Broken GRAS: Undermining the safety of dietary supplements and food

Tom Neltner, Chemicals Policy Director and Maricel Maffini, consultant

Over the years, we have seen a disturbing approach being taken by some dietary supplement companies to circumvent the Food and Drug Administration’s (FDA) oversight. Their strategy undermines both dietary supplement safety and food safety. These companies are leveraging FDA’s decision to allow manufacturers to secretly self-certify food chemicals as Generally Recognized as Safe (GRAS) in order to:

1. Bypass mandatory new dietary supplement ingredient (NDI) notice requirements; and
2. Expand their market from dietary supplements into conventional food.

We have long-challenged FDA’s interpretation of the GRAS exemption in the Food Additives Amendment of 1958 because it results in the agency being unable to fulfill its statutory duty to ensure food is safe.[1] When Congress passed the amendment, the GRAS exemption was expected to be for common substances like oils and vinegar. In this blog, we explain how the agency’s flawed approach to GRAS also undermines the safety of dietary supplements.

We call on FDA to revise its GRAS rule to close the loophole it created in 1997 and codified in 2016. Eliminating secrecy by requiring manufacturers to submit safety information would enable the agency to ensure both dietary supplements and foods are safe. If it doesn’t, Congress should clarify that FDA’s GRAS rule violates the law. As a stopgap measure, FDA needs to improve transparency around its assessment of voluntary GRAS notices it receives and use its enforcement authority to stop the misuse of GRAS.

Apoaequorin as a prime example of GRAS undermining both dietary supplement and food safety

An excellent example of the problem is apoaequorin, a controversial chemical commonly marketed as the dietary supplement Prevagen. An October 2020 article in Wired tells the saga in detail. We are focused on the GRAS-aspects of the story but need to briefly mention that FDA twice objected to the company’s NDI notices in 2008 and 2012 for a litany of reasons that include safety concerns. The agency also took a series of enforcement actions that the company claims have been resolved.

A year after FDA objected to the second NDI notice, Quincy Bioscience began selling NeuroShake – a protein shake containing apoaequorin – as conventional food, presumably based on a self-certification that the chemical’s use in dairy products was GRAS. In doing so, it no longer needed an NDI notice if the dose of the chemical in food is similar to what it will offer as a dietary supplement. The company effectively leveraged the GRAS loophole to avoid FDA review of the chemical as a new dietary supplement ingredient.

In late 2014, the company submitted to FDA a voluntary GRAS notice for conventional food use, relying on an expert panel it hired to review the safety information.[2] The notice stated that there had been more than 2,200 instances of user-reported adverse health effects from the chemical’s use as a dietary supplement. The reports, primarily consumer complaints, describe memory impairment, anxiety, hypertension, headaches, dizziness, insomnia, nausea, and diarrhea. The company identified 26 reports as “serious adverse events,” mainly neurological and cardiovascular problems. Despite these reports, two physicians hired by the law firm that filed the notice for the company concluded that apoaequorin was likely not the cause of the serious adverse events. One of the physicians found that “there is no alarming pattern of [serious adverse events] which would indicate a safety concern.” The other said he “found no pattern of events that led me to think there was a particular safety problem with the product.”

The company withdrew the notice in 2015. However, this withdrawal did not preclude the company from selling its product. And, as it does for all withdrawals, FDA did not make public any safety concerns with the product. According to the Wired article, FDA had concerns and sent Quincy Biosciences a letter questioning the safety of its NeuroShake stating, “we are concerned about the safety of your apoaequorin products because of, among other things, the large numbers of adverse events reported for them.” The company continues to offer Neuroshake for sale.

We await FDA’s response to our Freedom of Information Act (FOIA) request for its assessment of the GRAS notice and communications with the company[3] about apoaequorin.

Not an isolated incident

While the apoaequorin story is unusually egregious, it is not an isolated incident. In 2014, the Natural Resources Defense Council’s (NRDC) “Generally Recognized as Secret” report[4] identified 275 chemicals from 56 companies that appeared to be marketed for use in food based on undisclosed GRAS safety determinations. The report “found that almost all of the chemicals NRDC reviewed were also ingredients in dietary supplements and served no essential purpose in food other than to attract consumers’ attention.” It noted that “several dietary supplement manufacturers appear to be making a GRAS determination to avoid having to notify the FDA under both [the Dietary Supplement Health and Education Act of 1994] and the Food Additives Amendment of 1958.”

The situation did not change after NRDC’s 2014 report. We reviewed 78 voluntary GRAS notices that companies submitted to FDA for review between May 2014 and August 2021 but then withdrew the request. After removing duplicates there were a total of 46 GRAS substances of which 13 were marketed as dietary supplement ingredients. See a few examples in the table below.

GRAS substances have higher safety standard, but NDI has mandatory notice to FDA

In theory, a chemical must meet a more protective safety standard for its use in food to be considered GRAS as compared to its use as a new dietary supplement ingredient. A substance can only be considered GRAS if there is “a reasonable certainty in the minds of competent scientists that the substance is not harmful” considering three factors including “cumulative effect of the substance in the diet, taking into account any chemically or pharmacologically related substance or substances in such diet.” In contrast, a new dietary ingredient can only be use if it is “reasonably expected to be safe.” In other words, to be GRAS, there must be a reasonable certainty of no harm as compared to for NDIs where there need only be a reasonable expectation of safety.

Despite the differences in safety standards, in reality, many GRAS substances do not go through a rigorous safety review. FDA allows companies to self-certify the GRAS substance’s uses as safe in secret using staff, consultants, or an expert panel it has hired with no consideration to conflicts of interest or bias.

Even when the GRAS safety determination is voluntarily submitted to the agency and published, if FDA raises concerns, as with apoaequorin, the company can simply withdraw the notice and continue using the chemical in food. The agency’s concerns are only made public if someone chooses to request this information under FOIA. In addition, FDA is sensitive to demanding too much information because it does not want to discourage future notifications; as an agency reviewer said “[w]e cannot require anything, as this is a voluntary program and we don’t want to frighten anyone away”

Daniel Fabricant, a former director of FDA’s Dietary Supplement Program and current president of the trade group Natural Products Association, said in the context of apoaequorin that “GRAS is pretty compelling, especially if it’s published. My guess is that somebody higher up in the [Center for Food Safety and Applied Nutrition] looked at that and said we can’t make a case” The Wired article also quoted Robert Durkin, Fabricant’s successor at the agency, as saying “once this happens [apoaequorin entering the food supply via NeuroShake], the agency’s original position back in ‘07, that the ingredient in question isn’t a dietary ingredient, that argument goes away.” Through Durkin’s statement, FDA acknowledges that Quincy Bioscience successfully leveraged the GRAS loophole and circumvented agency oversight of its NDI notice requirement. In their quotes, neither Durkin nor Fabricant acknowledged that the company had withdrawn the GRAS notice.

In contrast to GRAS, the NDI notice is mandatory. It must be submitted at least 75-days before the product goes to market, and the agency makes a formal assessment that is public. There is no option for withdrawal.

Not surprisingly, the rates at which FDA accepts GRAS notices and NDI notices are starkly different, supporting the idea that mandatory agency review with a formal assessment makes a difference. FDA effectively objects to or allows to be withdrawn to avoid an objection for less than 20% of GRAS notices.. In contrast, FDA objects to more than 60% of NDI notices. According to an industry lawyer who said at a 2020 conference that “you were uncertain of what the standards for evaluation were going to be, it felt like the bar was being set impossibly high, and so people started looking for an alternative. And that’s when we see the rise of interest in the GRAS self-determination process.”

Is there a solution to the broken GRAS system?

After FDA adopted the 1997 proposed GRAS rule, we saw a tremendous increase in reliance on the GRAS notice. Formal petitions dropped dramatically in favor of voluntary GRAS notices. Now we see the GRAS rule undermining dietary supplement safety.

The agency needs to revise its rules to fix the GRAS system. If not on its own accord, then in response to a potential court decision or a legislative mandate that makes clear than FDA’s GRAS rule violates the law.

In the meantime, as a stopgap measure to improve transparency and help reduce misuse of the GRAS exemption, FDA needs to publicly post online its assessment of a chemical’s safety even if a notifier asks the agency to cease evaluating it This will help food manufacturers recognize potential problems with the substance and avoid using it without a more careful investigation. There is nothing in the rules that limit release of the agency’s assessment.

Conclusion

When Congress passed the Food Additive Amendment of 1958, the GRAS exemption was expected to be for common substances like oils and vinegar. In 2011, we showed that most new food chemicals were not reviewed by FDA for safety as food additives but were allowed to be used in our food supply by means of  industry certifications that the chemicals they produced are GRAS; indeed, we  estimated that there were at least 1000 chemicals determined to be GRAS without notice or review to FDA.

FDA’s expansive interpretation of the GRAS exemption provided the dietary supplement industry with a path that allows chemicals of unknown safety to enter the food supply without accountability, leaving consumers in the dark and undermining both dietary supplement safety and food safety.

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[1] When the agency finally formalized its approach in a 2016 rule, EDF, represented by Earthjustice and Center for Food Safety, challenged the rule and are awaiting a court decision.

[2] FDA’s 2016 rule does not protect against this type of conflicts of interest or even require an expert panel. In 2017, FDA issued a draft guidance on best practices to convene a best panel that would, if followed, limit this practice. But the agency has not finalized the guidance after four years.

[3] As well as 45 other withdrawn GRAS notices.

[4] The authors of the blog were also the authors of the NRDC study.