International guidelines and laws

1. International guidelines and laws Timo Nevalainen University of Eastern Finland Finland

3. The EU Directive 6106/10/EEC • Member States shall ensure that • wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used instead of a procedure. • the number of animals used in projects is reduced to a minimum without compromising the objectives of the project. • refinement of breeding, accommodation and care, and of methods used in procedures, eliminating or reducing to the minimum any possible pain, suffering, distress or lasting harm to the animals.

4. The EU Directive 6106/10/EEC • The Commission and the Member States shall contribute to the development and validation of alternative approaches which could provide the same or higher levels of information as those obtained in procedures using animals, but which do not involve the use of animals or use fewer animals or which entail less painful procedures, and they shall take such other steps as they consider appropriate to encourage research in this field. • Member States shall assist the Commission in identifying and nominating suitable specialised and qualified laboratories to carry out such validation studies.

5. The 3 R’s Reduction: any decrease in the numbers of animals used to obtain information of a given amount and precision Refinement: any decrease in the incidence or severity of procedures applied to animals necessarily used Replacement: the substitution of conscious living vertebrates by non-sentient material

6. Revised directive / Scope • This Directive shall apply to the following animals: • (a) live non-human vertebrate animals, including: • i) independently feeding larval forms, and • ii) foetal forms of mammals as from the last third of their normal development; • (b) live cephalopods.

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

8. Purposes of procedures • (a) basicresearch; • (b) translational or applied research with any of the following aims: • (i) the avoidance, prevention, diagnosis or treatment of disease, ill-health or other abnormality or their effects in human beings, animals or plants; • (ii) the assessment, detection, regulation or modification of physiological conditions in human beings, animals or plants; or • (iii) the welfare of animals and the improvement of the production conditions for animals reared for agriculturalpurposes.

9. Continues… • (c) for any of the aims in point (b) in the development, manufacture or testing of the quality, effectiveness and safety of drugs, foodstuffs and feed-stuffs and other substances or products; • (d) protection of the natural environment in the interests of the health or welfare of human beingsoranimals; • (e) research aimed at preservation of the species; • (f) higher education, or training for the acquisition, maintenance or improvement of vocationalskills; • (g) forensicinquiries.

10. Primates Great apes banned F2 requirement

11. Classification of severity of procedures Member States shall ensure that all procedures are classified as "non-recovery", "mild", "moderate", or "severe“ Member States shall ensure that a procedure is not performed if it involves severe pain, suffering or distress that is likely to be long-lasting and cannot be ameliorated.

12. Training • The staff shall be adequately educated and trained before they perform any of the • following functions: • (a) carrying out procedures on animals; • (b) designing procedures and projects; • (c) taking care of animals; or • (d) killing animals.

13. Animal-welfare body ..shall ensure that each breeder, supplier and user sets up an animal-welfare body. The animal-welfare body shall include at least the person or persons responsible for the welfare and care of the animals and, in the case of a user, a scientific member. The animal-welfare body shall also receive input from the designated veterinarian or the expert referred to in Article 25.

14. Retrospective assessment • …shall ensure that .. the retrospective assessment shall be carried out by the competent authority which shall, on the basis of the necessary documentation submitted by the user, evaluate the following: • (a) whether the objectives of the project were achieved; • (b) the harm inflicted on animals, including the numbers and species of animals used, and the severity of the procedures; and • (c) any elements that may contribute to the further implementation of the requirement of replacement, reduction and refinement.

15. Non-technical project summaries • The non-technical project summary shall provide the following: • (a) information on the objectives of the project, including the predicted harm and • benefits and the number and types of animals to be used; • (b) a demonstration of compliance with the requirement of replacement, reduction and refinement.

16. Infrastructure for the 3Rs • Union Reference Laboratory • Revised name and tasks for ECVAM • National committees for the protection of animals used for scientific purposes • Member States shall nominate a single point of contact to provide advice on the regulatory relevance and suitability of alternative approaches proposed for validation.

17. European housing and care guidelines of laboratory animals • Council of Europe (app A) • in effect from July 2007 on • European Union • adopted the same text in June 2007 • available in all EU languages

18. Old Appendix A • Quite similar to old – 1996 - US requirements (PHS policy) • revised 2010 • http://download.nap.edu/cart/download.cgi?&record_id=12910&free=1 • UK requirement considerably higher

19. Space: Rational of App A • minimum requirements - limits set arbitrarily • justified by science-based arguments-> exact values cannot be scientifically proven • a compromise between standard cage sizes, practical experience and economic reasoning • depend on minimum enrichment requirements

20. Space:Standard European Cages

21. Minimum floor area Earlier Now

22. Minimum cage height Earlier Now

23. Stocking densities for mice Earlier Now for experiments Now for breeding

24. Stocking densities for rats Earlier Now for experiments Now for breeding

28. Exposure Environmental complexity Structured environment Outcome Environmental enrichment Terms used in App A • Environmental complexity • Structured environment • Environmental enrichment

29. Efficacy Safety Method Any refinement should • be scientifically validated • be truly beneficial to the animals • not detract from the scientific integrity

30. App A - part B - minimum enrichment - rodents • Mouse -> nesting material • Rat -> refuges, such as nesting boxes, pipes, nesting material • Hamster -> nesting material, climbing rack, refuge area (e.g. tube, hut), roughage and gnawing objects • Guinea-Pig-> refuges (tubes, shelters) should be provided. Sterilized wood sticks may be considered

31. App A text - rodents • Nesting materials should allow the rodents to manipulate the material and construct a nest • Nest boxes should be provided if insufficient nesting material is provided to build a complete, covered nest • Guinea-pigs should always be provided with manipulable materials such as hay for chewing and concealment • To increase environmental complexity the addition of some form of enclosure enrichment is strongly recommended

32. Statistical tables / EU

34. Other guidelines ? • Grant application may require compliance with other guidelines • US Grants • Quality systems • GLP • OECD, FDA, Japani • http://www.cfsan.fda.gov/~dms/opa-pt58.html • ISO • AAALAC (www.aaalac.org )

35. GLP – why and where? • GLP is applied in safety evaluation studies • GLP is part of quality thinking • Originally established to prevent falsifications in safety evaluation • New chemicals directive in Europe

36. What Do GLPs Do? • GLPs define a process. • GLPs will NOT assure good science.

37. GLP inspections • GLP guidelines • FDA • OECD • Japan • Each country has national inspection body • Unit announces that GLP is applied • National body carries out inspections • Inspector can come from FDA or OECD

38. GLP in laboratory animal units • Pharmaceutical companies • Contract laboratories • Very few universities and government research institutes • Other studies do not require • Other quality systems may be better

39. FDA Laboratory animal U.S. Federal Register, Nonclinical Laboratory Studies, GLP Regulations, U.S. FDA, Department of Health, Education and Welfare. Fed Reg 43:59986-60025. 1978. OECD Test system OECD Guidelines for testing of Chemicals, Appendix, Decision of the Council, OECD. OECD Test Guidelines, OECD Principles of GLP, C(81) 30 Final, pp 1-29 http://www.oecd.org/document/63/0,2340,en_2649_34381_2346175_1_1_1_1,00.html FDA - OECD

40. AAALAC • Association for Assessment and Accreditation of Laboratory Animal Care International, Inc. • Private nonprofit organization that accredits organizations using animals in research, teaching or testing. • Available worldwide.

41. Why Accreditation? • Accreditation…. • Represents quality of a laboratory animal facility. • Promotes scientific validity of research results. • Provides a confidential peer-review process. • Impresses funding sources and research partners.

42. ISO • International Organization for Standardization (ISO) • ISO is a network of the national standards institutes of 148 countries, on the basis of one member per country, with a Central Secretariat in Geneva, Switzerland, that coordinates the system. • Non-governmental • Members are government agencies, institutes, and private entities (e.g., associations, trade partnerships)

43. ISO Practice Standards • ISO 9000 – Systematized Quality Management • Management system refers managing business processes or activities in order that the products or services produced meet the objectives desired, such as: • satisfying the customer's quality requirements • complying with regulations • meeting environmental objectives • Management system standards refers to all those features of a product (or service) which are required by the customer.

44. ISO 9000 for Animal Research • Laboratory animal diet manufacturers and dealers • Microbiology of animal feedstuffs • Composition of animal feedstuffs • (numerous ISO 9000 standards on feedstuffs) • Animal Experimentation • ISO 10993-2:1992 Biological evaluation of medical devices - Part 2: Animal welfare requirement • Specifies minimum requirements for the use of animals in biological testing. • Establishes guidelines which allow the scientist to respect life in general, to reduce the number of animal experiments and the number of animals used in experiments, to minimize suffering and maintain the quality of life of the animals used in the experiments. • Applies to the experimentation performed on vertebrates.

46. Future Chemicals Policy of the EU -A challenge and an opportunity for alternative methods • Up to 30100 existing chemicals that are currently marketed, but have not been tested so far • Appropriate alternative methods will be used as much as possible for the safety evaluation of these chemicals