Animal research - legislation, controversies and the need for future improvements

NB. The author has never been involved in any research using animals. 

The current state of animal research in the UK

Animal research has been essential to the discovery of many advances in medical science, including many within the field of neurology. It remains a vital tool, without which the current pace of medical progress would be impossible to sustain. It has, however, always divided opinion, as one balances the potential benefits from the research findings with the cost shouldered by the animals involved.

Around 2.13 million animals are used in non-breading research procedures each year in the UK alone.  98% of these are rodents, fish or birds, and it is illegal to use higher primates (chimps, orang-utans, gorillas) in the UK¹. Although overall there has been a significant reduction in the number of animals used in the last 30 years, the relatively new technology of transgenic models of disease has lead to an increase since 1995, and the use of mice and fish in research is expected to continue to rise.

Home Office; Working to reduce the use of animals in scientific research; 2014

Home Office; Working to reduce the use of animals in scientific research; 2014

This article aims to cover a brief summary of animal research legislation, recent controversies and how further improvements can be made.

Animal research legislation

Legal protection of animals dates back to 1822 in the UK. What first started with the Cruel Treatment of Cattle Act (aka Martin’s law) developed into the Cruelty to Animals Act 1835 – both stated what treatments were deemed unacceptable (including cock-fighting and bear-bating) and the potential fines that may result. The Protection of Animals Act 1911 consolidated much of the previous legislation and banned administering any poisonous substances or putting animals through inhumane operations. Advances in medical research necessitated the creation of much more detailed legislation, resulting in the creation of The Animals (Scientific Procedures) Act 1986, as is used today.

The Animals (Scientific Procedures) Act 1986

The act very broadly covers any living vertebrate animal, and restricts the use of any procedure that may cause such animals pain, suffering, distress or lasting harm. In order to carry out animal research, it essentially states that:

1. The institution where the experiments are to be carried out must hold a licence of designation. This demands that the facilities for housing the animals and conducting the experiments must be a sufficiently high standard, and that adequate staffing is provided for the day-to-day care of the animals
2. A senior scientist who wants to lead a project involving animals must apply for a project licence. This lengthy document must justify why animals are needed and explain what steps have been taken to, where possible, follow the principles of the 3R’s – Replace experiments on animals with other options, Reduce the number of animals required in the experiments, and Refine the techniques in order to minimise animal suffering. Every procedure to be carried out on animals during the project must be described in detailed protocols, and importantly, the expected level of suffering caused by such procedures estimated.
3. Anyone actually involved in carrying out the experiments and related procedures on animals must hold a personal licence. This requires the staff to have attended a two day course on the basics of animal care, the legal framework for animal research and introductions to the common procedures used. Significantly, possessing a personal licence only allows an individual to work with animals at an institution with the above licence of designation, and on a project covered by a relevant project licence; they may only carry out procedures specifically described on the project licence, and must work under a named, senior supervisor whilst they are relatively inexperienced.

A key protective barrier in the above system is the granting of project licences. The estimation of suffering caused to animals by each procedure and the number of animals required allows one to estimate the total amount of animal suffering the project may cause. In order for a licence to be granted, this must be weighed against the potential benefits of the project through its chance of significantly advancing scientific knowledge.

Such decisions are initially discussed at a local level by an ethics committee. These typically include senior members of the department, the named veterinary surgeon for the institution, other project licence holders, two lay persons (such as a priest or any member of the public), and a statistician. Only once the project has been approved locally is it submitted to the home office inspectorate, who makes the final decision. Such home office inspectors are also responsible for ensuring high standards of animal welfare are maintained throughout projects via regular, unannounced inspections of facilities and the powers to withdraw licences.

Recent controversies

Despite the above regulation, which is widely regarded as the gold standard for animal research worldwide, the welfare of animals used at UK research institutions has recently been called into question. In April 2013, undercover filming by the British Union for the Abolition of Vivisection (BUAV) at Imperial College revealed apparently substandard practice².

In particular, holders of personal licences where demonstrated to have relatively poor knowledge of the project licence under which they were working. During a procedure, two key features of the project licence to consider are:

      1. The predicted level of harm the procedure is expected to cause the animal (mild, moderate or severe). If, during the procedure it is deemed that this is being exceeded, the procedure must be stopped and the project licensee informed.

a.     For example, a simple injection of an animal might be expected to cause only mild harm. If, however, observation of the animals after the procedure lead to a suspicion of greater suffering, one must stop the procedure and reassess with the project licence holder why this greater level of suffering occurred.

      2. The end points of experiments must be known. These are stated in the project licence and determine the point at which the experiment is complete, and hence in order to prevent any further suffering, the animals should be euthanized.

On multiple occasions the BUAV investigation revealed inadequacies on the above two points, with the potential for animals to undergo unnecessary or unexpected suffering as a result.

A further problem was the extent to which relatively inexperienced researchers were allowed to carry out procedures they were unfamiliar with without supervision from senior colleagues. This was suggested to result in inadequate provision of anaesthesia during surgical procedures, and inadequate provision of pain relief following such procedures.

In response to the accusations, Imperial commissioned its own independent inquiry. The subsequent Brown report³ suggested that in terms of general animal husbandry, a high standard was being maintained, although staffing levels needed to increase in order to ensure animals were regularly monitored, particularly at weekends. In terms of the management of experimental procedures, however, many areas were deemed to be inadequate.

In particular, the ethical review process was criticised for failing to provide an adequate forum for the discussion of key decisions, such as how projects can better comply with the 3R’s (to reduce their use of animals, replace animals with alternative experiments and refine the techniques they used to reduce suffering). It was also failing to bring members of staff together from across the department to discuss the decisions regarding the balance of potential benefits of research vs. the potential harm to animals, and failing to retrospectively review on-going projects.

Further to this, it acknowledged that the provision of training and supervision to junior members of the research team was poorly organised, provided on an ad hoc basis.

In response to this, Imperial have accepted all recommendations and instigated changes, including a reorganisation of their ethical review process, improvements in communication and increasing staffing levels⁴. In addition, changes in the use of the Animals (Scientific Procedures) Act 1986 have also been made in order to address the problems related to poor training and supervision of junior researchers – on receiving a personal licence, they are now only allowed to carry out procedures on animals independently after a senior colleague has observed them and formally signed them off as being sufficiently competent.

It is also now a requirement that as well as the project licence containing information of the expected level of harm caused by each procedure protocol, those actually undertaking the procedure must also formally document the observed level of perceived harm experienced by the animal during the procedure (sub-threshold, mild, moderate or severe)¹.

The apparent culture of secrecy surrounding animal research is also being tackled¹. Section 24 of the Animals (Scientific Procedures) Act 1986 has previously prevented the release of information from research facilities in order to maintain the safety of its staff and their intellectual property, limiting the potential for informed public debate about current animal research practices and fuelling undercover exposé such as that conducted by the BUAV. Lord Taylor, speaking for the Home Office, has announced that a solution must be developed to “improve the overall transparency surrounding research using animals, to create an environment which fosters informed debate leading to greater public trust, and also must protect personal identities and intellectual property."⁵

A bigger problem?

Any improvements that can be made to ensure a reduction in unnecessary animal suffering should certainly be welcomed. The improvements currently being put in place by Imperial and the changes to the supervision of junior researchers represent significant progress, however, further questions remain over the quality of much animal research conducted today.

When it comes to scientific trials in humans, it has long been deemed unethical to recruit subjects into poorly designed trials. The trial itself may result in no harm to the participants and the intervention used may show considerable promise, but if it is subsequently revealed that poor trial design or reporting leaves considerable room for bias, the strength of the results will be diluted. The risk taken on by the participants themselves will therefore also be for a diluted benefit, rendering their recruitment unethical.

The need for improvements in the reporting of human clinical trials led to the publication of the CONSORT guidelines (Consolidated Standards of Reporting Trials)⁶. By providing a checklist of the information that must be provided in the reporting of a randomised clinical trial (such as power calculations for sample sizes, how participants were randomised, the extend of blinding, baseline characteristics, methods of statistical analysis, estimated effect sizes and a calculation of their precision, etc), readers will be able to better interpret the potential for bias in the studies, and hence the extent to which the results should change practice. A natural secondary consequence of such transparent reporting is that the design of such trials should improve – if authors are forced to report on the inadequacies of their trials, the design will have to be improved in the future if they wish to satisfy referees and publication editors.

In the world of animal research, such diligent scrutiny of the potential for bias has not always received such attention. Indeed, the presence of bias has been cited as one of the potential reasons why interventions that appear promising in animal models so rarely make the transitions to clinically useful treatments in humans⁷.

Where poor experimental design is seen as unethical in human trials, so too should it be seen as unethical in animals. A study must demonstrate that it is committed to replacing, reducing and refining the use of animals in research, and that the potential benefits of the study outweigh the costs to the animals; if the study design results in significant bias, then the potential benefit will be greatly reduced. The animals may therefore be exposed to suffering without sufficient justification. Indeed, whilst one must show commitment to reducing the number of animals involved, if power calculations are not properly used to identify the necessary sample size, using too few animals may well be less ethical than using more – having a smaller number of animals exposed to potential suffering where the potential for detecting a significant result is small may well be worse than having a larger number of animals exposed to such potential suffering, but where there is at least a good chance of detecting a significant result (if it is there to be found; the avoidance of type 2 error).

It has been estimated that only one in three animal research publications follow the basic principles of trial design required to minimise bias⁸; sample size calculation are reported in around 1%⁸, 86-87% do not comment on randomisation and blinding⁷, and <1% define in advance the primary and secondary outcome measures, instead reporting on any outcome that become significant when results are analysed.⁸

ARRIVE guidelines

In order to rectify this situation, similar to the CONSORT guidelines published for human randomised trials, the National Centre for 3Rs (replacement, reduction and refinement) published the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines in 2010⁹. By improving the reporting of animal research, they aimed to maximise the amount of information successfully published, whilst minimising the number of unnecessary studies as their requirements filter down to affect trial design.

Whilst such guidelines have been endorsed by over 300 journals, the extent of their impact has been questioned. It has been reported that in the two years since the endorsement of the ARRIVE guidelines, reporting of blinding, randomization and power calculations of sample size are unchanged^7,10.

Summary

Few can refute that if we wish to continue our current pace of scientific advancement, there will be a continuing need for animals in research. Where differences in opinion occur is in deciding whether this need justifies the inevitable animal suffering that results. Where animal research is used, it should certainly be conducted within the strict regulations currently enforced by the Home Office, and any sense of complacency should be replaced with a perpetual, team-based effort to improve welfare of the animals involved through a commitment to the Replacement, Reduction and Refinement mantra. The potential for short-sighted decisions regarding the use of too few animals in underpowered studies, however, should also be acknowledge. Furthermore, the apparently poor uptake of the ARRIVE guidelines on animal research should be seen as a significant failure in terms of our progress towards maximising the potential benefit we as a scientific community gain per unit of animal suffering.

The answer to this current failure is complex, but the responsibility of referees and journal editors cannot be understated. Success in research often comes down to funding and publications – until the provision of both of these becomes more dependent on the quality of the animal research, rather than headline-grabbing, potentially false results, significant improvements will not be  made⁸.

References

1. Home Office; Working to reduce the use of animals in scientific research; 2014
2. Today programme, BBC Radio 4; BUAV investigation of Imperial College animal research; https://www.youtube.com/watch?v=p__AqH0Dn9w; 2013
3. Brown S; Independent Investigation into Animal Research at Imperial College London; 2013
4. Imperial College London; Action plan for world class animal research; 2013
5. Lord Taylor; Scientific procedures on living animals; https://www.gov.uk/government/speeches/scientific-procedures-on-living-animals; 2013
6. Schulz F et al; CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials; BMJ 2010;340:c332; doi: 10.1136/bmj.c332
7. Baker D et al; Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies. PLoS Biol 2014 12(1): e1001756. doi:10.1371/journal.pbio.1001756
8. Macleod M; Why animal research needs to improve; Nature 2011, 477; 511
9. Kilkenny C et al; Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research; PLoS Biol 2010 8(6): e1000412. doi:10.1371/ journal.pbio.1000412
10. Schwarz F et al. Quality assessment of reporting of animal studies on pathogenesis and treatment of peri-implant mucositis and peri-implantitis.
A systematic review using the ARRIVE guidelines. J Clin Periodontol 2012; 39 (Suppl. 12): 63–72. doi: 10.1111/j.1600-051X.2011.01838.x.