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 degree of transparency of the process, and the information necessary to determine that a substance is GRAS for its intended use. Within the past month, FDA released the Final Rule for the process by which a person may notify the FDA of the conclusion of GRAS status. Within this Rule, the FDA has attempted to clarify (while also amending) the elements of a GRAS that FDA wants to be addressed in the notification. But does the Final Rule reach too far in its requirements? Are there elements of the GRAS regulation that have been minimalized in this Final Rule? Over the next few issues of the newsletter, we will look in detail at the different sections to address these and other questions, and how this Final Rule could potentially change the GRAS process.
Initial review of the Final Rule confirms that, contrary to some requests, the decision to notify FDA that the use of a substance is GRAS is still voluntary. FDA reaffirmed that it is beyond its legal authority to require notifications of GRAS status; a change which would require an amendment to the Food, Drug & Cosmetic Act. Estimates vary on how many GRAS conclusions are made, but it is assumed that only a fraction are notified to the FDA. GRAS conclusions notified to FDA are made publicly available on FDA’s GRAS Notification website. Other conclusions of GRAS status are not notified, but the company may promote (via advertisements) that use of a substance is GRAS. Finally, it is assumed that a significant number of GRAS conclusions are neither notified to FDA nor promoted. This GRAS notification Final Rule replaces both the interim voluntary GRAS notification Pilot Program that was initiated in 1997, which, in turn had replaced the voluntary GRAS Affirmation process (21 CFR §170.35). However, this Final Rule moves well beyond the elements of the GRAS Pilot Program and the Affirmation process in its “requirements” which a notification must meet, down to a change in terminology and implied FDA acceptance. Recall that the GRAS Affirmation process was a process by which a company would request FDA’s affirmation (i.e., confirmation) that a substance was GRAS i.e., FDA was essentially agreeing to a determination of GRAS status; that is, FDA took “ownership” of the GRAS decision. In contrast, in the Proposed GRAS notification program, a company was only “notifying” (i.e., informing) FDA that it had concluded the use of a substance was GRAS. FDA neither agreed nor rejected the GRAS determination, FDA only had “no questions at this time” or found that the “Notice does not provide a basis for a GRAS determination”. Within the Final Rule however, FDA is requiring specific statements and types of data by which FDA will evaluate the GRAS status; with these requirements, FDA is making their own conclusion of GRAS status, but yet is not accepting responsibility of that conclusion, as the Final Rule maintains that the notifier has concluded that the use of a substance is GRAS. FDA should either commit to stating agreement to the conclusion of GRAS status, or only accept that use of a substance was determined GRAS and FDA has been notified of that conclusion. To this last point, FDA has also modified the terminology that is to be utilized under a GRAS notification within this Final Rule, as the use of a substance is no longer “determined” to be GRAS (or “self-affirmed” which was commonly used), but there is now a “conclusion” of GRAS status, as stated above. In addition, the GRAS conclusion is no longer an “exemption” from filing a food additive petition (section 201(s) of the Act), as was stated in the proposed rule, but a conclusion of GRAS now “excludes” or “is not subject to” the use of a substance from the requirements of a food additive petition, the latter being consistent with the provisions of the FD&C Act.
FDA is also requiring that the GRAS notification be split into seven distinct parts, some of which are partially redundant in content…supposedly to streamline FDA’s ability to review notifications. Contained within one of the parts of this notification must be a “narrative” that explains “the basis for the notifier’s view that the notified substance is safe under the conditions of its intended use”, which is consistent with Burdock Group’s understanding that a “conclusion” of GRAS should not just be a “data dump” of information, but the conclusion of GRAS status should meet both the “burden of proof” as well as the “burden of persuasion.” The requirement of a “narrative” is a rational one, as it forces the notifier to actually demonstrate understanding and mastery of the science of food ingredient toxicology, eliminating amateurish notifications. 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. 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. Future issues on this discussion will explore specific aspects of the GRAS notification Final Rule, detailing the information required for increasing the probability of receiving a “no questions” letter from FDA for a notified conclusion of GRAS.Tags: FDA, final rule, GRAS