Speakers
Morning Session: Setting the Scene – Expert Perspectives
The primary objective of the pharmaceutical industry is to develop new medicines that are both safe and effective. Linked to this objective is a requirement for research tools that illuminate the psychopathology of diseases and disorders and provide mechanisms and targets that can be investigated and exploited in the search for new drugs.
The translational imperative for animal models in pharmaceutical development is consensus between the read-out from the experimental model and the effect of the drug-candidate in humans. Topics to be discussed are:
Safety Pharmacology testing is the mandatory programme of experimental studies to be performed on drug-candidates in humans, i.e. cardiovascular, respiratory and CNS safety, which in the case of CNS drug-candidates includes an evaluation of their potential for human abuse and dependence. In this field, the experimental evidence shows the established animal models have excellent translational validity.
Predicting therapeutic efficacy is more problematic – animal models based on pharmacological mechanisms, e.g. 5-HT2A-mediated head-twitches, and shared physiology between animals and humans, e.g. excessive food consumption and its cardiometabolic sequelae, show good translational and predictive validity. If the primary objective is to predict the clinical effectiveness of a drug‑candidate, congruence between the face and construct validity of the selected animal model and the relevant psychiatric disorder is a secondary consideration. A common error is the false assumption that if a clinically effective drug gives positive outcome in an animal test, both can be used to model the psychopathology of a psychiatric disorder and gain insights into new therapeutic interventions.
One of the planks of translational validity for an animal model of a psychiatric disorder is a reliance on clinical trials differentiating between efficacious and non-efficacious drugs. A clinical trial is an experiment, and therefore, not guaranteed to yield a true and accurate result. Many CNS drug-candidates that show robust efficacy in a psychiatric indication in a well-controlled, Phase 2 trial subsequently fail in large Phase 3 trials that attempt to achieve consistency in patient enrolment, diagnostic criteria, and efficacy assessment across multiple clinical sites and countries. A degree of caution should be applied when evaluating the clinical findings for CNS drug-candidates before assigning them to the “effective” and “ineffective” buckets and back-translating the results to the validation of animal models.
David is an Executive Director and co-founder of DevelRx Ltd. DevelRx provides consultancy support to pharmaceutical companies developing novel CNS drugs. His initial training was as a neuroscientist and behavioural pharmacologist at the University of Oxford.
After a career in academic research, he joined the pharmaceutical industry with responsibility for CNS and metabolic drug research at Boots Pharmaceuticals and BASF Pharma. He co-founded and for 20 years was an Executive Director at the non-clinical CRO, RenaSci, before leaving to set up DevelRx. His experience in R&D encompasses the approval of 15 novel drugs for indications including ADHD, binge-eating disorder, schizophrenia, Parkinson’s disease, epilepsy, opiate withdrawal, opiate-induced adverse events, anaesthesia, haemodialysis-induced pruritis, and obesity.
He was awarded a DSc by Kings College, London University for his contribution to pharmacology research. He is a Visiting Professor at the University of Bath, a Fellow of the Royal Society of Chemistry and a member of the American College of Neuropsychopharmacology. He has authored more than 200 scientific articles and reviews, co-edited books and journal special issues on a range of clinical topics and serves on the editorial boards of several international scientific journals.