W eight-of-Ev id ence Ap p roa ch for Risk Assessm ent of Toba cco - - PowerPoint PPT Presentation

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W eight-of-Ev id ence Ap p roa ch for Risk Assessm ent of Toba cco Prod ucts

Paige N. Wiecinski, Ph.D., D.A.B.T

Slides Presented at CTP’s Risk Assessment of Tobacco Products Public Workshop November 15, 2016

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Agenda

• Weight of Evidence (WoE) Defined
• Considerations for Tobacco Product Regulation
• Evolution of the WoE Approach
• Applying WoE
• Conclusions

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Definition and Scope of WoE

• “[T]he process of considering the

strengths and weaknesses of various pieces of information in reaching and supporting a conclusion concerning a property of the substance”1

• Hazard characterization is one

application, but can also be used for, e.g., endpoints of quantification, dose-response models or dose metrics

1 ECHA, Practical guide 2: How to report weight of evidence, 2010

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• Availability of epidemiological evidence by product category
• Sufficiency of in vitro or in vivo data for tobacco products
• Weighting various types of data
• Merging expert reviews to formulate a decision for various

tobacco categories

WoE Considerations for Tobacco Product Regulation

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Evolution of the WoE Approach

• 2011 – National Academy of Sciences (NAS)

National Research Council (NRC)

• 2012 – American Chemistry Council’s Center for Advancing Risk

Assessment Science and Policy (ARASP) International Workshop

• 2013 – Rhomberg et al. 2013 “A survey of frameworks for best

practices in weight-of-evidence analysis.” Critical Reviews in Toxicology

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Phases of WoE

Phase 1

Define Causal Question and Develop Criteria for Study Selection

Phase 2

Develop and Apply Criteria for Review of Individual Studies

Phase 3

Integrate and Evaluate Evidence

Phase 4

Draw Conclusions Based on Inferences Key Factors: Transparent / Defensible / Expert judgment

Rhomburg et al., Crit Rev Toxicol, 2013

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Causal Question Example

Solomon et al. Crit Rev Toxicol, 2016

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Data Gathering

Ingredient Review (1) = ~ 24,000 vs. Ingredient Review (2) = ~ 50 The WoE approach works regardless of the number of studies gathered during the study selection.

Examples of Exclusion Criteria

• Not mammalian animal model
• Not in vivo/in vitro toxicology study
• Acute effects only

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Phase 1

Define Causal Question and Develop Criteria for Study Selection

Phase 2

Develop and Apply Criteria for Review of Individual Studies

Phase 3

Integrate and Evaluate Evidence

Phase 4

Draw Conclusions Based on Inferences Key Factors: Transparent / Defensible / Expert judgment

Rhomburg et al., Crit Rev Toxicol, 2013

Phases of WoE

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Klimisch Criteria

Quality Score Requirements

1 Reliable without restriction

• Good Laboratory Practices (GLP)
• National Testing Guidelines (e.g., OECD)
• Methods comparable to a guideline method

2 Reliable with restriction

• Not performed under GLP or specific testing guideline
• Well documented
• Scientifically acceptable

3 Not reliable

• Methods not clearly defined
• Small number of animals
• Single dose administered

4 Not assignable

• Insufficient experimental details
• Secondary Literature
• Abstracts

Klimisch et al. Regul Toxicol Pharmacol, 1997

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Methyl Salicylate – Select Klimisch Scores

Study Study Quality Score Rationale for study quality score

Gulati et al. 1984 2

• Performed according to GLP, but not OECD
• Testing guideline is a published guideline.
• Testing guideline is well documented and scientifically

acceptable. Morrissey et al. 1989 2

• Performed according to GLP, but not OECD
• Testing guideline is a published guideline.
• Testing guideline is well documented and scientifically

acceptable. Webb and Hansen 1963 2

• No indication performed according to GLP or to any specific

published testing guidelines

• The study protocol well documented and scientifically

acceptable. Collins et al. 1971 3

• No indication performed according to GLP.
• The study was not performed according to any specific published

testing guidelines.

• Purity of test substance not specified

Packman et al. 1961 4 Only an abstract was available. Limited study details were available

Greene et al. Crit Rev Toxicol, 2016

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Phase 1

Define Causal Question and Develop Criteria for Study Selection

Phase 2

Develop and Apply Criteria for Review of Individual Studies

Phase 3

Integrate and Evaluate Evidence

Phase 4

Draw Conclusions Based on Inferences Key Factors: Transparent / Defensible / Expert judgment

Rhomburg et al., Crit Rev Toxicol, 2013

Phases of WoE

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Integration and Evaluation of Data Types

Epidemiology

Functional Biomarkers of Disease

Biomarkers of Potential Harm Biomarkers of Exposure

Non-clinical Measures

Relevance

LEAST MOST

Sensitivity

LEAST MOST

(to product differences) (to health effects)

Constituent Analysis

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Weight Assignment Considerations

• Weights defined explicitly
• Consistent application
• Biological relevance

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Phase 1

Define Causal Question and Develop Criteria for Study Selection

Phase 2

Develop and Apply Criteria for Review of Individual Studies

Phase 3

Integrate and Evaluate Evidence

Phase 4

Draw Conclusions Based on Inferences Key Factors: Transparent / Defensible / Expert judgment

Rhomburg et al., Crit Rev Toxicol, 2013

Phases of WoE

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Drawing Conclusions/ Expert Judgment

• Articulate rationale for conclusions clearly
• Include rationale for alternate, plausible hypothesis
• Apply a multidisciplinary approach

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Conclusions

A transparent, defensible WoE approach for tobacco products should:

• Evaluate the causal question critically
• Gather and score data comprehensively
• Assign weight to evidence rigorously, consistently and explicitly
• Explicitly state principle and alternate hypothesis and

conclusions

• Use multi-disciplinary expert judgment