Application of AOPs for Weight-of-Evidence Assessments: Rationalising Evidence for the ICH S1B(R1) Guidance Addendum

The recent publication of the ICH S1B(R1) draft addendum reflects the paradigm shift occurring across industry with respect to moving away from long-term animal studies for carcinogenicity. Using evidence gathered throughout the pharmaceutical development process, the guidance suggests that the totality of this data should be sufficient, using a weight-of-evidence (WoE) approach based around six factors, to indicate if conducting a rodent carcinogenicity study would be of any additional value. Adverse outcome pathway (AOP) networks have been advocated as a way of organising and contextualising evidence in a framework upon which an integrated approach to testing and assessment (IATA) can be built. Using the structure this concept provides, an approach to assess the evidence for ICH S1B(R1) and make a relevant decision has been developed, which is transparent, consistent, and robust. Practically, the results can be viewed in three different ways – as an AOP network, ICH S1B(R1) factor AOP networks, and as individual AOPs.