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 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 1
Agenda Weight of Evidence (WoE) Defined Considerations for Tobacco Product Regulation Evolution of the WoE Approach Applying WoE Conclusions Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 2 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 2
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 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 3 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 3
WoE Considerations for Tobacco Product Regulation 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 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 4 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 4
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 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 5 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 5
Phases of WoE Key Factors: Transparent / Defensible / Expert judgment Phase 1 Phase 2 Define Causal Question and Develop and Apply Criteria Develop Criteria for Study for Review of Individual Selection Studies Phase 3 Phase 4 Integrate and Evaluate Draw Conclusions Based on Evidence Inferences Rhomburg et al., Crit Rev Toxicol , 2013 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 6 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 6
Causal Question Example Solomon et al. Crit Rev Toxicol , 2016 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 7 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 7
Data Gathering Ingredient Review (1) = ~ 24,000 vs. Ingredient Review (2) = ~ 50 Examples of Exclusion Criteria • Not mammalian animal model • Not in vivo/in vitro toxicology study • Acute effects only The WoE approach works regardless of the number of studies gathered during the study selection. Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 8 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 8
Phases of WoE Key Factors: Transparent / Defensible / Expert judgment Phase 1 Phase 2 Define Causal Question and Develop and Apply Criteria Develop Criteria for Study for Review of Individual Selection Studies Phase 3 Phase 4 Integrate and Evaluate Draw Conclusions Based on Evidence Inferences Rhomburg et al., Crit Rev Toxicol , 2013 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 9 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 9
Klimisch Criteria Quality Score Requirements Reliable without restriction • Good Laboratory Practices (GLP) 1 • National Testing Guidelines (e.g., OECD) • Methods comparable to a guideline method Reliable with restriction • Not performed under GLP or specific testing guideline 2 • Well documented • Scientifically acceptable Not reliable • Methods not clearly defined 3 • Small number of animals • Single dose administered Not assignable • Insufficient experimental details 4 • Secondary Literature • Abstracts Klimisch et al. Regul Toxicol Pharmacol , 1997 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 10 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 10
Methyl Salicylate – Select Klimisch Scores Study Quality Study Rationale for study quality score Score • Performed according to GLP, but not OECD • Testing guideline is a published guideline. 2 Gulati et al. 1984 • Testing guideline is well documented and scientifically acceptable. • Performed according to GLP, but not OECD • Testing guideline is a published guideline. Morrissey et al. 2 1989 • Testing guideline is well documented and scientifically acceptable. • No indication performed according to GLP or to any specific Webb and Hansen published testing guidelines 2 1963 • The study protocol well documented and scientifically acceptable. • No indication performed according to GLP. • The study was not performed according to any specific published 3 Collins et al. 1971 testing guidelines. • Purity of test substance not specified 4 Packman et al. 1961 Only an abstract was available. Limited study details were available Greene et al. Crit Rev Toxicol , 2016 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 11 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 11
Phases of WoE Key Factors: Transparent / Defensible / Expert judgment Phase 1 Phase 2 Define Causal Question and Develop and Apply Criteria Develop Criteria for Study for Review of Individual Selection Studies Phase 3 Phase 4 Integrate and Evaluate Draw Conclusions Based on Evidence Inferences Rhomburg et al., Crit Rev Toxicol , 2013 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 12 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 12
Integration and Evaluation of Data Types Epidemiology LEAST Functional Biomarkers of MOST (to product differences) Disease Sensitivity Biomarkers of Potential (to health effects) Relevance Harm Biomarkers of Exposure Non-clinical MOST Measures Constituent LEAST Analysis Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 13 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 13
Weight Assignment Considerations Weights defined explicitly Consistent application Biological relevance Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 14 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 14
Phases of WoE Key Factors: Transparent / Defensible / Expert judgment Phase 1 Phase 2 Define Causal Question and Develop and Apply Criteria Develop Criteria for Study for Review of Individual Selection Studies Phase 3 Phase 4 Integrate and Evaluate Draw Conclusions Based on Evidence Inferences Rhomburg et al., Crit Rev Toxicol , 2013 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 15 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 15
Drawing Conclusions/ Expert Judgment Articulate rationale for conclusions clearly Include rationale for alternate, plausible hypothesis Apply a multidisciplinary approach Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 16 Altria Client Services l P. Wiecinski, Research Scientist | November 15, 2016 | CTP Risk Assessment Workshop | Final | 16
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