Overview
This webinar will focus on the identification and characterisation of hazards, identified for drugs in development, in preparation for ‘first in man’ clinical trials. Toxicity studies, of varying durations, in laboratory animal species, are required by government, drug regulatory, agencies worldwide, and are intended to characterise the hazards inherent in dosing small molecule chemical entities to biological systems, the dose response for these hazards, and the ‘dose limiting’ toxicity that could potentially occur when the same drugs are given to humans in clinical trials. Currently, only these animal studies can be used to assess the potential safety of dosing the same entity into humans. The results of these safety studies, together with other data, including the efficacy of the drug for the proposed therapeutic disease, are presented in a prescribed way, for review by regulatory agencies and the results will provide the basis for a decision as to the applicability of the drug for further development, including initial tolerability studies in humans.
In a practical sense, the output from the toxicity studies will typically generate a high dose level, where unacceptable and clearly adverse changes occur, a low dose level where changes will also occur, but which will not be considered adverse, and intermediate doses where any decision, as to whether observed changes are adverse or not, lies in a twilight zone where any decision is open to considerable debate. The dose level at which the non-adverse changes occur is referred to as the ‘no observed adverse effect level’ (NOAEL) from which the human equivalent dose (HED) will be calculated as the proposed starting dose for the subsequent human study. Hence the importance of defining a precise NOAEL to avoid protracted, and consequentially unnecessarily expensive, human trials. The laboratory animal studies will also identify the affected organ/tissue and the severity and type of toxicity occurring at the NOAEL. These additional variables are considered, together with the availability of safety biomarkers for detecting similar human toxicity, when approving the clinical starting dose level. Tissues for which safety/toxicity biomarkers are not available, or where irreversible, drug-induced, changes of high severity have been identified, may preclude approval of a proposed starting dose in the human trial.
Pathology end points constitute the most common contribution used to set NOAELs in toxicity studies, and the current presentation will illustrate the difficulties of assigning adversity using case examples, and will finally propose a set of rules that practicing toxicologists and pathologists can use to justify assigning a particular change as non-adverse and a subsequent dose level as a NOAEL.
This event will take place at 12:30pm and last approximately 1 hour.
CPD
This meeting is worth 1 CPD point (self credited).
Speaker Biography - Toxicology webinar
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Prof John R Foster
John obtained his first degree in Zoology from the University of Wales in 1975 before undertaking research, on liver pathology, for which he was awarded a PhD in 1978. He then joined the British Industrial Biological Research Association (BIBRA), at Carshalton in the UK, as an experimental pathologist and head of the electron microscopy unit. He left BIBRA in 1983 to join the Pathology Department of ICI Central Toxicology Laboratory in Cheshire, United Kingdom. He obtained a diploma of the Royal College of Pathologists (RCPath) in Toxicology in 1987 and passed the examination to become a member of the RCPath in 1988 and was elected a Fellow in 1997. He was chairman of the Specialty Advisory Committee for Toxicology for the RCPath from 2002–2005 and was Chair of the Panel of Examiners for the Toxicology Specialty of the RCPath from 2006–2012. He remains an examiner for the College.
He was a science–reviewing member of ECETOC’s Long Range Research Initiative on Carcinogenicity from 2000–2006 and he sat on the UK Food Standard Agency’s Committee on Toxicity from 2006–2012. He was President of the British Society of Toxicological Pathologists from 2002–2004 and was appointed a Fellow of the British Society of Toxicology in 2008. He was a visiting lecturer, and was made an Emeritus Professor in the Faculty of Faculty of Health and Medical Sciences at the University of Surrey in 2010 and was made an Honorary Fellow of the BSTP in the same year. In 2011 he was made an Honorary Fellow of the Latin American Society of Toxicologic Pathologists and became a Fellow of the International Academy of Toxicologic Pathology in September 2012. He was elected President of the International Academy of Toxicologic Pathology from 2019-2021.
Prof Foster has published over 150 research papers, review articles, and book chapters in toxicological pathology, and was the Editor in Chief of the journal, Toxicologic Pathology, from 2008–2013. Following 20 years working on the development of agrochemicals and industrial chemicals, at ICI, Zeneca and finally Syngenta’s Central Toxicology Laboratory, he joined AstraZeneca Pharmaceuticals in 2001 specializing in the development of oncology targeting drugs. He retired from AstraZeneca in 2013 as a Senior Principal Pathologist and Deputy Head of Pathology. He is currently an independent consultant pathologist working for an independent pathology consultancy company called ToxPath Sciences Ltd.
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Dr Jan Klapwijk
Chair, Toxicology SAC
I originally trained as a veterinarian at Liverpool University and practiced small animal medicine for 6 years before moving into laboratory animal medicine at Smith Kline Beecham in 1989.
In 1994 I joined Glaxo Wellcome to retrain as a toxicological pathologist. Since then I have gained 30 years’ experience in regulatory toxicology / safety assessment and discovery support across a range of therapeutic areas (including inhaled medicines, CNS, oncology) and modalities (small molecules and biopharmaceuticals) within large Pharma in the UK and Italy. From 2005 I worked at GlaxoSmithKline, including a number of years as Head of Pathology. In the last 15 years my experience has expanded to include cell and gene therapies for rare diseases, oncology, CNS and auto-immune disease. I was the nonclinical project team member for Strimvelis (for treatment of ADA-SCID) which achieved a successful marketing application in 2016 - the first licensed ex vivo gene therapy anywhere in the world.
After retiring from GSK in March 2021 I have been working as an independent pathology consultant in my own company (Cornelis Consulting Ltd). I have been a Member / Fellow of the RCPath for 25 years and currently chair the Toxicology Specialty Advisory Committee. I am also a former President of the British Society of Toxicological Pathology.
