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The Big 8:Advances in Food Allergy Risk Assessment and Management

October 11, 2018

Food Allergies: What are the Challenges?

Stefano Luccioli, MDUS FDA, Center for Food Safety and Applied Nutrition (CFSAN)

Medical Officer, Food Allergen Program Coordinator

Office of Compliance

5001 Campus Drive, HFS-605

College Park, MD 20740

Tel: 240-402-1283

Cell: 202-577-1687

Stefano.luccioli@fda.hhs.gov

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Conflict of Interest Statement

• I have no conflicts of interest to declare

• Disclaimer:

The views and clinical perspectives expressed in this presentation are those of the Author and do not necessarily represent the views of the Food And Drug Administration

Focus of discussion

Regulatory public health safety and management perspective

• Define food allergy

• Discuss unique mechanisms, prevalence, diagnostic and risk considerations and public health burden

• Discuss key FDA/regulatory activities and challenges in food allergen avoidance and management

• Data gaps and future goals

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Clinical case

• 46 yo male

• Longstanding springtime allergies, mild asthma, penicillin allergy

• Eating left-over tuna steak from last night’s dinner

• Develops immediate flushing, headache, diarrhea, shortness of breath and high blood pressure

• Is this a food allergy?

• No, likely Scombroid food poisoning (toxic reaction)

http://www3.niaid.nih.gov/topics/foodAllergy/clinical/PDF/guidelines.pdf

Adverse reactions to food

“Allergies”

*Gluten

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“Food Allergy”

Adverse reaction to food that is IgE antibody-mediated– “immediate gastrointestinal allergy/anaphylaxis”

Involves foods/proteins commonly consumed in diet

US: peanut, soy, egg, milk, wheat, tree nuts, fish, shellfish– Sesame, mustard, celery, lupin, buckwheat..

Affects 3-4% of Americans, mostly children

Genetic AND environmental

Lifetime risk for many

No effective treatment (?) – Labeling/ avoidance is key!

B cell T cell

Food protein

IgEAntibody

Mast cell/ Basophil

Sensitization

Elicitation/ Reactivity

Breakdown in oral tolerance

? Cause – dose, length or timing of exposure

One dose exposure/ above threshold

Amplification mechanism –severity endpoints variable

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Sampson 2018

Urticaria (hives))Angioedema(swelling) Conjunctivitis

FlushingHypotension

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Food allergy eliciting symptoms

Skin- itchiness, flushing, hives, swelling, conjunctivitis, eczema

GI- nausea, abdominal pain, vomiting, diarrhea

Respiratory- chest tightness, runny nose, wheezing, throat closing/swelling

Vascular- dizziness, fainting, arrythymias, hypotension, shock

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Subjective Objective  Anaphylaxis Death

EDII

EDII

EDII

EDII

Severity Continuum

ED=eliciting dose

EDII

EDII

EDII

Prevalence

Food *Children *Adults ^Objective

Milk 2.5% 0.3% 0.6-0.9%

Egg 1.3% 0.2% 0.3-0.9%

Peanut 0.8% 0.6% 0.4-0.8%

Tree nut 0.2% 0.5% 0.4%

Fish 0.1% 0.4% 0.2-0.3%

Shellfish 0.1% 2.0% 0.6%

Other - - Soy – 0.03-0.7%

Wheat- 0.2-1.2%

Total 6% 3.7% 3.0%

*Sampson, JACI, May 2004;

^NIH clinical guidelines, 2010

#Savage et al, JACI In Pract2016

FA: Self-reported (9- 13%) >> clinically diagnosed (3-4%); Infants >> adults Surveys: FA prevalence in US children doubled 1997-2007 (peanut); ↑ self-report in US adults

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Diagnosis

Observed history of characteristic allergic reaction symptoms to food **AND

Positive food skin prick test (SPT) or serum food-specific IgE

AND/OR

Positive oral food challenge (DBPCFC) – gold standard

**History alone or evidence of positive IgE test alone is NOTdiagnostic

Food Challenge

Dose escalation study of X dose (increment varies 2-10) to final dose (*)

Use for diagnosis, therapeutic trial and threshold assessment

Report LOAEL or eliciting dose - discrete (4X) or cumulative (7X)

Adverse effect= objective sign (? subjective symptoms)

X 2X 4X 8X 16X 32X 64X 108X *

Time[15 min –hours]

LOAELNOAEL

4X

7XAdverse

effect

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Population sensitivities

• Large (million-fold) inter-individual variability in eliciting dose responses

• Individual eliciting dose thresholds may vary from one exposure to next

• Minimal data on doses associated with severe reactions

Diagnostic considerations/ limitations

Poor risk prediction – to low dose and identifying severe responders– No valid biomarkers

– Symptoms or prior reaction history unreliable

– Food challenge is best tool but underutilized Mostly diagnostic tool –yes or no allergy

Utility to determine threshold and future risk of reactions?

No available treatments or prevention strategies

Most clinicians give patients the same advice about risks -everybody is at risk for severe, life-threatening reactions

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Public health burden

• Reactions/ Anaphylaxis in community common− Surveys: 30-50% report >1 reactions in past year [Verrill 2016]

2-3%(0.5%-anaphylaxis) of all CAERS food complaints [Oladipo 2014]

− #1 cause of ED visits: 20-30,000/yr; ≈ 2500 hospitalizations (↑) [Ross 2008]

− Deaths (150?): ≈ 20-30/ yr (teenagers)

− Tree nuts and peanuts most commonly involved

• Psychosocial impact = decreased quality of life (QOL)− Similar to chronic illness; limited food choices; anxiety/ fear of death from

accidental exposures; social stigma/ bullying, etc.

• ‘Allergic march’- development of asthma and/or other comorbidities

• Economic costs (?), poor nutrition

Food allergen avoidance and management

Avoidance is difficult – Allergenic food hazards are everywhere and not always labeled

– Proliferation of allergen labels and advisory statements limits food choices

Food allergen information often does not inform risk– Different doses and types of allergens in products

– Multiple types of advisory statements and cross contact risks- not linked to risk

Lack of training/knowledge in clinical community of food allergen labeling and risks in products– Avoidance advice and risk perceptions vary

– + risk taking: 30-40% report ignoring advisory statements [Marchisotto 2016]

– 8-31% of accidental reactions due to disregarding labels

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Blom et al. Accidental food allergy reactions: Products and undeclared ingredients. JACI. 2018; 142(3):865-875

Food allergen avoidance and management

• Allergenic food hazards difficult to control − Undeclared allergens have become most

common cause of food product recalls (30-40%) • Most likely cause is labeling error [Gendel 2013]

− Global food market – novel or emerging allergens

− Variable levels of allergen hazard from cross contact • dark chocolate (milk) is high risk product [ Bedford 2017]

− Analytical detection methods may be limited

− No thresholds established− No mechanism to distinguish low from high risk products

National Academy of Sciences study on food allergies (Nov, 2016) –recommended need for risk-based labeling approach

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Regulatory activities involving food allergies

CFSAN mission: ensuring that the nation's food supply is safe, sanitary, wholesome, and honestly labeled

• Implementation of food allergen labeling laws

• Compliance/ enforcement - Inspections and recalls

• Analytical methods to detect allergens in food

• Safety/risk assessments

• Postmarket surveillance – Medwatch and districts (CAERS)

• Policy, guidance and consumer education

Regulatory activities involving food allergies

Other FDA offices:

• Oral desensitization studies, allergen extracts, allergens in vaccines (CBER)

• Anaphylaxis treatment (e.g., Epinephrine autoinjectors), food allergen labeling in drugs (CDER)

• GM salmon (CVM)

Other agencies:

• TTB : distilled spirits, wine, beers with malted barley

• USDA: meat, poultry and some egg products (>2%)

• EPA: pesticides

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Food Allergen Labeling & Consumer Protection Act of 2004 (FALCPA)

FALCPA

• Involves packaged food and dietary supplements− Not drugs, cosmetics, other consumer products

− Not foods sold in most retail/ food service establishments

• Does not address unintentional introduction of allergens into products by “cross-contact” Manufacturers may voluntarily place allergen advisory or precautionary

allergen labeling (PAL) statements (‘may contain’, etc) to alert consumers

Regulatory concerns: truthful and not misleading? Not used in lieu of good manufacturing practices (GMPs)?

Industry concerns: Need for advisory statement?

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FDA Food Safety Modernization Act (FSMA) Final Rule for Preventive Controls for Human Food (2015)

• Defines “cross contact”

• Facilities that use major food allergens must establish and implement a food safety plan that includes an analysis of hazards and risk-based preventive controls

− Prevent allergen cross contact

− Ensure accurate labeling of finished foods

− Training

• Testing not required for validation; no thresholds establishedIndustry concern- How clean is clean?

• Guidance pending

Regulatory risk assessment and management

• Allergenicity of novel foods

• Health claims to prevent allergies

• Risk-based allergen thresholds

Exemptions from labeling requirements

Undeclared allergen hazard evaluations/ Recalls

Cross contact/ preventive controls

Public health needs

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Food allergy management issues and challenges

• Prevention of food allergies

• Novel foods/ cross-reactivity

• Thresholds

• Undeclared allergen and health hazard assessment

• Severity

• Diagnosis and risk prediction/communication

Novel foods/ proteins

Main question: Does the new protein have characteristics of a known allergenic epitope and/or can it bind IgE?

Focus on potential for sensitization - not always indicative of clinical reactivity or cross-reactivity

Source of protein

Amino acid sequence homology

Pepsin resistance

Specific serum screening

Optional: Targeted serum, animal models

High protein foods (e.g.pea, insect) – cross-reactivity concerns

EpitopeIgE (food-specific or crossreactive)

Codex Alimentarius, 2003

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camelLuccioli et al, in Immunology IV textbook 2012

Cross-reactive Food Allergies

Risk of reactivity (to at least one)

Lupin- 30%(?)

Insect proteins(?)

Threshold types

Individual

Population (most data)

Analytical

Regulatory

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FALCPA Labeling exemptions

• Statutory exemption: highly refined oils from MFA• Ingredient exemption standards:

“does not contain allergenic protein”Ex: Ice structuring protein (ISP- fish) “does not cause an allergic response that poses risk to human

health” [severity component]Ex: Solae-brand soy lecithin as release agent

Draft Guidance to Industry –Food Allergen Labelling Exemption Petitions and Notifications (May, 2014)

No thresholds defined by FALCPA

“Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food” (Journal of Food Protection.2008. 71(5):1043–88)

• Analytical methods-based− Is it there or not? peanut, milk, egg, gluten, hazelnut, almond, walnut, soy [ELISA] XMAP -14 food allergens + gluten

• Safety assessment-based• LOAEL/NOAEL + safety factors → ADI (“safe” dose)

• Risk assessment-based*• Risk in relation to dose, exposure – most robust• Threshold dose= interval between LOAEL and NOAEL• Used to propose risk-based reference doses for

advisory labeling (VITAL –Taylor EDx: Estimated dose to cause X% of population to react

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Population ED severity data

Analysis of peanut and milk EDs based on reaction severity score (mild, moderate, severe) using integrated scoring system (Zhu 2015)

Peanut may be different from milk, soy*

350+ peanut allergic individuals were fed a “one shot” dose equivalent to ED05 dose and none had severe reaction

Products with undeclared allergen - Need for recall? Determine class of recall? Class I: reasonable probability of serious health consequences Class II: temporary/reversible; serious consequences are remote Class III: not likely to cause adverse health consequences

Food recall hazard determinations

Case by case basis: have begun using population threshold information to

inform class I vs class II allergen recalls [with mitigating factor information]

Determining class III still a challenge

Undeclared allergen hazards and Recalls

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Cross contact/ preventive controls

Benefits public health

Prevent label confusion, risk taking

Good data quality and transparency

Is practical and enforceable

Prevent accidental reactions

Request for comments and information on Risk Assessment for Establishing Allergen Thresholds (Dec, 2012 – May, 2013) 405 submissions to docket 50% from consumers opposed to threshold concept; three

patient organizations expressed caution as well Industry and trade groups uniformly in favor of thresholds

Consumers/public are still unsure by thresholds

Need to develop outreach tools to educate consumers and clinicians about thresholds and reactivity risks

Thresholds- public health

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Current goals

Education of public and physicians about thresholds and risks of advisory statements

Encourage more diagnostic procedures to understand thresholds Implementation of FSMA

– Increase compliance with allergen label controls to reduce allergen recalls from preventable errors

– Allergen preventive control guidance pending; exploring risk-based strategies for addressing allergen cross contact

Independent data quality assessment of existing threshold data– Continue participation in global threshold discussions– Continue analytical test method development for all food allergens

Thank you for your attention

Stefano.Luccioli@fda.hhs.gov

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References

Bedford B, Yu Y, Wang X et al. A Limited Survey of Dark Chocolate Bars Obtained in the United States for Undeclared Milk and Peanut Allergens. J Food Prot. 2017;80(4):692-702.

Blom M, Michelsen-Huisman AH, van Os-Medendorp H et al. Accidental food allergy reactions: Products and undeclared ingredients. JACI 2018;142(3):865-875

Gendel SM, Zhu J. Analysis of U.S. Food and Drug Administration food allergen recalls after implementation of the food allergen labeling and consumer protection act. J Food Prot. 2013;76(11):1933-8

Marchisotto MJ, Harada L, Kamdar O et al. Food Allergen Labeling and Purchasing Habits in the United States and Canada. JACI Pract. 2017;5(2):345-351

Oladipo T and Luccioli S. Prevalence and Characteristics of Consumer-Reported Food Allergic and Anaphylactic Events in CAERS, 2007-2011. JACI. 2014. 133(2):S207 [abstract]

NIAID-Sponsored Expert Panel, Boyce JA, Assa'ad A, Burks AW, et al. 2010. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. Journal of Allergy and Clinical Immunology 126(6 Suppl):S1-58.

Ross MP, Ferguson M, Street D et al. Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System. JACI 2008;121:166-71

References

Sampson HA, O'Mahony L, Burks AW et al. Mechanisms of food allergy. JACI 2018;141(1):11-19.

Taylor SL, Baumert JL, Kruizinga AG, et al. Establishment of Reference Doses for residues of allergenic foods: report of the VITAL Expert Panel. Food Chem Toxicol. 2014;63:9-17

Verrill L, Bruns R, Luccioli S. Prevalence of self-reported food allergy in U.S. adults: 2001, 2006, and 2010. Allergy Asthma Proc. 2015;36(6):458-67

Zhu J, Kwegyir-Afful EJ, Luccioli S et al. A Retrospective Analysis of Allergic Reaction Severities and Minimal Eliciting Doses for Peanut, Milk, Egg, and Soy Oral Food Challenges. Food Chem Toxicol. 2015;80:92-100.