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In this blog, Pandora Pound, Research Director at Safer Medicines Trust, highlights the patient safety issues that come when we rely on animal testing to determine the safety of new drugs for use in humans. She looks at cases where animal testing has led to the belief that medications were safe to test in human clinical trials—with sometimes tragic results. Highlighting innovative technologies that offer a more accurate picture of the safety of medications in humans, she calls on policy makers to lead a move towards human biology-based approaches. A disaster unfolds It’s 2016 and in Rennes, North West France, six healthy male volunteers are taking part in the trial of a drug intended to treat a range of conditions including anxiety, chronic pain and neurodegenerative disorders such as Parkinson’s disease. So far, BIA 10-2474 has been tested in mice, rats, dogs and monkeys, and has been tolerated in humans at doses of up to 20mg. This trial is to assess its safety in humans at a daily dose of 50mg. However, after five days on this dose one man becomes ill and is hospitalised with symptoms similar to a stroke. On the sixth day, four of the five other men are hospitalised with similar symptoms, including headache, memory impairment and altered consciousness. Less than a week later, the first man to become ill lapses into a coma and dies. The remaining five survive, but two are left with residual neurological impairments.[1] A year later, Dr Annelot van Esbroeck and colleagues test the drug on human cells. They discover that the drug deactivates multiple proteins, causing disruption to the metabolism of human nerve cells, effects that could not have been identified in tests on animals.[2] Had such human biology-based tests been conducted prior to the first human trials of BIA 10-2474, disaster may well have been averted. The Rennes disaster came only 10 years after the infamous ‘Elephant Man’ clinical trial at Northwick Park, London, which saw six young men go into multiple organ failure minutes after receiving experimental drug TGN1412. This drug had also undergone extensive tests in animals which had raised no cause for concern.[3] So why do we continue to rely on animal tests? Faulty reasoning New drugs are tested on animals prior to human trials to study toxicity and to gain an idea of how the drug behaves in a whole living organism. The trouble is, while this may provide valuable information on how a drug behaves in a mouse, rat, dog or monkey, it gives only limited information on how that drug will behave in a human. The insights may translate to humans, or they may not. The differences between species make this translational process inherently unreliable and risky. If a drug is found to be toxic in animals, then it won’t proceed to human trials. Conversely, if it is found to be safe in animals it will likely proceed to tests in humans. Unfortunately, as the above disasters illustrate, just because a drug is safe in animals does not mean it will go on to be safe in humans. The only time we know how it will behave in humans is when the first human takes it. As I explain in my book ‘Rat Trap: The capture of medicine by animal research–and how to break free’,[4] volunteers and patients receiving experimental drugs frequently suffer serious and sometimes fatal reactions to experimental drugs. In the field of stroke, for example, the experimental drugs diaspirin, enlimomab, selfotel and tirilazad all improved outcomes in animals, but each led to a greater number of serious adverse events and deaths in stroke patients who took the drugs, compared with those in control groups. But even drugs that proceed successfully through the various stages of testing and go on to be approved and licensed can cause adverse reactions and deaths when used in the wider population. Troglitazone, for example, was approved in 1997 in the US for the treatment of diabetes but had to be withdrawn in 2000 after reports of deaths and severe liver failure. Animal studies had not identified any cause for concern, but a study conducted after the disaster found that tests on human cells and tissues showed strong indications that the drug would adversely affect the liver.[5] I’m not just selecting a few failures from a sea of successes here. An analysis of animal and human toxicity data for over 2,000 drugs found that while the presence of toxicity in animals correlates (although not very reliably) with the presence of toxicity in humans, an absence of toxicity in animal tests is unable to reliably predict an absence of toxicity in humans.[6] So as we’ve seen, if a drug appears safe in animals it can nevertheless go on to be toxic in humans. In other words, animal tests are failing to safeguard humans. Human biology-based approaches Organ chips are tiny, about the size of a computer memory stick. They contain microscopic channels which can be lined with living human cells taken from an organ, through which blood, air and nutrients can be pumped. They are intended to recreate the microenvironment that cells are exposed to within the human body – a home from home for cells. In 2022, Dr Lorna Ewart and colleagues reported an amazing study. They used 870 liver chips to test 27 drugs that, based on evidence from animal studies had been judged safe for human use, but which had gone on to cause serious adverse reactions in humans, including liver failure and death. The liver chips were able to detect toxicity in almost 7 out of every 8 drugs that were toxic to the human liver, far outperforming tests in animals.[7] And it’s not just organ chips that are revolutionising drug development. Computer modelling and AI are playing a significant part too. In the US, software known as DILIsym© has been developed to predict whether new drugs will cause liver injury. It predicted that two migraine drugs would be toxic to the human liver, leading to their development being terminated (despite animal studies failing to raise any significant safety concerns) and it predicted that a related drug would be safe, a finding subsequently confirmed in human trials and resulting in its approval by the FDA.[8],[9] The way forward Animal research and testing is not just an ethical issue for animals, but for humans too. For all our sakes we need to put pressure on our politicians to recognise this and lead a transition away from a reliance on animal testing and towards the more sophisticated, human biology-based approaches which have so much potential to keep us safe. References 1. Kerbrat A, Ferré J-C, Fillatre P, et al. Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase. N Engl J Med. 2016;375(18):1717-1725 2. van Esbroeck ACM, Janssen APA, Cognetta AB, et al. Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science (80- ). 2017;356(6342):1084-1087 3. Attarwala H. TGN1412: From Discovery to Disaster. J Young Pharm. 2010;2(3):332-336 4. Pound P. Rat Trap: The Capture of Medicine by Animal Research - and How to Break Free. Troubador Publishing; 2023. 5. Dirven H, Vist GE, Bandhakavi S, et al. Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review. Sci Rep. 2021;11(1):6403 6. Bailey J, Thew M, Balls M. An analysis of the use of animal models in predicting human toxicology and drug safety. ATLA Altern to Lab Anim. 2014;42(3):181-199 7. Ewart L, Apostolou A, Briggs SA, et al. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med. 2022;2(154):1-16 8. Watkins PB. DILIsym: Quantitative systems toxicology impacting drug development. Curr Opin Toxicol. 2020;23-24:67-73 9. Smith B, Rowe J, Watkins PB, et al. Mechanistic Investigations Support Liver Safety of Ubrogepant. Toxicol Sci. 2020;177(1):84-93

The Health Research Authority (HRA) rounds off Make it Public Week with a panel discussion, chaired by Professor Sir Terence Stephenson, HRA Chair. Sir Terence will be joined by a panel representing different parts of the research sector, who will revisit and reflect on the key topics of discussion during the week. We will also be looking forward and at what we – as individuals, organisations, and the sector as a whole – can do next to make research transparent from start to finish, and how we can keep the conversation around research transparency going. Participants can submit questions to the panel ahead of the meeting or live on the day using Slido. You can submit a question in advance when registering for the event. Book now to reserve your free space

The Health Research Authority is holding its first research transparency week. The effectiveness and relevance of research is improved when opportunities to be involved in research are made more visible, open and accessible to the public. This is because it gives a study the best chance to involve the full range of people who will benefit from the outcomes of research. By having research opportunities more publicly available, researchers will be able to recruit and retain a wide, diverse range of research participants. As a result of increased diversity and better opportunities to access diversity and better opportunities to access research for more people, research will be more relevant, effective, trusted and transparent. At the same time, health professionals, commissioners, researchers, policy makers and funders can use research findings to make informed decisions, which will enhance public trust in research evidence and enhance public accountability. It is equally important to have an awareness and understanding of potential barriers that may restrict members of the public getting involved in research. Identifying these challenges and putting measures in place to counter them is therefore essential in the delivery of transparent research. This will be a two-hour online workshop, chaired by the co-Chairs of the Make it Public campaign group, Matt Westmore, Chief Executive of the HRA, and Derek Stewart, public contributor. The objective for attendees of this workshop will be to work together in facilitated small groups to explore this theme, and produce a set of 'top tips' to support best practice for those active in research. There will also be a short panel discussion, where attendees can hear directly from the study leads and research participants of studies, as well as organisations, working creatively and progressively in this area. NIHR Be Part of Research Patient Research Ambassador scheme, Maidstone and Tunbridge Wells NHS Trust Register for the workshop

The Health Research Authority is holding its first research transparency week. This workshop will look at the importance of publishing summary results of trials We believe that publishing summary results and data – not just of trials, but of all research – in an open, accessible and public way is a key factor in ensuring research is transparent. Publishing results in a peer-reviewed journal is not always achievable, and findings published in this way may not be accessible to the public. Making the results of research studies public and as easy to access as possible helps builds trust and accountability, whilst ensuring participants are protected from unnecessary studies. It is also a process that helps ensure research funding is maximised by avoiding duplication. This will be a two-hour online workshop, chaired by the co-Chairs of the Make it Public campaign group, Matt Westmore, Chief Executive of the HRA, and Derek Stewart, public contributor. The objective for attendees of this workshop will be to work together in facilitated small groups to explore this theme, and produce a set of 'top tips' to support best practice for those active in research. There will also be a short panel discussion, where attendees can hear directly from the study leads and research participants of studies, as well as organisations, working creatively and progressively in this area. Abbvie Chief Scientist Office Scotland F1000 ISRCTN Registry Register for the workshop