Setting the Record Straight on GRAS: Part 2

By Ricardo Carvajal & Diane B. McColl –

In Part 1 of our effort to characterize the principal errors and mischaracterizations underpinning attacks on the GRAS exception, we focused on misrepresentations of the Food Additive Amendment’s legislative history and of the difficulties FDA allegedly faces in identifying and contesting the unlawful use of an ingredient in food.  In that context, we touched on the issue of conflict of interest (COI) in the conduct of GRAS determinations – an issue we take up in greater detail here.

Concerns over COI were expressed in the 2010 GAO report recommending that FDA strengthen its oversight of the GRAS exception.  GAO noted that, although there is guidance to minimize COI among FDA staff and individuals who serve on scientific and advisory panels, there is no guidance on COI “that companies can use to help ensure that the members of their expert panels are independent in their determinations of GRAS status.”   As noted in the report, companies sometimes use expert panels to demonstrate consensus for a GRAS determination – a particularly useful course of action when there are no secondary sources that evaluate the primary literature, or when a published study warrants interpretative analysis. 

GAO’s analysis of the potential for COI focused primarily on factors that could compromise an expert panel’s independence, such as “corporate or financial affiliations that could bias their decisions.”  GAO was concerned that, in such scenarios, an expert panel decision relied on by a company could be tainted by an expert panel member’s COI in much the same way as an advisory panel recommendation relied on by FDA could be tainted by an advisory panel member’s COI.  However, in drafting its recommendations, GAO used language that suggested the need to address the potential for COI more broadly: FDA should “develop a strategy to minimize the potential for conflicts of interest in companies’ GRAS determinations, including taking steps such as issuing guidance for companies on conflict of interest and requiring information in GRAS notices regarding expert panelists’ independence” (emphasis added).  Thus, GAO set the stage for consideration of at least two conceptions of COI.  The first conception is narrowly concerned with the potential for COI in expert panel decisions.  The second conception is more broadly concerned with the potential for COI in GRAS self-determinations generally.

In its response to the GAO report, FDA focused primarily on the narrow conception of COI in relation to expert panel decisions.  FDA noted that the agency’s review of a GRAS notice containing an expert panel report encompasses “the totality of the publically available and corroborative evidence about the safety of the substance for its intended use, including favorable and potentially unfavorable information.”  FDA further noted that “the use of an expert panel is one way to demonstrate consensus,” and that the agency “does not consider the view of an expert panel alone to be determinative for establishing safety.”  FDA made clear that, if it finds deficiencies in the composition of an expert panel or in the panel’s consideration of the data and information, the agency takes those deficiencies into account in reviewing and responding to the GRAS notice. 

However, FDA’s response also paid a nod to the broader conception of COI in GRAS self-determinations generally:

FDA recognizes that, because the notifier has an inherent interest in the outcome of its GRAS notice, there is the potential for a conflict of interest (this is also true for food additive petitions).  To address this concern, GRAS determinations are required to consider the totality of the publically available information, including potentially unfavorable information.

(Emphasis added.)  In other words, it is a given that a company interested in marketing a substance for a new use has an interest in establishing a regulatory basis for the use of the substance, but that interest is at play regardless of whether the company pursues a GRAS self-determination or a food additive approval.  That interest is kept in check by the regulatory requirement that the company consider all information that has a bearing on the safety of the proposed use.  Any company that fails to ensure the rigor and comprehensiveness of its GRAS determination or food additive petition does so at the risk of violating that requirement.  As we noted in our prior posting, the consequences could be severe, as the products in question could be deemed adulterated by virtue of being or containing an unapproved food additive.

How FDA conceives of the potential for COI has significant implications for any steps the agency might take to address it.  FDA has indicated its intent to focus on the narrow conception of COI (CFSAN’s plan for program priorities states that the agency intends to “publish draft guidance on conflict of interest for experts participating on GRAS panels” in 2014).  If that holds true, then industry can expect the agency to propose criteria for the consideration of the potential for COI in establishing expert panels.  The impact of those criteria would need to be carefully thought out, as overly restrictive criteria could have the effect of limiting the use of those experts most qualified to opine on the safety of the use of a substance – a particularly perverse consequence given the statutory requirement that GRAS status be based on general recognition of safety by qualified experts.  This concern is of little consequence if one regards the pool of available qualified experts as large (PEW’s publication on COI blithely noted that “[t]here are multiple schools offering food science, toxicology and risk assessment degrees, and the Institute of Food Technologists has certified 1200 food scientists”).  In our experience, the pool of available qualified experts is quite small, such that any unnecessarily restrictive standards for evaluating COI could significantly hamper the conduct of GRAS self-determinations generally.

Although even a narrowly targeted initiative on COI could have significant consequences, PEW (and now NRDC) are after much bigger game.  They have urged FDA to adopt a very broad conception of COI that sees the potential for COI in essentially all GRAS self-determinations, and that entirely discounts the value of post-market controls.  In doing so, they draw on a framework of questionable relevance, namely that set forth in the Institute of Medicine’s report on COI in medical research, education and practice (perhaps not coincidentally, COI in medicine is also of significant interest to PEW).  That framework was devised to address issues and concerns particular to the health care sector, in which life-or-death decisions are often made on the basis of data that often are not publicly available, and in which financial incentives that can skew decision-making are orders of magnitude greater than in the food sector.

Not surprisingly, PEW/NRDC’s prescriptions belie an underlying preference for mandatory premarket review of all GRAS self-determinations – a preference at odds with the fact that NRDC has questioned the competence of FDA’s evaluation of GRAS notices and of food additive petitions.  In any event, as we’ve noted elsewhere, mandatory premarket review is both unattainable and unworkable in the absence not just of a statutory amendment, but of a funding mechanism as well.  Those are tall orders in the current fiscal and political environment.

From our perspective, the controversy over COI in GRAS self-determinations is largely manufactured – designed to sow public confusion and anxiety in support of a broader attack on a regulatory program that has proven itself to be remarkably efficient and effective.  The next move is FDA’s, and we look forward to seeing how the agency addresses the COI issue in its forthcoming guidance.