Abstract
The Tg.rasH2 mouse was developed as an alternative model to the traditional 2-year mouse bioassay for pharmaceutical carcinogenicity testing. This model has found extensive use in support of pharmaceutical drug development over the last few decades. It has the potential to improve quality and timeliness, reduce animal usage, and in some instances allow expedient decision-making regarding the human carcinogenicity potential of a drug candidate. Despite the increased use of the Tg.rasH2 model, there has been no systematic survey of current practices in the design, interpretation of results from the bioassay, and global health authority perspectives. Therefore, the aim of this work was to poll the pharmaceutical industry on study design practices used in the dose range finding and definitive 6-month studies and on results relative to the ongoing negotiations to revise The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S1 Guidance. Twenty-two member companies of International Consortium for Innovation and Quality in Pharmaceutical Development DruSafe Leadership Group participated in the survey, sharing experiences from studies conducted with 55 test compounds between 2010 and 2018. The survey results provide very useful insights into study design and interpretation. Importantly, the results identified several key opportunities for reducing animal use and increasing the value of testing for potential human carcinogenicity using this model. Recommended changes to study designs that would reduce animal usage include eliminating the requirement to include positive control groups in every study, use of nontransgenic wild-type littermates in the dose range finding study, and use of microsampling to reduce or eliminate satellite groups for toxicokinetics.
Highlights
The Tg.rasH2 mouse model was developed as a short-term testing alternative to the traditional 2-year mouse carcinogenicity study
All but one of the 22 companies had completed at least 1 carcinogenicity study in any mouse model during the specified time frame
Among the companies giving a reason for not testing a compound in the Tg.rasH2 model, one indicated it was company policy not to use Tg.rasH2, and that company cited lack of sufficient historical control data (HCD) as one of the reasons
Summary
The Tg.rasH2 mouse model was developed as a short-term testing alternative to the traditional 2-year mouse carcinogenicity study (lifetime bioassay). The investment to complete such an assessment can be significant in terms of animal numbers, resources, and time such that often the carcinogenicity assessment is often on the critical path to pharmaceutical registration. Alternative animal models, such as the Tg.rasH2 have the potential to improve the quality and timeliness of the assessment and reduce the number of animals required.[1,2]. Mutations or initiating events in the NJ, USA 5 Toxicology, Drug Disposition &PK/PD Eli Lilly and Company, Lilly Corporate
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