What makes for a successful Generally Recognized as Safe (GRAS) determination? Over the next few issues of the newsletter, we hope to respond to that question and this will be the first installment. Estimates vary how many GRAS determinations are made, but only a fraction are made public and for fewer still, is it possible to obtain the GRAS dossier and examine the rationale behind the GRAS. That fraction publicly available are those that may be obtained via the Freedom of Information Act (FOIA) upon request to the Food and Drug Administration (FDA) Notification program. For an idea can be obtained as to what does not work, however, it is better to examine rejection letters posted at the Notifications website.
To date (14Nov08), of the 261 GRAS Notifications submitted to FDA under the GRAS Notification program, 232 have been acted upon by FDA. Of this number, 35 were voluntarily withdrawn by the petitioner and approximately half of these (16) were granted another bite at the apple and reconsidered under a new GRN (number), although not all were successful even the second time around. Another 16 notifications were rejected outright as “Notice does not provide a basis for a GRAS determination;” although six of these were re-submitted and all were subsequently successful.
Because it is true that more can be learned from failures than from successes, we have reviewed material online, material obtained through FOIA and, some withdrawn and rejected Notifications shared with us. We found that there were generally three categories of failed or withdrawn applications:
(1) Those that were otherwise well done, but relied on unpublished data and failed to meet FDA’s “threshold of common knowledge,” critical to fulfillment of the “generally recognized” concept;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) Those submissions that were poorly done e.g., poorly organized (some not even according to the format supplied by the Agency), inadequate or even non-existent toxicology data (often relying on anecdotal information) and/or where no NOEL or ADI could be established or, inadequate consumption (exposure) estimates that were based on guesses, or at best, per capita estimates based on projected sales. Many of these submissions appeared to be no more than attempts to throw something at the wall to see what sticks.
(3) The last category consisted of those that could not be easily grouped with (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. One thing we understood from the outset is that 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.
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. While there is clear statutory authority for GRAS and considerable case law substantiating (and refuting) GRAS determinations and, while FDA has promulgated several guidelines describing the criteria of the burden of proof for GRAS, no clear lines have been drawn as to what is actually needed to demonstrate safety-in-use. 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,” which we believe provides the final level of comfort to the Expert Panelist and the regulator.