Speakers: Todd Bourcier, CDER, FDA; Alisa Vespa, Health Canada; Arianna Bassan, Innovatune; Susanne Stalford, Lhasa Limited; Jose Lebron, Merck & Co., Inc.; Shigeru Hisada, Former ASKA Pharma., Former JPNA
Organizers: Doris Zane, PhD, DABT (Gilead Sciences)
Date: 2023-05-26
Time: 8:30-13:30 Pacific Time
Registration fee: Free
Location: Online via zoom
Major Sponsor:
Vendor show vendors registered to date:
Registration: http://www.PBSS.org
Registration deadline:2023-05-24  (it will close sooner if the seating cap is reached)

About the Topic

Our invited speakers will be providing seminars on topics related to carcinogenicity assessment of pharmaceuticals. General topics will cover some of the challenges faced with carcinogenicity assessments in the development of pharmaceuticals, Regulatory and Industry Perspectives on the ICH S1B(R1) Carcinogenicity Guideline, protocols to support the weight of evidence (WOE) assessment in the ICH S1B guideline, high dose selection by clinical exposure rations in the rasH2-Tg mouse study and use of a carcinogenicity AOP network to conduct a WOE assessment presented by speakers from Industry, Regulatory, and Contract Research Organizations. 

Dr. Todd Bourcier, Office of New Drugs, CDER, US FDA

Dr. Todd Bourcier is the Director in the Division of Pharmacology and Toxicology in the Office of Cardiology, Hematology, Endocrinology, and Nephrology (OCHEN) in the Office of New Drugs (joined FDA in 2004). He was part of the FDA delegation to the ICH Expert Working Group that developed the S1BR1 addendum.

In 2013, an expert working group of the ICH initiated a prospective study based on the premise that a set of WOE criteria centered on drug target pharmacology and general toxicology could, in certain cases, provide an adequate assessment of carcinogenic potential without the conduct of a long-term rat bioassay. This effort supported creation of an addendum to the ICH S1B guidance whereby an integrative WOE presentation of key biologic, pharmacologic, and toxicologic information is used to determine whether or not a 2 year rat study would add value in completing a human carcinogenicity risk assessment. The addendum does not replace but rather expands the testing scheme described in the original S1B guideline and progresses the field toward a more mechanism-based carcinogenicity assessment for small molecule pharmaceuticals.

Dr. Alisa Vespa, Pharmaceutical Drugs Directorate, Health Canada Representative

At Health Canada for 15 years; currently work to provide advice/consultation on the safety of various pharmaceuticals for both pre-market applications & post-market risk files in the Pharmaceutical Drugs Directorate; Involved in various international working groups most recently ICH S1B expert working group.

To assess the human carcinogenic risk of a small molecule pharmaceutical, carcinogenic potential is typically evaluated in 2-year rat carcinogenicity study in addition to a second rodent carcinogenicity study conducted in mice (2-year or short term). As a result of an independent prospective study conducted under the auspices of ICH, the testing scheme is being expanded to include a weight-of-evidence approach, which is based on a comprehensive assessment of various weight-of-evidence factors, to inform if the conduct of a 2-year rat study will or will not add value to the assessment of human carcinogenic risk. This session will provide an overview of the weight-of-evidence approach described in the ICH S1B Addendum. Case examples will be used to illustrate how the value of a 2-year rat study can be ascertained using a weight-of-evidence approach.

Dr. Arianna Bassan, Principal Consultant, Innovatune

Arianna Bassan is a chemist with long-term expertise in toxicology. She graduated at the University of Padova (Italy), and she earned her PhD in Chemical Physics at the Department of Physics of Stockholm University (Sweden). She had worked several years in international environments including Stockholm University, MSD/Merck&Co. and the European Commission. Her main interest lies in the use of computational toxicology for human health hazard assessment. She also led a number of different scientific projects with focus on data management (e.g., development of the EFSA’s Hazard database known now as OpenFoodTox, and management of pre-clinical data for pharma) and data curation. She is currently principal consultant in Innovatune, where she is also partner in the firm. Arianna partners with Instem on a variety of scientific activities, including coordination of a working group to support ICH S1B.

- There is no “one size fits all” approach for the novel strategy described in the ICH S1B addendum and its application must be tailored to the specific pharmaceutical being evaluated.
- To guide such a complex integrated assessment, more than 40 experts from different organizations have joined in an effort to establish a pragmatic consensus - This presentation will describe the work of this international working group, whose aim is to pragmatically standardize a procedure that frames the ICH S1B human carcinogenicity assessment ensuring as much as possible that any assessment is performed in a transparent, consistent, documented, repeatable, and defendable manner. The resulting pragmatic consensus procedure is meant to serve both as a guide to organizing the studies and displaying the data in the proper format as well as to clarify what would be expected in terms of the types of integrated evidence to be presented in the Carcinogenicity Assessment Document.

Dr. Susanne Stalford, Principal Scientist, Lhasa Limited

Susanne Stalford is a principal scientist at Lhasa Limited. After gaining a PhD in Biological Chemistry from the University of Leeds in the UK, she then went to work for Lhasa Limited and has been there for 15 years. Susanne has significant experience in the development of SAR models for multiple endpoints and now focusses on the development and application of AOPs for carcinogenicity. She currently leads the application of AOPs for ICH S1B(R1) within Lhasa Limited.

According to the ICH S1B(R1) addendum, evidence gathered throughout the pharmaceutical development process can be organised into a weight of evidence relating to six factors and conclusions drawn to reduce the animals required. Large amounts of complex evidence may need to be resolved using this approach and knowledge of modes-of-action and data gaps are important to determine human relevance and certainty. Hence a framework to support this assessment will be useful. Adverse outcome pathways (AOPs) provide the perfect means of addressing those needs. Using the structure the AOP concept provides, an approach to assess the evidence for ICH S1B(R1) to aid decision making has been developed, using multiple in vitro and in vivo assays and in silico predictions organised around 32 AOPs relating to cancer. This system has the advantage of being able to give consistent results as knowledge and data are logically organised, decreasing uncertainty in outcomes. This framework is also naturally adaptable, as inclusion of new approach methodologies and additional data can be achieved without a change to the framework protocol. Finally, transparency of the system allows for the probing of evidence in expert review, thus ensuring outcomes are scientifically robust. An overview of this approach along with an example of how it may be used to fulfil the new ICH S1B R1) addendum will be presented.

Dr. Jose Lebron, Scientific Associate Vice President, Nonclinical Drug Safety, Merck & Co., Inc.

Jose Lebron, Ph.D. is a Scientific Associate Vice president in the Nonclinical Drug Safety (NDS) department at Merck in West Point, PA. During his 23+ years at Merck, Jose’s career has spanned multiple facets of drug development and he has also supported several modalities, including small molecules, oligonucleotide therapeutics, peptides, monoclonal antibodies, and long-acting parenteral pharmaceuticals. Jose was the ICH S1B(R1) PhRMA topic lead for Steps 2-4 of the ICH process and at Merck he oversees the preparation of weight of evidence-based carcinogenicity risk assessments, among other responsibilities. Jose received his B.S. in Chemistry (Biology minor) from the University of Puerto Rico and his Ph.D. in Biochemistry, Molecular Biology, and Immunology from the California Institute of Technology (Caltech).

After ~9 months since the adoption of the new S1B(R1) Addendum, Industry has submitted several weight-of-evidence-based carcinogenicity risk assessments to HAs asserting that a 2-year rat carcinogenicity study would not add value for certain pharmaceuticals. This presentation will provide an overview of the industry’s experience to date with the process and the feedback received from HAs, including best practices and challenges encountered. Also discussed will be the Industry’s perspective on the importance of product development timelines, the need for a predictable process, and the value of securing intra- and inter-agency alignment to successful implementation of the Addendum.


Dr. Shigeru Hisada, DJSOT, DJSTP, Former ASKA Pharmaceutical C., Ltd., Former Non-Clinical Expert Committee, JPMA

- ASKA Pharmaceutical Co., Ltd., Safety Research Department (1979-2022): engaged in safety evaluation of pharmaceutical products as a toxicologic pathologist and toxicologist.
- Director of Safety Research Dept. (2004-2009), Research Fellow (2010-2022)
- Non-Clinical Evaluation Expert Committee, JPMA (1995-2022)
- ICH S8 Immunotoxicity guideline EWG JPMA Expert (2003-2005)
- ICH S1B carcinogenicity guideline EWG, JPMA Topic Leader (2012-2022)

To determine the appropriate clinical exposure margin for high-dose selection in rasH2-Tg mouse 6-month carcinogenicity studies, we surveyed the tumorigenic sensitivity of 53 compounds in rasH2-Tg mice. AMs (AUC margins) and DRs (body surface area-based dose ratios) in rasH2 Tg mice, in which tumors and hyperplasias occurred, were compared with those in 2-year rodent assays. These results indicate that it is of no value to administer at exposure margins greater than 50-fold in a 6-month rasH2-Tg mouse study.