ICH S1B(R1) Guideline and AI-Enabled Approaches

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) develops harmonized guidelines to support the evaluation and approval of new medicines. One of its key guidelines, ICH S1B: Testing for Carcinogenicity of Pharmaceuticals, provides guidance on approaches for evaluating the carcinogenic potential of pharmaceuticals, which may include a 2-year rat carcinogenicity study. In 2022, ICH updated this guideline with an Addendum, ICH S1B(R1), introducing a modern Weight of Evidence (WoE) framework to help determine whether the 2-year rat study adds value to understanding human cancer risk.

The ICH S1B(R1) Addendum identifies target biology evaluation as one of six key factors that contribute to an integrated assessment of human carcinogenicity risk. The aim is to determine whether a traditional two-year rat carcinogenicity study provides meaningful additional value to the overall human risk assessment. When the full Weight of Evidence (WoE) across all six factors supports that the rat study does not add value, this integrated assessment can be submitted directly to regulatory agencies in lieu of a 2-year bioassay, saving substantial time, cost, and animal use.

However, completing a full WoE assessment requires results from the chronic (six-month) rat repeat-dose toxicity study, which is typically conducted later in development. If the need for a 2-year rat study is only identified after this point, project timelines can be significantly affected. To avoid such delays, it is important to identify early indicators, prior to the chronic study, that suggest whether a long-term study will likely be required. For promising compounds, maintaining an ongoing, early-stage assessment of the WoE can justify starting the chronic study sooner, helping to mitigate potential risks to the development schedule.

The target biology factor offers a valuable early perspective on potential carcinogenic mechanisms. These may include cell proliferation, tissue-specific hypertrophy, cellular replication, or links to oncogenic pathways. Insights from this evaluation can inform decision making, shape data collection strategies, and ensure that later-stage studies are both targeted and efficient. An early robust WoE assessment can help ensure that the project timeline is not impacted by a late decision that a 2-year rat carcinogenicity bioassay is necessary and may also support interpretation of results of later phase nonclinical studies.

To support implementation of the ICH S1B(R1) Addendum, Onesum offers a technology-enabled service that combines advanced AI capabilities with expert scientific oversight to streamline WoE carcinogenicity assessments. Aligned with our published consensus procedure, this service enables structured, transparent, and reproducible evaluation of target biology and other key factors within the ICH S1B(R1) guidance. Our approach reduces time and resource demands while maintaining scientific rigor, enabling organizations to identify potential carcinogenic mechanisms earlier, determine the likely value of a 2-year rat study, and make confident, evidence-based decisions.