FRAME (Fund for the Replacement of Animals in Medical Experiments) Education and Outreach Manager Amy Beale discusses how current legislative and regulatory requirements for animal research could be strengthened to help prevent animal experiments and accelerate change. She also considers the factors influencing the lack of change within animal research.
In complex human diseases such as Alzheimer’s and dementia, the failure to translate outcomes from animal to human trials is clear. The complexity of neuroscience research and the specificity of neurological, human conditions arguably warrants the most human-relevant methods.In the UK in 2020, over 134,000 procedures were carried out on animals for basic research into the brain and nervous system, with a further 37,000 for research into specific human diseases of the nervous system and mental disorders. Yet we know many of these diseases do not naturally occur in animals, meaning the predictive value of such models is limited. This is reflected by the lack of recent progress in understanding and treating many neurological diseases.
Despite this, an article published last year suggests that the current focus on finding alternative, non-animal approaches and reducing animal use is hampering scientific progress in neuroscience research. The authors argue that legislation to protect animals used in science is geared towards regulatory testing rather than more open-ended research and propose that regulations need to be more flexible to allow changes to be made to long-term projects.
Moving away from animal research
In the ongoing move away from animal research methods and the continuing development of non-animal methods that can provide the same, or more relevant information, there is a struggle to evidence the existence and value of modern ‘alternatives.’ There are various factors working against this change: the first is the outdated view held by some researchers that animal tests are the ‘gold standard’ and the best way of answering research questions, even where those questions relate to human health and biology. Another is that animal use in disease research and drug development has been happening for decades, so even where it may be flawed, there is a wealth of historical animal data that current animal research can be compared to or built on. Both issues may explain the reluctance in some fields to move away from animal research, which in turn impedes the development and uptake of non-animal methods.
Finding non-animal approaches
Many areas of medical research still rely heavily on animal testing; however, legislation clearly states that the principles of the 3Rs must be followed with ‘replacement’ as the top priority. This requires the use of laboratory animals to be replaced with non-animal research approaches where it is scientifically possible to do so. Article 4 in Directive 2010/63/EU of EU legislation states that ‘member states shall ensure that, wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used instead of a procedure.’ The same wording is also present in the Animals (Scientific) Procedures Act 1986 (ASPA) governing the protection of animals used in scientific procedures in the UK.Finding non-animal approaches is generally more straightforward in regulatory testing than in basic, applied, and translational research. Regulatory testing is safety testing to meet legislation requirements for medicines, medical devices, household products and chemicals that are, for example, used in food production, cosmetics, or agriculture. Guidelines exist for these tests which stipulate which animal/non-animal tests should be used to provide the required safety data. The non-animal tests in these guidelines have gone through rigorous validation processes before being accepted and recommended. Other types of research are more complex. No such guidance or bank of tests exists in basic research to direct researchers towards the best approaches and methods to investigate specific aspects of biology, or disease mechanisms, be they animal tests or non-animal. Here, the onus is very much on the researcher to select the relevant methods and tools for their research. This can be more complex and depends on the researcher’s knowledge of alternatives, ability to search for them, and their willingness to explore non-animal research options.
Preventing unnecessary animal research
Animal research, where questions could be answered without the use of animals through one, or multiple, non-animal approaches, is unnecessary. Legally, and through the correct implementation of the 3Rs principles, no unnecessary animal research should ever happen. There are systems in place required by the legislation to ensure this, including the Animal Welfare Ethical Review Boards (AWERB) in the UK – as well as Animal Welfare Boards in the EU and Institutional Animal Care and Use Committees in the US – and support from regulatory bodies for specific legislation such as the Animals in Science Regulation Unit (ASRU) within the Home Office, the MHRA, FDA, and the European Medicines Agency (EMA).
When applying for a project license for animal research, the researcher must describe not only the importance of the research and the potential outputs, but also explain why they need animals, what alternatives they considered, how they searched for them and why they were not suitable. This information is included in a section called the NTS (Non-Technical Summary). This information is published annually on the Home Office website.
Explanations given in license applications for animal research (at the weakest end of the spectrum) simply provide justification such as: ‘non-animal methods do not exist to answer the question’ or ‘non-animal methods currently do not allow the study of multiple body systems and a whole organism is therefore required.’ This may be true, but with the multiple approaches offered by modern technology today, this is no longer always the case.
It can, however, be a challenge for researchers to have knowledge of multiple methods. Someone with years of expertise in animal research may not be familiar with a particular new computer software or organ-on-a-chip model, and even if they do identify an alternative method, they may not have the skills or equipment to implement it. Tools such as searchable databases exist to support scientists in fulfilling their obligation to identify potential ‘replacement’ approaches. There is also a wealth of published research that can be assessed through literature reviews, systematic reviews, or meta-analysis across a research area. These types of searches – when done correctly – can help to identify relevant non-animal methods but also give insight into the potential value, or lack thereof, of animal studies in the area.
Whilst regulatory bodies expect researchers to search for scientifically satisfactory alternatives before applying for a project license for regulated animal research, there is no mandatory requirement set out in current legislation or set process for doing this. Specific training to develop these searching and reviewing skills is critical to ensuring animal research is necessary and always a last resort.
Collaboration and education are therefore key to facilitating the transition away from animal research. This applies not only to researchers, but also to all those in the system who make judgements on whether animal research is justified, including members of AWERBs, journal editors, regulatory bodies, and to some extent, funding bodies.
Applications to use animals – or within some regulatory frameworks, to challenge their use and champion an alternative approach – must be evaluated as reliably as possible. Animal research is one tool available to researchers, but it must be the last one out of the toolbox.
Moreover, animal research that is poorly carried out through failures in experimental design could also be classed as unnecessary as the results have little or no value. Whilst this is an issue with all research and can hamper scientific progress and waste funding, the ethical concerns are greater where animals have been used.The value of any research methods, including animal studies, can only be accurately assessed if papers include details of the experimental method and analysis, so that these can be scrutinised to ensure the research was robust and reproducible. Sadly, this does not always take place and the outcomes of poorly conducted or reported research are often not shared.
The bigger picture of animal research
As we move forward, animal research – particularly basic and applied research into human biology and disease – should be scrutinised more rigorously to assess if it really is ‘necessary.’ Not only to assess the need for an individual project against the existence of potential non-animal approaches, but also to assess the bigger picture of progress across whole research areas. Where there are areas where thousands of animals have been used over many decades and where little or no progress has been made in improving scientific knowledge or understanding, what is the justification for continuing animal research in these areas?
These research areas are often looking at complex human diseases, where little is known about the mechanisms causing the disease and progress in treatments remains slow. Where there are sometimes promising results in animal research, there is poor translation of these findings to clinical trials. Diseases such as Alzheimer’s, Parkinson’s or research models for strokes are areas commonly cited as seeing little progress despite many years of animal research. Indeed, recent Alzheimer’s research1 led by the University of Cambridge indicates the disease does not progress in human patients in the way previous studies have suggested, evidencing ‘the value of working with human data instead of imperfect animal models.’
While robust alternatives do not yet exist in all research areas, would it not be better to put more funding, time, and education into new approaches? Ethically, there is an issue here which has not been sufficiently evaluated or addressed, and it is difficult to do so in the current research system. Whilst the required harm-benefit analysis in license applications for animal research looks at each project individually, when, and where is the bigger picture of animal research considered to assess the benefit added across a research area, for example, in Alzheimer’s research? The current regulatory framework does not provide sufficient opportunity to do this.
It must also be noted that this bigger picture cannot be sufficiently reviewed while there is no public record or register for all licensed animal research projects and their outcomes. This means that only published animal research can be assessed alongside projects that more progressive animal researchers have registered voluntarily or published with null results.
Opposing views in the fieldNeuroscience is the study of the brain and nervous system and seeks to increase understanding of the structure, function and development of the nervous system, as well as degeneration, disease, and treatments. It includes research into disease such as Alzheimer’s, Parkinson’s and strokes.
Considering the limited progress in understanding and treating some of these conditions despite ongoing animal use, it was perplexing last year to see an article2 published in the scientific journal Neuronarguing for the continued need for animal use to advance brain research. The article suggested that the ‘new trend toward further regulation of animal research would greatly increase the administrative burden for researchers and hinder progress in the field.’ The article was signed by 70 researchers from the Netherlands and beyond.
The piece says that considering ‘policymakers aim to move towards animal-free alternatives for scientific research’ that ‘for neuroscience research, until viable and translational alternatives become available, and the value of these alternatives has been proven, the use of animals should not be compromised’. Instead of further regulating animal research, the article suggests animal models must be refined– in line with the 3Rs – to optimise animal welfare and developed with high translational validity.
The article covers many accurate points including:
- Acknowledgement of the ethical issues around using animals in research.
- The undeniable fact that most animal researchers are compassionate and would rather not use animals in their research.
- Animal research has helped develop therapies such as retinal implants and deep brain stimulation.
- Brain research is highly complex and brain disorders are still poorly understood despite 50 years of research.
- New technologies have identified new types of brain cell which may influence conditions such as dementia – implying that more research is needed to understand these cells.
But the authors explain that, from their point of view, current ethical regulations are strict, and the time it takes to gain ethical approval for animal experiments takes too long. Due to the current requirements, if there are deviations from the original proposed protocol (experiment design), amendments to the ethical permits are required which takes yet more time.
It is suggested that this ‘bureaucracy’ impedes discovery research, and that current legislation is geared towards protecting animals in applied preclinical research (to test compounds as possible treatments and their efficacy), rather than more open-ended basic research. The authors go on to suggest more flexibility is needed in projects where researchers may not have a clear hypothesis at the start or are unable to conduct power analyses to estimate animal group sizes (leading to better experimental design). The overarching point of the article is that it’s not possible to lay out long-term plans for basic research: plans will likely need amending which will add time.The article advocates instead ‘that the public and the scientific community should come together as partners for an alliance for better animal welfare, which convinces governments and regulators to provide funding specifically for refinements in experimentation that benefit animal welfare’.
Whilst refinement is indeed important where laboratory animals are still being used, a lessening of regulations to protect these animals would be morally and ethically wrong and a massive step backwards. It is also unlikely to happen due to the commitment of the EU and UK to protecting animal welfare. Regulatory bodies and AWERBs must maintain the power to review all animal research programmes and amendments to protocols, to evaluate whether the changes impact the necessity and ethical justification for the project. In addition, replacement must remain the top priority to help drive the much-needed paradigm shift to animal-free research methods, and as discussed earlier, the framework for finding alternatives and justifying animal research must be strengthened, not weakened.
There are areas of research and testing where it can be validly argued that non-animal methods and tests do not yet exist to replace animal research. It is also true that if all animal testing and research was stopped, it would limit scientific progress into certain areas of disease research, albeit temporarily. This is however a complex point to prove and evaluate either way.
It is also most likely true to suggest that in many areas of disease research, if animal use was halted today, more funding, time and energy would be channelled into improving and advancing non-animal methods to answer these questions. The difficulty with all these points is knowing how close we might be to taking that final step towards human-centred approaches in different fields. The call from neuroscience researchers requires weight in the form of evidence to show where alternatives are currently falling short and how animal research is adding value.
What we do know is:
- Basic and applied research see the most uses of laboratory animals every year across the UK and the EU.
- Unlike animal testing to meet legislative requirements, there is no regulated system for finding or sharing non-animal approaches in these fields.
- There is no way of evaluating the contribution of animal research to any field completely without a public register for all projects granted licenses.
- The 3Rs approach does not prevent animal research in areas where little or no progress is being made (and there is only a small amount of effort to address this currently).
Whilst the current body of animal research cannot be assessed due to a lack of public registration, it is difficult to draw valid conclusions about the value of animal research across any field. We take the stance that, due to the complexity of brain research and specificity of human conditions, time and money should be channelled into human-centred alternatives. One thing is for certain: if continued use of animals is not progressing our understanding of treatment options, then for scientific and ethical reasons it should not continue. Using animals in areas where there is poor translation to human medicine and little progress raises ethical concerns, not only for the animals being used, but also for the patients who do not see any benefits, and for the funders who could be funding alternative research projects.
Volume 23, Issue 2 – Spring 2022
1: In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
2: The continued need for animals to advance brain research
About the author:
Amy Beale is Education and Outreach Manager at FRAME, a charity supporting the development and promotion of scientific alternatives to the use of animals in biomedical testing. Beale is responsible for overseeing FRAME’s education and training related work, running its grant programmes, and promoting the 3Rs philosophy of Replacement, Reduction and Refinement.