What is Needed for a Successful GRAS?

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 Of this number, 35 were voluntarily withdrawn by the petitioner and approximately half of these (16) were granted another bite at the apple and reconsidered under a new GRN (number), although not all were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learned from failures than from successes, we have reviewed material online, material obtained through FOIA and, some withdrawn and rejected Notifications shared with us. We found that there were generally three categories of failed or withdrawn applications:

(1) Those that were otherwise well done, but relied on unpublished data and failed to meet FDA’s “threshold of common knowledge,” critical to fulfillment of the “generally recognized” concept;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.