Putting thresholds into practice: where are we now?

Putting thresholds into practice: where are we now? Anaphylaxis Campaign Corporate Members Conference, The Brewery, London Allergen Thresholds: the complete picture René Crevel René Crevel Consulting Limited Outline Introduction The path to thresholds: significant milestones in threshold development Thresholds: what are they and why do we need them? Putting thresholds into practice: state of the art and gaps Conclusions 1

The path to allergen thresholds Hazard identification Early 1990s Nordic list 1994 ILSI-Europe Food Allergy Task Force founded 1995 FAO-WHO consultation Codex List (1999) Hazard characterisation 1997 Peanut threshold study (Hourihane et al) 1999 1 st Threshold conference (Taylor et al 2002) 2002 Dose-distribution feasibility (Bindslev-Jensen et al) 2007 Dose-distribution modelling and hazard characterisation (Crevel et al) Risk assessment 2008 US FDA Threshold Working Group supports quantitative risk assessment 2009 Europrevall-FSA workshop (Madsen et al) 2011 VITAL Scientific Expert Panel 2012 VITAL 2.0 published; ILSI-Europe Expert group workshop (Reading) 2013 ifaam starts 2016 EU Stakeholder workshop supports quantitative risk assessment and VITAL 2.0 3 What do we mean by thresholds (1)? Toxicological: a dose at, or below which, a response is not seen in an experimental setting Regulatory: an amount or concentration which defines whether a product meets certain criteria (e.g. glutenfree) Allergen management: an amount or concentration of allergen at or below which the risk is acceptable/tolerable 2

What do we mean by thresholds (2)? Even the toxicological Threshold can be subject to interpretation: In terms of dose does it mean one below which No reactions at all occur? No objective reactions occur? No severe reactions occur? there are only allergic reactions that do not pose a risk to human health [criterion for exemption, FALCPA, 2004]? How do we get from individual to population thresholds? What do we mean by thresholds (3)? To avoid these issues around terminology new concept was derived from dose distribution modelling: Eliciting Dose is used to describe a dose that is predicted to elicit a reaction in a specified proportion of the population. For instance, ED 10 describes a dose that is predicted to elicit a reaction in 10% of the allergic population. 3

Why we need thresholds The dose makes the poison (Paracelsus, ca. 1500) Managing the risk starts with setting safe limits Legislators based allergen labelling on presence alone Largely works for ingredient labelling (deliberate presence) But at all stages in the food chain sporadic, unintended presence of allergens in varying amounts may occur What does/can a Precautionary Allergen Labelling statement mean? Dunngalvin A, Chan CH, Crevel R et al. Precautionary Allergen Labelling: Perspectives from key stakeholder groups. Allergy 2015, 70, 1039-1051 8 4

Benefits of evidence-based thresholds Clear, transparent standards will help people with food allergies and their carers to make safe food choices through consistent and meaningful risk communication support transparency in safety risk management and enforcement decisions by regulators provide food businesses with confidence in assuring the safety of allergic consumers a level playing field in terms of what they need to achieve 9 Vision for Risk-Based Allergen Management Evolution from hazard-based approach to a risk-based approach Supply chain consistency in risk assessment and risk communication approaches Calibrated risk assessment against agreed (quantitative) action levels Best practices for risk management in manufacturing IMPROVED PROTECTION FOR AT RISK CONSUMERS Consistent risk communication vs. product status in market Optimal consumer recognition of distinct risk categories products 10 5

What do we need to put thresholds into practice? Defined and accepted thresholds Protection goals Risk assessment tools to translate them into practice Regulatory framework Acceptance by stakeholders (especially people with food allergies) 11 What do we have now? State of the art and gaps 6

What do we need to put thresholds into practice? Defined and accepted thresholds Protection goals Risk assessment tools to translate them into practice Regulatory framework Acceptance by stakeholders (especially people with food allergies) (Evidence of safety) VITAL 2.0 Reference Doses (VSEP 2011) Based on minimum eliciting doses derived from DBPCFC Lowest amount resulting in objective reaction Clearly documented dose escalation regime Allergen No of data Basis of Reference dose points reference dose (mg Protein) Peanut 750 ED01 0.20 Milk 351 ED01 0.10 Egg 206 ED01 0.03 Hazelnut 202 ED01 0.10 Soy 80 95%LCI ED05 1.00 Wheat 40 95%LCI ED05 1.00 Cashew 31 95%LCI ED05 2.00 Mustard 33 95%LCI ED05 0.05 Lupin 24 95%LCI ED05 4.00 Sesame 21 95%LCI ED05 0.20 Shrimp 48 95%LCI ED05 10.00 Celery 39 Insufficient data Fish 19 Insufficient data Dose distribution modelling for peanut 14 7

Frequency Using dose distribution of population responses to establish limits Probabilistic risk assessment: Dose distribution modelling is combined with modelling of other variables including allergen presence, allergen content, probability of consumption by allergic individuals, etc Can calculate likely number of reactions for any particular combination of variables Output can be used to set criteria for a particular product to be considered safe Dietary surveys Product consumption Amount of allergen Product Analyses Allergen concentration Cross-contact allergen content of product [intake] Clinical studies Minimum Eliciting Doses Probability of reaction Adapted from Spanjersberg et al, Food Chem Tox, 2006 15 What do we need to put thresholds into practice? Defined and accepted thresholds Protection goals Risk assessment tools to translate them into practice Regulatory framework Acceptance by stakeholders (especially people with food allergies) (Evidence of safety) 8

Protection goals: some considerations Primary purpose of limits for allergens is to protect allergic consumers effectively by minimising the incidence of reactions This will also protect food business operators (FBOs) if wellimplemented Limits will do this by Providing a single, consistent benchmark for allergen management decisions by FBOs relating to unintended allergen presence, including application of PAL Fostering good practice in assessing the risk from unintended allergen presence Ensuring that PAL s value is restored and maintained, so that it is an effective tool 17 The challenge in effective implementation of precautionary allergen labelling Proportion of products affected (%) 75 50 Risk Profile 75 Observance of precautionary labelling (%) 25 50 0 0.1 1 10 100 Reference dose (arbitrary units) MINIMISING THE RISK 18 9

VITAL 2.0: Protection goals The VITAL Scientific Expert Panel decided to to use ED01 where possible as the basis for reference doses, providing a minimum protection factor of 99% Use lower 95% CI of ED05 where data were insufficient to use ED01 Aim to protect vast majority against mild, selflimiting objective reactions, not requiring clinical intervention 19 Single dose challenges: peanut study Outline 378 clinic attendees with peanut allergy Three centres: Cork, Melbourne, Boston 6mg whole peanut (1.5mg peanut protein) in a cookie Open challenge 2-hour post-challenge follow-up Pre-determined criteria for positive response Results 8 positive reactions (2.1%; 95% CI, 0.6%-3.4%), All mild Hourihane J et al J Allergy Clin Immunol (2017) May;139(5):1583-1590 20 10

What do we need to put thresholds into practice? Defined and accepted thresholds Protection goals Risk assessment tools to translate them into practice Regulatory framework Acceptance by stakeholders (especially people with food allergies) (Evidence of safety) 21 Risk assessment and management tools ifaam tools 22 11

ifaam Tier 1 risk assessment tool 23 What do we need to put thresholds into practice? Defined and accepted thresholds Protection goals Risk assessment tools to translate them into practice Regulatory framework Acceptance by stakeholders (especially people with food allergies) (Evidence of safety) 24 12

Chapter V. Article 36 3. The Commission shall adopt implementing acts on the application of the requirements referred to in paragraph 2 of this Article to the following voluntary food information: (a) information on the possible and unintentional presence in food of substances or products causing allergies or intolerances; 25 25 New requirements for voluntary allergen information (Reg 1169/2011) Precautionary labelling remains voluntary (Article 36), but must meet the following requirements: (a) it shall not mislead the consumer: PAL should be accurate, i.e. use must be justified (b) it shall not be ambiguous or confusing for the consumer: terminology should be clear and limited to one (or a few) wellunderstood terms (c) it shall, where appropriate, be based on the relevant scientific data: PAL should be based on a thorough risk assessment (preferably quantitative) 26 13

What do we need to put thresholds into practice? Defined and accepted thresholds Protection goals Risk assessment tools to translate them into practice Regulatory framework Acceptance by stakeholders (especially people with food allergies) 27 DG SANTE-JRC stakeholder workshop (Geel, Belgium 16-17 June 2016) Participants (46): Delegates from Member States, food industry, patient advocacy groups, academic scientists AIMS (provided by DG SANTE-JRC) Background: Regulation (EU) 1169 /2011 on the provision of food information to consumers and the observed proliferation of precautionary allergen labelling by food producers. To identify the sequence of steps required for framing the current use of precautionary allergen information and its enforcement across the EU. 28 14

DG SANTE-JRC stakeholder workshop (Geel, Belgium 16-17 June 2016): Main conclusions PAL terminology should be simple, easy for consumers to understand ( may contain recommended) Use of PAL should be subject to defined conditions and transparent Benchmarks (reference doses) need to balance degree of protection/safety and choice for allergic consumers and need endorsement by EFSA Stakeholders want acceptance (by the authorities) of the Reference Doses defined by VITAL Protein is the hazard and should be basis of the risk assessment, with results expressed in units that can be directly applied to the risk assessment, i.e. mg total protein/kg of food Communication to users (both consumers and health care practitioners) is crucial Guidance on good risk assessment practice EU-wide required Guidance to good analytical practice for food allergens should be developed 29 Conclusions: where do we stand today? Defined and accepted thresholds ++++ Protection goals +++ Risk assessment tools ++++ Regulatory framework (++++)* Acceptance by stakeholders (especially people with food allergies) +++ * Once in place 30 15

External Bodies - working to define threshold levels for precautionary allergen labelling. - advocating for meaningful precautionary allergen labelling Allergen Ad Hoc Working Group Food Allergy Task Force 16