Evaluating Labeling Exemptions for Food Allergens
By Stefano Luccioli M.D., and Jeremiah Fasano, Ph.D.
The Food Allergen Labeling and Consumer Protection Act (FALCPA) was enacted by Congress to help consumers with food allergies by requiring labeling of protein ingredients from major allergenic foods in all products, unless these proteins qualify for exemption. This article summarizes the process that has been used by the Food and Drug Administration (FDA) for considering exemption of ingredients from allergen labeling under FALCPA and discusses the main scientific issues and considerations behind FDA decisions on allergenic ingredient exemption submissions evaluated thus far.
Food allergens represent a unique yet diverse group of foods or individual food proteins to which an ever-increasing number of those in the population have adverse reactions, some with fatal consequences. Food allergy remains one of the leading causes of anaphylaxis, resulting in 30,000 emergency room visits, 2,500 hospitalizations, and an estimated 150 deaths each year in the United States.
There are no current treatments for food allergies; thus, avoidance of the causative allergens by relying on ingredients listed on food labels and steering clear of the foods or food groups that account for most allergic reactions are the mainstays of prevention. This avoidance is not always easy, since major food allergens tend to be foods commonly consumed in the diet or those found in various ingredients intentionally or unintentionally added to food products.
Despite recommendations for specific labeling of food allergens being found in congressional documents dating back to the 1930s (prior to the Federal Food, Drug, and Cosmetic Act), the mandatory labeling of food allergens in food products has been a more recent phenomenon. With the development of analytical tests for detecting allergens in food products and a heightened awareness of food anaphylactic reactions as well as increased allergy prevalence in the past few decades, monitoring and subsequent recalls of food products for undeclared allergens increased substantially. As a result, food manufacturers voluntarily began alerting consumers of the possible presence of some allergenic foods by way of advisory label statements, such as, "may contain (peanuts)."
Prompted by a number of reports in which consumers experienced adverse reactions to undeclared allergenic substances in foods, FDA issued a Notice to Manufacturers  in 1996 warning about the presence of undeclared allergens in spices, flavorings, colorings, and incidental additives, such as processing aids. At that time, FDA expressed the opinion that any level of allergen in these ingredients could not be deemed insignificant and would need to be labeled.
At the same time, consumers were expressing concern that the names of allergenic ingredients listed on food labels did not identify the commonly recognized name of the allergenic source (e.g., "casein" vs. "milk casein"). This practice made it difficult for consumers to readily eliminate products containing ingredients from a particular allergenic source from their diets.
These were among the considerations that led to enactment of the Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA). Under FALCPA, a "major food allergen" is defined as one of the following foods or food groups or is an ingredient that contains protein derived from one of the following: milk, eggs, peanuts, tree nuts, soybeans, wheat, fish, and crustacean shellfish. FALCPA went into effect on January 1, 2006, and its requirements apply to products produced on or after that date.
The FDA is responsible for enforcing FALCPA in all packaged food and beverage products sold in the United States that are regulated under the Federal Food, Drug, and Cosmetic Act, including both domestically manufactured and imported foods. Some exceptions are: allergen labeling of meat, poultry, and egg products, which is regulated by the U.S. Department of Agriculture (USDA); allergen labeling of those alcohol beverages regulated by the Alcohol and Tobacco Tax and Trade Bureau (TTB), the labeling of which is also regulated by TTB; and allergen labeling of pesticide residues in food, regulated by the Environmental Protection Agency. FALCPA does not directly address the use of food allergen advisory label statements (i.e., "may contain" or "produced in a facility that also uses") and FALCPA’s labeling requirements do not apply to situations where a small amount of allergenic protein may be unintentionally transferred to a food product via cross-contact, such as during use of shared equipment or unclean processing lines in the manufacturing process. FDA is currently considering ways to best manage the use and effectiveness of these statements for consumers. 
As stated earlier, given the absence of preventative treatment, the proper labeling of allergens on food product packaging is one of the most effective strategies for avoiding exposure to food allergens and thereby preventing the harm posed to some consumers by such allergens in the food supply.
Among the many regulatory responsibilities assigned to the FDA under FALCPA is the evaluation of labeling exemption requests submitted by manufacturers and others for ingredients that are major allergens or contain protein from a major food allergen. Only "highly refined oils" from a major food allergen are automatically exempt from labeling requirements due to a specific provision in the law. FALCPA does, however, specify two processes for granting additional exemptions: notification and petition. The notification process allows a manufacturer or other interested party to notify the FDA that an ingredient "does not contain allergenic protein" and is therefore exempt. The petition process permits a petitioner to request that FDA grant an exemption from FALCPA’s allergen source labeling requirements on the grounds that the ingredient "does not cause an allergic response that poses risk to human health."
The FDA Approach
Since FALCPA’s enactment, FDA has evaluated submissions for FALCPA exemption by drawing together resources from throughout the Center for Food Safety and Applied Nutrition (CFSAN). A new review team has been formed for each submission, but the members may serve on successive teams to enhance the consistency and efficiency of the pro-cess. Further focus has been provided by the selection of a team charged with shepherding the process to completion, in consultation with an overall FALCPA submission coordinator. The teams have been interdisciplinary, generally including an immunologist, an allergist or medical officer, a food technologist or chemist, and an expert on the allergenic source. Other experts have been added as needed, and CFSAN staff with specialized expertise have been consulted on specific questions as they arise.
The review team has been charged with examining the submission with respect to the following criteria:
• Statutory standards for each class of FALCPA submission
• Appropriateness of the analytical methods used
• Technical accuracy of the information provided
• Completeness of the scientific information provided
• Approach to potentially problematic or contradictory scientific information
Once its evaluation has been completed, the team provides a recommendation to FDA’s decision-maker as to whether the agency should object to a notification or grant or deny approval of a petition. The agency’s decision is communicated in a letter to the submitter of the notification or the petitioner.
FALCPA requires the posting of all submissions within 14 days of receipt by FDA. This is a two-step process. First, the complete submission is placed in an FDA docket once any confidential information is removed. Second, basic information about the submission is listed on an inventory web page maintained by CFSAN. 
Unless the agency objects to a notification within 90 days of receipt, an exemption from FALCPA labeling requirements automatically applies. Conversely, if the agency does not respond to a petition for exemption from the labeling requirements within 180 days, that petition is automatically denied, unless the petitioner and FDA agree on an extension. In practice, this has resulted in a rapid and focused evaluation for notifications received by the agency that usually does not involve interaction with the notifier. Petition evaluations have been more iterative and have included multiple discussions, and in some cases FDA has asked petitioners to submit additional data.
Review of Notifications and Petitions
To date, FDA has completed the review of seven notifications (four for milk, one each for soy, fish, and wheat) and one petition (for soy). Table 1 highlights the inventory of these reviews and provides a brief synopsis of the key points in relation to ingredients(s), the scientific information or evidence presented, and the respective deficiencies in the submissions that have been summarized in response letters from FDA to the submitters. [Note: An exemption for the same ingredient in Food Allergen Labeling Notification (FALN) 003 was resubmitted as Food Allergen Labeling Petition (FALP) 001, after FDA objected to the original notification.
The review of each FALCPA petition or notification was, of course, particular to the submission and its contents. However, some general statements can be made about the review process. The scientific reviews of these notifications and petitions focused primarily on whether the scientific evidence, including the analytical methods used, met the specific statutory standard for exemption from FALCPA. For notifications, the teams looked for scientific evidence that the allergenic protein in the final ingredient was not present (i.e., notification standard). Since not all protein from an allergenic food is necessarily "allergenic," review teams were particularly interested in demonstrations that the ingredient from an allergenic food did not bind human allergen-specific IgE. For petitions, the teams looked for evidence that allergenic proteins were not present in quantities that would cause adverse health consequences for allergic individuals at expected food uses and exposure (i.e., petition standard). In the latter case, the level of allergen exposure not resulting in adverse health consequences is often equated to an "allergen threshold." Although FDA has addressed approaches for establishing these thresholds,  the agency has not yet determined or defined a threshold for any major food allergen. The teams were aware of this consideration, and therefore, in those cases where a threshold was implicitly or explicitly claimed, reviewers looked for a complete scientific justification of that threshold in the submission, including a detailed description of the ingredient and its related proteins as well as a comprehensive review of both clinical and exposure data on the major food allergen in question.
In the submissions received to date, FDA review teams observed three main areas of data deficiencies which led to denial of exemption requests. These are the following:
1. Issues of identity and protein characterization
2. Issues of appropriate use of current standards or methods (i.e., data quality)
3. Issues of comprehensiveness of data and presentation of exemption argument
Identity and Protein Characterization.
A recurring issue has been poor description of the ingredient’s identity. The review teams found that some submissions were without a clearly defined ingredient, making it difficult for the team to assess the significance of any of the other evidence presented in the submission. Some submissions focused on the identity of the native ingredient itself without necessarily considering the identity of the ingredient in the finished product, which is the form of ingredient to which potentially allergic consumers would be exposed. Similar problems were found when the constituent proteins of a particular ingredient were not clearly characterized. Since allergens are proteins, it is difficult to demonstrate whether a food ingredient is allergenic or not when there is limited information on or definition of proteins or protein structures from the allergenic food source in the ingredient. Some submissions noted trace amounts of large peptides (i.e., elements of protein) in the ingredient. In such cases, it proved difficult to demonstrate absence of allergenic "protein" in the ingredient. The teams also noted poor descriptions of the method of manufacture or degree of hydrolysis of some ingredients. This lack of information diminished the team’s confidence in the identity and characterization of the ingredient.
Standards, Methods, and Data Quality.
The teams found that notifiers and petitioners often relied on existing standards and assays associated with food allergy that were inappropriately applied to address exemption criteria. As an example, with notifications related to extensively hydrolyzed casein (EHC), the designation that these ingredients met the "hypoallergenic" standard was used to support the assertion that the ingredient did not contain allergenic protein. "Hypoallergenic" is a standard defined by the American Academy of Pediatrics for milk-derived infant formula. This standard is based on results from food challenge trials in infants and implies 90% certainty, with 95% confidence, that a milk-allergic infant will not react to the infant formula ingredients.  However, this standard does not necessarily mean that no infant will react to these ingredients, nor that that the ingredient would be non-allergenic. Examples in the scientific literature reporting that these ingredients bound milk-specific IgE and caused reactions in milk-allergic individuals was further evidence that these ingredients contained allergenic protein.
Some submissions based their entire argument for exemption on the notion or standard that the ingredient had undergone sufficient hydrolysis or other manufacturing method to reduce protein content. By having a reduced protein content, the notifiers or petitioners claimed that the allergenicity of the ingredient would therefore be negligible. However, none of these submissions provided clear evidence that all allergenic proteins had been eliminated, since there was still evidence of residual protein content in most cases. Furthermore, there was no clear evidence provided that the residual protein content posed no allergenic risk. The teams frequently observed that commercial ELISA test kits, which are generally designed to detect allergen residues found in foods due to cross-contact, were inappropriately applied to address the question of whether or not allergenic protein was present in an ingredient. Such kits do not necessarily detect all allergenic proteins from an allergenic source. In addition, these kits may have both qualitative and quantitative limitations with respect to validated detection of low levels of allergenic proteins, making them inappropriate for establishing the absence of such proteins.
The appropriateness or specificity of animal studies was also an issue in some submissions. Studies with animal models were sometimes presented to make conclusions about the absence of protein content in the ingredient(s). Although the teams recognized the potential of animal models, the submissions did not provide a clear explanation of why the studies would be appropriate or adequate to address the criteria established for FALCPA submissions. Moreover, no animal model of food allergy has yet been validated to answer questions regarding allergenicity of food proteins in humans.
Failure to incorporate a comprehensive overview of the relevant information. In some cases, literature reports of allergenic reactions to the ingredient(s) were either not mentioned or were not adequately addressed. Evidence of known (or lack of) reactions to the ingredient(s) following repeated challenges or exposures in sensitive individuals may highlight important information with regards to the ingredient’s allergenic potential. Moreover, some submissions presented scientific evidence on only one analytical approach or one type of testing method, and failed to examine other potential questions or existing scientific information, which made it difficult for the review teams to conclude that the exemption standard had been satisfied. Finally, the teams observed that the notifiers and petitioners did not take the opportunity to provide their own scientific statement about what studies, assays, and criteria would be sufficient to meet the FALCPA exemption standards or to present their own understanding of these standards. Lack of a clear scientific argument therefore made it difficult to attain demonstration of sufficient "scientific evidence" for labeling exemption.
Conclusions and Future Considerations
New food proteins and the presence of allergenic ingredients in the food supply present unique assessment issues and approaches for regulators. The approach to date has taken into consideration a variety of factors on a case-by-case basis using a weight-of-evidence approach which looks at the type and origin of protein, chemical, structural, or biological properties, estimated exposure to allergen, and relevant challenge history data or other epidemiological data. Nonetheless, difficulties in assessment of food allergens remain.
The FALCPA notification and petition processes are available to industry to request exemptions from required labeling for certain allergen-containing ingredients. However, no exemptions have been granted in response to the FALCPA notifications or petitions submitted and reviewed to date. Absent defined thresholds for any major allergenic food, FDA is considering whether agency guidance on notification or petition standard criteria would further assist notifiers and petitioners to include more complete data in their submissions and to present a clear and valid scientific argument for exemption from labeling requirements.
Stefano Luccioli, M.D., is a scientific advisor and reviewer for activities related to food allergies and hypersensitivity disorders. He is a member of CFSAN’s Office of Food Additive Safety.
Jeremiah Fasano, Ph.D., is a consumer safety officer in the Office of Food Additive Safety’s Division of Biotechnology and GRAS Notice Review at CFSAN. He has coordinated and participated in numerous reviews of food ingredient safety assessments, including some of the FALCPA submissions received by FDA.
Sue Challis is a writer/editor with CFSAN’s Office of Food Defense, Communication and Emergency Response.
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