Chimpanzees in Biomedical and Behavioral Research Assessing the Necessity (2011) / Chapter Skim
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Specifically, the committee was asked to review the current use of chimpanzees for biomedical and behavioral research and: • Explore contemporary and anticipated biomedical research ques tions to determine if chimpanzees are or will be necessary for re search discoveries and to determine the safety and efficacy of new prevention or treatment strategies. If biomedical research questions are identified: Describe the unique biological/immunological characteris o tics of the chimpanzee that make it the necessary animal model for use in the types of research.
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The committee agrees that cost should not be a consideration. However, the committee feels strongly that any assessment of the necessity for using chimpanzees as an animal model in research raises ethical issues, and any analysis of necessity must take these ethical issues into account.
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However, based on limited publications and public non-proprietary information, it is clear that the private sector is using the chimpanzee model, especially in areas of drug safety, efficacy, and pharmacokinetics. Although its use appears to be limited and decreasing over the 10 years examined by the committee, the chimpanzee model is being employed by industry in the development of antiviral drugs and vaccines for hepatitis B and C as well as in the development of monoclonal antibody therapeutics.
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Having reviewed and analyzed contemporary and anticipated biomedical and behavioral research, the committee concludes that: • No uniform set of criteria is currently used to assess the necessi ty of the chimpanzee in NIH-funded biomedical and behavioral research. • While the chimpanzee has been a valuable animal model in past research, most current use of chimpanzees for biomedical re search is unnecessary, based on the criteria established by the committee, except potentially for two current research uses: Development of future monoclonal antibody therapies will o not require the chimpanzee, due to currently available tech nologies.
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Specifi cally, the committee could not reach agreement on whether a preclinical challenge study using the chimpanzee model was necessary and if or how much the chimpanzee model would ac celerate or improve prophylactic HCV vaccine development. • The present trajectory indicates a decreasing scientific need for chimpanzee studies due to the emergence of non-chimpanzee models and technologies.
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Comparative genomics and behavioral research using stored samples are exempt from these criteria. The criteria set forth in the report are intended to guide not only current research policy, but also decisions regarding potential use of the chimpanzee model for future research.
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7 SUMMARY and future research projects would be strengthened and the process made more credible by establishing an independent oversight committee that builds on the Interagency Animal Model Committee and uses the recommended criteria.
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Keeling Center for Comparative Medicine and Research of the University of Texas MD Anderson Cancer Center, and the Yerkes National Primate Research Center at Emory University. Much of the research supported by the first three facilities is focused on proof-of-principle studies for hepatitis C vaccines and therapies, with a lesser amount of research devoted to assessing safety and efficacy of large molecules such as monoclonal antibodies (Watson, 2011)
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. Given the life expectancy of chimpanzees in captivity, it is estimated that by 2037 the federally funded chimpanzee research population will "largely cease to exist" in the United States (Cohen, 2007a; NCRR, 2007)
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TABLE 2 Ages of Chimpanzees Available in the United States for Researcha,b < 10 10 to 20 21 to 30 31 to 40 41+ Alamogordo Primate Facility 0 24 99 40 13 Michale E Keeling Center for 0 53 67 27 29 Comparative Medicine and Research New Iberia Research Center 100 134 84 6 23 Southwest National Primate 4 61 69 13 5 Research Center 1 29 30 12 13 Yerkes National Primate Research Centerc 105 301 349 98 83 TOTAL a Ages of chimpanzees as of October 2011 (Abee, 2011c; Else, 2011; Lammey, 2011; Landry, 2011; Langford, 2011)
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. As the NIH's 10-year contract with Charles River Laboratories to manage the Alamogordo Primate Facility neared its completion, the NIH stated that consolidating the chimpanzees into a single colony at the Southwest National Primate Research Center facility would save $2 million a year and make the animals available for future research (HHS, 2011a; Korte, 2010)
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If biomedical research questions are identified: Describe the unique biological/immunological characteristics of the o chimpanzee that make it the necessary animal model for use in the types of research. Provide recommendations for any new or revised scientific parame o ters to guide how and when to use these animals for research.
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However, it recognizes that any assessment of the necessity for using chimpanzees as an animal model in research raises ethical issues, and any analysis must take these ethical issues into account. The committee's view is that the chimpanzee's genetic proximity to humans and the resulting biological and behavioral characteristics not only make it a uniquely valuable species for certain types of research, but also demand a greater justification for their use in research than is the case with other animals.
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The objectives of the information-gathering sessions were to: • Obtain background data on the current use of chimpanzees in bi omedical and behavioral research; • Explore potential alternative models to chimpanzees; and • Seek public comment about the scientific need for chimpanzees in biomedical and behavioral research. In addition, during the course of the study the committee solicited and received over 5,700 comments via the Internet.
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; 6 As will be discussed later in the "Summary of Chimpanzee Research" section, the committee did find that investigators from countries outside the United States have supported limited use of chimpanzees in the United States.
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, further details in the new directive (European Union, 2010) stipulate that in order for a member state to authorize a study involving great apes the member state must obtain approval from the European Commission in consultation with a relevant Committee (European Communities and Office for Official Publications, 1986)
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The Animal Welfare Act stipulates that the Director-General must not give ap proval unless he or she is satisfied that the use of the non-human hominid in that research, testing, or teaching either (1) it is in the best interests of the non-human hominid; or (2)
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While such animals have never been used under the 1986 Act, the government decided that it would be unethical to use such animals for re search purposes due to their cognitive and behavioral characteristics and quali ties. In the Home Office "News Re lease" accompanying the publication of the Interim Report, Lord Williams is quoted as follows: "Although these proposed bans cannot be statutory un der current legislation, I do not foresee any circumstances in which the Home Office would issue licenses in such cases" (Reynolds and CEECE, 2001; Secretary of State for the Home Department and Parliament of the United Kingdom, 1998)
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A summary of this analysis is presented in the following section. Analysis of Federally Supported Research The largest percentage of federally funded chimpanzee research over the past 10 years has been supported by the NIH, with additional projects funded by other federal agencies, including the Food and Drug Administration (FDA)
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TABLE 4 Number of Projects and Types of Funding per Disease Area: 2001-2010 Types of Funding R1 P2 N3 Z4 U5 Projects Hepatitis 44 14 0 0 25 5 Comparative genomics 13 11 1 0 0 1 Neuroscience 11 7 1 0 3 0 AIDS/HIV 9 8 0 0 1 0 Behavioral 7 7 0 0 0 0 Malaria 2 2 0 0 0 0 Immunology 2 2 0 0 0 0 Other 11 2 0 0 8 1 Colony maintenance 11 2 1 3 0 5 110 55 3 3 37 12 TOTAL 1 Research project grants. 2 Program project/research center grants.
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While the CDC no longer funds chimpanzee research, previous research has included hepatitis vaccine development. Beyond these agencies, the committee did not find any evidence of current chimpanzee work funded by other federal agencies, including the Department of Defense.
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However, based on limited publications and public non-proprietary information, it is clear that the private sector is accessing both the whole-animal model as well as stored biological samples (Carroll et al., 2009; Olsen et al., 2011)
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. While the committee was able to determine that both U.S.- and nonU.S.-based companies conduct limited chimpanzee research in the United States, it was not able to determine if companies independently house chimpanzees, how often the animals are used, and what compounds, if any, currently on the market or in human clinical trials were tested using this model.
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. In preclinical safety evaluation guidance, the CHMP defines a relevant species as "one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies)
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For all projects, the investigator's institutional animal care and use committee must approve the study protocol. In addition, the NIH Interagency Animal Model Committee must determine that the chimpanzee is the appropriate model for any project approved by a Chimpanzee Research Center that will use an NIH-owned chimpanzee (Bennett et al., 1995; DHS, 2007)
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The animals used in the proposed research must be maintained either in ethologically appropriate physical and social environ ments or in natural habitats. Ethologically Appropriate Physical and Social Environments Chimpanzee research should be permitted only on animals maintained in an ethologically appropriate physical and social environment or in natural habitats.
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All future studies should conform to the need for ethologically appropriate housing. Criteria to Assess the Necessity of the Chimpanzee for Biomedical Research As previously discussed, the chimpanzee raises unique considerations due to the ethical issues that arise as a result of the chimpanzee's genetic proximity to human beings.
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When assessing the necessity of the chimpanzee as a model, a more stringent process of eliminating ("deselecting") models of species less closely related to human beings should be required, similar to the process adopted by many countries in Europe (European Union, 2010)
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Other species -- such as monkeys, dogs, mini-pigs, and rodents, including transgenic and chimeric animals modified to mimic specific disease attributes -- must be deselected by determining that ADME profiles do not adequately match the profile generated by humans. Other species -- such as monkeys, dogs, mini-pigs, and rodents, including transgenic animals modified to mimic specific disease attributes -- must be deselected prior to determining that pharmacokinetic data (bioavailability, distri bution, or metabolic data)
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Immunogenicity Other species -- such as monkeys, dogs, mini-pigs, and rodents, including transgenic animals modified to mimic specific disease attributes -- must be dese lected if there is a scientifically based expectation for significant antigenicity for test articles not intended to be immunogenic. Vaccine research and develop ment requires an appropriate immunogenic response to the vaccine and/or to an adjuvant, which in some cases may necessitate the use of chimpanzees, if human experiments cannot be ethically performed (see below)
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These standards and additional protective restrictions mean that more research may take place using animal models than would otherwise be the case if additional risks to human subjects were deemed acceptable. Assessing Advancements to Treat Potentially Life-Threatening or Debilitating Conditions The standard non-rodent and NHP species may be deselected if it can be demonstrated that forgoing the use of chimpanzees for the research in question will significantly slow or prevent important advancements to treat potentially life-threatening conditions in humans or debilitating conditions that have a significant impact on a person's health, and thus slow or prevent important advancements for the public's health.
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Therefore, based on the principles previously defined, the committee developed the following criteria to guide its assessment of NIH-funded comparative genomics and behavioral research using the chimpanzee: 1. Studies provide otherwise unattainable insight into comparative genomics, normal and abnormal behavior, mental health, emotion, or cognition; and 2.
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This is especially true inasmuch as other animals, including other nonhuman primates, have been used to model these disorders. It is for the forgoing reasons that the majority of comparative genomics or behavioral studies using chimpanzees have focused on continua of behavioral and developmental phenomena from normal to abnormal, taking advantage of similarities in behavioral and brain complexity that mark chimpanzees and humans apart from virtually all other species.
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The committee assessed the following research areas: monoclonal antibodies, RSV, hepatitis C virus (HCV) antiviral drug development, HCV vaccine development, comparative genomics, cognition, and neurobehavioral function.
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. Köhler and Milstein developed robust cell culture methods to immortalize individual B cells and thus create clonal cell lines that produce one type of antibody, hence the term "monoclonal antibody." The ability to produce essentially unlimited supplies of a unique monoclonal antibody provides a powerful technological platform for the generation and use of a wide range of affinity reagents in a myriad of applications.
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The chimpanzee/human chimeric monoclonal antibodies produced in these manners have proven to be effective in both in vitro and in vivo assays to neutralize infectious viruses or to block the action of bacterial toxins. Criteria 1: Alternative Models It is possible to develop monoclonal antibodies with these types of binding specificities in species other than chimpanzees.
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Safety Testing of Monoclonal Antibody Therapies Monoclonal antibodies used in treatment of human disease bind to a carefully chosen antigen, often a protein, and through this interaction interfere with a cellular process that underlies disease development. Therapeutic monoclonal antibodies have become important front-line treatments for a wide range of human diseases and clinical procedures,
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Criteria 1: Alternative Models When developing monoclonal antibody therapies for human clinical use, it is important to determine what, if any, unexpected effects these treatments might provoke in humans (see ICH Harmonized Tripartite Guideline, 2011, for regulatory practices and Chapman et al., 2009, and Tabrizi et al., 2009, for discussions of the process and needs for preclinical safety testing)
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Two other approaches to lower the need for chimpanzees in safety testing rely on changes in how monoclonal antibodies are chosen for potential clinical development. As mentioned above, the development of
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While surrogate antibodies may not have all of the best properties of a true clinical development candidate, studying the responses to multiple agents can increase the confidence of the potential safety profiles of monoclonal antibodies prior to introduction into humans. Criteria 2: Testing on Human Subjects A fourth approach that may lower the dependence on safety testing in the chimpanzee relies on microdosing in humans.
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Not all companies and few academic laboratories have fully adopted monoclonal antibody approaches, such as recombinant antibody production, that allow the selection of monoclonal antibody therapeutic agents that meet these more defined criteria. Therefore, there may be a limited number of monoclonal antibodies currently in the development pipeline that may require the continued use of chimpanzees.
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. Palivizumab, the only approved prophylactic RSV drug, is a humanized monoclonal antibody that is administered intramuscularly every 30 days during RSV season.
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Therefore, animal models of human RSV (hRSV) provide an important link between mechanistic cell culture research and human clinical trials.
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Their availability and suitability, along with increasing number of cell culture systems, indicates that the first criteria for the use of chimpanzees are not met in the case of RSV research. Criteria 2: Testing on Human Subjects RSV antiviral drug and prophylactic vaccine clinical trials progress from Phase I studies in adults to trials with seropositive children and then seronegative infants (Nair et al., 2011)
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Criteria 3: Impact of Forgoing Chimpanzee Use Forgoing the use of the chimpanzee will not significantly slow or prevent advancement of either therapeutic or prophylactic drugs for RSV and therefore, chimpanzee use does not meet the third criteria. This finding is based, in part, on both the availability of multiple non-human animal models that recapitulate several aspects of RSV disease and the ability to conduct proof-of-concept trials in a human model of infection.
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. Additional inhibitors of HCV's NS5A replication complex assembly factor and the NS5B RNA polymerase are currently in advanced clinical development, offering future hope for a highly effective, completely oral, and interferon-free therapeutic regimen for patients chronically infected with HCV (Ilyas and Vierling, 2011)
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However, it is very likely that infectious molecular clones will soon emerge for these genotypes -- a blueprint for their development now exists -- and further alternative small animal models supporting the growth of these viruses will also likely progress rapidly. The currently available experimental systems, coupled with the challenges inherent to chimpanzee experiments, including limited numbers of animals and high costs, have resulted in a steady deemphasis of the chimpanzee model in HCV antiviral drug design and development.
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Additionally, new small animal models are further reducing the need for chimpanzees in HCV antiviral drug development (Dorner et al., 2011; Galun et al., 1995; Mercer et al., 2001; Wu et al., 2005)
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. This finding suggests it may be possible to create a therapeutic HCV vaccine eliciting the type of missing immune response required for a sustained viral response and viral clearance (Houghton and Abrignani, 2005)
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Criteria 2: Testing on Human Subjects Subjects chronically infected with HCV are frequently used to test therapeutic HCV vaccine candidates. Therapeutic vaccine candidates are now being tested in humans without prior testing in the chimpanzee model (Halliday et al., 2011)
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The unique tropism of HCV for chimpanzee and human hepatocytes makes the chimpanzee model of experimental infection valuable for studies of pathogenesis, including mechanisms of persistence, and for development and testing of prophylactic HCV vaccine candidates by helping to identify those that are safe and efficacious. The chimpanzee model could also provide important insights into the correlates of immune protection (Strickland et al., 2008)
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Currently, no other suitable animal models exist for evaluation of a prophylactic HCV vaccine. Although progress is being made in the development of various mouse models that can be infected with HCV, these do not allow evaluation of the human protective immune response against HCV.
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Finding The committee finds that while there are limitations to the current chimpanzee preclinical model, it has provided valuable knowledge for the development of prophylactic HCV vaccines. The committee is aware of progress on non-chimpanzee models that can be infected with HCV.
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Specifically, the committee could not reach agreement on whether a preclinical challenge study using the chimpanzee model was necessary and if or how much the chimpanzee model would accelerate or improve prophylactic HCV vaccine development.10 Comparative Genomics Molecular genetics and comparative genomics hold enormous potential for developing biomedical therapies as well as for a more basic understanding of the origins of our own species. However, true genomic advances require two components beyond genetic material: (1)
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, the macaque (Gibbs et al., 2007) , and other species, has shown that changes that set human beings apart from other species not only involve amino acid substitutions, but also to a large extent relate to minor alterations in regulatory regions, gene transcription, and gene expression (Marques-Bonet et al., 2009)
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. Criteria 1: Studies Provide Otherwise Unattainable Insight Using human neuronal cell lines that express either the human or chimpanzee forms of FOXP2, the investigators examined the function of the FOXP2 protein (Konopka et al., 2009)
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(2009) provides an informative example of the unique insights that access to captive chimpanzee phenotypes, genotypes, and tissue can provide on the gamut of research from comparative genomics to behavior and biomedical.
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Finding Given the information provided in the publication regarding the collection of material, the chimpanzee study used as this case example meets the committee's criteria regarding unattainable insight, acquiescence, and the minimization of pain and distress. Other examples of the application of genomic tools to behavioral or neurobehavioral investigations include the collection of tissues (including blood)
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. Criteria 1: Studies Provide Otherwise Unattainable Insight The research objectives of the study question addressed clearly fall within the broad NIH mission to "seek fundamental knowledge about the nature and behavior of living systems" (NIH, 2011)
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Many such studies would be similarly approvable under the proposed guidelines; in other instances they might be limited if, for example, they provided unattainable insights but did not meet the need for acquiescence and minimization of distress.
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Criteria 1: Studies Provide Otherwise Unattainable Insight The forgoing description suggests that the study does fulfill the need to provide fundamental knowledge gain. Moreover, because the chimpanzee and humans both uniquely share a highly convoluted and lateral
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in conjunction with other cortical and subcortical brain areas, providing strong evidence in support of the hypothesis that the neurological substrates underlying language production in the human brain were present in the last common ancestor of humans and chimpanzees. Criteria 2: All Experiments Are Performed on Acquiescent Animals and in a Manner That Minimizes Distress Chimpanzees were initially separated from groupmates, but maintained within their home enclosure.
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The total time required for the manipulation was probably 28-32 hours. However, the effects of this amount of separation from the social group and handling must be judged against the unique contribution made by the study and the small number of acquiescent animals involved.
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. The same has been the case for early evaluation of therapeutic concepts based on RNAi, microRNA, and antisense RNA (e.g., for treating chronic HCV infection)
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CONCLUSIONS AND RECOMMENDATIONS Animal models serve as a critical research tool in facilitating the advancement of the public's health. The chimpanzee's genetic proximity to humans and the resulting biological and behavioral characteristics not only make it a uniquely valuable species for certain types of research, but also demand a greater justification for conducting research using this animal model.
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The committee was evenly split and unable to reach consen o sus on the necessity of the chimpanzee for the development of a prophylactic HCV vaccine. Specifically, the committee could not reach agreement on whether a preclinical challenge study using the chimpanzee model was necessary and if or how much the chimpanzee model would accelerate or im prove prophylactic HCV vaccine development.
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Application of the committee's criteria would provide a framework to assess scientific necessity to guide the future use of chimpanzees in comparative genomics research that requires samples collected from living animals. Conclusion 3: Assessing the Necessity of the Chimpanzee for Behavioral Research Having explored and analyzed contemporary and anticipated behavioral research questions, the committee concludes that chimpanzees may be necessary for obtaining otherwise unattainable insights to support understanding of social, neurological, and behavioral factors that include the development, prevention, or treatment of disease.
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Comparative genomics and behavioral research using stored samples are exempt from these criteria. The criteria set forth in the report are intended to guide not only current research policy, but also decisions regarding potential use of the chimpanzee model for future research.
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Membership on the Interagency Animal Model Committee is restricted to federal employees from the Department of Health and Human Services (including the NIH, CDC, and FDA) , Department of Veterans Affairs, and Department of Defense.
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