Page 1 Executive Summary 2 2 Introduction

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1 ANIMALS (SCIENTIFIC PROCEDURES) ACT 1986 USE, CONTINUED USE AND RE USE OF ANIMALS Contents: Page 1 Executive Summary 2 2 Introduction 3 Definition of Terms: 3.1 use Continued use 3.3 Re use 4 Authorisation of Re use 4 5 Further constraints on continued and re use 5 6 How to get authorities needed for re use and continued use 7 Examples: 7.1 use and continued use use and continued use 7.3 re use 7.4 more complicated situations 7 8 Examples as protocols 8 9 Flow diagram of decision points for re use 10 1

2 Executive Summary This guidance is intended to help project licence holders understand the terms use, reuse and continued use and prepare their applications appropriately. If in doubt, especially in complex situations, you should consult your local inspector. Re use is subject to legal limitations intended to minimise suffering. Any and all re use, or continued use, must be authorised by the Secretary of State. This can either be done in the project licence at the time of issue in which case, you should make sure you ask for it in the application or by amendment of the project licence. There is rarely any reason why consideration of potential re use and continued use cannot be included when the project licence application is being prepared. It is important that you show in your project licence application that you have identified criteria which will be used to determine whether an animal is fit for reuse. Your NVS should be consulted on determining these criteria. Records should be kept of re use or continued use and should be available for inspection by the Home Office if requested. Re use must be coded and reported accurately in your Annual Return of Procedures. Introduction This note: consolidates various sources of information previously published by the Home Office explaining the concepts of use, continued use and re use of protected animals under the Animals (Scientific Procedures) Act 1986 (ASPA); and provides examples of the project authorities needed. It is aimed principally at existing licensees and first time applicants for project licence authorities under ASPA. It will also be of assistance to non practitioners wishing to know more about these issues. 2

3 Definition of terms Use of protected animals The use of a protected animal i under project licence authorities extends from the time the first regulated procedure ii is applied to the animal up to the time when the observations, or the collection of data (or other products) for a particular scientific purpose (usually a single experiment or test), are completed. Continued use of protected animals Continued use is an administrative concept to describe the use of an animal in a series of regulated procedures for a particular scientific purpose extending over more than one project licence protocol iii (and often over more than one project licence). The use of the same animal must be essential in order to achieve the objectives of the second or subsequent protocols. It is not necessary that all of the protocols are on the same project licence for continued use to apply. The arrangement helps minimise duplication of information, and avoids undue repetition and over complex licence authorities. Re use of protected animals Re use is a term used where, after completion of one series of regulated procedures, an animal is used again in the same or a different protocol, where a previously unused animal would have equally sufficed to meet the objectives of the second and subsequent use. i ASPA defines a protected animal as any living vertebrate other than man, and one invertebrate species Octopus vulgaris. Protection extends to certain immature forms. ii A regulated procedure is defined by Section 2(1) of ASPA as any experimental or other scientific procedure applied to a protected animal which may have the effect of causing that animal pain, suffering, distress or lasting harm. Pain, suffering, distress and lasting harm encompass any material disturbance to normal health, including disease, injury and physiological or psychological discomfort, whether immediately (such as at the time of an injection) or in the longer term (such as the consequences of the application of a carcinogen). Regulated procedures may be acts of commission (such as dosing or sampling) or of deliberate omission (such as withholding food or water). iii The term protocol is used to describe a series of regulated procedures applied for a particular experimental or other scientific purpose to a protected animal. Protocols are set out in section of a project licence or application. 3

4 Authorisation of re use All re use of protected animals requires the consent of the Secretary of State and must be specifically authorised. Section 14 of ASPA establishes the framework under which the Secretary of State may consider requests to re use animals. The Secretary of State's consent for re use is generally conditional upon the animal having suffered no significant adverse effects as a consequence of the first use, and its not having been subjected to any intervention which compromises its suitability, in welfare or scientific terms, as a subject for the second or subsequent use. Severe pain and distress The Secretary of State may not authorise the use of any animal more than once in a procedure entailing severe pain or distress. Authority to re use any animal that has experienced significant adverse effects in its previous use is, therefore, unlikely to be granted other than where the well being of the animal has been restored and it is to be re used on a non recovery (unclassified) protocol with the minimum of delay. Administration of a general anaesthetic The Act places additional restraints on the powers of the Secretary of State to authorise a protected animal s use for any further regulated procedures where it has been subjected to and has completed a series of regulated procedures for a particular purpose; and given a general anaesthetic for any of those procedures; and allowed to recover consciousness. In this context, the Secretary of State may only give his consent for re use when: the procedure for which the general anaesthetic was given consisted only of surgical preparation essential for the subsequent procedures (for example, the preparation of animals with carotid artery loops, or the implantation of telemetry devices); or the general anaesthetic was administered solely to immobilise the animal and not to prevent pain (for example, to allow x rays to be taken); or if the re use of the animal will be under general anaesthesia throughout and the animal will not be allowed to recover consciousness. 4

5 Further constraints on re use and continued use If animals are to be re used or subject to continued use they must meet the following criteria to ensure that science and welfare are not compromised. 1. On completion of the previous series of regulated procedures animals may be kept alive for re use only if a veterinary surgeon has determined that they are not suffering, or likely to suffer, adverse effects as a result of the procedures. 2. Previous use should not compromise any subsequent use, e.g.: a. an animal which has been used in such a way that liver function has been compromised should not subsequently be used to study normal liver function; b. appropriate wash out periods should be applied when studying the metabolism of a series of drugs to avoid confounding drug interactions. 3. If the first use involves surgery, the animal should not be further used unless: a. it has recovered from the anaesthesia and surgery and effects from these will not compromise either the study or the animal s welfare; b. previously implanted telemetry devices can be shown to be functional to a level which will allow satisfactory results to be achieved. 4. The criteria which have to be met before an animal is subject to re use should be made explicit in the project licence and should be known to all appropriate staff dealing with the animals. To safeguard the animal s welfare, the Named Veterinary Surgeon (NVS) should be actively involved, together with the relevant personal licensees and other named persons, in determining these criteria. Note that while the NVS must determine that an animal may be kept alive after the first and any subsequent series of procedures have been completed, it is not necessary that the NVS physically inspects or certifies that any particular animal is fit for reuse/continued use, but he/she should be involved in determining the criteria which must be met. How to get the authorities needed for re use or continued use You should think about possible re use or continued use when drafting your project licence application, or when seeking an amendment to an existing project licence, and specify the criteria which have to be met in any individual case for an animal to be subject to re use or continued use. This is the preferred way to get the necessary consents. You should specify both scientific criteria (e.g. a minimum wash out period for drugs previously used) and welfare criteria (e.g. clinical criteria for recovery from surgery and anaesthesia), and describe how the NVS advises on determining whether animals are fit for such use. This is usually done in the form of written guidance to the personal licensees and named persons (either included in the project licence or referred to from it). It is usual to set limits on the amount of re use which is allowed. These can either be a certain number of re uses (e.g. not more than five times), a certain time limit (e.g. over a period of not more than one year), or subject to certain criteria determined by the NVS being met. It may be a combination of some or all of these factors. 5

6 Examples 1. Use and continued use (one purpose, one series of regulated procedures) Purpose: to determine the effects of genetic defect X in mice by measuring changes in blood parameters with age and undertaking a histological analysis of adult brain structure. This could be undertaken within a single protocol or split between a protocol under which the mouse with the genetic defect was produced and genotyped (Protocol A) with the use continued under a second protocol (Protocol B), possibly on a different project licence, on which the sampling and final preparation for histology are carried out. In this example Protocol A might be on a project at an establishment that specialises in breeding mice with genetic alterations and Protocol B on the project of the scientist studying that particular genetic defect. This constitutes continued use as only a mouse with genetic defect X would be a suitable experimental animal for Protocol B. 2. Use and continued use (one purpose, one series of regulated procedures) Purpose: to determine the effects of hormones and a potential antitumour agent on vascularity and growth of a tumour line known to be sensitive to ovarian hormones. For this use a mouse with both ovaries removed is needed. The ovary removal, the subsequent injection of tumour cells, administration of hormones and antitumour agents, and the procedures needed to measure tumour vascularity and growth could all be on one protocol. Alternatively the ovary removal could be performed under one licence with authority to transfer the animal for subsequent scientific study, and the other procedures undertaken as continued use under a protocol on a second licence which states that an oviarectomised animal is needed for the studies. In cases like this one which involve surgical preparation (in this example, removal of the ovaries) the use may be continued in a variety of ways and the first protocol need simply state that the animal will be transferred to a protocol which requires animals prepared in that way. 3: Re use (two purposes, two series of regulated procedures) Purpose 1: to determine the effect on blood parameters in sheep of a dietary supplement that may cause adverse effects. Purpose 2: to obtain sheep blood to make diagnostic plates for bacteriology. A sheep is used on a first protocol to study the metabolism of a dietary supplement, blood samples are taken for analysis and other non invasive measurements are made. The same animal is then used on a second unrelated protocol to provide blood to make diagnostic plates for bacteriology. The two studies are not related. Any naive sheep could have been used for the second study. Therefore the use of the sheep for providing blood for diagnostic plates would be re use of that animal. 6

7 In some cases the regulated procedures for the subsequent use are exactly the same as in the previous use, and provided the different purposes are made clear elsewhere, there is no need to have two different protocols. 4: More complicated situations Depending on the project licence holder s intention and the specific design of the study, it may not be immediately clear whether some studies should be regarded as re use or continued use. If in doubt, consult your local inspector. Examples: Drug Metabolism Studies If the metabolism of a series of drugs is studied in an individual animal this will constitute continued use if serial data from individual animals which had been used for each preceding study is needed to interpret each subsequent study (a within animal design) and data from a different animal would not have satisfied the scientific objective. However, if each study is to be interpreted independently of the others and without reference to earlier findings (and therefore any animal could have been used) this will constitute re use. What actually happens to the animal is the same in each series of studies, but the way in which data need to be analysed determines whether the subsequent use is regarded as re use or continued use. Effects of novel pharmaceutical materials on blood pressure An animal is surgically prepared on one protocol. For example, an animal may be prepared under general anaesthesia with an indwelling telemetry device to measure blood pressure, activity and temperature. Following recovery from surgery, the animal will be dosed orally with a test material to assess the impact on blood pressure and activity. [This use may be presented on a single protocol, that is dosing on the same protocol as the surgical preparation (use) or on a separate protocol (continued use) ] As part of a cross over design the animal may be given further test materials and their effects assessed. (This would constitute continued use, as the data from the same individual animal are required to investigate within animal differences). After completion of the original study, and subject to still being suitable experimental subjects, these animals may subsequently be re used on further studies for the same purpose, where a surgical preparation of that type is necessary for the study and where each study is to be interpreted independently of the others and without reference to earlier findings (and therefore any animal could have been used). 7

8 The Examples as Protocol Subsections Note: these use simplified wordings to illustrate the differences between re use and continued use. For actual protocols some details on, for example, frequency and volume of samples or doses would be expected. 1. Use and continued use Purpose: to determine the effects of genetic defect X in mice by measuring changes in blood parameters with age and undertaking a histological analysis of adult brain structure. A single use Mating of mice to produce offspring with genetic defect X Removal of tissue for DNA analysis Withdrawal of blood from superficial veins at different age points Killing by perfusion fixation A single use over two protocols (continued use) Protocol A Protocol B Breeding genetically Effect of X deficiency altered animals Mating of mice to produce offspring with genetic defect X Removal of tissue for DNA analysis Transfer to a project with authority to use genetically modified animals of this type. (iv) Continued use: Mice with genetic defect X will be obtained from projects with authority to breed and maintain genetically altered mice and provide them for use on other projects. Withdrawal of blood from superficial veins at different age points Killing by perfusion fixation In this example protocol A might be on a project at an establishment that specialises in breeding mice with genetic alterations and protocol B on the project of the scientist studying that particular genetic defect. Only a mouse with genetic defect X would be a suitable experimental animal for Protocol B. 2. Use and continued use Purpose: to determine the effects of hormones and a potential antitumour agent on vascularity and growth of a tumour line known to be sensitive to ovarian hormones. A single use Removal of both ovaries under general anaesthesia with recovery. Subcutaneous injection of a set dose of tumour line Y Administration of hormones and/or antitumour agent into a superficial vein Infra red scanning of tumour site under general anaesthesia and tumour diameter measurement at various time points Killing by a Schedule 1 method A single use over two protocols (continued use) Protocol A Protocol B Ovariectomy Tumour growth Continued use: Ovariectomised mice will (iv) be obtained from projects with authority to prepare such animals and provide them for use on other projects. Removal of both ovaries under general anaesthesia with recovery Transfer to a project with authority to use ovariectomised animals. Subcutaneous injection of a set dose of tumour line Y Administration of hormones and/or antitumour agent into a superficial vein Infra red scanning of tumour site under general anaesthesia and tumour diameter measurement at various time points Killing by a Schedule 1 method 8

9 This is one example of a Protocol B. Any protocol that required ovarectomised mice could be suitable as a protocol B. 3: Re use Purpose 1: to determine the effect on blood parameters in sheep of a dietary supplement which is not known to be without ill effects. Purpose 2: to obtain sheep blood to make diagnostic plates for bacteriology. Purpose 1 first use. Purpose 2 second use Protocol 7 Protocol 10 (iii) Sheep Sheep (iv). Re use: Animals which have been subject to regulated procedures with no more than mild adverse effects and which have not included the giving of a general anaesthetic. Withdrawal of blood (baseline sample) from a superficial vein without general anaesthesia. Withdrawal of blood from a superficial vein without general anaesthesia. Administration of supplement Z or control substance in the diet. Withdrawal of blood from a superficial vein without general anaesthesia at various time points after dietary change. At the end of the regulated procedures animals will be kept alive at the designated establishment. 9

10 Flow Diagram of Decision Points for re use. At the end of a series of procedures is the animal suffering or likely to suffer as a result of the procedures? YES NO PPL condition 16 PPL condition 17 PIL condition 8 Kill the animal NVS to determine that the animal can be kept alive at the PCD under the supervision of the NVS Possible outcomes PCD condition 22 Section 14 Killed Re use Discharge from ASPA requires NVS certification At the same PCD, same or different PPL (requires PPL authority to re use the Animal) At a different PCD (requires SoS authority to move the animal and PPL authority to re use the animal) Home Office, December