Our commentary warns that the UK must not fall behind in the race to ‘humanise’ drug discovery. Current research models and regulation are blocking the development of human-relevant approaches to drug discovery and perpetuating animal-based approaches. The UK has world-leading research in this area but significant investment in non-animal technologies is taking place in the US and Europe. The UK should seize the initiative to revolutionise medicine through more intelligent, human-relevant research.
The authors make a compelling argument that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences. They suggest that to improve clinical translation and ultimately benefit patients, research should focus instead on human-relevant research methods and technologies.
Medicines can cause serious unwanted side effects in some patients. These include drug-induced liver injury (DILI), which is poorly predicted by the currently used safety test methods. Assays that focus on human-relevant mechanisms can provide more useful data. One important mechanism is inhibition of a liver cell membrane transport protein called the Bile Salt Export Pump (BSEP). This article reviews the evidence linking BSEP inhibition with DILI and describes methods to evaluate and interpret BSEP inhibition. It also recommends how these data can be used to aid the design and selection of safer medicines. The authors from Safer Medicines Trust, major pharmaceutical companies, universities and biotechnology companies were brought together by the International Transporter Consortium.
Our Pharmaceutical Director, Dr Gerry Kenna co-authored the paper with Dr Jack Uetrecht, Professor of Pharmacy and Medicine at the University of Toronto and the Canada Research Chair in Adverse Drug Reactions
Many new medicines cause undesired side effects in humans that are not predicted by the drug safety studies performed currently. This review focuses on liver injury, which is an especially important human adverse drug effect. It highlights both the promising progress made in developing human-relevant in vitro methods that can anticipate and reduce drug induced liver injury risk, and outstanding challenges which remain to be addressed.
Our Research Consultant, Dr Pandora Pound, gives a fascinating insight into the introduction of the use of systematic reviews in preclinical animal research, in which she played an instrumental role.
Systematic reviews have become accepted as powerful tools that should be deployed routinely to improve the quality of the evidence base in clinical research. Although their use is not yet routine in preclinical research, they have been instrumental in provoking debate about the reliability, validity, and value of preclinical animal research.
We are delighted to announce that Dr Andrea Wraith BDS, MA, MB BChir, MMedSci has joined us as our new Medical Director. Andrea qualified as a dentist from Kings College London in 1990 and as a doctor from Cambridge in 2002. She has worked as a hospital anaesthetist and in A&E. Her professional life has centred on promoting the provision of safe and effective sedation in medicine and dentistry through both education and regulation. She provides sedation services for dentists in the primary care setting and runs courses teaching the dental team how to manage medical emergencies. From 2016 to 2017, she was President of the Section of Anaesthesia of the Royal Society of Medicine. Dr Wraith has acted as an expert advisor to local health authorities and lectured on sedation related issues to dentists, doctors and nurses both nationally and internationally. Patient safety has always been at her core.
We are delighted that Dr Pandora Pound, PhD has joined us as our new Research Consultant. Pandora has been conducting research since 1990 and has worked within universities and medical schools throughout London and the South West, mainly in the field of public health. She was an early proponent of the need for systematic reviews of animal research and has published widely on the need for an evidence-based approach in this field. Two of her seminal publications include “Where is the evidence that animal research benefits humans?” and “Is animal research sufficiently evidence based to be a cornerstone of biomedical research?”. In 2017 she left academia to focus on this issue and to work towards more human-relevant approaches to the development and testing of medicines.
The harm-benefit analysis is a cornerstone of animal research regulation in the EU and elsewhere. When applications for research projects involving animals are submitted for licensing the regulators weigh up the harms that animals are expected to suffer against the anticipated benefits of that research to humans.
Researchers at the University of Bristol reviewed a sample of animal research studies from 1967 to 2005. All the studies were judged to be of poor quality and most involved severe harms to animals. When the harms to animals were weighed against the benefits to humans less than 7% of the studies were judged to be permissible in terms of minimising harms to animals whilst being associated with benefits for humans.
Dr Pandora Pound, who led the research, says, “The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted.” The research is published in PLOS ONE
Excerpt: Animals are used in biomedical research to study disease, develop new medicines, and test them for safety… A revolution in science and technology has produced a new generation of more relevant and predictive tools, which could be used to create safer medicines more quickly and at less cost: a win-win situation that should be supported by everyone. The obstacle preventing this from happening is governments’ continued insistence on animal testing. Yet the evidence is clear that reliance on animals as surrogate humans puts patients at risk, can delay medical progress, and can cause effective treatments to be wrongly discarded. There is a compelling case to be made that animal research is an ethical issue for humans as well as for animals.
A report was published in January by the Medicines Discovery Catapult and the BioIndustry Association, entitled: State of the Discovery Nation 2018. Based on surveys and in-depth interviews with more than 100 senior executives of drug discovery companies, the report offers a blueprint for successful pharmaceutical research, where patients and human data are placed at the heart of drug discovery. The current research process depends on animal models of disease and toxicology that are “poor approximations of humans”; consequently 40 per cent of new drugs fail when first tried in real patients. The rate at which new drugs are launched per $1bn spent on pharma R&D is one-30th of the level 40 years ago but “humanising” the early stages of research would ease the “productivity crisis” in pharmaceutical research.
“Discovery must start with biological targets derived from patient data and samples, which create candidate drugs that are highly selective for proven human disease targets in well-defined patient subgroups, not animal models,” said Chris Molloy, chief executive of the Medicines Discovery Catapult, quoted in the Financial Times.
Dr Azra Raza, Professor of Medicine at Columbia University in New York, and Science Adviser to Safer Medicines Trust, gives a fascinating one-hour interview on the human imperative in cancer research in this highly informative podcast. In 2014, Professor Raza gave a powerful and moving 13-minute TEDx Talk on the same theme, which you can view on YouTube.
Abbreviated abstract: Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity… The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern… Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.
Sir David Amess MP hosted the launch event, which was full to capacity with senior scientists and MPs whose enthusiasm and support were palpable.
Working together, the Alliance will help to speed the transition away from animal testing, towards more efficient and predictive models based on human biology. Many breakthroughs are lost in translation from animals to humans. There is now a tremendous opportunity to make drug development faster and safer, using human relevant technologies. Some exciting technologies were highlighted at the meeting, including cutting-edge models of the liver, linked together with other organs to realistically mimic the human body.
Sir David said: “Britain is a world leader in life science research. But we had better look to our laurels if we do not want to be left behind, while others take the lead in embracing more predictive tools based on human biology. I wish the new Alliance every success with this hugely important initiative.”
We are delighted to welcome Rebecca Ram, MSc as our new Scientific Consultant. Rebecca is also a Scientific Consultant to the Lush Prize team at the Ethical Consumer Research Association. She holds an MSc in Toxicology with Bioinformatics and has worked as a Clinical Data Manager at University College London Hospital, and in pharmaceutical clinical trials for GlaxoSmithKline. She was a Project Manager of cancer clinical trials and whole genome sequencing for Genomics England, as part of the 100,000 Genomes Project. In addition to her role with Safer Medicines Trust, she is also the Communications Officer for the Alliance for Human Relevant Science.
Dods conducted an online survey of 2,512 UK health and care professionals in March 2016.
They were asked one question about their perception of pharmaceutical testing regulations on behalf of Safer Medicines Trust.
The overwhelming majority of health professionals (79 per cent) agree that pharmaceutical companies should be legally obliged to test new medicines using methods demonstrated to be the most predictive of safety for humans.
Just three per cent of health professionals disagreed that pharmaceutical companies should be legally obliged to test new medicines using methods demonstrated to be the most predictive of safety for humans.
We are delighted to welcome Dr Gerry Kenna to Safer Medicines Trust, and look forward to him continuing to innovate and forge a route to improved safety of medicines, through human-relevant methods.
Dr Gerry Kenna is a Drug Safety Consultant and a leading figure in the field of human drug induced liver injury. Following his initial scientific training in biochemistry, at the Universities of Leeds (BSc Hons) and London (PhD), Dr Kenna established and led academic research teams which, for 19 years, studied the mechanisms by which medicines and other chemicals may damage cells of the liver. He then moved to industry (at Zeneca, Syngenta and AstraZeneca), where for 14 years he used his expertise to support human safety assessment of new medicines and agrochemicals. During this time, he also led research teams which developed improved human safety testing methods. These used human tissues and did not require use of animals. Dr Kenna is committed to ensuring that such human-relevant approaches are used routinely, by scientists in industry and in regulatory agencies, to aid the invention and development of safe new medicines.