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Report Questions Independence of Experts in GRAS Determinations

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CHICAGOAre experts who make determinations about the safety of food ingredients biased?   

A report published in JAMA Internal Medicine cites widespread conflicts of interest in cases in which experts determine whether an additive is "generally recognized as safe" (GRAS). GRAS determinations are helpful to food manufacturers because they excuse the businesses from the requirement to obtain pre-approval from FDA before introducing a substance into the market.

"We found no instances where a manufacturer who submitted a GRAS notice to the FDA used a standing expert panel selected by a third partythe method least likely to involve a conflict of interestto establish whether an additive met the GRAS criteria," authors with The Pew Charitable Trusts wrote in the report (Conflicts of Interest in Approvals of Additives to Food Determined to Be Generally Recognized as Safe Out of Balance").

Still, Pew researchers acknowledged conflicts of interest don't necessarily mean experts are biased.

"I understand that theoretically conflicts of interest could exist," Robert McQuate, Ph.D., co-founder and CEO of the consulting firm GRAS Associates LLC, said in an interview. "I don't see the conflict of interest topic as having a major impact on the food supply."

Expert Panels Crucial

Expert panels often consisting of three individuals play the central role in making GRAS determinations under FDA regulations. Companies may submit such determinations to FDA, which has authority to evaluate the science and disagree with a panel's conclusion. McQuate estimates 15 to 20 percent of submissions are withdrawn because of questions FDA raises.

However, the GRAS submissions are voluntary, giving companies the right to introduce a food ingredient so long as their experts have made a GRAS determination. And once a company determines a food ingredient is safe, it "may market the substance, even if FDA finds that the notice does not provide a sufficient basis for a GRAS determination," according to a 2010 report from the U.S. Government Accountability Office (GAO).

The regulatory process was more cumbersome in the 1990s before FDA implemented changes. The agency no longer affirms that a substance has been GRAS, although a "no questions letter" from FDA in response to a GRAS submission is "as close as you are going to get to approval from FDA," McQuate said. (This is a letter in which FDA states it has no questions about the companys conclusion that the substance is safe).

"For a substance to be GRAS, the scientific data and information about the use of a substance must be widely known, and there must be a consensus among qualified experts that those data and information establish that the substance is safe under the conditions of its intended use," FDA officials explained in an article that was republished on its website.

Dietary supplement firms that want to introduce a new ingredient into the market follow a different regulatory process. However, there is a connection to GRAS. In draft guidance issued two years ago, FDA stated that if a substance is GRAS or an approved food additive and used in food, the substance can be added into a dietary supplement without submitting a so-called new dietary ingredient (NDI) notification, McQuate explained.

Are Opinions Biased?

In the report that was published Wednesday, researchers raised the question as to whether the GRAS determinations are biased based on the experts' relationships with food manufacturers. Thomas Neltner of The Pew Charitable Trusts and his colleagues used conflict of interest criteria developed by a committee of the Institute of Medicine (IOM) to analyze 451 GRAS notifications that were voluntarily submitted to FDA between 1997 and 2012.

Among their findings: 22.4 percent of the safety assessments were made by an employee of an additive manufacturer; 13.3 percent by an employee of a consulting firm chosen by the manufacturer; and 64.3 percent by an expert panel tapped by either a consulting firm or the manufacturer.

Of the 290 panels that made the GRAS determinations, researchers found 10 individuals served on 27 or more panels while one person was a member of 128 panels. Another individual served on 225 panels.

As the researchers posit, "the lack of independent review in GRAS determinations raises serious questions about the public health implications of unregulated additives in the food supply, particularly the additives that the FDA does not even know about," Marion Nestle, Ph.D., M.P.H., of New York University, wrote in related commentary. "It also raises questions about conflicts of interest in other regulatory matters."

Multiple Factors Influence Decisions   

But the Pew researchers acknowledged they did not examine whether the conflicts of interest actually influenced the decisions of experts, observed Duffy MacKay, N.D., vice president, scientific and regulatory affairs with the Council for Responsible Nutrition (CRN).

"While conflicts of interest represent a potential bias, raising the issue is not a determination that actual bias exists," Pew's Food Additive Project cautioned in a draft document that was circulated Wednesday during a meeting with stakeholders to discuss the report. 

MacKay said other factors, such as the experts' reputation and strong interest of food manufacturers to introduce only safe ingredients, may influence the experts to give candid assessments.

The experts "have a lot of forces at play that will force them to be true to the science," he said. "There is a system in place that creates credibility and transparency."

McQuate, for instance, cites instances in which his firm has determined that a food substance is not safe.

"We're very careful to make sure we don't tell a potential customer, 'if you want GRAS, we will give it to you,'" he said. "There are times when the data simply don't support a GRAS conclusion, and we are not willing to comply with the client's wishes if the safety documentation isn't there."

Still, McQuate acknowledged that employees of food manufacturers may feel pressured to give favorable assessments.

Pew's Food Additive Project recommended that conflicts of interest should be revealed to FDA for its review and that an expert should refrain from conducting a GRAS evaluation if the person would be ineligible to serve on an FDA advisory committee without an agency waiver because that individual had "disqualifying financial interests."

GRAS Critiques Date Back Years  

This isn't the first time the integrity of the GRAS process has been questioned. For example, in a 2010 report, the U.S. GAO (Government Accountability Office) recommended FDA conduct randomized audits and other measures to strengthen oversight of the process.

The Pew Health Group argued federal law limits FDA's ability to effectively regulate substances added to food. For instance, it declared the 1958 Food Additives Amendment does not require food manufacturers to notify FDA when health reports suggest there are new hazards linked to additives that are already used in food.

From 1990 through 2010, roughly one-third of the more than 10,000 substances that may be added to food represented GRAS determinations, according to a 2011 report ("Enhancing FDA's Evaluation of Science to Ensure Chemicals Added to Human Food Are Safe: Workshop Proceedings") that was published in the peer-reviewed journal Comprehensive Reviews in Food Science and Food Safety and spearheaded by The Pew Health Group.

Antonia Mattia of FDA and Robert McQuate of GRAS Associates LLC will discuss FDA's current GRAS practices and related food-safety issues during a session at SupplySide West in Las Vegas on Nov. 14.

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