FUNCTIONAL STANDARDS

ANDREW SCOTT

4th February 2016

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orHOW DO WE BUILD CONFIDENCE IN MODELS?

WHY DO WE NEED CONFIDENCE IN MODELS?

We want to make claims on efficacy, and provide assurance on safety & sustainability

• It is important to have confidence in these claims

• These claims must be grounded in evidence

» Models are increasingly becoming a source of evidence for our assessments...

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3Why do we have confidence in this approach?

…BUT WE’VE ALWAYS RELIED ON MODELS! EXAMPLE: HUMAN HEALTH RISK ASSESSMENT

NOAEL

NOAEL ÷ 10 - 1000

Tox Endpoint

Skin Sensitisation

Carcinogenicity

Systemic Tox

…

“animals are intact biological systems -a good model of the

human system”

“there's an established quality of science, reporting and audit framework for studies that use

in vivo models”

“not the ideal model of uncertainty but it

is pragmatic”

“there’s a broad level of acceptance in the approach (scientific

& regulatory)”

“we've done it this way for decades and it seems to

work”

TRANSLATION TO MATH MODELS - WHAT WE’RE DOING

“animals are intact biological systems -a good model of the human system”

Case studies in Argumentation- Is mathematical model an adequate

representation of the system?

“there's an established quality of science, reporting and audit

framework for studies that use in vivo models”

Best Modelling Practice (BMP)- 2015: case studies to establish

transparent reporting template- 2016 onward: specific guidance

on technical procedures & establish governance process

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Explicit on Uncertainty in model predictions- Parameter & model uncertainty- Elicitation, Bayesian Stats & Monte Carlo

“not the ideal model of uncertainty but it is pragmatic”

WHERE DEVELOPMENT OF PERFORMANCE STANDARDS CAN HELP

• Currently we evaluate systems by determining how well they perform in predicting a specific effect

• How do we qualify the system itself rather than qualify the use of the system for a specific purpose?

• Need to focus on functionality rather than predictive capacity in the first instance

» How do we develop standards for functionality?

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CASE EXAMPLE – HUMAN RELEVANT SKIN MODELS

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INGREDIENT DISCOVERY FOR PERSONAL CARE

Mechanistic Insight

Target ID & Validation

ScreeningIngredient

testing in vitro

Validation in human studies

Representative in vitro models needed

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MICROCIRCULATION AND THE SKIN

• Skin is highly vascularised:

• Superficial plexus - below the skin

surface

• Sub papillary plexus - at the dermal-

subcutaneous junction.

• A complex molecular dialogue exists

between vascular derived cells and

mesenchymal skin cells impacting on skin

function.

• Investigation of complex signalling

pathways and cross talk mechanisms

apparent in vivo.

Li et al 2006

65 years old,

hand

Hembold et al 2006

old

young

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DEVELOPMENT OF SCALP SKIN MODELS

Scalp Skin

Development of scalp skin modelsReconstructed Models

Epiderm – skin equivalent Scalp epidermal model

Measure barrier

integrity (TEER)+ ‘SEBUM’

+ MICROBES

(lab grown or ex-vivo)

Microbes removed

‘microbially challenged’epidermal model

T-cell priming

Measure protein and mRNA biomarkers of

immune response

Measure epidermal inflammatory

response (transcript)

Measure epidermal inflammatory

response (protein)Epiderm embeddedwith Dendritic cells

Measure protein and mRNA biomarkers of

immune response

+ immune components

epidermal

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NEW APPROACHES TO RISK ASSESSMENT WITHOUT ANIMALS

• Focus on non-animal approaches for consumer safety risk assessment

• Data required for safety decision should be driver

• Dose response information is essential

• Understanding the underpinning human biology

• We are not looking for a way to do the animal test without the animal

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Adapted from ‘Adverse Outcome Pathway (AOP) for Skin Sensitisation’, OECD

SKIN SENSITISATION AOP

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HUMAN RELEVANT SKIN MODELS –SKIN SENSITISATION AOP

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Replace ex vivo human skin for measurement of skin bioavailability (binding, metabolism,

penetration)

HUMAN RELEVANT SKIN MODELS –SKIN SENSITISATION AOP

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Replace ex vivo human skin for measurement of skin bioavailability (binding, metabolism,

penetration)

Characterise impact of chemical/drug/product exposure on skin micro-environment

(e.g. induction of inflammatory response, interplay between skin microbiome and local immune cells)

HUMAN RELEVANT SKIN MODELS –SKIN SENSITISATION AOP

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Replace ex vivo human skin for measurement of skin bioavailability (binding, metabolism,

penetration)

Characterise impact of chemical/drug/product exposure on skin micro-environment

(e.g. induction of inflammatory response, interplay between skin microbiome and local immune cells)

Develop skin models recreating different skin

disease pathologies to inform ‘sensitive’ sub-population

risk assessments

HUMAN RELEVANT SKIN MODELS –SKIN SENSITISATION AOP

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A ROLE FOR PERFORMANCE STANDARDS

• Adoption of new methods - increased emphasis on confidence that the model represents the biology

• Model development needs to focus on functionality rather than predictive capacity

• Performance standards - ‘quality’ reassurance on alternative methods

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