By Riëtte van Laack –
On August 17, FDA published in the Federal Register the long awaited final rule, “Substances Generally Recognized as Safe.” The final rule is based on the proposed rule from 1997, and a reopening of the comment period with supplemental questions in 2010. . The final rule includes a number of tables that provide an overview of the differences between the proposed rule and the final rule.
The final rule does two main things: 1) it clarifies the criteria for determining when the use of a substance in a food for humans or animals is “generally recognized as safe” (GRAS) for its intended use and therefore exempt from the food additive definition in the Federal Food, Drug, and Cosmetic Act (FDC Act), and 2) officially replaces the voluntary GRAS affirmation petition (GRASP) process with a voluntary GRAS notification (GRN) procedure. FDA’s Center for Food Safety and Applied Nutrition (CFSAN) implemented the GRN process soon after publication of the 1997 GRN proposed rule, operating it successfully for nearly two decades, whereas FDA’s Center for Veterinary Medicine (CVM) did not establish a pilot process for GRAS notices for animal feed ingredients (AGRNs) until 2010 (see our previous post here). As of Dec. 31, 2015, CFSAN had filed 614 GRNs for use of human food ingredients and CVM had filed a mere 18 AGRNs for use of animal food ingredients.
A major driver for FDA’s shift from GRASPs which involve notice-and comment rulemaking to GRNs and AGRNs is the ability to respond in a timely manner. Under the final rule, FDA commits to respond to the notifier within 180 days of the date of filing the GRN or AGRN, with a possible extension by another 90 days. Thus, the notifier may not receive a substantive response until 270 days after filing. For purposes of comparison: during the 10-year period from 1990 through 1999, CFSAN completed the rulemaking process for 24 GRASPs, with an average elapsed time of approximately 7.9 years (median elapsed time of approximately 6.9 years).
In recent years, the integrity of GRAS determinations and FDA’s reliance on the voluntary GRN process has been under attack. Critics allege that, among other things, GRAS determinations employ outdated science, are rife with conflicts of interest, and the data supporting GRAS determinations are secret. As we previously reported, in October, 2014 the International Society for Regulatory Toxicology and Pharmacology (ISRTP) held a Workshop on GRAS determinations. The ISRTP Workshop provided a forum for experts in the food safety scientific community to respond to criticisms of the FDA’s GRAS processes. The manuscripts from the Workshop are now available in a special GRAS Supplement of Regulatory Toxicology and Pharmacology Journal (2016), including an Overview of the Workshop co-authored by Diane McColl, Past President of ISRTP. FDA’s 97-page final rule also addresses many of these critiques and explains the law and public nature of GRAS conclusions.
A main thread through the preamble is FDA’s emphasis on the public availability of information supporting GRAS status. With respect to GRAS status based on scientific procedures – the principal basis for GRAS conclusions in the modern era – the critical difference between a GRAS use and an approved food additive use is that the conclusion of GRAS status (FDA’s new terminology for what used to a GRAS determination) must be based on safety information that are generally available and accepted. As explained in the preamble, “[a]lthough general recognition of safety through scientific procedures may be corroborated by the application of unpublished scientific data, information, or methods, . . . to satisfy GRAS criteria, qualified experts must be able to conclude the substance is not harmful under the conditions of intended use without access to 'corroborative' information.” As FDA further explains, there can be no basis for a conclusion of GRAS status if trade secret information (or other non-public information) is necessary for qualified experts to reach a conclusion that the notified substance is safe under the conditions of its intended use. Also, if the public description of the method of manufacture that a notifier includes in a GRAS notice does not provide sufficient detail to evaluate the safety of the notified substance as manufactured, there would be inadequate basis to support a conclusion of GRAS status.
FDA acknowledges that there are differences between the “evaluation” of a GRAS notice and the “review” of a GRASP. Among other things, the data and information in a GRN are summary data and information whereas GRASPs would include the underlying data from studies described in the petition. This does not mean, however, that FDA’s evaluation of a GRAS notice does not constitute a substantive evaluation, or that the safety standard for a GRAS notice is different from that of a GRAS affirmation. Because of questions and potential confusion resulting from FDA’s standard language in a “no questions letter” (i.e.,“The Agency has not . . . made its own determination regarding the GRAS status of the subject use of the notified substance”), FDA will use different language in the future, i.e., “the Agency has not affirmed the GRAS status of the notified substance under the conditions of its intended use in accordance with 21 CFR 170.35.”
In terms of data quality and quantity to support a conclusion of GRAS status, the final GRN rule does not impose any substantially different data requirements than did the GRN process operated under the proposed rule. However, the final regulations include more specific descriptions of what must be included in a GRAS notice.
A GRN must include seven parts. For parts that may not be applicable (e.g., self-limiting levels of use (part 4), experience based on common use in food (part 5)), the GRN must include an explanation for the “omission.” Under the new regulation, a GRN must include a certification that the GRN is “complete” in addition to “representative” and “balanced.” FDA clarifies that it is the notifier’s responsibility to identify, discuss, and place in context, data and information that are, or may appear to be, inconsistent with a conclusion of GRAS status. Such data need not be publicly available.
Although the decision to submit a GRN is voluntary, the information included in a GRN is mandatory. The final rule stipulates that the data and information in a GRN are considered a mandatory, rather than voluntary, submission for purposes of its status under the FOIA and 21 C.F.R. Part 20.
FDA will make a GRN available for public disclosure immediately upon receipt, and will make certain information pertaining to filed GRAS notices readily accessible to the public so as to provide an opportunity for outside parties to make FDA aware of dissenting views about whether the available data and information support a conclusion that the notified substance is GRAS under the conditions of its intended use.
FDA’s final regulations do not specify the data and information that the Food Safety and Inspection Service (FSIS) of the U.S. Department of Agriculture will need to evaluate whether the intended use of the notified substance complies with applicable statutes and regulations enforced by FSIS.
A change from the past is that FDA no longer requires that a GRN provide the common or usual name for the notified substance. Instead, the GRN must provide an appropriately descriptive term. What constitutes a common or usual name of the substance is not considered in the evaluation of the GRN.
FDA’s final rule does not address potential conflicts of interest of an expert panel. FDA explains that an expert panel, often called a GRAS panel, is not mandatory. “Convening a GRAS panel has historically been a way to provide evidence that generally available data and information are generally accepted by the expert scientific community, but convening a GRAS panel is not the only way to provide such evidence.” Therefore, the issues of potential conflict of interest and ways to avoid a conflict of interest are not addressed by the final rule. FDA plans to address these issues in guidance.
The regulations concerning AGRNs for animal food ingredients largely track the regulations for human food ingredients.
The final rule becomes effective on October 17, 2016. As of the effective date of the final rule, FDA will close the docket for any pending GRASPs. There are 45 pending GRASPs. The Agency plans to contact the affected petitioners and provide them with the option to submit a GRN that incorporates the GRASP.
As we previously reported, in 2014, FDA and the Center for Food Safety (CFS) entered into a consent decree that required FDA to issue the final rule by August 31, 2016. CFS reserved the right to “challenge . . . the merits of the final rule.” As we indicated at that time, CFS’s posture suggests that FDA’s issuance of a final rule could beget additional litigation. Litigation remains likely (see here).