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Rodent Carcinogenicity Testing: Changes to ICH Guidance Proposed

Posted 02 March 2016 | By Zachary Brennan 

Rodent Carcinogenicity Testing: Changes to ICH Guidance Proposed

The European Medicines Agency (EMA) is considering changes to International Council for Harmonisation (ICH) guidance on rodent carcinogenicity testing to improve the evaluations, reduce use of animals and drug development resources and reduce timelines to market authorization in some cases without compromising patient safety.

The goal of the potential changes to the S1 guidance, according to EMA, is to introduce a better way to address the risk of human carcinogenicity of small molecule pharmaceuticals and to define the conditions under which two-year rat carcinogenicity studies add value to that assessment. The changes, if implemented, will not be applicable to biologics.


Back in May 2012, ICH set up a new expert working group to try to develop the changes, and then in 2013, the US Food and Drug Administration (FDA) said it was considering the update, alongside Health Canada, and called for public comment.

"It is hypothesized that consideration of this information can provide sufficient information to conclude that a given pharmaceutical in certain cases presents a negligible risk or, conversely, a likely risk of human carcinogenicity without conducting a 2-year rodent study," FDA said.

If this hypothesis is proven true, FDA, EMA, Japan’s MHLW, Health Canada and Swissmedic would be able to provide waivers to companies seeking to bypass the two-year rodent studies.


In January 2016, ICH updated the Regulatory Notice Document (RND) on the S1 guidance to:

  • Further clarify and improve the procedures for review by regulators of Carcinogenicity Assessment Document (CAD) and final two years rat carcinogenicity study reports;
  • Catalyze the numbers and quality of submissions by sponsors of CADs and final study reports;
  • Improve alignment on CAD category decisions between sponsors and regulators, and among regulators;
  • Clarify expectations for the successful completion of the Prospective Evaluation Period (PEP).

The PEP has been extended for two years with the expectation of continuing through the end of December 2017, with the final study report expected to be submitted by November 2019, ICH says.

The extension is expected to allow for at least 20 Category 3 CADs (which would be the compounds representing the most notable departure from current guidance) along with the matching final study reports that will be needed to consider the revisions of S1 guidance.

Sponsors will be provided the opportunity to respond to requests from the regulators for clarification or to provide additional information deemed necessary to make decisions on sponsor proposals for Category 3 submissions.

In addition, ICH says the longest duration of ongoing two-year rat carcinogenicity studies allowable for CADs to be submitted has been reduced from 18 months in the original RND to 14 months, effective 1 June 2016. 

EMA in late February disclosed that retrospective analyses of various datasets from PhRMA, FDA, Juvenile Products Manufacturers Association, and EU + FDA, “it was concluded that based on pharmacology, genotoxicity, and chronic toxicity data (usually present at the end of Phase II in the development of a new pharmaceutical) the outcome of the 2-year rat carcinogenicity study can be predicted with reasonable assurance at the two extremes of the spectrum.

“Negative predictions can be made when predictive carcinogenic signals are absent and positive predictions can be made when such signals are present. In between a category of compounds still remain for which the outcome of the carcinogenicity studies cannot be predicted with sufficient certainty.”

Datasets evaluated by the ICH S1 expert working group also suggest that knowledge of pharmacologic targets and pathways, used alongside toxicological and other data, can in certain cases, provide sufficient information to anticipate the outcome of two-year rat carcinogenicity studies and their potential value in predicting the risk of human carcinogenicity of a given pharmaceutical.

All of the regulators are still working to collect more data on the carcinogenicity studies, according to ICH.

ICH guideline S1 Regulatory notice on changes to core guideline on rodent carcinogenicity testing of pharmaceuticals

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