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International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary (2012)

Chapter: 7 Core Principles for the Care and Use of Animals in Research

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Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
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7

Core Principles for the Care and Use of Animals in Research

In this session, government, industry, and other animal research regulation stakeholders discussed the feasibility of developing core principles governing the use of animals in research (key points and overlapping core principles are summarized at the end of the chapter in Box 7-3). To start the discussion, Richard Nakamura, session chair and then scientific director of the National Institute of Mental Health, presented his personal perspective on the use of animals and animal welfare.

BALANCING SCIENTIFIC PROGRESS AND ANIMAL WELFARE

The goal of biomedical research is to understand living systems, with a particular focus on human biology and human disorders, Nakamura said. Scientists can learn much about the principles of human biology and behavior from animal models and use discoveries in human biology to help understand other animals. Animals are studied instead of humans in many situations where manipulating humans is not possible or acceptable. The use and sacrifice of these animals bred for research might be considered an acceptable ethical cost if there is appropriate consideration for their welfare in life. A key welfare consideration for animals in research, Nakamura said, is to minimize pain and distress and improve overall well-being.

The ethical challenge to conducting animal research is balancing the gains in scientific knowledge with the costs to animals, especially in terms of pain and distress. While there is no satisfactory calculus for doing this, scientists and others have tried to reach an acceptable balance by using approaches such as the 3Rs (replacement, refinement, and reduction),

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

Nakamura said. This, however, may have the counterproductive effect of limiting scientific gains from studies while increasing the costs. Because many medical needs remain unmet and much needs to be learned about living systems and disorders, Nakamura said the growth of welfare considerations and regulations must be constrained to allow some proportionality to the world outside of research (e.g., animals used for food, organisms displaced by humans or killed as pests). Nakamura suggested that animal welfare should not be considered in isolation from scientific goals or the larger needs of society.

The 3Rs are used when considering approval of animal research studies. However, the 3Rs are not a core principle, because as a core principle the 3Rs, specifically the principle of replacement, would translate into a goal to end animal research, Nakamura observed. If people are not ready to apply this to the world outside research, including the eating of meat or killing of pests, it should not be a core principle in research, Nakamura opined.

The key principle of animal regulation in research might be finding a balance among scientific progress, animal welfare, and cost effectiveness that is better than, yet proportionate to, the larger treatment of animals by humans, Nakamura concluded.

EUROPEAN REGULATORY PERSPECTIVE

Judy MacArthur Clark of the UK Home Office discussed core principles and considerations from a European regulatory perspective. She reiterated that a goal of regulatory balance might be to provide the public with confidence that animals will be appropriately protected and that science will not be inhibited from discovering solutions to many global health problems (see Chapter 2). While public opinion polls on animal research informed the development of the directive, MacArthur Clark noted that there is little direct support in the directive of high-quality science in Europe.

Core Principles

According to MacArthur Clark, three basic core systems are necessary in animal research regulations: a system of authorization of people, places, and projects; ethical, impartial, and independent evaluation of projects based on a cost-benefit balance; and impartial and independent verification of compliance involving some form of inspection.

MacArthur Clark referred participants to Chapter 7.8 of the World Organisation for Animal Health (OIE) Terrestrial Animal Health Code, which provides basic core principles of a regulatory system framework for use of animals (OIE, 2011). Per this code, components of the systems described above would include implementation of the 3Rs, evidence of

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

training and competence of individuals (ethical, legal, and specific skills), provision of veterinary care, viable sources of animals and transport, and inspection of facilities.

There are consequences of applying core principles, MacArthur Clark suggested. First, some proposals may not be considered justifiable. They may, for example, involve long-lasting severe pain that cannot be alleviated or the cost-benefit assessment may not balance. Second, bureaucracy may become part of the evaluation of “marginal” projects. When challenged with a difficult decision, assessors ask more and more questions, resulting in what is sometimes called “paralysis of analysis.” Eventually, either the project is approved or the applicant gives up. If the project is approved, it is often on the basis that the work will be heavily monitored, MacArthur Clark noted. This process occurs equally in different models of governance (both the U.S. self-regulated Institutional Animal Care and Use Committee [IACUC] model and the European Union [EU] centralized Competent Authority).

Project Authorization Without Bureaucracy

MacArthur Clark raised the concept of “thin slicing” as an approach to making project authorization decisions. The concept is that spontaneous decisions are often as good as, or even better than, carefully planned and considered ones. The goal would be to make better decisions early on and foster compliance without bureaucracy. Another goal would be to identify marginal projects as early as possible and develop a separate process to review them and facilitate faster decisions. Reject the project and provide reasons, or accept the marginal project and build in milestones that are not overly restrictive, MacArthur Clark asserted. Once the decision to authorize has been made, it might be easier to focus on other aspects of approval, such as implementing the 3Rs. MacArthur Clark noted that efficient processing could reduce costs while supporting science and welfare.

Training and Competence

From the outset, the European commission declared its intention that there should be free movement of staff, including scientists, veterinarians, and animal care staff, throughout Europe. This means a need for common training standards. Training, however, does not necessarily equate with competence, MacArthur Clark noted. Individuals acquire competence through their work, so in addition to training and supervision, a mechanism to maintain competency could be included.

Another core principle could be the delivery of appropriate and relevant training that is acceptable and palatable to those who receive it.

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

Such a core training program could cover legislation, ethics, and the 3Rs. Recall that each EU member state has its own legislation, so even though staff can move freely among countries, they might need to understand the local legislation and how it is implemented. There could also be modules of additional training appropriate to the particular needs of the individual and continued training to maintain developing skills.

Harmonization and Consistency

Harmonization is a key aim of the EU directive, MacArthur Clark noted. Portions of the directive involve significant changes for some of the 27 EU member states. Areas of harmonization across the member states might include the types of animals that are protected; minimum housing standards; project authorization and severity classification; accountability for training and competence requirements; animal welfare body and a designated veterinarian; and some form of inspectorate for compliance. Member states will be allowed to apply higher standards, as long as they do not interfere with market competitiveness. Consistency is very important, and could be considered a core principle, MacArthur Clark noted. Harmonization is a step in the right direction, but is not likely to achieve total consistency, in large part because each member state has its own legal system. The ability for member states to apply different standards may impact harmonization of regulations. The extent of harmonization might not be known until all member states transpose the directive in 2013.

In closing, MacArthur Clark quoted from the directive:

This Directive represents an important step toward achieving the final goal of full replacement of procedures on live animals for scientific and educational purposes as soon as it is scientifically possible to do so. (European Union, 2010)

This “full replacement” is a goal of the directive and would lead to the discontinuation of animal research. MacArthur Clark stressed that it is important that scientists in Europe continue to speak up about the importance of animals in biomedical research.

U.S. REGULATORY PERSPECTIVE

Patricia Brown, director of the Office of Laboratory Animal Welfare at the National Institutes of Health (NIH), discussed U.S. government principles as they apply to research funded by the NIH. The U.S. system is different in that NIH-supported research is a partnership with the grantee institutions. Brown noted that both sides share a mutual need for compli-

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

ance with the laws, regulations, and policies that apply to animal research. Each partner has responsibilities and obligations as stewards of public funds. Institutional self-governance is the foundation of the Public Health Service (PHS) Policy, and all research institutions receiving funds within the United States must agree to follow the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training.1

U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training

Brown reviewed the aspects of the three primary entities involved in oversight of animal use in the United States.2 The PHS Policy requires an institutional program of animal care and use, with an IACUC appointed by the chief executive officer. There must be an institutional official who is responsible for the general administration of the program, including the provision of resources to support the animal care and use program. The IACUC and the attending veterinarian must report to an institutional official. Institutional self-regulation is based on the PHS Policy, the Guide for the Care and Use of Laboratory Animals, and if there are regulated species in the program, the Animal Welfare Act regulations.

The U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training were formulated in 1985, and formed the foundation for the Animal Welfare Act Amendments and the PHS Policy. They are basic tenets of animal care and use, Brown said. The expectation of the PHS Policy is that IACUCs use the U.S. Government Principles as the basis for protocol review. Brown highlighted several principles that illustrate where the United States is in terms of animal care and use (Box 7-1).

International Guiding Principles for Biomedical Research Involving Animals

The International Guiding Principles for Biomedical Research Involving Animals were issued in 19853 and were the basis for the development of the U.S. Government Principles. They were developed by the Council of International Organizations of Medical Sciences (CIOMS) and are endorsed by both the European Medical Research Council (EMRC) and the World Health Organization (WHO).

image

1 See http://www.grants.nih.gov/grants/olaw/references/phspol.htm#USGovPrinciples.

2 See discussion by Bennett in Chapter 2 for further detail on the PHS Policy and the Animal Welfare Act.

3 See http://www.cioms.ch/publications/guidelines/1985_texts_of_guidelines.htm.

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

BOX 7-1
Excerpts from the U.S. Principles

Principle II Rationale: “Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society.”

Principle III Justification: “The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered.”

Principle IV Minimize Pain and Distress: “Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals.”

Principle VI Humane Endpoints: “Animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure or, if appropriate, during the procedure.”

Principle VIII Training: “Investigators and other personnel shall be appropriately qualified and experienced for conducting procedures on living animals. Adequate arrangements shall be made for their in-service training, including the proper and humane care and use of laboratory animals.”

Principle IX Ethical Review: “Where exceptions are required in relation to the provisions of these Principles, the decisions should not rest with the investiga-tors directly concerned but should be made . . . by an appropriate review group such as an IACUC. Such exceptions should not be made solely for the purpose of teaching or demonstration.”

SOURCES: Brown presentation, U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training.

More recently, the International Council for Laboratory Animal Science (ICLAS) and CIOMS convened a working group to revise and update the International Guiding Principles. A draft was released for comment in April 2011 and the final draft is expected in 2012.4 Among the proposed revisions, the draft now states that the use of animals is a privilege that carries with it a moral obligation. Brown quoted from the draft revision

image

4 See http://www.ora.msu.edu/ICLAS/topics.html.

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

to Principle II: “Individuals working with animals have an obligation to demonstrate respect for animals, to be responsible and accountable for their decisions and actions pertaining to animal welfare, care, and use, and to ensure that the highest standards of scientific integrity prevail.” The 3Rs are now specifically mentioned in Principle III whereas previously they were only implied. Principle VII more fully addresses pain and distress in animals and calls for consultation with a veterinarian. Principle VIII calls for establishing endpoints before animal use begins, with assessment throughout the course of the study. Finally, Brown noted that the idea of risk-benefit analysis for animal use, balancing the benefits derived from the research with the potential for pain and distress experienced by an animal, is now addressed in the draft Principle X.

PHARMACEUTICAL PERSPECTIVE

Margaret Landi, vice president of Global Laboratory Animal Science and chief of Animal Welfare and Veterinary Medicine for GlaxoSmithKline (GSK) Pharmaceuticals,5 noted that a challenge for multinational corporations is developing an animal care system that meets the required standards, but that also recognizes the global diversity of rules, regulations, policies, and guidance. She also pointed out that while pharmaceutical companies have extensive internal capabilities, they also have numerous external collaborations, contracts, and alliances.

Landi noted that developing global guidance on animal care and use can be hampered by a lack of consensus on what “best practice” is. Lack of regulatory harmony, evolving regulations and guidelines, and cultural differences can add to the challenge.

Landi questioned whether variations in rules, regulations, policies, and practices really result in a substantive difference in animal care, and suggested that alignment of principles can be achieved independent of differing practices.

GSK, Landi said, is aligned to follow the guiding principles:

•   Performance standards: Identify clear accountability, responsibility, and desired outcome. Standards describe the desired outcome, but allow flexibility in achieving the outcome.

•   Professional judgment: The ability of a person to recommend a course of action due to specialized knowledge and/or skills.

•   Harmonized (consistent) approaches or outcomes: For example, one consistent approach is a program of veterinary care; however,

image

5 GSK is headquartered in the United Kingdom, with facilities in North America, Spain, France, China, and Singapore.

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

    what that program looks like may differ at each company site because of the availability of drugs in different countries, or their use of different models or species at different sites. Standard operating procedures foster consistency.

Ultimately, the goal would be to articulate a set of core principles for care of animals within and for the institution. Landi stressed that difference in practices do not necessarily equate to difference in care or “dual standards.”

As noted above, multinational companies can influence animal care and use practices in regions where they conduct research. Landi shared the GSK core principles for the use of animals in research (Box 7-2), which apply to both in-house research and external collaborations, regardless of location.

DEVELOPING CORE PRINCIPLES

Timo Nevalainen, from the National Research Council’s Institute of Laboratory Animal Research (ILAR) Council, said there are several potential target populations for core principles of animal research: specific fields of research (e.g., neuroscience), institutions, regulators, and the general

BOX 7-2
Core Principles for GlaxoSmithKline Animal Work

At a minimum the following Core Principles must be followed:

•   Access to species-appropriate food and water.

•   Access to species-specific housing, including appropriate temperature and humidity.

•   Access to humane care and a program of veterinary care.

•   Animal housing that minimizes the development of abnormal behaviors.

•   Adherence to principles of replacement, refinement, and reduction in the de-sign of in vivo or ex vivo studies.

•   Review of study design and purpose by institutional ethical review panel.

•   Commitment to minimizing pain and distress to the animal during in vivo and ex vivo studies.

•   Work performed by staff trained to conduct the procedures for which they are responsible.

•   Documented and verified training.

•   Processes in place to minimize animal use.

SOURCES: Landi and Wang presentations.

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

public. Nevalainen raised several questions for consideration. First, should the scientific community be proactive and establish core principles for the regulators? One example of core principles of animal welfare developed by scientists and referred to by government policy makers is the ILAR Guide for the Care and Use of Laboratory Animals (NRC, 2010).

Next, how specific should core principles or regulations be? The EU animal care and housing regulations, for example, are species specific, but do not go to the level of stocks and strains. Strains differ in many ways, such as how they react to environmental enrichment items placed in the cage. Optimally, Nevalainen said, housing and care regulations or guidelines could be specific to the level of strains and stocks, but this may be unrealistic due to the vast number of different strains. In the EU directive, there is some division by type of research (e.g., basic, translational research, regulatory testing for quality, efficacy, and safety), but not by field.

Third, would regulations specific to neurosciences be helpful? Nevalainen noted that in 2003, ILAR issued Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (NRC, 2003).

Focusing on Refinement and Reduction

Nevalainen discussed a “2Rs” approach, seeking to maximize both refinement and reduction, but not replacement, to achieve less harm and better science. A 2Rs method could be scientifically validated, beneficial to the animals, and not detract from the scientific integrity. Even small changes to improve conditions for individual animals might have considerable impact overall, Nevalainen noted. For example, habituating animals to handling can reduce their anxiety and stress.

CORE PRINCIPLES FOR ANIMAL USE IN NEUROSCIENCE RESEARCH

During the discussion that followed the presentations, several panelists and participants observed that the core principles described above are generally applicable to all research areas and procedures involving animals. Specific recommendations or guidance on neuroscience procedures may be needed, but the core principles by which animal studies in neuroscience can be conducted might be the same as those for any discipline. Citing the GSK example discussed above, few participants noted that the basic principles of performance standards, professional judgment, and a harmonized approach or outcome is independent of the therapeutic area being investigated or the pathway being explored. It also was noted that with so many disciplines and research areas, it is unlikely that a directive or legislation could specifically address individual research areas (e.g., neuroscience).

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×

BOX 7-3
Summary of Session Points

•   Target populations for core principles of animal research may be specific fields of research, institutions, and regulators.

•   Considerations for animals in research could include

   o   Welfare: Minimize pain and distress and improve overall well-being.

   o   Regulatory balance: Deliver public confidence that

image  animals are appropriately protected.

image   science will not be inhibited from discovering much-needed solutions to global problems.

•   Overlapping core principles from presentations:

   o   Humane care: Minimizing pain and distress and improving overall well-being.

   o   Unbiased ethical evaluation of projects (balancing the cost-benefit ratio).

   o   Training and maintenance of a competent workforce.

   o   Adherence to principles of replacement, reduction, and refinement.

•   Alignment of principles could be achieved independent of differing practices.Difference in practice does not necessarily equate to difference in care or “dual standards.”

•   Although recommendations or guidance on neuroscience procedures may be needed, the core principles by which animal studies in neuroscience could be conducted might be the same as those for any discipline.

SOURCE: Individual panelists and participants.

Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
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Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
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Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 63
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 64
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 65
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 66
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 67
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 68
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
Page 69
Suggested Citation:"7 Core Principles for the Care and Use of Animals in Research." Institute of Medicine and National Research Council. 2012. International Animal Research Regulations: Impact on Neuroscience Research: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13322.
×
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Animals are widely used in neuroscience research to explore biological mechanisms of nervous system function, to identify the genetic basis of disease states, and to provide models of human disorders and diseases for the development of new treatments. To ensure the humane care and use of animals, numerous laws, policies, and regulations are in place governing the use of animals in research, and certain animal regulations have implications specific to neuroscience research.

To consider animal research regulations from a global perspective, the IOM Forum on Neuroscience and Nervous System Disorders, in collaboration with the National Research Council and the Institute for Laboratory Animal Research, held a workshop in Buckinghamshire, UK, July 26-27, 2011. The workshop brought together neuroscientists, legal scholars, administrators, and other key stakeholders to discuss current and emerging trends in animal regulations as they apply to the neurosciences. This document summarizes the workshop.

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