Notice – Implementation of International Council for Harmonisation (ICH) S1B(R1): Testing for Carcinogenicity of Pharmaceuticals

December 1, 2023
Our file number: 23-110144–993

As a standing regulatory member of the International Council for Harmonisation (ICH), Health Canada is committed to the adoption and implementation of all ICH guidance. By way of this Notice, Health Canada is advising of its implementation of ICH S1B(R1): Testing for Carcinogenicity of Pharmaceuticals. This guidance has been developed by the appropriate ICH Expert Working Group (EWG) and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. The ICH Assembly endorsed the final draft and recommended its implementation on August 4, 2022. Health Canada implemented ICH S1B(R1) on June 20, 2023.

The ICH S1B(R1) Guideline integrates a new Addendum with the original S1B Guideline, which was finalised in July 1997. This Addendum expands the evaluation process for assessing human carcinogenic risk of pharmaceuticals by introducing an additional weight of evidence approach, which is documented in a Carcinogenicity Weight of Evidence (WoE) document [previously referred to as a Carcinogenicity Assessment Document (CAD)], that is not described in the original S1B Guideline. Application of this approach reduces the use of animals in accordance with the 3R (reduce/refine/replace) principles and shifts resources to focus on generating more scientific mechanism-based carcinogenicity assessments, while continuing to promote safe and ethical development of new pharmaceuticals.

Since publication of the S1B Guideline, 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 adequately assessed based on a comprehensive assessment of all available pharmacological, biological, and toxicological data.

To determine whether the conclusions from these retrospective analyses could be confirmed in a real-world setting (i.e., prior to knowledge of the 2-year rat carcinogenicity study outcome), a subsequent international prospective study was conducted under the ICH S1(R1) Proposed Change to Rodent Carcinogenicity Testing of Pharmaceuticals – Regulatory Notice Document. The process and several status updates reporting results are posted and available on the ICH website.

ICH S1B(R1) should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances.

Submitting a Carcinogenicity WoE document prior to the New Drug Submission (NDS)

Process changes are being undertaken that will allow sponsors to submit a Carcinogenicity WoE document via the Common Electronic Submissions Gateway (CESG). In the interim, to seek an opinion from Health Canada on the acceptability of the proposed WoE approach prior to filing an NDS, the Carcinogenicity WoE document should be submitted to carcinogenicity.WoE@hc-sc.gc.ca, with the subject line: 'Carcinogenicity Weight of Evidence Document'. A response with an opinion on the acceptability of the submitted Carcinogenicity WoE document will be sent within 90 days of submission.

In addition to the Carcinogenicity WoE document, please include a cover letter with the following information:

1. Name of drug substance (and proposed name of drug product, if available)
2. Proposed indication (for processing purposes only, indication not being assessed at this stage)
3. Opinions from international regulators on the acceptability of the submitted Carcinogenicity WoE document (if available, please include attachment(s) if necessary)

Submitting a Carcinogenicity WoE document as part of the NDS

If stakeholders wish to submit a Carcinogenicity WoE document as part of their NDS package, it should be placed in Module 4.2.3.4 of the Common Technical Document (CTD) structure. It is also recommended that their inclusion is mentioned in the submission cover letter.

In order for Health Canada to appropriately track these documents upon submission, either prior to filing the NDS or as part of the NDS, it is recommended that stakeholders use the current title: Carcinogenicity Weight of Evidence (WoE) document, and not the old Carcinogenicity Assessment Document (CAD).

This and other ICH Guidance documents are available on the ICH Website. Please note that the ICH website is only available in English. If you would like to request a copy of the French version of the document, please contact the ICH Coordinator inbox.