In the wake of the infant formula crisis of last year, and U.S. Food and Drug Administration (FDA or Agency) Commissioner Robert Califf’s appointment of the Reagan-Udall Foundation to assess and report on FDA’s food regulatory structure, the Commissioner announced a “new, transformative vision for the FDA Human Foods Program.” The functions of the Center for Food Safety and Applied Nutrition (CFSAN) and Office of Food Policy and Response (OFPR) and certain functions of the Office of Regulatory Affairs (ORA) will be unified under a new Human Foods Program.1 According to Commissioner Califf’s announcement, the overriding goal of this reorganization is to centralize responsibility for food safety in a single leader who reports directly to the Commissioner, ultimately ensuring oversight of human food in a more effective and efficient way.
What should not go unnoticed — while we await the rollout of the Human Foods Program and other organizational changes directed by Congress in the 2022 omnibus bill — is the comment in the Reagan-Udall report regarding the “generally recognized as safe” (GRAS) process to establish ingredient safety. The Reagan-Udall report recommends that FDA “work with stakeholders to better structure the approach to the GRAS designation, including exploring a routine assessment of what qualifies for GRAS designation.”2
In December, FDA issued a final guidance, “Best Practices for Convening a GRAS Panel,” offering a partial response to the Reagan-Udall report’s call for more clarity on what kind of information is necessary to support a GRAS designation. These points, which are outlined below, are important for any stakeholder considering GRAS status for an ingredient. Companies considering GRAS determinations should take a hard look now before investing in science that may fall short.
1. What is the scope and type of information adequate to support GRAS status?
FDA introduces a two-pronged approach for assessing the weight of information used to support GRAS status. According to the Agency, this information “is composed of both ‘general availability’ and ‘general acceptance’ aspects.”
FDA makes clear that the “general availability” prong simply means “publication in a peer-reviewed scientific journal.”
In contrast, “general acceptance” is a case-by-case analysis determined in part by the strength of the generally available evidence of safety.
Thus, according to the FDA, “general availability” and “general acceptance” should be evaluated together, along a continuum, in a weight-of-the-evidence approach. Notably, FDA makes clear that a GRAS panel has limited use in this weight-of-the-evidence assessment. FDA offers the following examples:
- Published peer-reviewed primary studies consistent with generally accepted safety assessment strategies can be sufficient to satisfy both the general availability and general acceptance GRAS criteria, with the caveat that “data published in the primary scientific literature may not provide a basis for expert consensus if those data raise unresolved safety questions.”
- Secondary literature, such as reviews of primary literature, can provide sufficient evidence of general acceptance as it may supplement data and information in the primary literature.
- Findings and opinions of an authoritative body may support a conclusion that the safety of a substance under the conditions of its intended use is generally accepted by qualified experts. The findings of an authoritative body may also be the most appropriate type of evidence to support general acceptance in those cases where the safe level of intake is a narrow range because the difference between the intended or recommended dietary intake (e.g., of a nutrient) and the intake at which the substance exhibits toxic properties is small.
2. What scientific information is inadequate to establish “general acceptance” and therefore will not support GRAS status?
FDA provides three scenarios where the scientific information does not establish “general acceptance” and therefore cannot support GRAS status:
- Available data raise ongoing scientific discussion or controversy about safety concerns.
- The safe level of intake is in a narrow range.
- There is severe conflict among experts regarding safety of use.
3. When is a GRAS panel necessary or useful to support GRAS status?
A GRAS panel is generally insufficient to correct problems with “general acceptance” or “general availability.” FDA offers two narrow circumstances where a GRAS panel can be helpful in establishing GRAS status:
- when multiple studies bearing on the safety of a substance are published, but there are no secondary sources that evaluate these studies and draw general conclusions based on this comprehensive body of knowledge
- where the published results of a particular safety study raise safety questions that require additional data to be resolved; in such cases where published primary or even secondary literature might not be sufficient, a well-constructed GRAS panel may provide the type of evidence necessary to conclude that the published safety data are generally accepted
4. Can unpublished scientific information be used to establish GRAS status?
FDA reiterates its previously stated position that unpublished scientific information is not useful in supporting a GRAS determination. Moreover, the Agency is clear that a GRAS panel cannot make trade secret or other nonpublic information the basis for a GRAS determination.
While the GRAS program still stands, this is important guidance for those relying on the GRAS process to support ingredient safety for their products. It may also serve as a roadmap to pressure-test prior self-affirmed GRAS reviews, to critique whether there is too much reliance on the expert panel and not enough on the required data. In any event, we expect that there will be more from FDA as the Human Foods Program is developed and FDA reacts to the Reagan-Udall recommendation to take another look at the GRAS program.
1FDA Proposes Redesign of Human Foods Program to Enhance Coordinated Prevention and Response Activities, FDA Statement (Jan. 31, 2013).
2Report, Operational Evaluation of the FDA Human Foods Program, Reagan-Udall Foundation, at 37 (Dec. 2022).