Yesterday FDA announced the release of draft guidance that outlines the Agency’s approach to evaluating the public health risks of allergens that are not among the nine major food allergens (milk, eggs, crustacean shellfish, tree nuts, peanuts, wheat, soybeans and sesame). FDA was instructed to issue the guidance in the Food Allergy Safety, Treatment, Education & Research (FASTER) Act, which is the same law that recognized sesame as the 9^th major food allergen effective January 1, 2023. The draft guidance indicates that FDA may evaluate the public health risk posed by an allergen either on its own initiative or in response to a citizen petition submitted in accordance with 21 CFR 10.30.

The draft guidance identifies four scientific factors that FDA will generally consider in its evaluation of the public health importance of a food allergen:

1. Evidence of IgE-mediated food allergy. Immunoglobulin E antibody (IgE)-mediated food allergic reactions are characterized by a two-step immune process, sensitization and reactivity. Sensitization is the production of IgE specific to a food or food protein, while reactivity is the development of symptoms when the food or food protein is consumed. These steps can occur independently in certain people, so evidence of one alone does not establish clear evidence of an IgE-mediated food allergic reaction. The “gold standard” evidence for a IgE-mediated food allergy is a double-blinded, placebo-controlled food challenge (DBPCFC) in a population of documented sensitized individuals, although historical information from scientific literature and community reports that provide evidence of both sensitization and reactivity can still provide robust evidence of IgE-mediated food allergy.

2. Prevalence of IgE-mediated food allergy in the U.S. population. Although the most robust evidence is obtained from a population with documented evidence of both IgE sensitization and IgE-mediated food allergic reaction (a “well-characterized” population), in practice such information is rarely available, and so epidemiological studies that estimate probable food allergy rates based on self-reported responses to questionaries must be relied on. The guidance includes recommendations to improve the accuracy of these studies.

3. The severity of IgE-mediated food allergic reactions. Since there are no biomarkers for assessing or predicting reaction severity, data from clinical studies and community reports are used to evaluate severity. The most robust evidence is a study reporting objective symptoms in well-characterized allergic individuals evaluated in a clinical setting and that are classified according to a scientifically accepted classification system and treated accorded to an accepted algorithm.

4. The allergenic potency, which is the amount of food allergenic protein required to elicit an IgE-mediated food allergic reaction in a sensitized individual. Useful measurements include the frequency dose-response, which is the population distribution of doses provoking an IgE-mediated food allergic reaction, and the severity-dose response, which is the gradient of severity of the reaction.

The draft guidance further discusses how FDA will evaluate the strength of the identified evidence and includes in Table 6 characterizations of the strength of different types of evidence for each of the four scientific factors on a “low-medium-high” scale. FDA will employ a case-by-case approach, although it generally expects that only food or food proteins with high or medium evidence will be considered allergens of public health importance. Furthermore, if robust (i.e., high or medium) evidence is not available for factor 1 (evidence of IgE-mediated food allergy), FDA does not generally expect to consider the other factors. FDA may also consider other information such as prevalence of IgE-mediated food reactions attributed to exposure to food that is not disclosed on the label of food products, data on clinically cross-reactive IgE-mediated food allergies, and whether such cross-reactivity would not be well-recognized in the U.S. allergic population.