> ## Content Index
> Fetch the complete content index at: https://www.fdaweb.com/llms.txt
> Use this file to discover other available public pages before exploring further.

# ICH Guide Aims to Reduce Rat Carcinogenic Studies: FDA
- URL: https://www.fdaweb.com/ich-guide-aims-to-reduce-rat-carcinogenic-studies-fda/
- Published: 2022-11-01T12:00:00.000Z
- Updated: 2026-09-14T18:04:45.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5153105

FDA has released a final guidance, “[S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals; International Council for Harmonization; Guidance for Industry](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s1br1-addendum-s1b-testing-carcinogenicity-pharmaceuticals?ref=fdaweb.com),” which outlines a “weight of evidence” approach for assessing human carcinogenic risk in drugs. The International Council for Harmonization document is part of FDA’s and other global regulators’ work to reduce the use of animals in research. It outlines an approach that, in certain situations, could determine that a two-year rat study is not necessary to assess a drug’s carcinogenic risk.

In an [online post](https://www.fda.gov/drugs/news-events-human-drugs/cder-conversation-fdas-final-guidance-carcinogenicity-testing-pharmaceuticals?utm%5Fmedium=email&utm%5Fsource=govdelivery), CDER associate director of pharmacology and toxicology **Timothy McGovern** says a *“*greater understanding of the mechanisms of carcinogenicity, the publication of several retrospective analyses indicating that two-year rat carcinogenicity studies might not add value to human risk assessment in some cases, and our commitment to patient safety, expediting drug development, and animal welfare, led us to consider how to amend the original S1B guidance… We ultimately determined, and have described in the guidance, that a ‘weight of evidence’ approach can provide an adequate assessment of carcinogenic risk in certain cases without using data from a two-year rat study.”

McGovern explains that weight of evidence refers to a systematic approach in which investigators look at all relevant evidence to make an assessment or determination. “In this case, some factors included in our weight of evidence assessment include information on the mechanism of action and the toxicological profile of a pharmaceutical, the potential for genetic toxicity, evidence of immune modulation (or change), and evidence of hormonal perturbation. The guidance goes into more detail about these and other factors.”

He says an FDA prospective research study suggests that the weight of evidence approach could reduce rat carcinogenicity studies by about 25%. “I also want to emphasize that this guidance continues to recommend a carcinogenicity study in mice as a component of a carcinogenicity assessment plan,” he notes. “Drug developers would still be responsible for conducting those studies to assess carcinogenic risk. So this guidance is one step in our broader effort to improve assessment of this important safety endpoint and to consider alternatives to animal testing, but we must continue to tread carefully and keep patient safety at top of mind when considering changes in drug development.”

Additionally, he says the guidance introduces the use of a drug exposure-based approach for setting the high dose in a recommended mouse model. “This approach has been used for two-year studies but not for six-month transgenic studies,” he says. “We concluded that a 50-fold exposure ratio is an adequate criterion for high-dose selection for this model in addition to the other criteria described in the S1 guidances.”