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Impact on Pharmaceutical Development of the New Addendum to Testing for Carcinogenicity of Pharmaceuticals Within the ICH S1B(R1) Guideline

The ICH S1B(R1) Guideline provides international regulatory guidance on approaches for evaluating the carcinogenic potential of small molecule pharmaceuticals.  An addendum to this Guideline was finalized in August 2022, implementing several key updates to the original 1997 guidance which are supported by significant scientific advances, retrospective analyses, and an independent, international prospective study.   

The updated guidance introduces an integrative, mechanism-based method for assessing human carcinogenic risk using a Weight of Evidence (WoE) approach.  While a mouse carcinogenicity study (either 2-year standard mouse study or 6-month transgenic rasH2-Tg study) is still required in most cases, a 2-year rat study is now only required when the WoE approach cannot adequately assess human carcinogenic risk without it.  This new approach reduces the use of animals in accordance with the 3Rs principles and without compromising patient safety.  The addendum also clarifies high dose identification for rasH2-Tg studies, with a plasma exposure ratio-based option now acceptable.   

This updated guidance is a major step forward, both in reducing the use of animal studies and in answering open questions related to test article dose selection for rasH2-Tg studies. But what could it mean for your drug development program? 

The updated guidance encourages a shift towards mechanism-based carcinogenicity risk assessment starting earlier in drug development. 

  • What does that look like from a practical standpoint? 
  • If a 2-year rat study is not required, how could that change the timeline for safety assessment and marketing approval.
  • Does it change the calculus regarding use of a 2-year standard mouse study versus a 6-month rasH2 study?  


Watch this virtual presentation as Dr. Frank Sistare, Rapporteur of the ICH S1 Carcinogenicity Expert Working Group, provides an overview of the changes made through this Addendum to ICH S1B and a discussion of the anticipated real-world impact on pharmaceutical drug development.  


Watch this webinar to learn about:

  • The strength of the scientific basis for supporting international acceptance for the changes provided within the new Addendum to both rat and rasH2-Tg carcinogenicity testing.
  • How the weight-of-evidence criteria are expected to be applied for evaluating the potential value and need for conducting a 2-year rat carcinogenicity study.
  • The anticipated expanded practical role and value of the rasH2-Tg study to pharmaceutical carcinogenicity testing.
  • The anticipated real world impact of the ICH S1B(R1) Guideline on animal use, on pharmaceutical drug development, and on the evolution of new carcinogenicity tool development to bolster future WoE based decision making.

Watch It Now!


Frank D. Sistare, PhD

Adjunct Professor, University of North Carolina

Frank served for 16 years, most recently as Scientific Associate Vice President, within Safety Assessment at Merck & Co., Inc., West Point, PA. His responsibilities at Merck included investigative toxicology research to support drug development & safety lead optimization, incorporating novel models, endpoints, and technologies into drug discovery & development.

Since retiring from Merck in 2019, he is currently Adjunct Professor within the Department of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill. He continues to support HESI and FNIH collaborations, consults, and serves on the Scientific Advisory Boards for several companies. Before Merck, he was employed for 15 years in the FDA’s Center for Drug Evaluation and Research as a Captain in the USPHS Commissioned Corps.

Frank earned his Ph.D. in Pharmacology at the University of Virginia and was awarded a postdoctoral PRAT Fellowship at the NIH. He has served as President of the Regulatory and Safety Evaluation Specialty Section of the Society of Toxicology, Co-Director of the Critical Path Institute's Predictive Safety Testing Consortium, Chairperson of the FNIH Biomarker Consortium's Clinical Kidney Safety Biomarker Qualification Project Team, Chairperson of the PhRMA Carcinogenicity Working Group, and Rapporteur of the ICH S1 Carcinogenicity Expert Working Group.

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