Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review
Hubert Dirven, Gunn E. Vist, Sricharan Bandhakavi, Jyotsna Mehta, Seneca E. Fitch, Pandora Pound, Rebecca Ram, Breanne Kincaid, Cathalijn H. C. Leenaars, Minjun Chen, Robert A. Wright & Katya Tsaioun
Our research consultant Dr Pandora Pound recently guest edited a special issue of the journal ‘Animals’ entitled “Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?” The key question she posed is whether there is value in refining animal models for medical research, or whether these should be relinquished in favour of new, human-focused research approaches. The seven open access, scientific papers that attempt to address this question, including Dr Pound’s editorial, can be found below.
Bhumika Singh, Mohamed Essameldin Abdelgawad, Zulfiqur Ali, Jarrod Bailey, Elisa Budyn, Prospero Civita, Martin J D Clift, John T Connelly, Samuel Constant, Marius Hittinger, Helena Kandarova, Victoria Rosalind Kearns, Tony Kiuru, Tomasz Kostrzewski, Sebastian Kress, Victoria Marsh Durban, Claus-Michael Lehr, Hayley McMillan, Julia Katharina Metz, Vivian Monteban, Dania Movia, Catia Neto, Carla Owen, Lauri Paasonen, Kerri Anne Palmer, Geoffrey John Pilkington, Karen Pilkington, Adriele Prina-Mello, Clive Roper, Jonathan Sheard, Sheree Smith, Janette Ellen Turner, Ipsita Roy, Melissa Anne Tutty, Eirini Velliou, John Malcolm Wilkinson. Towards More Predictive, Physiological and Animal-free In Vitro Models: Advances in Cell and Tissue Culture 2020 Conference Proceedings https://doi.org/10.1177/02611929211025006
Pound P, Ram R. Are researchers moving away from animal models as a result of poor clinical translation in the field of stroke? An analysis of opinion papers. BMJ Open Science. 2020;4:e100041. doi: 10.1136/bmjos-2019-100041
Open Access https://openscience.bmj.com/content/4/1/e100041
Pound P, Ritskes-Hoitinga M. Can prospective systematic reviews of animal studies improve clinical translation?. Journal Translational Medicine. 2020;18:15 doi:10.1186/s12967-019-02205-x
Open Access https://doi.org/10.1186/s12967-019-02205-x
Baker EJ, Beck NA, Berg EL, Clayton-Jeter HD, Chandrasekera PC, Curley JL, Donzanti BA, Ewart LC, Gunther JM, Kenna JG, LeCluyse EL. Advancing nonclinical innovation and safety in pharmaceutical testing. Drug Discovery Today. 2018 Nov 20.
Open Access https://doi.org/10.1016/j.drudis.2018.11.011
Archibald A, Tsaioun K, Kenna JG, Pound P. Better science for safer medicines: the human imperative. Journal of the Royal Society of Medicine 2018;
Open Access http://doi.org/10.1177%2F0141076818812783
Pound P, Ritskes-Hoitinga M. Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. Journal Translational Medicine 2018; 16:304. Open Access https://doi.org/10.1186/s12967-018-1678-1
Kenna JG, Taskar KS, Battista C, Bourdet DL, Brouwer KL, Brouwer KR, Dai D, Funk C, Hafey MJ, Lai Y, Maher J. Can BSEP Inhibition Testing In Drug Discovery And Development Reduce Liver Injury Risk?‐An International Transporter Consortium Perspective. Clinical Pharmacology & Therapeutics. 2018 Aug 23. Open Access https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1222 DOI: https://doi.org/10.1002/cpt.1222
Kenna JG, Uetrecht J. Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk? Drug Metabolism and Disposition. 2018; DOI: https://doi.org/10.1124/dmd.118.082719
Archibald K. Animal research is an Ethical issue for humans as Well as for Animals. Journal of Animal Ethics. 2018 Apr 1;8(1):1-1. https://www.jstor.org/stable/10.5406/janimalethics.8.1.0001?refreqid=robotstxt-sitemaps:1f1ee917778948ed08858f4972018b4a&seq=1#page_scan_tab_contents
Kenna JG. Human biology-based drug safety evaluation: scientific rationale, current status and future challenges. Expert Opinion on Drug Metabolism & Toxicology. 2017;13(5):567-74.
Kenna G. Integrating DILI hazards enables prediction, assessment, and management of human risk. Drug Metabolism and Pharmacokinetics. 2017;1(32):S3.
Kenna G. DILI: What is the problem? Drug Metabolism and Pharmacokinetics 2017; 32(1):S2. Doi:10.1016/j.dmpk.2016.10.013
Ram R. Launch of the Alliance for Human Relevant Science. Alternatives to laboratory animals: ATLA. 2017 Mar 1;45(1):49-53.
PDF: Ram 2017
Atienzar FA, Blomme EA, Chen M, Hewitt P, Kenna JG, Labbe G, Moulin F, Pognan F, Roth AB, Suter-Dick L, Ukairo O. Key challenges and opportunities associated with the use of in vitro models to detect human DILI: integrated risk assessment and mitigation plans. BioMed Research International. 2016; http://dx.doi.org/10.1155/2016/9737920
Archibald K, Drake T, Coleman R. Barriers to the uptake of human-based test methods, and how to overcome them. Alternatives to Laboratory Animals. 2015;43(5):301-8.
PDF: Archibald et al 2015
Coleman RA. Human-based systems in drug and chemical safety testing–toward replacement, the ‘single R’. Alternatives to laboratory animals: ATLA. 2014;42(6):357-66.
PDF: Coleman 2014
Clotworthy M, Archibald K. Advances in the development and use of human tissue-based techniques for drug toxicity testing. Expert Opinion on Drug Metabolism & Toxicology. 2013;9(9):1155-69.
Clotworthy M. Proceedings of the human tissues conference, House of Lords, 20 October 2009: Introduction. Cell and tissue banking. 2011 Feb 1;12(1):1-2.
PDF: Clotworthy 2011
Coleman RA. Efficacy and safety of new medicines: a human focus. Cell and tissue banking. 2011 Feb 1;12(1):3-5.
PDF: Coleman 2011
Clotworthy M, Archibald K. Introduction to the proceedings of the Speed and Safety in Drug Discovery Symposium hosted by the Safer Medicines Trust. Preface. Alternatives to Laboratory Animals: ATLA. 2009:37;i-ii.
Clotworthy M, Coleman RA, Archibald K. The European Commission’s opinion backing use of non-human primates in research is flawed. Regulatory Affairs Journal Pharma. 2009
PDF: Clotworthy 2009
Archibald K, Clotworthy M. Comment on ‘The ethics of animal research’ by Festing & Wilkinson. European Molecular Biology Organisation. 2007;8(9):794-6.
PDF: Archibald and Clotworthy 2007
Bailey J. Non-human primates in medical research and drug development: a critical review. Biogenic Amines. 2005;19(4):235-56.
PDF: Bailey 2005
Bailey J, Knight A, Balcombe J. The future of teratology research is in vitro. Biogenic Amines. 2005;19(2):97-146.
PDF: Bailey et al 2005
Coleman RA (Ed). Human based systems for translational research. 2014, Royal Society of Chemistry.
Pound P. Animal models and the search for drug treatments for traumatic brain injury. In
Johnson L, Fenton A, Shriver A (Eds) Neuroethics and nonhuman animals. 2020, Springer,
Switzerland. Link to ebook
Archibald K, Coleman C, Drake T. Replacing animal tests to improve safety for humans. In Herrmann K and Jayne K. (eds). Animal Experimentation: Working Towards a Paradigm Change. Leiden/ Boston: Brill; 2019. See book (open access)
Ram R. Extrapolation of animal research data to humans: an analysis of the evidence. In Herrmann K and Jayne K. (eds). Animal Experimentation: Working Towards a Paradigm Change. Leiden/ Boston: Brill; 2019. See book (open access)
Pound P. Animal models: problems and prospects. Chapter 18, p239-52. In Fischer B (Ed) The Routledge Handbook of Animal Ethics. 2019, Taylor and Francis, New York. https://doi.org/10.4324/9781315105840
Kenna JG, Ram R. Safety assessment of pharmaceuticals. In M Balls, R Combes (eds) The history of alternative test methods in toxicology pp167-174. 2018, Academic Press, London. https://www.elsevier.com/books/the-history-of-alternative-test-methods-in-toxicology/balls/978-0-12-813697-3
Kenna JG, Waterton JC, Baudy A, Galetin A, Hines CD, Hockings P, Patel M, Scotcher D, Sourbron S, Ziemian S, Schuetz G. Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury. In Chen M., Will Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. 2018 Humana Press, New York, NY.https://doi.org/10.1007/978-1-4939-7677-5_30
Light DS, Aleo MD, Kenna JG. Interpretation, Integration, and Implementation of In Vitro Assay Data: The Predictive Toxicity Challenge. In Chen M., Will Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. 2018 Humana Press, New York, NY.
Kenna JG, Thompson RA. Integrated reactive metabolite strategies. Chapter 5. In Iverson SL, Smith DA (Eds) Metabolite Safety in Drug Development. 2016 John Wiley and Sons. DOI:10.1002/9781118949689
Archibald K, Coleman R, Foster C. Open letter to UK Prime Minister David Cameron and Health Secretary Andrew Lansley on safety of medicines. The Lancet. 2011;377(9781):1915.
Archibald K, Baxter AD, BeruBe K, Bunton D, Clotworthy M, Coleman R, Foster CS, Hillier C, McFarlane M, Patel A, Pierscionek B. Safety of medicine and the use of animals in research. Lancet 2011;378(9802):e2.
PDF: Archibald et al 2011
Archibald K. Moving away from animal research for clinical benefit. BMJ January 29, 2007.
Archibald K. Medical progress: thanks to clinical research, not animal research. BMJ January 23, 2007.
Archibald K. Animal testing: call for open, scientific debate. The Lancet. 2004;364(9444):1486.
PDF: Archibald 2004
Archibald K, Kenna G, Pierscionek B. Brain models could replace primates. The New Scientist 2016; 231(3083):52-52
Archibald K et al. Animal Research. The Times. July 4, 2015. https://www.thetimes.co.uk/article/animal-research-gsw3klcd27b
Archibald K et al. Using animals to test drugs is outdated and unreliable. The Observer. August 31, 2014.
Archibald K et al. Politicians impeding medical advances. The Sunday Times. September 7th, 2014.
Archibald K. Scientists versus evidence. The New Statesman. January 4, 2013.
Archibald K. New techniques mean animal testing is totally out of date. The Observer. August 5, 2012.
Archibald K. Interview with KA about Safer Medicines. Live a Better Life magazine. Issue 1, November 2012.
Archibald K. Vivisection value. The New Scientist 2010; 207(2767): 28-29
Archibald K. Animal testing futile. The Herald. January 12, 2009.
Archibald K. Alternatives to animal experimentation. The Herald. November 17, 2008.
Clotworthy M. Hypocrisy on animal tests. The Scotsman. November 7, 2008.
Clotworthy M. The Telegraph. October 30, 2008.
Archibald K. Monkey tests don’t work. The Daily Mail. May 29, 2008.
Clotworthy M. Testing animal tests. The New Scientist 2008 (2652): 16-17.
Archibald K. Monkey trials are doomed to fail. Mail on Sunday. December 17, 2006.
Archibald K. Animal testing helps us discover cures for mice, not men. The Independent. November 18, 2006.
Archibald K. No need for monkeys. New Scientist 2006; 191(2558): 26 https://www.newscientist.com/letter/mg19125580-100-no-need-for-monkeys/
Archibald K. Trial by Species. New Scientist 1 February 2006. https://www.newscientist.com/letter/mg18925370-600-trial-by-species/
Bailey J. Drugs Blunder. The Independent on Sunday, 2 April 2006.
Archibald K. Of mice but not men. What Doctors Don’t Tell You. August 2016 (Vol. 27 Issue 5)
Coleman RA, Tsaioun K, Archibald K. A pragmatic comparison of human in vitro with animal in vivo approaches to predicting toxicity in human medicines. March 27, 2014.
Archibald K, Coleman RA. A humane solution. How to stop adverse drug reactions. The New Scientist 2012: 216 (2895): 32-33.
Coleman RA, Archibald K. How human biology can prevent drug deaths. The New Scientist 12 December 2012
Archibald K. The dead end of animal research. Guardian 7 Aug. 2009
Clotworthy M. Could we have safer medicines through non-animal testing? Scientists for Global Responsibility Newletter. Issue 37, Spring 2009.
PDF: Clotworthy 2009
Archibald K. Which would you trust to protect your health? Lifescape Magazine 2009.
PDF: Archibald 2009
Clotworthy M. Safer Medicines. Lifescape Magazine. Feb/ March 2008.
PDF: clotworthy 2008
Archibald K. It’s time to test the testers. Guardian 5 May 2006.
Archibald K. Vivisection is not a reliable means of testing human drugs. The Oxford Student.
Archibald K. Animal testing: science or fiction. The Ecologist, 2005 May:14-7. http://www.safermedicines.org/articles/static03.shtml
Archibald K. Test people, not animals. The New Scientist 2005; 187(2518): 24.
Archibald K. Animal testing for drug safety is unreliable. Spiked. 3 March, 2005.
Pandora Pound and Merel Ritskes-Hoitinga. Let’s work together to explore the evidence base for all preclinical research methodologies. In response to: Drug discovery and preclinical drug development – have animal studies really failed?
Pandora Pound and Merel Ritskes-Hoitinga. Species differences: the elephant in the room. Blog for NEAVS https://neavs.org/blog/2019/1/23/species-differences-the-elephant-in-the-room
Pound, P. The problem of evidence in pre-clinical animal research: how systematic reviews can help. Blog for the Animals in Science Policy Institute
Kathy Archibald. Replacing animal testing – the future is already here. 4-part blog for Veganuary.
Finn, K. New UK ethics debate on human tissue sharing. Regulatory Affairs Journal (RAJ) Pharma. 19 July 2010
Brizmohun, N. Is the End in Sight for Animal Trials? Regulatory Affairs Journal (RAJ) Pharma. 5 Feb 2009.
Bhogal, N. Speed and safety in drug discovery: a brief conference report. Alternatives to laboratory animals: ATLA. 2009;37(1):143-5.
PDF: Bhogal 2009
McColl, I. Testing conditions. The House Magazine. 19 October 2009.
PDF: McColl 2009
Matthews, R. Why cats should all say no to an aspirin. Daily Express. July 11 2007.
Stephenson, J. While the debate rages on, lab rats are still suffering. The Independent. 16 January 2006.
James, P. Scientist: Animal tests don’t work. The Newcastle Journal. 24 Feb 2005.
Meiklem, PJ. Testing on animals has slowed search for cures claims leading UK scientist. Big Issue Scotland. 25 July 2005.
Stephenson, J. A victory for good sense – and guinea pigs. The Independent. 29 August 2005.
Smith, K. The human guinea pigs. Could animal testing become redundant? Some scientists believe technology has the answer. The Times. 17 December 2005
By Rebecca Ram I was pleased to be invited to give a presentation on the issues concerning use of animals in research at a recent workshop hosted by Advocates for Animals, the UK’s first legal organisation devoted to animal protection. The theme of the workshop was “Animal experiments; the law, the framework and the alternatives”. […]Safer Medicines Trust at the 11th World Congress on Alternatives (WC11)
Scientific consultant Rebecca Ram presented during a virtual session as part of the ‘YOU-WC11’ mentoring programme. The session theme was ‘Challenges and Opportunities for Expanding the 3Rs’’ and was particularly aimed at early career scientists. The session was further divided to discuss two topics; ‘Dropping an R: Is it Time to Retire Refinement?‘ featuring Charu Chandrasekera of […]