRAS Notification website, 620 have been acted upon by FDA. The remaining 35 are listed as “Pending”. Of the 620 that have had final FDA responses, 106 were voluntarily withdrawn by the petitioner. Approximately one-quarter of these (26) were granted another chance and reconsidered under a new GRN (number), although not all were successful the second time around. Another 17 notifications were rejected outright as “Notice does not provide a basis for a GRAS determination” (nine “no basis” letters occurred in the first three years of implementation of the notification process); although six of these GRAS Notifications were re-submitted and were subsequently successful.
We have reviewed withdrawn or rejected notifications available online or shared with us because more can typically be learned from failures than from successes. We found that there were generally three categories of failed or withdrawn applications:
(1) Those that were otherwise well done, but relied on unpublished data and failed to meet FDA’s “threshold of common knowledge,” critical to fulfillment of the “generally recognized” concept;
(2) Submissions that were poorly organized (some not even according to the format supplied by the Agency), contained inadequate or no toxicology data (often relying on anecdotal information), did not identify a level of safe use or used inadequate consumption (exposure) estimates that were based on guesses, or at best, per capita estimates based on projected sales.
(3) GRAS Notifications that could not be easily grouped within (1) or (2), but had some unique flaw.
On the basis of knowledge obtained from the unfortunate circumstances befalling others, we will describe what we believe constitutes a substantive and successful GRAS determination. Any successful GRAS dossier to an Expert Panel or submission to FDA is more than a collation of documents and a narrative describing why the petitioner would like a favorable response; it also includes a rationale on why the ingredient is safe for the intended use and use level.
For a successful submission, the petitioner must meet the “burden of proof” as well as the “burden of persuasion”. The burden of proof involves a thorough discussion of all of the evidence (direct, indirect and antithetical), all of which must withstand the test for relevance. No clear lines have been drawn as to what is actually needed to demonstrate safety-in-use for GRAS, even though there is clear statutory authority for substances to be determined GRAS, considerable case law substantiating (and refuting) GRAS determinations, and FDA has promulgated several guidelines describing the criteria of the burden of proof for GRAS. There remains a great deal of subjectivity in the approval process. We believe that more than one GRAS determination has been lost because of this subjectivity. Therefore, because the “facts cannot always speak for themselves”, the petitioner must also meet the “burden of persuasion” through what we call the “theory of approvability”. We believe this provides a final level of comfort to the Expert Panelist and the regulator. Future issues on this discussion will explore specific aspects of providing sufficient burden of proof to successfully obtain GRAS status for the intended use of a food ingredient.