By Mark L. Itzkoff
As someone who has worked with numerous food companies on food additive and GRAS issues for 25 years, I read with interest the August 7, 2013, article, Conflicts of Interest in Approvals of Additives to Food Determined to Be Generally Recognized as Safe, in JAMA Internal Medicine. The article reports on a study conducted by the Pew Charitable Trusts (Pew) on conflicts of interest in the determination of GRAS (generally recognized as safe) status of food ingredients. Pew is currently conducting “a comprehensive assessment of the FDA’s regulatory oversight of chemicals added to food” and has called for a reconsideration of the GRAS process.
The study, which was covered by USA Today and other mass media, raises some important issues regarding the process used to establish GRAS status, such as the over-reliance on a limited number of experts to make GRAS determinations. However, the study’s conclusion that “there is a lack of independent review in GRAS determinations” appears to be based on a misunderstanding of how GRAS status is established. The author overestimates the discretion of expert panels who evaluate the information used to make GRAS determinations.
Under the Federal Food, Drug, and Cosmetic Act (FFDCA), a “food additive” may not be used as a food ingredient unless the additive has been cleared by FDA for such use under an applicable food additive regulation. However, a substance that is “generally recognized, among experts …, as having been adequately shown through scientific procedures … to be safe under the conditions of its intended use” is not a food additive and, therefore, not subject to the mandatory pre-market clearance for food additives. Such substances are commonly referred to as GRAS (generally recognized as safe).
A GRAS determination made by a food ingredient supplier prior to marketing a new food ingredient or marketing an ingredient for a new application is commonly called a “GRAS self-determination.” The supplier may market the ingredient based on the self-determination without any interaction with FDA, or may voluntarily submit a GRAS Notification to the agency. In either case, a GRAS determination will often include the opinion of an “expert panel.”
The PEW study reviewed the 451 GRAS Notifications that have been submitted to the Food and Drug Administration (FDA) under the GRAS Notification Program since the inception of that program in 1997. Unsurprisingly, the authors found that all of the safety determinations had been made by either an employee of the manufacturer, an employee of a consulting firm hired by the manufacturer, or an expert panel selected by either the manufacturer or the consulting firm. The authors concluded that this relationship results in a conflict of interest.
It is important to understand the role of the expert panel in preparing the GRAS determination. The panel has two responsibilities: (1) to determine that published information on the food ingredient and similar compounds, both positive and negative, is sufficient to conclude that the proposed use of the food ingredient is safe, and (2) to determine whether there is a consensus among qualified experts regarding the safety of the ingredient. See FDA, Substances Generally Recognized as Safe; Proposed Rule (GRAS Proposal), 62 Fed. Reg. 18938 (April 17, 1997). Neither the panel nor its members conduct the actual safety studies or write the articles on which the panel’s determination is based.
The Pew report gives the impression that food manufacturers make GRAS determinations without any independent review. In the Pew Trusts article, the authors state that “[t]o qualify for a GRAS determination, manufacturers of additives must conclude that the use of the additive is safe.”
What the authors do not take into account is the fact that the safety evaluation in a GRAS determination must be based on peer-reviewed data that has been published in scientific journals.
Before an article is published in a peer-reviewed journal, it is examined by independent experts in the same field. When the article reports on scientific studies, such as toxicology studies, the experts review the study methodology, test data, and validity of any conclusions reached in the article. This is similar to the review that would be performed by FDA if the study were submitted to support a food additive petition. Thus, contrary to Pew, the data used to support a GRAS determination is subject to independent review before it is even considered by the expert panel.
Further, the expert panel has limited discretion when evaluating the sufficiency of the available data. The minimum data requirements for food ingredient applications are set forth in FDA regulations and guidance documents. A substance is not GRAS unless there is sufficient published toxicology data to meet these requirements.
The Pew study also concludes that employees of manufacturers or consulting firms selected by the manufacturer have significant discretion “especially if safety data are limited.” However, under FDA requirements, the expert panel has very limited discretion, particularly when only limited data is available. FDA regulations require that GRAS status be based on “the same quantity and quality of scientific evidence as is required to obtain approval of a food additive regulation …” 21 C.F.R. § 170.30(b). For a food additive petition, i.e., a petition asking FDA to approve a new food additive, the requirements are published in Guidance for Industry and Other Stakeholders Toxicological Principles for the Safety Assessment of Food Ingredients, commonly called “The Redbook.” For added clarity, the minimum toxicology data required to demonstrate the safety of a new food additive, and therefore the GRAS status of a food ingredient, is detailed in Section III of the Redbook and summarized in Guidance for Industry: Summary Table of Recommended Toxicological Testing for Additives Used in Food. Thus, the toxicology data required before a substance may be deemed to be GRAS are clearly set forth, and the members of the expert panel reviewing the data actually have limited, if any, discretion.
Finally, under the definition of conflict of interest used in the Pew study, any person who works for an ingredient supplier or a consulting firm hired by the ingredient supplier has a conflict of interest. The only logical conclusion to be drawn from this definition of conflict of interest is that it is necessary to eliminate GRAS “self-determinations,” so that all decisions on the safety of food ingredients would need to be made by FDA. Not only is this inconsistent with the definition of “food additive” in the FFDCA, it would also place a major new responsibility on an agency with limited resources, and would likely result in a return to the near glacial pace of GRAS affirmations experienced in the late 20th century.
