ICH S1A - S1C Carcinogenicity Studies Guidelines


S1A - S1C Carcinogenicity Studies 

S1A  Need for Carcinogenicity Studies of Pharmaceuticals

The ICH Harmonised Guideline was finalized under Step 4 in November 1995. This document provides a consistent definition of the circumstances under which it is necessary to undertake carcinogenicity studies on new drugs. These recommendations take into account the known risk factors as well as the intended indications and duration of exposure.

Date of Step 4: 29 November 1995

Status: Step 5

Guidelines (Click the links below for complete guidelines)

S1B  Testing for Carcinogenicity of Pharmaceuticals

The ICH Harmonised Guideline was finalized under Step 4 in July 1997.

This document provides guidance on approaches for evaluating the carcinogenic potential of pharmaceuticals.

The Guideline embraces all pharmaceutical agents that need carcinogenicity testing as indicated in Guideline S1A.

This document provides guidance on the need to carry out carcinogenicity studies in both mice and rats, and guidance is also given on alternative testing procedures which may be applied without jeopardizing safety.

Date of Step 4: 16 July 1997

Status: Step 5

Guidelines (Click the links below for complete guidelines)

S1B(R1) EWG  Rodent Carcinogenicity Studies for Human Pharmaceuticals

This topic was endorsed by the ICH Steering Committee in April 2012. A change to the current S1 Harmonised Guidelines on rodent carcinogenicity testing is proposed to introduce a more comprehensive and integrated approach to addressing the risk of human carcinogenicity of pharmaceuticals, clarify and update, without compromising safety, the criteria for deciding whether the conduct of a two-year rodent carcinogenicity study of a given pharmaceutical would add value to this risk assessment.

In November 2012, the Steering Committee endorsed the revision of both the S1 Concept Paper and Business Plan to provide clarification concerning how the prospective data gathering period should be integrated in the normal ICH Step process. The revised S1 Concept Paper and Business Plan describe the S1 strategy which consists of first preparing a draft "Regulatory Notice for Public Input" which would be issued by each ICH regulatory health authority to solicit comments from the public to the proposal, the procedure, and the specific weight-of-evidence criteria. In August 2013, the S1(R1) EWG finalized the Regulatory Notice that specifies the agreed upon details of the prospective trial data collection period.

In April 2015, the Regulatory Notice Document was amended to include Health Canada, Canada as one of the Drug Regulatory Agencies that will begin receiving and reviewing Carcinogenicity Assessment Documents and Summary Study Reports in accordance with the process described in the document.

 In January 2016, an update to the Regulatory Notice Document (RND) has been posted on January 21, 2016 following discussions by the S1 Expert Working Group at the ICH Meeting held Dec 7-10, 2015. The changes to the RND are intended: a) to further clarify and improve the procedures for review by DRAs of Carcinogenicity Assessment Document (CAD) and final 2 years rat carcinogenicity study reports, b) to catalyze the numbers and quality of submissions by sponsors of CADs and final study reports, c) to improve alignment on CAD category decisions between sponsors and DRAs, and among DRAs, and d) to clarify expectations for the successful completion of the Prospective Evaluation Period (PEP). The specific changes made to the RND are as follows: 1) Swiss medic has been added as a DRA member along with the address for CAD submissions; 2) the Prospective Evaluation Period for submission of CADs has been extended for 2 years with the expectation for continuation through the end of Dec, 2017 (with the final study report expected to be submitted by Nov, 2019); 3) this extension is expected to allow for the target number of at least 20 Category 3 CADs along with the matching final study reports, that will be needed to consider revision of S1 Guidance; 4) sponsors are given opportunity to respond to requests from DRAs for clarification to CADs, or to provide additional information that may be deemed necessary by DRAs to make decisions on sponsor proposals for Category 3 submissions; 5) the longest duration of ongoing 2 years rat carcinogenicity studies allowable for CADs to be submitted has been reduced from 18 months in the original RND to 14 months effective June 1, 2016; 6) the content and format for executive summary 2 years rat study reports has been clarified.

In April 2016 and December 2017, the S1(R1) EWG completed Prospective Evaluation Period Status Reports. These Status Report provide a brief overview of the study’s progress and actions taken by the EWG to ensure successful completion of the study.

Date of Step 2b: 10 May 2021

Status: Step 3

Guidelines (Click the links below for complete guidelines)

Endorsed Document (Click the links below for complete guidelines)


WG Presentations/Trainings (Click the links below for complete guidelines)

S1C(R2)  Dose Selection for Carcinogenicity Studies of Pharmaceuticals

This document addresses the criteria for the selection of the high dose to be used in carcinogenicity studies on new therapeutic agents to harmonise current practices and improve the design of studies. The Addendum on "Addition of a Limit Dose and Related Notes", finalized in July 1997, has been incorporated into the core Guideline in November 2005, which was then renamed S1C(R1).

The second revision has been approved by the ICH Steering Committee under Step 4 in March 2008 (S1C(R2)). In the second revision, the pharmacokinetic endpoint of 25 is declared to be applicable also for pharmaceuticals with positive genotoxicity signals. This change has implications on "Refinement" (one of the 3R's) in enhancing the welfare, e.g., reducing the pain or discomfort of the animals at the maximally tolerated dose (MTD).

Date of Step 4: 11 March 2008

Status: Step 5

Guidelines (Click the links below for complete guidelines)

Endorsed Document (Click the links below for complete guidelines)

WG Presentations / Trainings (Click the links below for complete guidelines)

*These Guidelines Belongs to ICH website.

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