On April 18, 2022, the Food and Drug Administration (FDA) issued a draft guidance document outlining the agency’s proposed approach to evaluating the public health importance of food allergens that are not among the nine major food allergens listed in the Federal Food, Drug and Cosmetic Act (FDCA) (non-listed allergens). FDA intends this guidance to assist in evaluating whether to establish regulatory requirements (eg, labeling or other disclosure requirements) for a particular non-listed allergen based on public health importance.

While the FDCA only requires that the nine major food allergens – milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, soybeans, and, as of January 1, 2023 sesame – be declared as allergens on a food label, FDA recognizes that these nine allergens do not currently represent all foods that can trigger allergic responses that potentially pose serious human health risks. FDA’s draft guidance sets out the agency’s proposed approach to evaluating the public health importance of non-listed food allergens to inform decisions on potential regulatory requirements for such allergens. The guidance focuses specifically on immunoglobulin E antibody (IgE) -mediated food allergies, which are the most severe food allergies because they can cause anaphylaxis and be life-threatening. FDA identifies the types of evidence that can establish a food as a cause of IgE-mediated food allergy and other key scientific factors that FDA intends to consider. The draft guidance also provides recommendations for identifying and evaluating the relevant body of evidence applicable to the scientific factors that FDA lists, and describes how FDA generally intends to weigh such evidence in assessing the public health importance of a particular allergen.

Importantly, the draft guidance states that FDA may elect to evaluate the public health importance of a non-listed allergen on its own initiative, or in response to a citizen petition requesting that FDA establish regulatory requirements for such an allergen. FDA specifically directs petitioners to identify and evaluate information relevant to the scientific factors in the guidance in order to facilitate such requests. If FDA concludes that the public health importance of an allergen requires a label disclosure under sections 201 (n) and 403 (a) (1) of the FDCA, FDA could undertake rulemaking or could recommend such a disclosure through guidance. As an example, prior to the Food Allergy Safety, Treatment, Education, and Research (FASTER) Act amendment to add sesame to the major food allergen definition, FDA issued guidance recommending that manufacturers voluntarily label for sesame under certain circumstances. Below, we provide a high level summary of key recommendations in the draft guidance. Interested stakeholders should consider submitting comments to FDA on or before the due date of August 17, 2022.

Key Recommendations

I. Scientific Factors for Evaluation

The draft guidance outlines four scientific factors that FDA intends to consider when evaluating the public health importance of a non-listed food allergen in the US

  1. Evidence of IgE-mediated food allergy. The draft guidance focuses on IgE-mediated food allergies. An IgE-mediated food allergic reaction is characterized by a two-step immune process: sensitization (the production of IgE specific to the food) and reactivity (allergic signs or symptoms when the food is consumed). The “gold standard” method for obtaining evidence of an IgE-mediated food allergy is a double-blinded, placebo-controlled food challenge in a population of individuals who have documented evidence of IgE sensitization to the food (but who do not have documented evidence of IgE-mediated food allergic reaction). However, other historical information from the scientific literature or community reports that provide evidence of sensitization and reactivity can also provide robust evidence of IgE-mediated food allergy. Other evidence can include the identification of a protein listed in the WHO / IUS Allergen Nomenclature Subcommittee database and clinical evidence of foods causing IgE-mediated reactions from non-oral exposure routes.
  2. Prevalence of IgE-mediated food allergy in the US population. A defined population of individuals having (1) documented history of IgE-mediated food allergic reactions; and (2) documented evidence of IgE sensitization to the relevant food or food proteins (“well-characterized allergic individuals”) provides the most robust estimate of the prevalence rate of an IgE-mediated food allergy. In lieu of such evidence, epidemiological studies such as self-reported questionnaires can be used. The draft guidance provides guidelines to obtain robust estimates from such studies.
  3. Severity of IgE-mediated food allergic reactions. No validated biomarkers currently exist for assessing / predicting reaction severity. However, data from clinical studies and community reports can be used to evaluate severity of IgE-mediated food allergic reactions. The most robust evidence is collected from studies reporting objective signs in well-characterized allergic individuals evaluated in a clinical setting. The draft guidance notes that one approach to evaluating severity data is the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) system, which provides a methodology to score the severity of a given reaction.
  4. Allergenic potency. Allergenic potency is the amount of allergenic protein required to elicit an IgE-mediated allergic reaction in a sensitized individual. Evidence regarding the potency of a food allergen generally is more robust when collected from studies conducted by a trained health care professional, rather than from community reports. The draft guidance delineates a number of potential endpoints for assessingenic potency, including the “frequency dose-response” (the population distribution of doses provoking an IgE-mediated food allergic reaction), and the “severity-dose response” (the gradient of severity of the IgE-mediated allergic reactions caused by the food).

II. FDA’s Evaluation of the Public Health Importance of a Non-Listed Food Allergen

The draft guidance describes how the agency generally intends to evaluate and weigh the evidence for each scientific factor: FDA will evaluate each allergen on a case-by-case basis based on “a robust identified body of evidence,” which means an identified body of evidence receiving a grade of high or medium using the GRADE system (as set forth at Table 6 of the draft guidance). This means that FDA is unlikely to consider a food or food component to be a food allergen of public health importance if most or all of the available data and information have a low GRADE. Further, FDA will generally consider whether robust evidence of IgE-mediated food allergy exists as a threshold matter, and will not consider the remaining three factors if it determines that evidence of IgE-mediated allergy is insufficient. Finally, in addition to evidence relating to the four factors, FDA may also evaluate information relevant to the labeling and production of food containing the food allergen. This might include, for example, information on the prevalence and amounts of the undisclosed food allergen in foods and characteristics of relevant food products and food production practices, among others.


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