As promised in the August 17, 2016 "generally recognized as safe" (GRAS) Final Rule (81 Fed. Reg. 54960), FDA has released a draft guidance for public comment on the use of an expert panel to demonstrate common knowledge among qualified experts of the safety of a substance under the conditions of its intended use. The November 15, 2017 draft guidance, titled "Best Practices for Convening a GRAS Panel: Guidance for Industry," addresses a recommendation from the U.S. Government Accountability Office (GAO) February 2010 "Report to Congressional Requestors: FDA Should Strengthen Its Oversight of Food Ingredients Determined to Be Generally Recognized as Safe (GRAS)," Report No. GAO-10-246; namely that FDA issue guidance on conflicts of interest when convening GRAS Panels. Comments on the draft guidance are due by May 15, 2018 to assure they are considered by FDA before the guidance is finalized.
The draft guidance provides an intricate discussion of various conflicts and appearance issues and suggests flexible approaches for identifying and managing these issues, as well as other strategies to enhance the credibility of a GRAS panel. "Appearance issues" are a newly distinguished concern with respect to potentially affecting the credibility of GRAS panels. FDA's recommended best practices are drawn from its guidance for assuring the impartiality and independence of FDA advisory committees, and the policies of several organizations on handling conflict of interest and appearance issues to address bias, balance of expertise, and related topics. Some of FDA's recommended steps in convening a GRAS Panel include:
- Implement a written GRAS panel policy with documentation and transparency regarding the selection and vetting of each member of the GRAS panel;
- Identify GRAS panel members who have appropriate and balanced expertise;
- At a minimum, such as when the available data and information relevant to the intended conditions of use of the substance raise no safety questions that experts would need to interpret and resolve, include members with expertise in chemistry or biochemistry, toxicology, and exposure assessment;
- Include only unrelated third parties with no financial interest in the outcome of the panel's deliberations on a GRAS panel;
- Permit an employee, attorney, or other individual closely associated with the proponent of the GRAS conclusion to serve only in the capacity of a scientific advisor to the GRAS panel and only in circumstances where such a person's specialized knowledge would be helpful;
- Minimize the amount of non-public information provided to a GRAS panel (except that all data and information that could raise a safety question should be provided to the GRAS panel) and if any confidential details are provided to the GRAS panel, explain in a GRAS notice (preferable) or otherwise document how a GRAS conclusion is possible without public availability of such data or information;
- Identify in deliberations and in the GRAS panel's report the particular data or information that form the basis of each member's opinion on whether the intended use of the substance is safe (each member should do this personally);
- Document the available data and information that the GRAS panel reviewed, how the GRAS panel handled its deliberations, and the basis for the conclusion in the report by the GRAS panel;
- Follow the draft guidance on GRAS panels in the event a GRAS panel is convened for GRAS conclusions that will not be submitted to FDA as well; and
- Do not make any honorarium provided to a member of a GRAS panel contingent on the outcome of deliberations by a GRAS panel.
The circumstances, if any, under which FDA anticipates reviewing the recommended documentation noted above - on the selection and vetting of each member of a GRAS panel - are not mentioned in the draft guidance. Specifically, there is no indication that such information should be included in a GRAS notice. Further, while FDA encourages transparency and making public the written procedures for organizing and managing a GRAS panel, there is no explicit recommendation to include the procedures in any GRAS notice that may be submitted.
Further, the use of a GRAS panel is clearly voluntary. In this regard, the draft guidance on convening GRAS panels repeats an observation that also appears in FDA's GRAS Final Rule and elsewhere. Specifically, "A GRAS panel is one mechanism that proponents have used to demonstrate that the safety of a substance under the conditions of its intended use is generally recognized by qualified experts. However, the use of a GRAS panel is not the only mechanism for doing so and the use of a GRAS panel does not necessarily mean that the GRAS criteria have been met." See 81 Fed. Reg. 54960 at 54974-75 (Aug. 17, 2016).
A second guidance document titled "Regulatory Framework for Substances Intended for Use in Human Food or Animal Food on the Basis of the Generally Recognized as Safe (GRAS) Provision of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry" was issued on November 15, 2017, the same day as the draft guidance on GRAS panels was issued. This guidance document reiterates FDA's comments, advice, and recommendations on meeting the GRAS criteria that are already available in the preamble discussion from FDA's GRAS Final Rule. Key points include FDA's advice to voluntarily submit a GRAS notice for FDA oversight, and the recommendation to use the framework for a GRAS notice (seven parts) for independent GRAS conclusions as well.
Importantly, regarding the validity of independent GRAS conclusions, the GRAS Final Rule and both of FDA's November 2017 guidance documents recognize that the definition of a "food additive" under Section 201(s) of the Food, Drug, and Cosmetic Act (21 U.S.C. 321(s)) excludes GRAS substances. GRAS substances, therefore, are not subject to mandatory premarket review by FDA under section 409 of the Federal Food, Drug and Cosmetic Act (FD&C Act; 21 U.S.C. 348). As noted in FDA's response to the 2010 GAO report, however, FDA believes that its ability to oversee the safety of added food ingredients, including GRAS substances, would be enhanced if the manufacturer were required, prior to marketing any new substance or new use of an existing substance, to notify FDA and submit scientific evidence demonstrating the safety and legality of the intended use. Despite the GAO report and FDA's comments, there is no imminent action by Congress to make the submission of GRAS conclusions to FDA mandatory, or to otherwise modify the GRAS provision of the FD&C Act or provide funding for FDA to audit companies to confirm agreement with independent GRAS conclusions.