The Ministerial foreword states:
‘More recently, there has been an increase in the use of alternative methods that can replace animals in some circumstances. However, the adoption of these alternatives has been limited by their ability to accurately replicate biological systems to satisfy the needs of regulators, science and quality control.’
‘Phasing out the use of animals in science and product development must be supported by reliable and effective alternative methods, so this strategy aims to create a system that drives their use. However, as this strategy is implemented, we recognise that some animal research will continue, due to the maturity of alternatives available. In the meantime, we will continue to support and enable well justified and designed animal research where alternatives do not exist.’
Commentary:
These statements set the tone for what will follow in the document. These statements sadly omit the fact that routinely accepted animal tests have never undergone rigorous validation and would never attain validation by current standards. The following quotes support this thesis.
‘Most of the animal tests we accept have never been validated. They evolved over the past 20 years and the FDA is comfortable with them.’ 1
‘However, the validation process is under threat because of vested interests of various kinds, and it is clear that many currently-accepted animal tests and candidate animal and non-animal tests do not, and could never, meet the agreed criteria for necessity, test development, prevalidation, validation and acceptance.’ 2
These Government statements also ignore the widely reported failure of animal tests, as predictive models of humans, as reported by many experts publishing in the peer reviewed scientific literature, including by the British Medical Journal; 3 the US-based National Cancer Institute 4 and by many experts working in the pharmaceutical sector. 5 Current Parliament EDM 187 cites Drs. Shanks and Greek’s Trans Species Modelling Theory (TSMT) 6: named in 2009 and founded upon evolutionary biology and current understanding of complexity science, TSMT is the overarching scientific explanation on why animal tests have a 90 – 96% failure rate, when trying to replicate biological responses in humans.
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In the Executive Summary of the document, the following is stated:
‘Our vision is for a world where the use of animals in research and development is eliminated in all but exceptional circumstances achieved by creating a research and innovation system that replaces animals with alternative methods wherever possible.’
‘This strategy lays out the steps we, the Government, will take over the next five years towards achieving this vision across the whole of the UK.’
Commentary:
To the general public, these statements sound reassuring. However, the devil lies in the detail. The language is sufficiently vague so as to allow the government plenty of wiggle room. What exactly is meant by the reference to ‘five years’? Does this refer to the amount of time required to spell out the final road map, or does it refer to the replacement of a clear set of animal experiments over the next five years?
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The Executive summary continues thus:
‘The use of animals in science provides an insight into human and animal biology and disease. Animals are also used in many sectors to test the safety and efficacy of chemicals in consumer products, and in new human and veterinary vaccines, medicines and medical devices before they are trialled in their intended populations or marketed. Enabling the properly regulated use of animals is essential to improving the health and lives of humans and animals and to the safety and sustainability of our environment, and we will continue to support the appropriate use of animals where reliable and effective alternatives are not yet available.’
Commentary:
These statements confuse human medical research with veterinary research, which is disingenuous, to say the least. They betray a basic lack of understanding of the importance of species differences, complex systems and evolutionary biology. Worse still, they lend weight to the idea that animal tests are reliable and predictive for human outcome with respect to prescription drugs and other social chemicals. In other words, the main reason for replacing animal experiments and animal testing is simply to reduce animal suffering. There is no suggestion that animals are failed models for human medicine. There is no suggestion that a paradigm shift is urgently needed, away from 19th century animal laboratories to 21st century human based technologies currently available to replace cruel and outdated animal tests.
Two quotes immediately come to mind:
In 2004, the FDA estimated that 92 percent of drugs that pass preclinical tests, including “pivotal” animal tests, fail to proceed to the market. More recent analysis suggests that, despite efforts to improve the predictability of animal testing, the failure rate has actually increased and is now closer to 96 percent. The main causes of failure are lack of effectiveness and safety problems that were not predicted by animal tests. 7
The second quote is from Dr Ralph Heywood at the Huntingdon (Animal) Research Centre, which dates back to 1978 : ‘Toxicological investigations are increasingly subject to criticism and scrutiny because, despite the large number of animal experiments performed, which in itself causes considerable public disquiet, we are apparently failing to predict accurately the human toxic hazard of many compounds ; for example practolol, diethylstilboestrol, vinyl chloride and clioquinol.’ 8
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The Executive summary further states:
‘But we will not accept a slow pace of change when scientific and technical advances mean that a faster transition away from animal use is possible.’
Commentary:
History has clearly demonstrated time and again that massive public outcry is needed for change to happen on a political level. The government is finally responding to massive public opinion, but is this just another smokescreen to buy time for the pharmaceutical and chemical industries, neither of which is in a hurry to replace the outdated animal tests that facilitate marketing approval by the regulatory authorities with currently available human-based test methods.
The Executive summary makes it plain for all to see that the government is out of step with 21st century technology, since it equates cruel and outdated animal tests with modern, evidence-based test methods that completely surpass anything that animal tests could deliver:
II. Achieve equal or better research and testing outcomes using alternative methods.
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We, the Government, will deliver this by focusing on five key commitments (page 6)
- Driving alternative method development and uptake in discovery research:
Commentary:
What is required is a complete paradigm change away from a broken method and instead, the adoption of rigorous, evidence based human relevant research and testing methods. The use of the term ‘alternatives’ is semantically misleading, because it does not fundamentally challenge the flawed science that underpins animal experimentation. A new bicycle is not a valid ‘alternative’ to an old bicycle in a formula one car race.
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- Accelerating alternative methods validation and uptake for regulatory decision making: We will establish a national approach to accelerating the validation and regulatory acceptance of alternative methods. At its core will be a new UK Centre for the Validation of Alternative Methods (UKCVAM)
Commentary:
As the saying goes, ‘those who ignore history are doomed to repeat it’.
What the government is suggesting is a copy and paste of ECVAM (the European Centre for the Validation of Alternative Methods), that was set up in 1991. Although the concept appeared promising at its inception, it has sadly fallen short of its original aims, partly due to funding shortages and partly due to not being able to keep up with the pace of technological developments. Over the years, ECVAM has seen its annual budget reduced from a high of 15 million euros to a low of 5 million euros. In other words, the EU flagship is now barely afloat anymore. 9
The lack of funding has drastically slowed down the validation process for any new and promising technologies waiting patiently in line. The result has been catastrophic since ECVAM has managed to validate only two new test methods per year, on average. In addition, the validation process conceived in the 1980s is no longer fit for purpose in the 21st century. A new test method may require
up to six or seven years to be validated, by which time it has already been surpassed by newer test methods.
As its name suggests, ECVAM validates ‘alternative methods’. Alternative methods are in fact synonymous with the 3Rs principle of reduction, refinement and replacement. On closer inspection, the vast majority (80%) of the test methods validated by ECVAM over its 30-year existence involve the use of fewer animals (reduction, not replacement of live animals). Of the remaining 20% of validated ‘alternatives’ about half necessitate killing animals in order to obtain their cells and tissues (so-called ‘relative replacement’) while the other half are completely animal free (so-called ‘absolute replacement’). Thus, only 10% of the total number of validated alternative methods do not involve animals.
Finally, it should be noted that ‘validation’ does not imply regulatory acceptance. A validated method will only be used once it has obtained regulatory approval by the relevant government or international authorities. In the case of prescription medicines, the relevant authority in the UK is the Medicines and Healthcare products Regulatory Agency (MHRA). This process will usually add one or more years to the acceptance of the newly validated test method. In the case of industrial chemicals, the relevant authority is usually the Organisation for Economic Cooperation and Development (OECD).
The fly in the ointment however, is the fact that there is no legal obligation for industry to adopt a validated method that has been accepted by the regulatory authorities. Some animal protection organisations have discovered this sad fact at great expense and legal costs.
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Part I – The current UK context of animals and alternatives research (page 8)
Despite the known limitations, the use of animals in science provides an important insight into the complexity of human and animal biology and disease. They are also used to test the safety and efficacy of chemicals in consumer products, and in ensuring the safety of new human and veterinary vaccines, medicines and medical devices before they are trialled in their intended populations or marketed. Enabling the properly regulated use of animals is currently essential to improving the health and lives of humans and animals and to the safety and sustainability of our environment.
Commentary:
The government ensures that the public receives the same message of assurance over and over again and leaves no doubt that animal testing is still important and scientifically relevant for the human species. No scientific debate in sight or independent parliamentary inquiry, no discussion is required.
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In the UK, the Animals (Scientific Procedures) Act 1986 (ASPA) provides the legislative framework governing the use of animals in research. It mandates the development and application of alternative methods, including non-animal methods, as part of implementation of the 3Rs (the Replacement, Reduction and Refinement of animals used in research).
Commentary:
The 3Rs principle was an excellent initiative at the time it was proposed in 1959. It was initially ignored by the animal research community but later gained support from the animal protection community. Ironically, this has played into the hands of the animal research community, who continue to tout the 3Rs principle as the only game in town. It should be obvious to everyone that the science and technology available today bears little resemblance to what was available in 1959. It’s time to accept the winds of change.
It would take nearly three decades after the creation of the 3Rs for the government to promulgate the Animals (Scientific Procedures) Act 1986.
Prior to 1986 in the UK, the use of animals in scientific procedures was regulated by the Cruelty to Animals Act 1876, which enforced a licensing and inspection system for animal experiments. Although both the UK Animal Welfare Act 2006 and the Animals (Scientific Procedures) Act 1986 currently outlaw the causing of ‘unnecessary suffering’ the major difference between these two pieces of legislation is that specific exemptions apply to animal experiments licensed under the 1986 Act (Select Committee on Animals in Scientific Procedures Report 2001). Thus, identical acts of deliberate animal cruelty potentially punishable by custodial sentencing under the Animal Welfare Act 2006 are essentially immune from prosecution under the Animals (Scientific Procedures) Act 1986. The 1986 Act effectively enshrines animal suffering by means of legal definitions, whereby an animal experiment becomes a ‘regulated procedure’ licensed to potentially cause pain, suffering, distress or lasting harm to a ‘protected animal’, which encompasses all living vertebrates other than humans, under the responsibility of humans. 10 To add insult to injury, animal researchers are not required by the Act to demonstrate that their animal experiments are reliable and relevant to human health. This effectively provides animal researchers with a blank cheque to conduct procedures on animals in the name of scientific curiosity with virtually no independent or public oversight, since animal ethics committees (including Animal Welfare and Ethical Review Bodies) are always weighted in favour of the animal researchers. This situation highlights the irrelevance and weakness of the 3Rs principle, since researchers simply focus their efforts on reduction and refinement but very rarely, on actual replacement of animal experiments.
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Modelling disease (page 10)
Advancing our ability to combat diseases in both humans and animals relies on a deep understanding of complex and often subtle biological processes. Significant physiological and genetic similarities can make animals useful in studying complex human biological processes, disease pathogenesis and therapeutic interventions. Genetically, species like mice share approximately 85% of their genome with humans, making them widely used for studying conditions such as cancer, metabolic disorders and neurodegenerative diseases
Commentary:
Once again, this government document muddies the waters by lumping together human and veterinary medicine. If your child is ill, do you go to the doctor or to your local vet?
The above paragraph refers to the word ‘similarities’ to justify the use of animals in human medical research. But how scientific is the word ‘similar’?
It is true that we share 85% of our genome with mice. However, we are separated from mice by 90 million years of evolution. For example, Seok et al. reported that mouse models poorly mimic human inflammatory diseases, and observed a random correspondence between murine genomic responses to inflammation and their human gene counterparts. Mestas and Hughes pointed to important species differences in the immune systems of mice and humans, while Yue et al. explained these species differences in terms of species-specific gene regulation. Such species differences also extend to the use of non-human primates. 11
What the government document omits is the fact that the chimpanzee is far closer to humans than mice, yet the chimp is immune to several deadly human diseases, including HIV/AIDS, hepatitis, common malaria and has different cancers to humans. The use of chimps has essentially been banned in the EU since 2013 and in the US since 2015.
The chimpanzee is our closest evolutionary cousin and therefore the best ‘animal model’ possible, if such a thing exists. And since all other animal species are evolutionarily more distant, the inescapable conclusion is that they are even less appropriate ‘models’. Abandoning the chimpanzee must inevitably lead to a domino effect in terms of all the other models, including other primates, dogs, cats, pigs, rats, mice, zebra fish, finches…
Barriers to the adoption of alternative methods (page 21)
Despite the recognised scientific, economic and animal welfare benefits offered by alternative methods, barriers that limit their widescale adoption remain. These include:
• Lack of scientifically robust and validated alternative technologies that are sufficiently mature enough to replicate complex human biology for use in discovery research and acceptance by regulators.
• Funding of insufficient scale and duration to enable model development, qualification and transfer between laboratories to overcome current scientific limitations.
• Lack of organisational and personal expertise, and access to specific technology or equipment.
• Lack of accessible case studies supporting cross-sector learning and best practice on risk assessments using alternative methods.
• Concerns about lack of support and acceptance from peers, scientific journals and regulators.
*Poor knowledge about the availability of alternative methods and institutional commitment to in vivo models.
• Requirement for validation and international agreement of testing methods and standards that need streamlining to allow timely regulatory acceptance
Commentary:
While some of these barriers are real, there are several other factors that play an important role in slowing down the adoption of 21st century technology and human relevant test methods.
- The animal model is still the current paradigm in medical research and product testing. It is far easier for a researcher to obtain ethical committee approval to experiment on 100 mice than to obtain human surgical waste destined for incineration.
- There is a glaring double standard in the current system. Any new non animal test systems must undergo a rigorous process of “validation” while animal experiments are historically exempt from this process.
- The government is trying to compare apples and oranges. It is impossible to compare data generated from animal experiments to data obtained from human based test methods when the species of interest is the human.
- No-one is joining the dots. Some of the technologies available today are ripe and far more predictive and scientifically robust for the purpose of safety evaluation of prescription drugs than animal tests. One good example is the human liver on a chip, which far surpasses animal tests at predicting drug induced liver injury (DILI) in humans. 12 The human liver on a chip has been around since at least 2022 and should by now have been incorporated in all preclinical tests for any new prescription drug. The MHRA, instead of fulfilling its duty of care to protect public health, prefers to sit on the fence and allow the pharmaceutical industry to decide if and when to begin using the liver on a chip in clinical trials. This is akin to medical negligence.
Part III – Priorities for targeted replacement of animal tests (page 36)
This chapter identifies ‘3 baskets’ to group animal tests, providing a structured basis for identifying priorities and informing decisions on where support is most urgently needed.
Basket 1 – Tests with potential for rapid transition to non-animal methods (page 37).
Commentary:
The first example cited in this category is the replacement of the use of rabbits as living test tubes for quality control of injectable prescription drugs. It is worth
examining the history behind the development of the test method used to replace rabbits.
In 1988, a team of researchers at the UK National Institute for Biological Standards and Control (NIBSC) published a study in which they described the use of human white blood cells to identify pyrogens (contaminants, such as bacteria that can cause fever). 13 The human white blood cells were sourced from expired human blood from blood banks.
It would take more than 35 years for this wonderful replacement method to be validated and attain regulatory acceptance at the EU level. In fact, only on July 1st 2025 was the replacement method officially recognised and published in the EU Pharmacopoeia. 14
There are some vital lessons to be learned from this example of institutional inertia.
- The UK government completely ignored its own researchers for decades.
- If the pharmaceutical or the chemical industry prefer to use animals out of habit and convenience, they will ignore non animal replacement methods for as long as they can get away with it.
- It is still possible for industry to use live rabbits by citing ‘exceptional circumstances’ rather than adapting or modifying the in vitro replacement test to meet their specific needs.
Another example cited in Basket 1 is the replacement of animals in botulinum toxin (Botox) batch potency testing. Once again, it is worth examining some history.
In 1999, a researcher at the NIBSC proposed a non-animal in vitro test to replace the use of mice in the batch testing of botulinum products (such as Botox). 15
Once again, this wonderful non animal test method would be ignored by government and industry for decades, resulting in the needless suffering and death of hundreds of thousands of mice.
Ironically, the US and not the UK, would be the first country in the world to adopt the non-animal test on a commercial scale. This is an opportunity to pay tribute to a visionary in the animal protection community, namely Marty Stephens, who chose quiet diplomacy over flamboyance in animal advocacy, to achieve groundbreaking results. 16
Working at the Humane Society of the United States, Marty Stephens managed to attend a shareholders’ meeting of the pharmaceutical company, Allergan, the foremost manufacturer of cosmetic Botox products. He presented the shareholders with the possibility of replacing the use of mice as living test tubes with a human cell based in vitro method, for the batch testing of cosmetic Botox products.17
The proposal was accepted and the company Allegan completed the necessary validation studies, which subsequently received regulatory approval by the US Food and Drug Administration (FDA) in 2011. 18
In Europe, the principal manufacturer of Botox products, Ipsen pharmaceuticals, would not achieve the same result until 2020.19
There are some vital lessons to be learned from this example of institutional inertia.
- While governments respond to massive public outcry, the same result can be achieved in industry simply by informing its shareholders. The challenge is to be able to communicate directly with shareholders.
- Once industry makes up its mind to replace cruel and outdated animal tests, it does not need to wait for government approval, nor for outside validation studies. Industry, more than anyone else, has the financial resources to validate new test methods in record time, provided the political will to do so is there.
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Basket 2 – Tests that require further development in the medium term (page 42).
Commentary:
The first example cited in this category is that of the forced swim test (FST). The government position is that the test has limited scientific validity, particularly its translational relevance to human mental health disorders, yet it will continue to authorise three current active licences to use the FST until 2028.
In this example, the government is trying to play ‘catch-up’ to the pharmaceutical industry, which has already largely abandoned the FST.
The government appears to support research into ‘alternatives’ to the FST such as larval zebrafish, fruit fly models, and AI-based screening.
Animal models represent a poor choice because the cause and mechanism of the human condition under investigation may not be fully understood. In addition, researchers are using a relatively simple system (receptor activation or inactivation) to represent a more complex and less readily studied system (human mental disorders). 20
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Basket 3 – No suitable alternative methods currently exist (page 45).
Commentary:
The example cited in this category involves reducing the use of fish in assessing endocrine disrupting chemicals for environmental protection and public health safety. The government plans to reduce the use of fish in this category by 2035.
The problem of endocrine disrupting chemicals (EDCs) is now widely recognised as impacting negatively on human health and the environment. In humans, it is associated with increased risk of cancer and type II diabetes as well as decreased fertility in both women and men.
The primary source of the problem is the production (or perhaps over production) of synthetic chemicals, most of which were commercialised before scientists discovered the endocrine disrupting properties of many of these chemicals. The EU chemical testing programme REACH has not lived up to its expectations of providing reliable safety data on the tens of thousands of synthetic chemicals to which the public is exposed, via the water that we drink, the air that we breathe and the food that we eat. This failure is in large part due to its reliance on cruel and outdated animal tests. 21
Traditionally, the regulatory authorities, such as the OECD, have readily accepted very limited data from industry when authorising marketing approval of synthetic chemicals. Tests on earthworms, water fleas and zebra fish may suffice to demonstrate that an industrial chemical will not cause significant damage to the environment. Similarly, the rat is generally considered to be sufficiently representative of mammals (including humans) to serve as a safety screen before authorising marketing approval. It may take 30 to 40 years for a synthetic chemical to reveal its true impact on human health. This is because, unlike pharmacovigilance for prescription drugs, there is essentially no government biomonitoring of industrial and synthetic chemicals in peoples’ bodies or in the environment.
Hence the need and the importance to accurately assess the health risks of new, as well as existing chemicals, which have not been screened for endocrine disrupting potential. If we want to understand the effects of EDCs on fish, then we should study fish and fish embryos. However, if we wish to accurately identify EDCs with respect to human health, then we should study human cells, human organs on chips, the human placenta and the like.
An example of 21st century thinking can be found in a recent publication entitled « Novel Approach to Screen Endocrine-Disrupting Chemicals via Endocrine-Enhanced Reduced Human Transcriptome » which illustrates the use of a battery of human relevant tests to achieve a far higher level of prediction of human outcome than any animal test. 22
Conclusion
The government document to « phase out » animal experiments appears glossy on the surface but does not stand up to scientific scrutiny, nor historical fact. The government document omits key evidence that animal models are today widely reported to be failing as predictive models of humans, and scientific experts are able to explain, based on current understanding of evolutionary biology and complexity science, exactly why that failure occurs. The government document lists a host of vague strategy commitments. The only concrete deadlines apply to established replacement methods, some of which have already been around for more than a decade.
The government document covers largely toxicological tests but fails to address fundamental or basic research, mostly conducted in universities. This is an important omission as fundamental research accounts for at least 50% of all animal use in scientific procedures.
References
- Anita O’Connor, Office of Science, Food and Drug Administration (USA). Written communication to Dr Andre Menache in 1998.
- The need for a formal invalidation process for animal and non-animal tests – PubMed
- BMJ 2014; 348:g3719
- Gura T: Cancer Models: Systems for identifying new drugs are often faulty. Science. 1997, 278 (5340): 1041-1042.
- Pharmaceutical Company Quotes
- R. Greek L. A. Hansen: Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse.
- The flaws and human harms of animal experimentation – PubMed
- Animal Studies in Drug Safety Evaluation – Ralph Heywood, 1978
- Removal of key animal researcher stirs controversy – POLITICO
- Menache, A. (2017). Book chapter in The Palgrave International Handbook of Animal Abuse Studies | SpringerLink
- The European Citizens’ Stop Vivisection Initiative and the revision of Directive – PubMed
- Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology | Communications Medicine
- Poole S, Thorpe R, Meager A, Gearing AJ (1988) Assay of pyrogenic contamination in pharmaceuticals by cytokine release from monocytes. Dev Biol Stand. 69,121-3.
- Ph. Eur. bids adieu to rabbit pyrogen test in its monographs – European Directorate for the Quality of Medicines & HealthCare
- Alternatives to the use of animals for bacterial toxins and antitoxins – PubMed
- Marty Stephens, 68, chose footnotes over flamboyance in animal advocacy – Animals 24-7
- HSUS Nomination of Alternative Methods to Replace Animal Use for Botulinum Toxin Potency Testing
- FDA Nod For Allergan’s Cell-Based Assay For Botox – Update
- 00-IAW-ONLINE-POSITION-STATEMENT_Ipsens-CBA-implementation-EN-2020-02-25.pdf
- Are Animal Models Relevant in Modern Psychiatry? | Psychiatric Times
- REACH, animal testing, and the precautionary principle | MB
- Novel Approach to Screen Endocrine-Disrupting Chemicals via Endocrine-Enhanced Reduced Human Transcriptome | Environmental Science & Technology
Animal Interfaith Alliance 