Conflicts of interest are ‘ubiquitous’ in GRAS determinations, alleges study

Tom Neltner: 'The lack of independent review in GRAS determinations raises concerns about the integrity of the process and whether it ensures the safety of the food supply'

Conflicts of interest are “ubiquitous” in GRAS [Generally Recognized As Safe] determinations, while there are major flaws in a system that allows firms to affirm the safety of food ingredients without the approval - or even the knowledge - of regulators, according to a new study.

The study - which is published in JAMA Internal Medicine and has been challenged by several food safety experts - alleges that in a significant minority of cases, manufacturers are effectively judging their own work.

Between 1997 and 2012, financial conflicts of interest were ubiquitous in GRAS determinations

Using conflict of interest criteria developed by the Institute of Medicine, Tom Neltner and colleagues from the Pew Health Group analyzed 451 GRAS notifications voluntarily submitted to the Food and Drug Administration (FDA) between 1997 and 2012.

They found that 22.4% of the GRAS assessments in question were conducted by an employee of the manufacturer of the ingredient being scrutinized, 13.3% were conducted by an employee of a consultancy selected by the manufacturer and 64.3% by an expert panel selected by a consultancy or the ingredient manufacturer.

“Between 1997 and 2012, financial conflicts of interest were ubiquitous in determinations that an additive to food was GRAS”, claim Neltner et al.

The lack of independent review in GRAS determinations raises concerns about the integrity of the process and whether it ensures the safety of the food supply, particularly in instances where the manufacturer does not notify the FDA of the determination.”

FDA has no central record of GRAS determinations

And as firms choosing to go down the self-affirmed GRAS route are not legally required to notify the FDA that they have done so, the FDA has no central record of all GRAS determinations and no means of checking the quality of the evidence supporting them or the credentials of the experts reviewing that evidence, claim the authors.

Another concern is that if a company does submit a GRAS determination to the FDA, and gets feedback suggesting the agency has significant concerns or questions, it can withdraw its notification voluntarily - and still take its product to market without having to resubmit its data to the agency, they add.

Narrow pool of experts

Finally, an analysis of the composition of the 290 expert panels involved in the 451 GRAS determinations studied shows that they draw on a very small pool of experts, 10 of which served on 27+ panels; one of which served on 128 panels and another on 225 panels, say the authors, who find this “concerning”.

The only way to address these issues is to change the law such that the FDA must be notified of “all GRAS determinations and the financial conflicts of interest of those who make these determinations”,and make this information available to the public, they conclude.

Dr Marion Nestle: ‘The findings are alarming’

Dr Marion Nestle, professor in the department of nutrition, food studies and public health at New York University, said the findings were “alarming”.

An astonishing 100% of the members of 290 expert panels included in their review worked directly or indirectly for the companies that manufactured the additive in question.”

She added: “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.”

GRAS Associates: Our standards for self-affirmed GRAS or GRAS determinations that are voluntarily submitted to the FDA are exactly the same

However, toxicology experts we contacted for comment disagreed with Neltner et al’s conclusions, although some said requiring firms to notify the FDA of all GRAS determinations would address transparency concerns.

Dr Bob McQuate, CEO of Oregon-based GRAS Associates, said: “We have no ownership positions with companies using our services, and our standards for self-affirmed GRAS or GRAS determinations that are voluntarily submitted to the FDA are exactly the same.

“You’ve also got to look at whether the costs of introducing new regulation are commensurate with the benefits given that public health issues are not pushing this issue [Neltner et al provide no evidence that scores of harmful substances have slipped through the net owing to flaws in the GRAS system].”

Meanwhile, the fact that the same names appeared on many panels was not in itself a cause for concern, given that many of the individuals in question were highly-respected toxicology experts with decades of experience and a solid understanding of the GRAS process, he said.

“But this study does raise some legitimate concerns as we know that there are variations in the quality of self-affirmed GRAS determinations”, he acknowledged.

“If a company comes to us for a quote and they don’t like what we tell them it’s going to cost to convene an expert panel of people qualified by training and experience, they can go to someone cheaper, and with no external scrutiny, I can see that the system would allow for possible abuses.”

Spherix Consulting: It is inappropriate for a single employee of a company to sign off on a GRAS determination for that company’s product

Dr Claire Kruger, president, and Dr Nancy Booth, senior science director, at Spherix Consulting (now part of ChromaDex) agreed that it is “inappropriate for a single employee of a company to sign off on a GRAS determination for that company’s product”.

They also agreed that informing the FDA about all GRAS determinations“would improve the transparency of the process”.

However, they also observed that Neltner et al did not provide any evidence that the safety evaluations of the products in question “were inadequate, inappropriate, flawed, or represent a public health risk”.

Meanwhile, the paper's suggestion of using a 'standing expert panel selected by a third party' for GRAS assessments raised more questions than answers, they said.

Who would fund such a panel? How would the membership be selected? And how long would panel members serve such that they would have adequate experience to provide consistency in decision making and yet not be in jeopardy of the appearance of bias due to their long tenure in a ‘paid’ position?”

Marc Ullman, partner at law firm Ullman, Shapiro & Ullman LLP, added: “When you consider the myriad of conflict issues that surround the scientists doing the research for Pharma and the reviewers for publications like JAMA Internal Medicine, this is kind of funny.”

Dr Alex Schauss: The authors are making assumptions based on mistrust, not evidence

Meanwhile, Seattle-based AIBMR Life Sciences, which has helped several firms prepare GRAS determinations for FDA review, notes that Neltner et al “fail to document that ingredients that have achieved GRAS-determination have resulted in harm to the public”.

Senior research director Dr Alex Schauss said: “The authors are making a lot of assumptions based on mistrust, rather than evidence to substantiate the claim that somehow GRAS self-determined ingredients might not have sufficient evidence in support of safety.

“If manufacturers of ingredients seeking GRAS affirmation want to circumvent the integrity of the process as is being implied, how does this explain the remarkable number of companies that ask AIBMR Life Sciences, which does not manufacturer any ingredients or products sold as foods, functional foods, or dietary supplements, or have any secondary interests, to perform an evaluation before it is sent to an impartial independent expert panel?”

As for the “highly acclaimed emeritus professor of toxicology” whose presence on multiple GRAS panels was so concerning to the study’s authors, they “should be pleased that someone of this person's caliber, experience, and expertise, a former editor in chief of one of the most respected journals in toxicology, has been involved in GRAS determinations”, he observed.

Source: JAMA Internal Medicine, published online August 7, 2013. doi:10.1001/jamainternmed.2013.10559.  

‘Conflicts of Interest in Approvals of Additives to Food Determined to Be Generally Recognized as Safe: Out of Balance’

Authors: Thomas G. Neltner JD, Heather M. Alger PhD, James T. O’Reilly JD, Sheldon Krimsky PhD, Lisa A. Bero PhD, Maricel V. Maffini PhD

Commentary by Dr Marion Nestle: Conflicts of Interest in the Regulation of Food Safety’ JAMA Intern Med. Published online August 7, 2013. doi:10.1001/jamainternmed.2013.9158

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Comments (1)

Arun Gupta - 08 Aug 2013 | 12:59

Conflict of Interest is Universal Phenomenon

It is becoming unmanageable and truly universal problem. One of the most recent example is by 'association' The Lancet Series on Maternal and Child Nutrition was launched in June, 2013. Two of its authors declared their conflict of interest as a members of the board of ‘Nestle Creating Shared Value Advisory Committee. The Lancet’s rules on conflict of interest do make a reference to ‘financial’ and ‘personal’ conflict of interests; however, what is not clear is how these rules were applied in this case. Was there any effort made to eliminate or manage conflict of interests, is a question that comes up. Should the readers interpret it as just a coincidence and let it go, considering the honest declaration? Or the authors are of such a repute that cannot be questioned.? And if you dont question , how do you trust ?

08-Aug-2013 at 12:59 GMT

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