Society of Toxicology (SOT)



Eminent Toxicologist lectureRuth A Roberts – Regulatory (Pharmaceutical) ToxicologyNotes prepared by Rebecca DearmanLearning Objectives:Understand the purpose of regulatory toxicology testing for pharmaceuticalsUnderstand how nonclinical data (general toxicology studies) inform clinical trial design protecting volunteers and patients Describe common principles for regulatory toxicology testing across different sectorsUnderstand the global framework provided by the International Council for Harmonization (ICH) for testing pharmaceuticalsConsider the principles and caveats of the design of general toxicology studies for pharmaceuticalsConsider the scope for scientific interpretation/expert knowledge in decisions regarding safety (guidelines versus rules)Consider future challenges to the current paradigm of toxicology testing in support of regulatory submissions?Recommended prerequisite topicsGeneral understanding of toxicity testingGeneral understanding of toxicological risk assessment (eg concept of NOELs etc)Study questionsWhy do safety margin levels developed for clinical studies differ between indications?What do the different phases of clinical trials (phase I, II, III and IV) mean?What role does the International Council for Harmonization (ICH) play in the regulatory toxicology testing for small drug molecules?What are the key studies in the pre-clinical work (the GLP toxicology package) that need to be done in order to determine whether a drug will go into man?Why are two species (rodent and nonrodent) used, what are the key considerations and why is the rodent species usually tested first and in higher numbers?How does the use of two species fit with the need to implement the 3Rs?How are doses selected for the toxicology studies (low, mid and high doses)? How are the different doses used?What is the formula for the Safety Margin calculation?Why are “recovery” groups also used in first into man (FITM) toxicology studies?What are the commonest “target” organs that are affected in the first into man (FITM) toxicology studies and do they differ between species? What adverse effects on clinical trials are difficult for animal studies to predict?What are the similarities/differences between the stepwise approaches to toxicology testing in the different sectors (Pharmaceuticals, Chemicals and Agrochemcials) What is the evidence that preclinical toxicology studies prevent toxic drugs getting into man?What three assumptions have been made for general toxicology testing for small molecule drugs that might need to be reconsidered?What type of products are only assessed for toxicological end points by in silico/in vitro methods at this current time in Europe?Application of this Lecture to Vision and Change Core Concepts and Competencies. ?Core Concepts?EvolutionThe lecture considers species differences and extrapolation of findings to humans ?and the extent to which the toxicological findings are reflected in the adverse effects observed in the clinic. Structure and FunctionThe example of the examination of ?attrition of candidate drugs through cardiovascular effects in later GLP regulatory studies and the ability to demonstrate detectable cardiovascular pathologies in earlier general toxicology studies shows the relationship between cell biology and function of living organisms. Information flow, exchange, and storagePathways and transformations of energy and matter?SystemsThe lecture discusses the benefits of using two species to determine toxicological endpoints and examines similarities and differences in toxicological findings, demonstrating the interconnectedness of living systems. ?Core Competencies?Ability to apply the process of science.The different stages of the drug discovery and development process from target selection, to lead optimization, toxicology testing and phase I, II and II clinical trials illustrate the processes of experimentation, observation and hypothesis testing.Ability to use quantitative reasoningThe modelling and application of safety margins (slide 7) and the consideration of statistical approaches to experimental design to ensure that experiments are appropriately powered to detect the desired effect demonstrates quantitative analysis and mathematical reasoning.Ability to use modeling and simulationThe lecture considers the application of in vitro and in silico methods to model in vivo exposure Ability to tap into the interdisciplinary nature of scienceThe interpretation and understanding of the preclinical studies requires consideration of the chemistry of the molecules, the pharmacology (metabolism) and a number of biological disciplines (eg cancer, reproductive biology) demonstrating the interdisciplinary nature of science. Ability to communicate and collaborate with other disciplinesThe example of the oncology drug (slide 15) demonstrates how communication between the toxicologists and the clinical staff running the phase I study allows for the most cost effective and beneficial phase I trial can be designed and implemented.Ability to understand the relationship of science and societyThe societal impact of the use of animals in toxicology studies and the need to consider the 3Rs is discussed.?Vision and Change Core Concepts.Evolution. The diversity of life evolved over time by processes of mutation, selection, and genetic change. Structure and Function. Basic units of structure define the function of all living things. Information flow, exchange, and storage. The growth and behavior of organisms are activated through the expression of genetic information in context.Pathways and transformations of energy and matter. Biological systems grow and change by processes based upon chemical transformation pathways and are governed by the laws of thermodynamics.Systems. Living systems are interconnected and interacting. Core Competencies and Disciplinary Practice. Ability to apply the process of science. Biology is evidence based and grounded in the formal practices of observation, experimentation, and hypothesis testing.Ability to use quantitative reasoning. Biology relies on applications of quantitative analysis and mathematical reasoning.Ability to use modeling and simulation. Biology focuses on the study of complex systems.Ability to tap into the interdisciplinary nature of science. Biology is an interdisciplinary science.Ability to communicate and collaborate with other disciplines. Biology is a collaborative scientific discipline.Ability to understand the relationship of science and society. Biology is conducted in a societal context. ................
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