The perspective by Pieter Cohen, MD, from Cambridge Health Alliance and Harvard Medical School, and Emily Broad Leib, JD, from the Food Law and Policy Clinic at Harvard Law School, focuses on the FDA’s Generally Recognized As Safe (GRAS) approach to ingredients.
Food ingredient companies have two approaches for their novel products: The first approach is to notify the FDA via a detailed dossier, which the Agency evaluates and decides 1) it does not have any questions (and issues a so-called good day letter) or 2) it does not have sufficient information to support the GRAS determination. The petitioner may also withdraw the notification, whereby FDA will cease to assess the notice. The FDA makes these notifications and its decisions public via the GRAS Notice Inventory.
The second approach is to self-affirm the GRAS status of an ingredient by convening an independent expert panel to review the safety data. The company is not required to notify the FDA or make these self-affirmations public (although some companies do issue press releases).
Cohen and Broad Leib note that the GRAS pathway was “originally conceived as a designation that could allow commonly used food ingredients, such as vinegar and baking powder, to remain on the market. But over time, the GRAS exception has increasingly been applied to not only well-known food ingredients but also various new substances used to affect the flavor, texture, or shelf life of products or used as substitutes for meat, eggs, or nuts”.
They subsequently claim that companies today “overwhelmingly choose to bypass the formal approval pathway for food additives and instead introduce new substances that they have privately determined to be GRAS.”
“This is unfortunately a very accurate account of the current state of GRAS review," said Scott Bass, partner at Sidley Austin LLP, and founder of the firm’s Global Life Sciences and Food and Drug Law practices in the United States, China and Europe. "And the same lax standards that some irresponsible manufacturers follow with the help of outside advisors plays even more strongly in the dietary supplement context.”
The tara flour incident
To highlight shortcomings in the GRAS process, Cohen and Broad Lieb highlighted cases of liver injury in 2022 linked to production of a new ground-beef substitute. An extensive investigation revealed that the product only contained what was listed on the label and there were no manufacturing problems or contamination issues. The cause of the problems was eventually linked to the presence of a new ingredient: tara flour.
“Nearly 2 years later, in May 2024, the FDA completed an independent safety evaluation of tara flour, finding that it was not 'generally recognized as safe' (GRAS) and, therefore, is an unapproved food additive," Cohen and Broad Leib wrote. "Before the new ingredient was introduced into the food supply, the FDA hadn’t vetted tara flour, nor had toxicologic studies assessing its safety been published.
"In the case of tara flour, the chief supply-chain officer of the company that distributed the ground-beef substitute explained that the ingredient had been used after a U.S. importer claimed that it was GRAS."
The tara flour incident should "serve as a warning that the agency’s laissez-faire approach to monitoring the safety of ingredients under its authority poses a threat to public health,” they wrote.
Recommendations
In the final part of their Perspective, Cohen and Broad Lieb called for FDA to take "proactive steps to ensure the safety of new food substances," among which should be the requirement that all GRAS determinations are shared with the FDA.
"We believe the FDA has the regulatory authority to enact these requirements, even in light of recent Supreme Court jurisprudence limiting deference given to agencies," they wrote, referring to the June 28 opinion by the U.S. Supreme Court in Loper Bright Enterprises v. Raimondo to overturn 40 years of deference to administrative agencies as held by Chevron U.S.A. Inc. v. Nat. Res. Def. Council, Inc.
Even if the Agency does not think it has the authority to do this, FDA could petition Congress for this, they said.
Cohen and Broad Lieb also called on the FDA to systematically revisit the safety of previously introduced GRAS substances, as the Government Accountability Office recommended in a 2010 report.
“In the absence of FDA action, states such as California have banned certain food additives, and lawmakers in Illinois and New York recently proposed similar bans; a bill recently introduced in New York would require manufacturers to publicly post the evidence supporting a GRAS determination before marketing a new ingredient in that state,” Cohen and Broad Lieb noted.
GRAS and NDI
Commenting on the new perspective, Loren Israelsen, founder and president of the United Natural Products Alliance (UNPA), told us: “Dr. Cohen is right to urge FDA to begin a systematic process of reviewing old (we are talking 50 years in many cases) food additive and GRAS approvals/recognitions. This month the FDA will hold a public meeting to tell us what they plan to do about this.
"GRAS affirmation is a bit trickier as we have to calculate the problems around the NDI [New Dietary Ingredient] process which is not final after 30 years, and many feel has drifted from the intent of the authors of DSHEA.
"GRAS has been an avenue to move dietary ingredients into the market given the disagreements around the NDI process, which is a logical response given the lack of finality or agreement on NDI notifications."
Israelsen added that not all GRAS affirmations are created equal and this should be addressed both within the dietary supplement industry and by FDA.
"While Pieter and I have butted heads a few times, I think his perspective is accurate and timely," he said.
Source: New England Journal of Medicine
Published online ahead of print, doi: 10.1056/NEJMp2403165
“Ingesting Risk — The FDA and New Food Ingredients”
Authors: P.A. Cohen, E.M. Broad Leib,