ICH signs off on carcinogenicity testing addendum

The International Council for Harmonisation (ICH) recently announced that its S1B(R1) addendum outlining a “weight of evidence” (WoE) approach to assess the human carcinogenic risk for certain pharmaceuticals in lieu of conducting a two-year rat study has reached Step 4 and is awaiting sign-off by regulators.

The document contains several changes from the Step 2 guideline released in May 2021. (RELATED: To speed drug development, ICH proposes reducing rat carcinogenicity testing, Regulatory Focus 14 May 2021)

Since the publication of the original S1B guideline on carcinogenicity testing in 1998, “scientific advances toward elucidation of mechanisms of carcinogenicity, greater understanding of the limitations of rodent models, and several retrospective analyses of pharmaceutical datasets indicate that 2-year rat carcinogenicity studies might not add value to human carcinogenicity risk assessment in some cases and the carcinogenic potential could have been assessed adequately based on a comprehensive assessment of all available pharmacological, biological, and toxicological data,” said an ICH announcement.

The addendum describes how to use the WoE approach to assess the human carcinogenic potential of pharmaceuticals. This approach uses three factors to consider whether the test compound is either likely carcinogenic and two-year rat studies would not add much value; likely not to be carcinogenic and a two-year rat study would not add much value; or with uncertain carcinogenic risk and a study is likely to add value to the human risk assessment.

It also describes the factors to consider for a WoE assessment, how to integrate these factors for assessing the human carcinogenic risk and describes when mouse carcinogenicity studies are needed. An appendix provides some examples of how to apply these WoE approaches.

The addendum revises the previous version by incorporating the original ICH S1B guideline on carcinogenicity testing as a new Part 1 section. This change was to accommodate public comments requesting the original guideline be published along with the addendum to reduce confusion and ensure the new WoE approach is adequately used and implemented rather than publish the addendum as a separate document.

The update also includes a new flow chart outlining key steps in developing a carcinogenic assessment strategy to determine the value of a two-year rat study, as well as a flow chart showing how to integrate the WoE factors for assessing a pharmaceutical’s human carcinogenic risk.

With the implementation of the addendum, “It is anticipated that industry will generate and submit a WoE based carcinogenicity assessment for DRA [Drug Regulatory Authority] consideration when a sponsor concludes that a 2-year rat study does not add value to human carcinogenicity risk assessment,” according to an ICH presentation.

ICH guideline

ICH signs off on carcinogenicity testing addendum

Related topics

Recommended content

Welcome to the new RAPS Digital Experience