Written Evidence Submitted by

People for the Ethical Treatment of Animals (PETA) Foundation

(RRE0082)

As one of the largest animal protection organisations in the UK, we are submitting these comments on behalf of our 1.3 million members and supporters.

Summary

• Animal models are recognised as the area most susceptible to reproducibility issues within preclinical research. Efforts to improve reproducibility within animal research, such as through PREPARE and ARRIVE guidelines, are poorly implemented. However, the reproducibility crisis within animal research goes beyond issues of standardisation and reporting compliance. The true crisis for the life sciences is one of translation between animal models and human clinical outcomes. Inherent species differences mean that non-human animals cannot serve as analogues for understanding the specific biological details necessary to understand human diseases and develop safe and effective therapies.
• Systematic reviews published in peer-reviewed journals document limitations in translating results from studies using animals into treatments for humans in numerous disease areas. Similarly, animals used for toxicity assessment of substances do not adequately predict human health outcomes.
• There is growing scientific consensus that far more can be gained from human-relevant research methods and technology that are better suited to solving human biomedical and regulatory assessment paradigms than from reliance on animal studies. As a recent UK industry report emphasised, the time has come to humanise drug discovery and toxicology, and a government-funded report highlights the potential of advanced non-animal technologies to drive future UK economic growth.
• We introduce PETA’s Research Modernisation Deal as a strategy for replacing the use of animals in biomedical research and regulatory testing and highlight the economic, public health, and animal welfare benefits of developing and applying state-of-the-art, human-relevant approaches to the current research paradigm.
• For the UK to maintain its position at the forefront of global science, research, and innovation, it needs to embrace scientific and technological progress. Redirecting resources away from unreliable research on animals and instead investing in superior, non-animal methods will benefit humans, animals, the economy, and the future of science.

The reproducibility crisis

It is estimated that between 50% and 89% of preclinical research is not reproducible, with the use of animal models frequently highlighted as a serious problem area.[1],[2] Francis Collins, director of the US National Institutes of Health (NIH), has noted that “[p]reclinical research, especially work that uses animal models, seems to be the area that is currently most susceptible to reproducibility issues”.[3]

There have been considerable efforts to improve the quality of animal studies, for example, there are recommendations for “hypothesis-testing research, a prospective, rigorous, research plan for preclinical studies, training and more appropriate use of statistics, and performance of requisite studies, such as pharmacokinetic analyses before any evaluation of potential efficacy… blinding of outcome assessment, randomized allocation of animals, power calculation to determine sample size, use of positive and negative controls, determination of dose-response, replication in different models, and independent replication”.[4] The Academy of Medical Sciences, the Biotechnology and Biological Sciences Research Council, the Medical Research Council, and Wellcome Trust published a symposium report which discussed the reproducibility and reliability of biomedical research and makes recommendations for strategies to counteract poor practices.[5],[6] Among these are the PREPARE (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence)[7] and ARRIVE (Animal Research: Reporting of In Vivo Experiments)[8],[9] guidelines, which provide researchers with a checklist to improve their planning and reporting of animal experiments. Similar initiatives around Transparency and Openness Promotion (TOP)[10] have also been promoted to enhance reproducibility issues within science. Despite all these recommendations being endorsed and supported, they are still widely neglected.[11],[12],[13],[14]

Problems with internal and external validity contribute to the failure of animal experiments in the translation of biomedical research from basic research and preclinical testing to the clinical setting. Poor internal validity means that many experiments on animals cannot be reproduced, a critical aspect of the scientific process that speaks to the potential validity of a finding. The internal validity of animal experiments is undermined by poor study design, including the failure of experimenters to implement processes to prevent bias, such as blinding the individuals conducting the experiments or those analysing the data. For instance, following a meta-analysis of systematic reviews of preclinical animal experiments across a wide variety of disease areas, University of Oxford scientists found that a lack of measures to reduce bias in animal experiments likely results in overestimation of the benefits of the treatment studied. The authors concluded, “Biased animal research is less likely to provide trustworthy results, is less likely to provide a rationale for research that will benefit humans, and wastes scarce resources.” They also advised, “[s]ince human studies are often justified based on results from animal studies, our results suggest that unduly biased animal studies should not be allowed to constitute part of the rationale for human trials.”[15]

The reproducibility crisis within animal research, however, goes beyond issues of standardisation and reporting compliance. There are huge problems in publication bias for studies that confirm hypotheses, with researchers warning that, of the interventions that appear promising in animal studies from the published literature, “few had favourable results when tested in humans”.[16] This highlights that the true crisis for the life sciences is one of translation between animal models and human clinical outcomes, not simply one of reporting.

Weaknesses of animal experiments cannot be overcome by simply improving study design, because external validity, or the “extent to which research findings derived in one setting, population or species can be reliably applied to other settings, populations and species”,[17] can never be achieved. Inherent species differences mean that non-human animals cannot serve as analogues for understanding the specific biological details necessary to develop safe and effective drugs for humans. As Wall and Shani write, even the “extrapolated results from studies using tens of millions of animals fail to accurately predict human responses”.[18]

Consequently, animal experiments lack both internal and external validity – they are usually poorly executed, but even if experimental methods are improved, the results do not adequately translate to humans.

Animal experiments compound the reproducibility crisis

Systematic reviews published in peer-reviewed journals document limitations in translating results from studies using animals into treatments for humans in numerous disease areas. Some examples include cancer,[19] cardiovascular disease,[20] diabetes,[21] HIV/AIDS,[22] immunology,[23] nerve regeneration,[24] neurodegenerative disease,[25] neuropsychiatric disorders,[26] sepsis,[27] and stroke.[28] It is estimated that fewer than 10% of highly promising basic science discoveries enter routine clinical use within 20 years.[29] In 2021, an advisory committee to the director of the US NIH reported: “High rates of failure in the development of novel therapeutics whose progression to human clinical trials was supported by animal studies has prompted concern that animal models of the human condition are more imperfect than presumed. That concern has instigated a useful and critical reflection on how and why we use animals in research as models either for humans or for particular aspects of human biology or behavior.”[30]

A 2018 review in the Journal of Translational Medicine, discusses species differences as an insurmountable problem of external validity for preclinical animal models. Attempts to control for or correct species differences result in what the authors refer to as the “extrapolator’s circle”: “[I]f we want to determine whether a mechanism in animals is sufficiently similar to the mechanism in humans to justify extrapolation, we must know how the relevant mechanism in humans operates. But if we already know about the mechanism in humans then the initial animal study is likely to have been redundant.”[31] They also discuss the concerning trend among those involved in animal experimentation to minimise the issue of species differences and its effects on external validity, a problem that is acknowledged by a number of researchers.[32],[33] The authors go on to state that it is unsurprising that the issue of species differences is downplayed, as not doing so would force experimenters to confront the “possibility that the preclinical animal research paradigm no longer has a great deal to offer”.[34] There is growing scientific consensus that far more is to be gained from human-relevant research methods and technology that are better suited to solving human biomedical and regulatory assessment paradigms than from reliance on animal studies. As a recent UK industry report emphasised, the time has come to humanise drug discovery and toxicology.[35]

Given the problem of poor validity and reproducibility inherent in studies using animals, it comes as no surprise that their results often fail to translate into clinical relevance for human patients. NIH reports that novel drugs fail “in about 95 percent of human studies”[36]– even though they appeared safe and effective in preclinical experiments using animals. A 2014 analysis published in BMJ found that – contrary to public perception – studies using animals have not furthered knowledge in the field of human health or led to the development of treatments for conditions affecting humans. The authors note, “if research conducted on animals continues to be unable to reasonably predict what can be expected in humans, the public’s continuing endorsement and funding of preclinical animal research seems misplaced.”[37]

Reducing the reproducibility crisis

The Department for Business, Innovation & Skills (now the Department for Business, Energy & Industrial Strategy),[38] Innovate UK,[39] and the Medicines Discovery Catapult and BioIndustry Association[40] have previously published reports that highlight concerns around the translation of animal models to human clinical benefits, alongside the potential business opportunities for human-relevant non-animal research methods in the UK; including the commercial benefits of advanced non-animal research methods with the potential to drive economic growth and attract international investment. However, to date, the government has done little to implement the recommendations from these reports for humanising biomedical research in the UK.

In view of this, we would like to bring to your attention PETA’s Research Modernisation Deal,[41] which provides a detailed strategy for freeing up funds for non-animal methods, including by immediately eliminating the use of animals in areas in which they have already been shown to be poor surrogates for humans, critically reviewing other areas of research to determine where animal use can be ended, and applying a robust system for ensuring the most up-to-date, human-relevant methods are used. In line with the Research Modernisation Deal, we suggest that proposals for projects using animals in areas with established, peer-reviewed records of poor translation rates – including neurodegenerative diseases, neuropsychiatric disorders, cardiovascular disease and stroke, cancer, diabetes and obesity, inflammation and immune responses, HIV/AIDS research, and addiction studies[42] – not be funded.

Resources diverted from research using animals should be used instead for the development and use of human-relevant, non-animal models of human biology and disease. Such research could build upon and complement the already impressive array of technologies available – including organs-on-chips, organoids, and in silico modelling – and offer tangible benefits to society by addressing the reproducibility crisis and high attrition rate in drug development. At the most conservative US estimate, the abundant failure to reproduce preclinical research results is approximately $28 billion per year wasted on misleading experimentation,[43] not to mention the costs to society of frustrating the development of effective treatments and disregarding potentially helpful therapies and interventions. Additionally, Innovate UK has identified non-animal technologies “as one of a series of emerging technologies with the potential to drive future UK economic growth”,[44] so by facilitating their development and use, the UK will be in a position to drive economic as well as scientific progress.

In the Netherlands, the government-coordinated Transition Programme for Innovation without the use of animals (TPI) was initiated to help fulfil the country’s ambition to be a frontrunner in innovation without animal testing. The TPI aims to bring together regulators, scientists, funding bodies, and industry and offer them a platform for identifying and developing innovative activities within their fields that will increase the pace of the transition to animal-free research. Similarly, the US Environmental Protection Agency is prioritising efforts to reduce animal testing and allocating substantial funds to the development of non-animal methods.

Given that the EU is looking to develop an action plan[45] to move away from animal experiments and focus on the transition to animal-free innovation to better protect human health and the environment, there is growing pressure for the UK to move away from using animals in research. The British public want to see greater investment in non-animal methods. For example, 75% of respondents to an Ipsos MORI poll backed increased efforts to develop alternatives to animal use. Particularly in light of the UK’s exit from the EU, it is vital that the UK keeps pace with scientific advancements and that our evolving policies reflect this. Redirecting resources away from unreliable research on animals and instead investing in superior, non-animal methods will benefit humans, animals, and the future of science, and will allow the UK to boost its status as a world leader in science, research, and innovation.

We hope the Research Modernisation Deal will be a useful tool for your reference and decision-making on policies regarding reducing and replacing animal use and increasing the uptake of human-relevant biomedical research methods to improve reproducibility within UK science. We welcome the opportunity to discuss these matters further.