On Aug. 17, 2016, the FDA published a final rule that amends and clarifies the criteria for determining when a substance may be considered “generally recognized as safe” (GRAS) for an intended use in food and therefore is excluded from the premarket approval requirements applicable to food additives. The final rule provides information that is very useful to companies interested in establishing the GRAS status of substances used in food.
The final rule, issued 19 years after publication of the proposed rule on the GRAS notification process, does not differ significantly from FDA’s current position on the level of support required to reach a GRAS “conclusion”(either when submitting a voluntary GRAS Notice to FDA or making a self-GRAS conclusion). But the final rule mandates new format requirements for GRAS Notices, which must include the following seven parts:
- Signed statements and certification
- Identity, method of manufacture, specifications, and physical or technical effect
- Dietary exposure
- Self-limiting levels of use
- Experience based on common use in food before 1958
- List of supporting data and information
Even if not all parts are relevant to a particular GRAS Notice, a submission should have information regarding each part, even if merely to state that the topic is not relevant.
The final rule applies to both human and animal food, and essentially leaves intact the GRAS framework and interpretation that FDA has long held. In other words, the final rule does not impose new information requirements for GRAS Notices or self-GRAS conclusions (apart from changes that are primarily administrative in nature). For this reason, FDA confirms that recipients of “no questions letters” received in response to GRAS Notices submitted since 1998 need not resubmit such notices or provide supplemental information.
FDA plans to respond to GRAS Notices within a reasonable period of time, usually 180 days. FDA may extend the time by 90 days as needed. Under the final rule, a notifier may amend a GRAS Notice prior to FDA’s response, and/or supplement a GRAS Notice following FDA’s response.
FDA confirms that both a GRAS Notice and a GRAS self-determination must establish the safety of the substance under the intended conditions of use and also establish that such safety is “generally recognized,” as required under the FD&C Act and 21 C.F.R. 170.30. But FDA explicitly declined to “define the extent of agreement needed to establish” general recognition of safety.
The final rule includes a detailed discussion of the use of unpublished data to support a “GRAS conclusion,” which covers GRAS conclusions in both self-determinations and Notices. FDA states that a GRAS conclusion “must be based on data that are generally available and accepted, and as such, are publicly available,” although of course the “mere fact that data and information are published or otherwise publicly available does not satisfy the criteria for general recognition of safety.”
For publicly available information to be supportive of a GRAS conclusion, it “must be plausible that qualified experts would be accessing those data and information using that mechanism.” Accordingly, publishing scientific data on a company website would not meet the “GRAS through scientific procedures requirements,” as experts may avoid such publications and do not offer an opportunity for peer review.
If a company is relying on “scientific procedures,” FDA states that “all relevant data should be used in evaluating GRAS status, including unpublished data” which can corroborate or counter a GRAS conclusion. FDA clarifies that unpublished data can confirm a conclusion of GRAS status, but that to achieve GRAS status, qualified experts must be able to determine safety without corroborative unpublished information.
An example of information that is unpublished but supportive of a GRAS conclusion is a preliminary toxicology study conducted for the purpose of selecting doses for a 90-day study. Certainly the 90-day study should be published, but the fact that the dose-finding study is unpublished would not be problematic because the GRAS conclusion would not be based on the preliminary information.
Importantly, the new GRAS regulations expressly require the notifier to ensure that all data, including inconsistent or unfavorable unpublished data, are discussed. Under the new regulations, GRAS Notices submitted to FDA must either discuss information that may be inconsistent with the notifier’s GRAS conclusion or state that the notifier has reviewed the available data and is not aware of any information that would be inconsistent with the GRAS conclusion. A failure to include relevant information in the GRAS Notice could result in FDA issuing an “insufficient basis letter” in response to the filing.
FDA also discusses whether a published GRAS panel opinion (i.e., the opinion of experts convened by the entity conducting a GRAS evaluation) would satisfy the requirement of “general availability,” based on the view that a GRAS panel is equivalent to or exceeds peer review. FDA categorizes a GRAS panel opinion as an example of “secondary scientific literature,” which would be supportive of a GRAS conclusion if both the underlying data considered by the panel are generally available and the experts have the expertise appropriate to evaluate the underlying data.
If the experts did not have appropriate expertise to evaluate the data and/or if the underlying data were not publicly available, FDA confirms that a published GRAS panel opinion would not support a GRAS conclusion. Further, information that is not generally available to qualified experts (i.e., unpublished information) cannot serve as the basis for a GRAS conclusion merely because a GRAS panel has reviewed it. FDA states explicitly that GRAS panels are not equivalent to determinations by authoritative bodies and peer-reviewed published articles.