11

International guidelines and International guidelines and lawslaws

Timo NevalainenTimo Nevalainen

University of Eastern FinlandUniversity of Eastern Finland

Finland Finland

22

European regulations

Council of EuropeCoE, Strasbourg

European UnionEU, Brussels

EU DirectiveCoE Convention

Appendix Ahousing and care

EU statistical tables

Articles Articles

The EU Directive 6106/10/EECThe EU Directive 6106/10/EECMember States shall ensure thatMember States shall ensure that wherever possible, a scientifically satisfactory method wherever possible, a scientifically satisfactory method

or testing strategy, not entailing the use of live or testing strategy, not entailing the use of live animals, shall be used instead of a procedure.animals, shall be used instead of a procedure.

the number of animals used in projects is reduced to the number of animals used in projects is reduced to a minimum without compromising the objectives of a minimum without compromising the objectives of the project.the project.

refinement of breeding, accommodation and care, refinement of breeding, accommodation and care, and of methods used in procedures, eliminating or and of methods used in procedures, eliminating or reducing to the minimum any possible pain, suffering, reducing to the minimum any possible pain, suffering, distress or lasting harm to the animals.distress or lasting harm to the animals.

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The EU Directive 6106/10/EECThe EU Directive 6106/10/EEC

The Commission and the Member States shall contribute The Commission and the Member States shall contribute to the development and validation of alternative to the development and validation of alternative approaches which could provide the same or higher approaches which could provide the same or higher levels of information as those obtained in procedures levels of information as those obtained in procedures using animals, but which do not involve the use of using animals, but which do not involve the use of animals or use fewer animals or which entail less painful animals or use fewer animals or which entail less painful procedures, and they shall take such other steps as they procedures, and they shall take such other steps as they consider appropriate to encourage research in this field.consider appropriate to encourage research in this field.

Member States shall assist the Commission in identifying Member States shall assist the Commission in identifying and nominating suitable specialised and qualified and nominating suitable specialised and qualified laboratories to carry out such validation studies.laboratories to carry out such validation studies.

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The 3 R’sThe 3 R’s

Reduction: Reduction: any decrease in the numbers of any decrease in the numbers of animals used to obtain information animals used to obtain information of a given amount and precisionof a given amount and precision

Refinement:Refinement: any decrease in the incidence or any decrease in the incidence or severity of procedures applied to severity of procedures applied to animals necessarily usedanimals necessarily used

Replacement: Replacement: the substitution of conscious living the substitution of conscious living vertebrates by non-sentient vertebrates by non-sentient materialmaterial

Revised directive / ScopeRevised directive / Scope

This Directive shall apply to the following This Directive shall apply to the following animals:animals: (a) live non-human vertebrate animals, (a) live non-human vertebrate animals,

including:including: i) independently feeding larval forms, andi) independently feeding larval forms, and ii) foetal forms of mammals as from the last ii) foetal forms of mammals as from the last

third of their normal development;third of their normal development; (b) live cephalopods.(b) live cephalopods.

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Stricter national measuresStricter national measures

Member States may, while observing the Member States may, while observing the general rules laid down in the Treaty, general rules laid down in the Treaty, maintain provisions in force on …*, aimed maintain provisions in force on …*, aimed at ensuring more extensive protection of at ensuring more extensive protection of animals falling within the scope of this animals falling within the scope of this Directive than those contained in this Directive than those contained in this Directive.Directive.

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Purposes of proceduresPurposes of procedures

(a) basic research;(a) basic research; (b) translational or applied research with any of (b) translational or applied research with any of

the following aims:the following aims:(i) the avoidance, prevention, diagnosis or treatment of (i) the avoidance, prevention, diagnosis or treatment of disease, ill-health or other abnormality or their effects in disease, ill-health or other abnormality or their effects in human beings, animals or plants;human beings, animals or plants;

(ii) the assessment, detection, regulation or (ii) the assessment, detection, regulation or modification of physiological conditions in human modification of physiological conditions in human beings, animals or plants; orbeings, animals or plants; or

(iii) the welfare of animals and the improvement of the (iii) the welfare of animals and the improvement of the production conditions for animals production conditions for animals reared for agricultural reared for agricultural purposes.purposes.

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Continues…Continues… (c) for any of the aims in point (b) in the development, (c) for any of the aims in point (b) in the development,

manufacture or testing of the quality, effectiveness and manufacture or testing of the quality, effectiveness and safety of drugs, foodstuffs and feed-stuffs and other safety of drugs, foodstuffs and feed-stuffs and other substances or substances or products;products;

(d) protection of the natural environment in the interests (d) protection of the natural environment in the interests of the health or welfare of human of the health or welfare of human beings or animals;beings or animals;

(e) research aimed at preservation of the species;(e) research aimed at preservation of the species; (f) higher education, or training for the acquisition, (f) higher education, or training for the acquisition,

maintenance or improvement of maintenance or improvement of vocational skills;vocational skills; (g) forensic inquiries.(g) forensic inquiries.

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PrimatesPrimates

Great apes bannedGreat apes banned

F2 requirementF2 requirement

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Classification of severity of Classification of severity of proceduresprocedures

Member States shall ensure that all Member States shall ensure that all procedures are classified as "non-procedures are classified as "non-recovery", "mild", "moderate", or "severe“ recovery", "mild", "moderate", or "severe“

Member States shall ensure that a Member States shall ensure that a procedure is not performed if it involves procedure is not performed if it involves severe pain, suffering or distress that is severe pain, suffering or distress that is likely to be long-lasting and cannot be likely to be long-lasting and cannot be ameliorated.ameliorated.

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TrainingTraining

The staff shall be adequately educated The staff shall be adequately educated and trained before they perform any of theand trained before they perform any of the

following functions:following functions: (a) carrying out procedures on animals;(a) carrying out procedures on animals; (b) designing procedures and projects;(b) designing procedures and projects; (c) taking care of animals; or(c) taking care of animals; or (d) killing animals.(d) killing animals.

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Animal-welfare bodyAnimal-welfare body

..shall ensure that each breeder, supplier ..shall ensure that each breeder, supplier and user sets up an animal-welfare and user sets up an animal-welfare body.body.

The animal-welfare body shall include at The animal-welfare body shall include at least the person or persons responsible for least the person or persons responsible for the welfare and care of the animals and, in the welfare and care of the animals and, in the case of a user, a scientific member. the case of a user, a scientific member. The animal-welfare body shall also receive The animal-welfare body shall also receive input from the designated veterinarian or input from the designated veterinarian or the expert referred to in Article 25.the expert referred to in Article 25.

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Retrospective assessmentRetrospective assessment

……shall ensure that .. the retrospective assessment shall ensure that .. the retrospective assessment shall be carried out by the competent authority which shall be carried out by the competent authority which shall, on the basis of the necessary documentation shall, on the basis of the necessary documentation submitted by the user, evaluate the following:submitted by the user, evaluate the following:

(a) whether the objectives of the project were achieved;(a) whether the objectives of the project were achieved;

(b) the harm inflicted on animals, including the numbers (b) the harm inflicted on animals, including the numbers and species of animals used, and the severity of the and species of animals used, and the severity of the procedures; andprocedures; and

(c) any elements that may contribute to the further (c) any elements that may contribute to the further implementation of the requirement of implementation of the requirement of replacement, replacement, reduction and refinement.reduction and refinement.

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Non-technical project summariesNon-technical project summaries

The non-technical project summary shall The non-technical project summary shall provide the following:provide the following: (a) information on the objectives of the (a) information on the objectives of the

project, including the predicted harm andproject, including the predicted harm and benefits and the number and types of animals benefits and the number and types of animals

to be used;to be used; (b) a demonstration of compliance with the (b) a demonstration of compliance with the

requirement of replacement, reduction and requirement of replacement, reduction and refinement.refinement.

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Infrastructure for the 3RsInfrastructure for the 3Rs

Union Reference LaboratoryUnion Reference Laboratory Revised name and tasks for ECVAMRevised name and tasks for ECVAM

National committees for the protection of National committees for the protection of animals used for scientific purposesanimals used for scientific purposes

Member States shall nominate a single Member States shall nominate a single point of contact to provide advice on the point of contact to provide advice on the regulatory relevance and suitability of regulatory relevance and suitability of alternative approaches proposed for alternative approaches proposed for validation.validation.

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European housing and care guidelines of European housing and care guidelines of laboratory animals laboratory animals Council of Europe (app A)Council of Europe (app A)

in effect from July 2007 onin effect from July 2007 on European UnionEuropean Union

adopted the same text in June 2007adopted the same text in June 2007

available in all EU languagesavailable in all EU languages

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Old Appendix AOld Appendix A

Quite similar to old – 1996 - US Quite similar to old – 1996 - US requirements (PHS policy)requirements (PHS policy) revised 2010revised 2010 http://download.nap.edu/cart/http://download.nap.edu/cart/

download.cgi?download.cgi?&record_id=12910&free=1 &record_id=12910&free=1

UK requirement considerably higherUK requirement considerably higher

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Space: Rational of App ASpace: Rational of App A

minimum requirements - limits set arbitrarilyminimum requirements - limits set arbitrarily

justified by science-based arguments-> exact justified by science-based arguments-> exact values cannot be scientifically provenvalues cannot be scientifically proven

a compromise between standard cage sizes, a compromise between standard cage sizes, practical experience and economic practical experience and economic reasoningreasoning

depend on minimum enrichment depend on minimum enrichment requirementsrequirements

2020

Space:Space:Standard European CagesStandard European Cages

Floor area Floor area cmcm22

Height cmHeight cm Acceptable Acceptable

Type IType I 180180 12-1412-14 NoNo

Type IIType II 330330 12-1412-14 Mice onlyMice only

Type IIIType III 815815 14-1814-18 Yes Yes

Type IVType IV 18001800 19-2019-20 YesYes

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Minimum floor areaMinimum floor area

Mouse Rat Hamster Gerbil Guinea pig

0

500

1000

1500

2000

2500

Appendix A ProposalEarlier Now

2222

Minimum cage heightMinimum cage height

Mouse Rat Hamster Gerbil Guinea pig

0

5

10

15

20

25

Appendix A ProposalEarlier Now

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Stocking densities for miceStocking densities for mice

Weight in grammes<20 <25 <30 <40

0

20

40

60

80

100

Appendix A Proposal, exp

Proposal, breeding

Earlier

Now for breeding

Now for experiments

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Stocking densities for ratsStocking densities for rats

Weight in grammes<50 <100 <150 <200 <300 <400 <600 >600

0

100

200

300

400

500

600

Appendix A Proposal, exp

Proposal, breeding

Earlier

Now for breeding

Now for experiments

2525

2626

2727

2828

Terms used in App ATerms used in App A

Environmental complexityEnvironmental complexity

Structured environmentStructured environment

Environmental enrichmentEnvironmental enrichment

Exposure

Environmental complexity

Structured environment

Outcome

Environmental enrichment

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Any refinement shouldAny refinement should

be scientifically validatedbe scientifically validated

be truly beneficial to the animalsbe truly beneficial to the animals

not detract from the scientific integrity not detract from the scientific integrity

Efficacy

Safety

Method

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App A - part B - minimum App A - part B - minimum enrichment - rodentsenrichment - rodents

Mouse -> nesting materialMouse -> nesting material

Rat -> refuges, such as nesting boxes, Rat -> refuges, such as nesting boxes, pipes, nesting material pipes, nesting material

Hamster -> nesting material, climbing rack, Hamster -> nesting material, climbing rack, refuge area (refuge area (e.g.e.g. tube, hut), roughage and tube, hut), roughage and gnawing objectsgnawing objects

Guinea-Pig-> refuges (tubes, shelters) Guinea-Pig-> refuges (tubes, shelters) should be provided. Sterilized wood sticks should be provided. Sterilized wood sticks may be consideredmay be considered

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App A text - rodentsApp A text - rodents

Nesting materials should allow the rodents to manipulate Nesting materials should allow the rodents to manipulate the material and construct a nestthe material and construct a nest

Nest boxes should be provided if insufficient nesting Nest boxes should be provided if insufficient nesting material is provided to build a complete, covered nestmaterial is provided to build a complete, covered nest

Guinea-pigs should always be provided with manipulable Guinea-pigs should always be provided with manipulable materials such as hay for chewing and concealmentmaterials such as hay for chewing and concealment

To increase environmental complexity the addition of To increase environmental complexity the addition of some form of enclosure enrichment is strongly some form of enclosure enrichment is strongly recommendedrecommended

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Statistical tables / EU

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Other guidelines ? Other guidelines ?

Grant application may require compliance Grant application may require compliance with other guidelineswith other guidelines US GrantsUS Grants

Quality systemsQuality systems GLP GLP

OECD, FDA, JapaniOECD, FDA, Japani

http://www.cfsan.fda.gov/~dms/opa-pt58.html http://www.cfsan.fda.gov/~dms/opa-pt58.html ISOISO AAALAC (www.aaalac.org )AAALAC (www.aaalac.org )

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GLP – why and where?GLP – why and where?GLP – why and where?GLP – why and where?

GLP is applied in safety evaluation GLP is applied in safety evaluation studiesstudies

GLP is part of quality thinkingGLP is part of quality thinking Originally established to prevent Originally established to prevent

falsifications in safety evaluationfalsifications in safety evaluation New chemicals directive in EuropeNew chemicals directive in Europe

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What Do GLPs Do?What Do GLPs Do?

GLPs define a process.GLPs define a process.

GLPs will NOT assure good science.GLPs will NOT assure good science.

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GLP inspectionsGLP inspectionsGLP inspectionsGLP inspections

GLP guidelinesGLP guidelines FDAFDA OECDOECD JapanJapan

Each country has national inspection bodyEach country has national inspection body

Unit announces that GLP is appliedUnit announces that GLP is applied National body carries out inspectionsNational body carries out inspections

Inspector can come from FDA or OECDInspector can come from FDA or OECD

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GLP in laboratory animal unitsGLP in laboratory animal unitsGLP in laboratory animal unitsGLP in laboratory animal units

Pharmaceutical companiesPharmaceutical companies

Contract laboratoriesContract laboratories

Very few universities and government Very few universities and government research institutesresearch institutes Other studies do not requireOther studies do not require Other quality systems may be betterOther quality systems may be better

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FDA - OECDFDA - OECDFDA - OECDFDA - OECD

FDAFDA Laboratory animalLaboratory animal U.S. Federal Register, U.S. Federal Register,

Nonclinical Laboratory Nonclinical Laboratory Studies, GLP Regulations, Studies, GLP Regulations, U.S. FDA, Department of U.S. FDA, Department of Health, Education and Health, Education and Welfare. Fed Reg 43:59986-Welfare. Fed Reg 43:59986-60025. 1978.60025. 1978.

OECDOECD Test systemTest system OECD Guidelines for testing of OECD Guidelines for testing of

Chemicals, Appendix, Decision Chemicals, Appendix, Decision of the Council, OECD. OECD of the Council, OECD. OECD Test Guidelines, OECD Test Guidelines, OECD Principles of GLP, C(81) 30 Principles of GLP, C(81) 30 Final, pp 1-29Final, pp 1-29

http://www.oecd.org/document/http://www.oecd.org/document/63/0,2340,en_2649_34381_23463/0,2340,en_2649_34381_2346175_1_1_1_1,00.html 6175_1_1_1_1,00.html

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AAALACAAALAC

Association for Assessment and Association for Assessment and Accreditation of Laboratory Animal Care Accreditation of Laboratory Animal Care International, Inc. International, Inc.

Private nonprofit organization that Private nonprofit organization that accredits organizations using animals in accredits organizations using animals in research, teaching or testing.research, teaching or testing.

Available worldwide.Available worldwide.

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Why Accreditation?Why Accreditation?

Accreditation….Accreditation…. Represents quality of a laboratory animal Represents quality of a laboratory animal facility.facility.

Promotes scientific validity of research results.Promotes scientific validity of research results.

Provides a confidential peer-review process.Provides a confidential peer-review process.

Impresses funding sources and research Impresses funding sources and research partners.partners.

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ISOISO

International Organization for Standardization (ISO)International Organization for Standardization (ISO)

ISO is a network of the national standards institutes of ISO is a network of the national standards institutes of 148 countries, on the basis of one member per country, 148 countries, on the basis of one member per country, with a Central Secretariat in Geneva, Switzerland, that with a Central Secretariat in Geneva, Switzerland, that coordinates the system. coordinates the system.

Non-governmentalNon-governmental Members are government agencies, institutes, and private Members are government agencies, institutes, and private

entities (e.g., associations, trade partnerships)entities (e.g., associations, trade partnerships)

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ISO Practice StandardsISO Practice Standards

ISO 9000 – ISO 9000 – Systematized Quality ManagementSystematized Quality Management

Management systemManagement system refers managing business refers managing business processes or activities in order that the products or processes or activities in order that the products or services produced meet the objectives desired, such as:services produced meet the objectives desired, such as:

satisfying the customer's quality requirementssatisfying the customer's quality requirementscomplying with regulationscomplying with regulations

meeting environmental objectivesmeeting environmental objectives

Management system standards refers to all those Management system standards refers to all those features of a product (or service) which are required by features of a product (or service) which are required by the customer. the customer.

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ISO 9000 for Animal ResearchISO 9000 for Animal Research

Laboratory animal diet manufacturers and dealersLaboratory animal diet manufacturers and dealers Microbiology of animal feedstuffsMicrobiology of animal feedstuffs Composition of animal feedstuffsComposition of animal feedstuffs (numerous ISO 9000 standards on feedstuffs)(numerous ISO 9000 standards on feedstuffs)

Animal ExperimentationAnimal Experimentation ISO 10993-2:1992 Biological evaluation of medical devices - Part 2: ISO 10993-2:1992 Biological evaluation of medical devices - Part 2:

Animal welfare requirementAnimal welfare requirement

Specifies minimum requirements for the use of animals in biological Specifies minimum requirements for the use of animals in biological testing.testing.

Establishes guidelines which allow the scientist to respect life in general, Establishes guidelines which allow the scientist to respect life in general, to reduce the number of animal experiments and the number of animals to reduce the number of animal experiments and the number of animals used in experiments, to minimize suffering and maintain the quality of life used in experiments, to minimize suffering and maintain the quality of life of the animals used in the experiments.of the animals used in the experiments.

Applies to the experimentation performed on vertebrates.Applies to the experimentation performed on vertebrates.

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4646

Future Chemicals Policy of the EU -Future Chemicals Policy of the EU -A challenge and an opportunity for A challenge and an opportunity for

alternative methodsalternative methods

Up to 30100 existing chemicals that are Up to 30100 existing chemicals that are currently marketed, but have not been tested currently marketed, but have not been tested so farso far

Appropriate alternative methods will be used Appropriate alternative methods will be used as much as possible for the safety as much as possible for the safety evaluation of these chemicalsevaluation of these chemicals