second Expert Working Group (EWG) on Retrospective Severity Assessment
FELASA/ECLAM/ESLAV Contribution
Background
In 2010, FELASA, ESLAV and ECLAM set up two working groups to prepare additional guidance on severity for those involved in the care and use of animals under EU Directive 2010/63/EU.
One group has worked on the severity classification of procedures and the other on reporting on the severity of procedures retrospectively.
The groups will finish their work later this year, but in advance of publication and to inform discussions at the EWG meeting in May, the WG has prepared an extract from their work containing some of the guiding principles together with a few worked examples on severity.
Contents
Introduction 2
How should Severity be assessed? 2
Welfare Assessment Systems 4
Re-use and Cumulative Suffering 4
Selected References 5
Appendix I – Severity Classification and Retrospective Severity Assessment
Stroke model in rat
Drug Dependence model in non-human primate
Appendix II – Examples of Different Severities
Arthritis models
Stroke models
Animal models in Oncology Studies
Pharmaco-kinetic studies
Pain Models
Introduction
As with the previous Directive 86/609/EU, the new Directive requires that experiments are designed to cause the least pain, suffering, distress or lasting harm. However, there are a number of additional requirements, including the need for procedures to be assigned a severity classification prospectively, and the actual severity of procedures reported retrospectively.
With the additional requirements in 2010/63/EU, it is important for all involved in the use of animals, including those responsible for project evaluation to develop and agree a common understanding of and approach to Severity in order to promote a “level playing field” within the European research community, and assist with a common reporting of severity in the statistical returns.
How should Severity be assessed?
Many factors have to be taken into consideration in order to determine a suitable severity classification for a procedure (see below).
Although assessment is largely subjective, as more scientific information becomes available, our understanding of how to recognise pain, suffering and distress improves, and it is therefore important to remain abreast of developments in this rapidly evolving field of research.
One useful starting point is to consider the impact on the animal within the planned procedure:-
What is being done to the animals?
What effect will this have on the animals?
How much suffering may it cause?
What interventions can be included to reduce the impact on the animals?
What is being done to the animals?
Consider all the steps involved in the procedure –
changes to normal environment, husbandry and care practices
handling & restraint
administrations/injections of substances – routes, volumes, frequency
sampling – what is being sampled ; from where is the sample being taken; how much and how frequently are the samples being taken
surgical interventions
use of anaesthesia – local, general, regional
duration of study
in the case of work in the wild – method and frequency of capture
What effect will these interventions have on the animals?
Changes in behaviour (e.g. increased aggression) caused by environment, husbandry and care practices, handling and restraint procedures.
Habituation will reduce potential distress.
Administration of substances and sampling procedures may have a negative impact on welfare (dependent on the routes, volumes and the effects of the administered substances).
Surgical interventions are likely to cause some pain, even with good peri-operative care, including the use of analgesics.
How much suffering will these interventions cause?
Consideration needs to be given to
the nature, intensity and duration of each intervention;
the frequency of interventions and recovery time between interventions;
the duration of the study and the period over which the animal may experience pain, suffering or distress.
For example, in a safety evaluation/toxicology study, depending on the dose, an acute study may cause major discomfort as a consequence of drug administration but this would be of short duration. In contrast, an animal may be exposed to scrapie/BSE material as a juvenile with no adverse effects and, due to the very long incubation period, will remain in good health until the onset of clinical disease. In chronic toxicology studies animals may experience some adverse effects over many months, a combination of daily dosing and the effects of the test substance.
What interventions can be included to reduce the impact on the animals?
How can suffering be minimised?
How are the principles of the 3 R’s embedded in the procedure/project?
Plan to minimise disruption to accommodation, husbandry and care practices.
Develop acclimatisation, training programmes as appropriate.
Consider dosing and sampling procedures to minimise impact on animals.
For example mini-pump administration may have reduced welfare impact versus multiple daily dosing which may require stressful restraint procedures, but this needs to be balanced with the need for surgery, the relative size of the implant which may impact on behaviour, and also the acclimatisation to handling which can occur with regular dosing.
Surgical interventions shall be accompanied by effective peri-operative care, ensuring appropriate post-operative analgesia.
Consider the development of monitoring/scoring system, identifying likely clinical effects and determining early end-points (consistent with the scientific objectives).
Each factor should be challenged to ensure that the 3Rs have been properly addressed.
The 3Rs issues should be considered initially by the Project Applicant, and should be informed by discussions with the veterinarian, animal care staff, and the Animal Welfare Body before the details of the procedure are finalised, and the severity assigned.
Prospective discussions with all relevant personnel will allow for development of the most refined procedure.
Discussions should continue throughout the procedure to ensure that all opportunities are taken to further develop and adopt refinements as these become available (e.g., through elements retrieved in publications).
Welfare Assessment Systems
The use of tailored assessment systems specific to the project, using trained and experienced personnel can make significant refinements to animal models.
A good knowledge of normal and abnormal behaviour in the species/strain being used is essential. Appropriate training and oversight of the procedure will be required to promote consistency. Standardized recording is essential, although inevitably certain scoring systems will be subjective to a degree.
All those involved in severity assessment should have a sound understanding of animal welfare and of the indicators of poor welfare, pain and/or suffering in the species being used.
Re-Use and Cumulative suffering
Re-use of animals in further procedures is permissible under the Directive, but is dependent on a number of factors including the actual severity of the previous procedure, demonstration that the animal’s general state of health and well-being has been fully restored and is in accordance with veterinary advice taking into account the lifetime experience of the animal.
Life-time or cumulative suffering can be considered as the combination of direct suffering (the application of scientific procedures), any clinical conditions from which the animal has suffered (which may or may not be due to the procedure being carried out e.g. intercurrent disease or surgical wound) and contingent suffering (housing, husbandry, transport etc.); the duration of these events must be taken into account.
The key issues which need to be taken into account when considering life-time experience are:
the duration of exposure to the pain, suffering, distress or lasting harm - longer duration is more likely to cause higher severity
the nature and intensity of the effects on the animals
the interval between procedures – the shorter the interval (usually), the less opportunity the animal has to return to normal
the nature of interventions and actions that will be taken to relieve the suffering
consideration of any contingent suffering
Appendices I & II
The Appendices to this paper provide some worked examples of how severity classification and retrospective assessment of severity should be approached, highlighting the welfare and scientific issues to be considered, suggesting improvements which can be made through critical review of a study design, and providing illustrative severity classifications.
The animal models included in this Interim Report have been chosen from an extensive range of different models in preparation by the group. These include examples of different severities, re-use and consideration of cumulative severity.
Selected References
Morton DB, Griffiths PHM (1985) Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Veterinary Record 116, 431 - 6
Hawkins P (2002) Recognizing and assessing pain, suffering and distress in laboratory animals: full results of a survey of current practice in the UK with recommendations. http://www.lal.org.uk/pain/
JWGR (BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement) (2011) A guide to defining and implementing protocols for the welfare assessment of laboratory animals. Laboratory Animals 45: 1-13
Langford DJ, Bailey AL, Chanda ML et al. (2010) Coding of facial expressions of pain in the laboratory mouse. Nat. Methods 7: 447-449
NRC (National Research Council) (2009) Recognition and Alleviation of Pain in Laboratory Animals. Washington, DC: National Academies Press
FELASA (1994) Pain and distress in laboratory rodents and lagomorphs. Laboratory Animals 28: 97-112
A good practice guide to the administration of substances and removal of blood, including routes and volumes. Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C; European Federation of Pharmaceutical Industries Association and European Centre for the Validation of Alternative Methods. J Appl Toxicol. 2001 Jan-Feb;21(1):15-23.
Becker MJ, De Marie S. Clinical signs predicting imminent death in a rat model of invasive pulmonary aspergillosis. In: Hendriksen FM, Morton DB (eds). Humane Endpoints in Animal Experiments for Biomedical Research . Zeist, The Netherlands: The Royal Society of Medicine Press, 1998: 127_/132.
Honess P & Wolfensohn S (2010). A matrix for the assessment of welfare and cumulative suffering in experimental animals. Alternatives to Laboratory Animals. 38(3): 205-212
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