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Introduction and Overview
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Animals are widely used in neuroscience research to explore normal and abnormal 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. Numerous laws, policies, and regulations are in place governing the use of animals in research. These measures are intended to ensure the humane care and use of animals, including the implementation of practical steps to use the smallest number of animals necessary to achieve significant results while minimizing pain and distress. Many animal care and use issues are generic to all types of biomedical research; however, animal regulations have implications specific to neuroscience research.

To consider these issues from a global perspective, the Institute of Medicine Forum on Neuroscience and Nervous System Disorders, in collaboration with the National Research Council Committee on Science, Technology, and Law and the Institute for Laboratory Animal Research,

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1 This workshop was organized by an independent planning committee whose role was limited to identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Forums or the National Academies, and they should not be construed as reflecting any group consensus. Furthermore, although the current affiliations of speakers and participants are noted in the report, many qualified their comments as being based on personal experience over the course of a career and are not being presented formally on behalf of their organizations (unless specifically noted).



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1 Introduction and Overview1 Animals are widely used in neuroscience research to explore normal and abnormal biological mechanisms of nervous system function, to iden- tify the genetic basis of disease states, and to provide models of human disorders and diseases for the development of new treatments. Numerous laws, policies, and regulations are in place governing the use of animals in research. These measures are intended to ensure the humane care and use of animals, including the implementation of practical steps to use the smallest number of animals necessary to achieve significant results while minimiz- ing pain and distress. Many animal care and use issues are generic to all types of biomedical research; however, animal regulations have implications specific to neuroscience research. To consider these issues from a global perspective, the Institute of Medicine Forum on Neuroscience and Nervous System Disorders, in col- laboration with the National Research Council Committee on Science, Technology, and Law and the Institute for Laboratory Animal Research, 1 This workshop was organized by an independent planning committee whose role was limited to identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Forums or the National Academies, and they should not be construed as reflecting any group consensus. Furthermore, although the current affiliations of speakers and participants are noted in the report, many qualified their comments as being based on personal experience over the course of a career and are not being presented formally on behalf of their organizations (unless specifically noted). 1

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2 INTERNATIONAL ANIMAL RESEARCH REGULATIONS convened the workshop “U.S. and European Animal Research Regula- tions: Impact on Neuroscience Research.” Held at the Kavli Royal Society International Centre in Buckinghamshire, UK, on 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. As outlined by co-chairs Colin Blakemore, professor of neuroscience at the University of Oxford, and Arthur Sussman, of the University of Chicago Law School, the work- shop was designed to • identify and discuss current international animal use regulations; • examine the implications of current policies on the research enter- prise, including the impact of disparate policies; • discuss developments in law school curriculums, animal law prac- tice, and activity in the courts that may affect the use of animals in research; • explore the reasons for the establishment of specific regulations; and • discuss opportunities for harmonization of regulations and/or the development of global core principles. ANIMAL RESEARCH IN THE NEUROSCIENCES: INTRODUCTION BY COLIN BLAKEMORE As background for the workshop discussions, Blakemore highlighted some of the current issues surrounding the use of animals in neuroscience research. In research involving animals, he acknowledged a necessary ten- sion between the desire to benefit from the advances in knowledge that accrue from studies in animals and the desire to avoid deliberate harm to the animals. Opinions on the use of animals in research are polarized. Re- searchers, clinicians, and institutions that support animal research, along with a portion of the general public, accept its importance for progress in medicine. The principal argument for using animals in biomedical research states that it is ethically more acceptable than neglecting the suffering of the sick (human or animal, as animal research also benefits animals). Some individuals and organizations, however, oppose animal research on ethical grounds; they contend that humans should not benefit from animal suf- fering (a deontological argument: actions are either intrinsically right or wrong, regardless of the consequences). Some challenge the validity of ani- mal models and the unreliability of treatments developed through the study of non-human species (a utilitarian argument: the correct action is the one that maximizes the overall good, specifically considering the consequences). Others claim that alternative methods to animal use are already available or could be available with increased efforts to develop them.

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3 INTRODUCTION AND OVERVIEW BOX 1-1 Particular Issues Surrounding Animal Use in Neuroscience • odels of nervous system disease may include behavioral and cognitive phe- M notypes that have the potential to result in suffering: o esearch on conditions such as addiction, depression, anxiety, and fear R may be problematic. • ain, which is normally avoided in the design of experiments, is an important P topic of study. • odification of sensory experience may be considered a form of suffering. M • on-human primate use raises concerns due to costs and public perception. N • esearch may involve invasive methodology, restriction or control of food or R water intake, and/or prolonged or repetitive procedures. SOURCE: Blakemore presentation. Animal Use Issues Specific to Neuroscience Blakemore highlighted several issues associated with the use of animals that are specific to neuroscience research, such as the use of non-human primates, pain as a topic of study, and the use of invasive methodologies (Box 1-1). Non-human primates, due to their close phylogenetic relatedness to humans, make them the preferred species to study issues such as fine motor control, high-level cognitive functions, and decision making. This close evolutionary proximity to humans increases scrutiny of the use of non-human primates and raises special concerns, including public attitude about their use, supply issues, and costs. The 2006 Weatherall Report2 concluded that there is scientific justification for the carefully regulated use of non-human primates when there is no other way to address clearly defined questions, including those raised by certain neuroscience studies (MRC, 2006). Another issue is the use of genetically modified animals. Modification of genes that regulate the nervous system and neurologic development can produce a particular phenotype with behavioral and cognitive consequences. The impact of the phenotype itself, in terms of suffering, must be taken into account even before considering the impact of procedures to be carried out on genetically modified animals. The introduction of human genetic mate- 2 Note that a comprehensive 5-year follow-up review of the quality and impact of primate research has been published. Review of Research Using Non-Human Primates: Report of a Panel Chaired by Professor Sir Patrick Bateson FRS is available at http://www.mrc.ac.uk/ Utilities/Documentrecord/index.htm?d=MRC008083.

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4 INTERNATIONAL ANIMAL RESEARCH REGULATIONS rial into animals is another topic of much discussion. For example, a variety of mouse models for Huntington’s disease, a neurodegenerative disorder, incorporate a portion of the human Huntington gene. Blakemore referred participants to an Academy of Medical Sciences (UK) report on the use of animals containing human genetic material that was released the same week as the workshop (AMS, 2011). Neuroimaging is increasingly being used in animal studies. While im- aging is noninvasive, such studies are generally longitudinal, involving repetitive procedures. It is not always clear, Blakemore noted, that imaging is preferable to invasive methodologies. A Framework for Research on Animals Blakemore suggested there is a strong need for a regulatory framework that is ethically secure, consistent, legally strong, and defensible but not so overly burdensome that it impedes scientific progress. Such a framework might include strict requirements for and a commitment to high-quality welfare and good husbandry; good recordkeeping; transparency and ac- countability; provisions for public engagement; certification of researchers so that their skills are documented and controlled; and a system for ap- proval of individual projects based on cost-benefit analysis. Cost-benefit analysis, while theoretically straightforward, is challenging to apply to animal research. By definition, research involves the unknown, and potential future benefits cannot definitively be known in advance. In contrast, the immediate costs relative to the suffering of animals can be determined before and during animal experiments. Therefore, individuals continually weigh potential benefits against definite costs, Blakemore said. A 1999 poll published in the New Scientist found that 83 percent of those surveyed would support research on mice to study childhood leuke- mia if there were no pain involved (Aldhous et al., 1999). If pain or death was involved, 63 and 69 percent respectively still supported the research. In a 2000 poll by the UK-based Ipsos Market and Opinion Research Inter- national (Ipsos MORI) firm, only 32 percent of those surveyed supported research on animals in general if there were no alternatives, but when the same group was asked whether they would accept the use of animals for medical research if there was no unnecessary suffering, 84 percent agreed (Ipsos MORI, 2000). This, Blakemore said, shows that people are perform- ing quite complex personal calculations and shifting their views depending on the perceived costs and benefits. Opinion has changed dramatically and progressively over the past 10 years in the United Kingdom, Blakemore noted. The greatest change in opinion was between 1999 and 2004. Since 2004, polls conducted by Ipsos MORI have consistently shown that 87 percent of the public conditionally

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5 INTRODUCTION AND OVERVIEW accepts the use of animals in research for medical benefit, if suffering is minimized and/or there is no alternative to the use of animals (Ipsos MORI, 2010). A key component of the shifting views toward animal research in the United Kingdom has been due to increased openness and public engage- ment. It is important, Blakemore stressed, that scientists themselves speak out to win the trust of the public, politicians, and the media. Ipsos MORI polls show that the majority of the public trusts scientists to tell them the truth, yet scientists do not normally engage with the public to provide in- formation about their research (Ipsos MORI, 2008). Blakemore noted that in recent years, against the backdrop of political support, including new legislation to prevent violence, there has been an increase in the willing- ness of researchers to talk openly about their work. In addition, there was growing public support of animal research with groups such as Pro-Test3 holding rallies in support of animal testing in medical research. In reports of advances resulting from research, more institutions are openly identifying the animal species used in the research, which, Blakemore noted, has had a positive impact on public opinion. ORGANIZATION OF THE WORKSHOP AND REPORT Following the overview of issues presented by Blakemore, the work- shop considered current and emerging international regulations governing animal research and the impact of legal trends, including animal rights laws, Freedom of Information requests, and state “sunshine laws,” on the use of animals in research (Chapters 2 and 3). The next session of the workshop focused on the implications of these laws, regulations, and policies for neuroscience research, and considered case studies applying the “3Rs” (re- placement, refinement, and reduction) to neuroscience research (Chapters 4 and 5). The final portion of the workshop focused on engaging the public, politicians, and the media in animal research issues, and developing core principles for regulating the use of animals in research (Chapters 6 and 7). In the closing session, session chairs identified what they viewed as the key points that emerged (Chapter 8 and summarized below). Highlights of Workshop Sessions Session chairs noted key points that emerged during workshop presen- tations and discussions: 3 In February 2011, 5 years after it formed, Pro-Test wound up its UK operations because it had successfully met its goals. See http://www.pro-test.org.uk/.

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6 INTERNATIONAL ANIMAL RESEARCH REGULATIONS • Regulatory Harmonization (Session I): Animal research regulations in the United States and the European Union are more similar than different. International collaborations are helping to influence new regulations, raise standards in emerging regions (e.g., Asia, South America), and contribute to global harmonization. • Administrative Burden (Sessions I and III): Regulatory systems have a variety of costs, including financial costs, the costs of increased oversight for regulators, and the costs of lost research time for scientists. Appropriate measures of the success of animal welfare regulations can be useful because it is unclear whether increased costs and burdens result in improved animal welfare. • Legal Trends (Session II): The effect of increased attention on ani- mal rights laws is unclear. Freedom of Information requests and state sunshine laws are used in the United States to allow the public to access detailed information about the use of animals in research. The effect of these laws on animal research is not yet known. • Non-Human Primates in Neuroscience (Session III): Non-human primates continue to be used in biomedical research, including neuroscience research. Such studies complement in vitro studies, in silico modeling, human brain imaging, and parallel investigations in rodents and other species. • Data Sharing (Session IV): Systematic reviews of preclinical data could potentially support the 3Rs (replacement, refinement, and reduction), improve the quality and value of animal studies, and better inform clinical trials. Research might benefit if pre- clinical animal data are more accessible, including negative data, primary data, and precompetitive data. • Engaging the Public (Session V): Communication between the sci- entific community and the public, the media, and policy makers about the role and welfare of animals in neuroscience research is critical. In some countries, public engagement and education can impact the public view of the use of animals in research. • Aligning Core Principles to Achieve Consistent Animal Care and Use Outcomes (Sessions I and VI): Animal research regulations might benefit from a careful balance of quality science, animal welfare, and public confidence. Animal welfare can be considered together with scientific goals and the larger needs of society. Align- ment of animal research principles can be achieved independent of differing policies or practices. Core principles governing how animal studies might be conducted are the same for any discipline, including neuroscience.