In 1959, two scientists, Russell and Burch, proposed a new applied science that would improve the treatment of laboratory animals while at the same time advancing the quality of science in studies that use animals. With the benefit of hindsight, it may not have occurred to them that these alternative methods for minimizing use of animals in biomedical research would still be trending six decades later. At the SOT 2019 Annual Meeting and ToxExpo, the Ethical, Legal, Forensics, and Societal Issues Specialty Section, as well as the In Vitro and Alternative Methods and the Regulatory and Safety Evaluation Specialty Sections, endorsed a Symposium Session on “Scientific and Regulatory Update in the Application of the 3Rs Principle in Chemical and Drug Development.”
To address this topic, they assembled experts from industry, government, and academia. Dr. Brinda Mahadevan of Abbott Laboratories lectured on “3Rs in the Development of Nonproprietary Pharmaceuticals.” She pointed out that while innovator drugs must undergo preclinical studies, generic drugs may not compulsorily undergo preclinical testing based on a case-by-case evaluation. She identified comparative exposure assessment, innovator and literature support, in silico analysis, in vitro assessment, and systemic exposure evaluation as some of the strategies adopted to minimize animal studies in the development of generic drugs.
To drive home her point, Dr. Mahadevan cited the preclusion of preclinical studies in certain scenarios involving different forms of an active drug substance. Specifically, in migrating from diclofenac sodium to diclofenac potassium, preclinical supports were obtained from literature and approved listed drugs. Contrariwise, a bridging study may be necessary based on fundamental composition of the drugs. For example, a transition from esomeprazole magnesium to esomeprazole strontium could involve reproductive and developmental toxicity studies largely due to concern that strontium has an adverse effect on bone growth and development. However, Dr. Mahadevan identified insistence by regulatory authorities on repeated-dose toxicity data and preclinical toxicity studies on final formulation as the major challenges in the implementation of 3Rs in the development of generic drugs. In conclusion, Dr. Mahadevan listed some of the latest guidelines on the 3Rs, including ARRIVE (Animal Research: Reporting of In Vivo Experiments, by the UK-based National Centre for the Replacement Refinement & Reduction of Animals in Research), PREPARE (Planning Research and Experimental Procedures on Animals, anchored by the Norwegian Veterinary Institute), and EUSAAT (European Society for Alternatives to Animal Testing).
Subsequently, Dr. Anna Lowit of the US Environmental Protection Agency (US EPA) took the stage to give an update on the Agency’s initiative to implement alternatives to acute systemic testing. Summarily, Dr. Lowit informed that the US EPA had a policy that accepts eye irritation assays for antimicrobial cleaning products, adding that there were current efforts to extend the use of alternative assays for other classes of pesticides.
For the icing on the cake, Dr. Marcel Leist of the University of Konstanz, Germany, expounded on the novel strategies for implementation of the 3Rs, buttressing his talk with case studies from Europe. A particularly compelling case study used new approach methods, guided by adverse outcome pathways, to support a read-across from Rotenone (a data-rich source) to Deguetin (a data-poor target). In this instance, nonanimal methodologies (NAM) deployed to predict toxicity included a molecular initiating event confirming the existence of a common binding site for Rotenone and Deguetin. Other NAM approaches were studies on inhibition of mitochondrial complex 1, loss of membrane potential, assays on impaired proteostasis by measurement of the C/EBP homologous protein (CHOP), and the use of ADME parameters/PBPK modeling. In his concluding remarks, Dr. Leist stated that NAM could be used to improve the reach across for hazardous compounds by providing more clarity and less uncertainty.
This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.