Summary

At the request of National Institutes of Health (NIH), and in response to congressional inquiry, the Institute of Medicine (IOM) in collaboration with the National Research Council (NRC) convened an ad hoc committee to consider the necessity of the use of chimpanzees in NIH-funded research in support of the advancement of the public’s health.

Specifically, the committee was asked to review the current use of chimpanzees for biomedical and behavioral research and:

•  Explore contemporary and anticipated biomedical research questions to determine if chimpanzees are or will be necessary for research discoveries and to determine the safety and efficacy of new prevention or treatment strategies. If biomedical research questions are identified:

ο  Describe the unique biological/immunological characteristics of the chimpanzee that make it the necessary animal model for use in the types of research.

ο  Provide recommendations for any new or revised scientific parameters to guide how and when to use these animals for research.

•  Explore contemporary and anticipated behavioral research questions to determine if chimpanzees are necessary for progress in understanding social, neurological, and behavioral factors that influence the development, prevention, or treatment of disease.



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Summary At the request of National Institutes of Health (NIH), and in response to congressional inquiry, the Institute of Medicine (IOM) in collaboration with the National Research Council (NRC) convened an ad hoc commit- tee to consider the necessity of the use of chimpanzees in NIH-funded research in support of the advancement of the public’s health. 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. Provide recommendations for any new or revised scientific o parameters to guide how and when to use these animals for research. • Explore contemporary and anticipated behavioral research ques- tions to determine if chimpanzees are necessary for progress in understanding social, neurological, and behavioral factors that influence the development, prevention, or treatment of disease. 1

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2 ASSESSING THE NECESSITY OF THE CHIMPANZEE In addressing the task, the committee explored existing and antici- pated alternatives to the use of chimpanzees in biomedical and behavior- al research. The committee based its findings and recommendations on available scientific evidence, published literature, public testimony, sub- mitted materials by stakeholders, and a commissioned paper, as well as its expert judgment. To conduct this expert assessment and evaluate the necessity for chimpanzees in research to advance the public’s health, the committee deliberated from May 2011 through November 2011. During this period, the committee held three 2-day meetings and several conference calls, including two public information-gathering sessions on May 26, 2011, and August 11-12, 2011. Each information-gathering session included testimony from individuals and organizations that both supported and opposed the continued use of chimpanzees. The committee also reviewed a number of background documents provided by stakeholder organiza- tions and commissioned a paper, “Comparison of Immunity to Pathogens in Humans, Chimpanzees, and Macaques.” The committee identified a set of core principles and criteria that were used to assess the necessity of chimpanzees for research now or in the future. Ethical Considerations Neither the cost of using chimpanzees in research nor the ethical im- plications of that use were specifically in the committee’s charge. Rather, the committee was asked for its advice on the scientific necessity of the chimpanzee model for biomedical and behavioral research. The commit- tee agrees that cost should not be a consideration. However, the commit- tee 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. 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 de- mand a greater justification for conducting research using this animal model.

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3 SUMMARY Summary of Chimpanzee Research The committee was asked, as part of its task, to review the current use of chimpanzees for biomedical and behavioral research. To assess the use of the chimpanzee as an animal model, the committee explored research supported by the NIH and other federally and privately funded research over the past 10 years. The largest percentage of federally funded chimpanzee research has been supported by the NIH, with additional projects funded by other fed- eral agencies, including the Food and Drug Administration (FDA), Cen- ters for Disease Control and Prevention (CDC), and National Science Foundation. Of the 110 identified projects sponsored by the NIH be- tween 2001 and 2010, 44 were for research on hepatitis; comparative genomics accounted for 13 projects; 11 projects were for neuroscience research; 9 projects were for AIDS/HIV studies; and 7 projects were for behavioral research. The remaining projects funded a limited number of studies in areas such as malaria and respiratory syncytial virus and pro- jects supporting chimpanzee colonies. Committee analysis of the use of chimpanzees in the private sector was hindered by the proprietary nature of the information. 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. Principles Guiding the Use of Chimpanzees in Research The task given to the committee by the NIH asked two questions about the need for chimpanzees in research: (1) Is biomedical research with chimpanzees “necessary for research discoveries and to determine the safety and efficacy of new prevention or treatment strategies?” and (2) Is behavioral research using chimpanzees “necessary for progress in understanding social, neurological, and behavioral factors that influence the development, prevention, or treatment of disease?” In responding to these questions, the committee concluded that the potential reasons for undertaking biomedical and behavioral research as well as the protocols used in each area are different enough to require different sets of criteria.

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4 ASSESSING THE NECESSITY OF THE CHIMPANZEE However, the committee developed both sets of criteria guided by the following three principles: 1. The knowledge gained must be necessary to advance the public’s health; 2. There must be no other research model by which the knowledge could be obtained, and the research cannot be ethically per- formed on human subjects; and 3. The animals used in the proposed research must be maintained either in ethologically appropriate physical and social environ- ments or in natural habitats. These principles are the basis for the specific criteria that the committee established to assess current and future use of the chimpanzee in biomed- ical and behavioral research (see Recommendations 1 and 2). Conclusions and Recommendations The committee based the following conclusions and recommenda- tions in large part on the advances that have been made by the scientific community using alternative models to the chimpanzee, such as studies using other non-human primates, genetically modified mice, in vitro sys- tems, and in silico technologies as well as human clinical trials. 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. However, there may be a limited number of mono- clonal antibodies already in the developmental pipeline that may require the continued use of chimpanzees.

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5 SUMMARY The committee was evenly split and unable to reach consen- o sus on the necessity of the chimpanzee for the development of a prophylactic hepatitis C virus (HCV) vaccine. 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. • Development of non-chimpanzee models requires continued support by the NIH. • A new, emerging, or reemerging disease or disorder may present challenges to treatment, prevention, and/or control that defy non- chimpanzee models and available technologies and therefore may require the future use of the chimpanzee. • Comparative genomics research may be necessary for under- standing human development, disease mechanisms, and suscep- tibility because of the genetic proximity of the chimpanzee to humans. It poses no risk to the chimpanzee when biological ma- terials are derived from existing samples or minimal risk of pain and distress in instances where samples are collected from living animals. • Chimpanzees may be necessary for obtaining otherwise unat- tainable insights to support understanding of social and behav- ioral factors that include the development, prevention, or treatment of disease. • Application of the committee’s criteria would provide a frame- work to assess scientific necessity to guide the future use of chimpanzees in biomedical, comparative genomics, and behav- ioral research.

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6 ASSESSING THE NECESSITY OF THE CHIMPANZEE Recommendation 1: The National Institutes of Health should limit the use of chimpanzees in biomedical research to those studies that meet the following three criteria: 1. There is no other suitable model available, such as in vitro, non- human in vivo, or other models, for the research in question; 2. The research in question cannot be performed ethically on hu- man subjects; and 3. Forgoing the use of chimpanzees for the research in question will significantly slow or prevent important advancements to prevent, control, and/or treat life-threatening or debilitating conditions. Animals used in the proposed research must be maintained either in ethologically appropriate physical and social environments or in nat- ural habitats. Biomedical research using stored samples is exempt from these criteria. Recommendation 2: The National Institutes of Health should limit the use of chimpanzees in comparative genomics and behavioral re- search to those studies that meet the following two criteria: 1. Studies provide otherwise unattainable insight into comparative genomics, normal and abnormal behavior, mental health, emo- tion, or cognition; and 2. All experiments are performed on acquiescent animals, using techniques that are minimally invasive, and in a manner that minimizes pain and distress. Animals used in the proposed research must be maintained either in ethologically appropriate physical and social environments or in nat- ural habitats. 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 cur- rent research policy, but also decisions regarding potential use of the chimpanzee model for future research. The committee acknowledges that imposing an outright and immediate prohibition of funding could cause unacceptable losses to research programs as well as have an impact on the animals. Therefore, although the committee was not asked to consid- er how its recommended policies should be implemented, it believes that the assessment of the necessity of the chimpanzee in all grant renewals

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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 rec- ommended criteria.

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STUDY BACKGROUND AND CONTEXT The chimpanzee (Pan troglodytes) is a current animal model in bio- medical and behavioral research supported by the U.S. government and industry. In fiscal year 2011, of the more than 94,000 active projects sponsored by the National Institutes of Health (NIH), only 53 used the chimpanzee (0.056 percent). However, members of the public, Congress, and some scientists question this use. They argue that research that has relied on chimpanzees could be accomplished using other models, meth- ods, or technologies (Bailey, 2010a, 2010b; Bettauer, 2011) or that chimpanzees are not appropriate models for human disease research (Bailey, 2008; Physicians Committee for Responsible Medicine, 2011). Ongoing biomedical and behavioral research on chimpanzees is largely conducted at four facilities: the Southwest National Primate Research Center, the New Iberia Research Center at the University of Louisiana-Lafayette, the Michale E. 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 Uni- versity. Much of the research supported by the first three facilities is fo- cused 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). In addition, research supports studies on deriving chimpanzee cell lines, antibodies and other biological materials, as well as comparative genomics research. The Yerkes Center primarily sponsors studies pertaining to developmental and cognitive neuroscience, as well as ag- ing-related comparative neurobiology (Yerkes National Primate Research Center, 2011). In addition to these four centers, the National Center for Research Resources (NCRR) also supports the Alamogordo Primate Facility (APF). Unlike the other facilities, Alamogordo is a re- search reserve facility that does not have an active chimpanzee research program; no invasive research is conducted on these chimpanzees while on the premises1 (NCRR, 2011a). However, the animals may be used for cardiovascular disease and behavioral studies with data obtained during their annual physicals (Watson, 2011). If these chimpanzees are needed 1 According to solicitation NHLBI-CSB-(RR)-SS-2011-264-KJM (HHS, 2011c), “the current agreements between the National Institutes of Health (NIH) and the U.S. Air Force (USAF) prescribe that no invasive research shall be conducted on chimpanzees currently held at the APF.” 9

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10 ASSESSING THE NECESSITY OF THE CHIMPANZEE for other types of research, they are relocated to another facility and, once removed, cannot return to Alamogordo Primate Facility (HHS, 2011d). As of May 2011, 937 chimpanzees, ranging in age from less than 1 year old to greater than 41, were available for biomedical and behavioral research (Tables 1 and 2). The U.S. government currently supports 612 of these animals at four NCRR-supported facilities; the remaining ani- mals are privately owned and supported (HHS, 2011a). The NCRR at the NIH provides programmatic oversight of these facilities and ensures they comply with the Animal Welfare Act, and with policies concerning laboratory animal care and use. Within the NCRR, the Division of Com- parative Medicine oversees the NIH Chimpanzee Management Program (ChiMP), which supports the long-term, cost-effective housing and maintenance of chimpanzee facilities (NCRR, 2011a). In 1995, the NIH instituted a moratorium on the breeding of chim- panzees that they owned or supported (NCRR, 2011b). Soon after, the Chimpanzee Management Plan Working Group was created to periodi- cally assess the need for chimpanzees in research and report its findings to NCRR’s advisory body, the National Advisory Research Resources Council. This Working Group of non-government scientists and non- scientists analyzes relevant issues and drafts proposed position papers. In 2007, this Working Group issued a report2 that “did not make a definitive recommendation as to whether the chimpanzee breeding moratorium should be continued,”3 but the NIH National Advisory Research Resources Council extended the breeding moratorium indefinitely (Cohen, 2007b). 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). 2 Report of the Chimpanzee Management Plan Working Group—March 9, 2007 (NCRR, 2007). 3 The 1997 National Research Council report, Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use also recommended a 5-year breeding morato- rium (NAS, 1997).

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11 ASSESSING THE NECESSITY OF THE CHIMPANZEE TABLE 1 Number of Chimpanzees Available in the United States for Research Number of Chimpanzees Total Number Supported by the NCRR, of Chimpanzeesa NIHb Alamogordo Primate 176 176 Facility Michale E. Keeling 176 159 Center for Comparative Medicine and Research New Iberia Research 347 124 Center Southwest National 153 153 Primate Research Center Yerkes National Primate 85 0 Research Centerc 937 612 TOTAL a Number of chimpanzees as of October 2011 (Abee, 2011c; Else, 2011; Lammey, 2011; Landry, 2011; Langford, 2011). b Number of NIH-supported chimpanzees current as of April 15, 2011 (HHS, 2011a). c The Yerkes National Primate Research Center does not use any core funds from the NCRR to support the costs for maintaining humane care and welfare of chimpanzees. 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). b The committee was unable to match the age of each chimpanzee with the funding source. Numbers represent a mix of federal and other sources of funding. c The Yerkes National Primate Research Center does not use any core funds from the NCRR to support the costs for maintaining humane care and welfare of chimpanzees.

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60 ASSESSING THE NECESSITY OF THE CHIMPANZEE (Okasha, 2010). It is argued that studies of chimpanzees may be particu- larly relevant for addressing complex behaviors such as altruism because of our shared evolutionary history and recent common ancestry. Even for chimpanzees, however, disagreement remains over the degree to which the animals are sensitive to the needs of conspecifics (Horner et al., 2011). Chosen here for a case evaluation is one study that attempts to de- termine whether chimpanzees actively choose to help others, and wheth- er such help is spontaneous—and thus could be interpreted as reflecting sensitivity to the needs of another animal—or is triggered by a solicita- tion from the partner (Horner et al., 2011). The study design involves allowing chimpanzees to choose between two different tokens, a “self- ish” token that provides a reward for the actor only, and a “prosocial” token that rewards both the actor and a partner. Seven females were test- ed, each with three different partners. The actors demonstrated a signifi- cant overall bias for the prosocial token, but more so when the partner either showed no reaction or engaged in neutral attention getting (not directed at the actor); attempts to pressure the actor resulted in reduced prosocial choice (Horner et al., 2011). 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) and more specifical- ly, meets the first criteria: to provide “otherwise unattainable insight into evolution, normal and abnormal behavior, mental health, emotion, or cognition.” The insights derive from the arguably close genetic relation- ship between chimpanzees and human beings and the substantial similar- ity in brain structure and complexity—a similarity that is much less pronounced in monkeys (Sakai et al., 2011). The less complex brain structures in other old worlds of monkeys result in a tendency toward a simpler pattern of signaling and signal recognition. It was of particular interest that, in this study, actors behaved prosocially toward their part- ners irrespective of relative social status, genetic relationship, or expecta- tion of reciprocity. These results imply that human beings may have a tendency to help other individuals unconditionally, at least when the help can be given at no cost.

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61 ASSESSING THE NECESSITY OF THE CHIMPANZEE Criteria 2: All Experiments Are Performed on Acquiescent Animals and in a Manner That Minimizes Distress In assessing the degree of acquiescence and distress on the part of the subjects, the study reported that the seven adult female chimpanzees “volunteered to participate and were willing to exchange tokens with an investigator.” However, no details regarding the definition of “volunteer” were given in the manuscript or the associated methodology. The study did describe the conditions under which the animals were maintained. Specifically, they were housed in a large outdoor grass enclosure with climbing structures as part of a long-established social group comprising 11 females and one male. There were two associated buildings, one with indoor sleeping quarters and a second building designed for cognitive research testing. No details were provided on the dimensions of these buildings. Finding This study involved temporary removal of animals from their usual housing and social group to engage in a cognitive task paired with other chimpanzees. The information provided suggests that chimpanzee use in this study could meet all criteria if more complete descriptions of the handling and housing were provided. Specifically, the investigators would have to substantiate the statement that the animals “volunteered” for the procedures, confirm that the indoor sleeping quarters were of suf- ficient size for the species, and demonstrate that the cognitive testing apparatus would meet all enrichment requirements for this species. This study exemplifies the numerous cognitive investigations that have been done in chimpanzees. As a group, these studies have demon- strated that human cognitive abilities with respect to the manipulation of the social environment extend to chimpanzees in a variety of domains that include altruism, deception, and grief. 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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62 ASSESSING THE NECESSITY OF THE CHIMPANZEE Cognition Joint attention occurs when one animal alerts another to the presence of a stimulus by means of gestural or vocal communication. It is general- ly thought that a breakdown in the ability to initiate joint attention may be a predictor for autism spectrum disorders or other neurodevelopmen- tal disorders (Mundy et al., 2010). Unfortunately, knowledge of devel- opmental mechanisms of joint attention are poorly understood because some functional imaging techniques used in adults are difficult to admin- ister to children while others, like positron emission tomography (PET), cannot be administered without some risk to normal young subjects. The chimpanzee has been used as a model organism to study the neurodevel- opmental basis of joint attention and similar phenomena and to increase the understanding of the development trajectory of human communica- tive phenomena. This is because, in humans, joint attention (including both gestures and vocalization) is associated with hemispheric lateraliza- tion, particularly in the portion of the inferior frontal gyrus (IFG), termed Broca’s area, and is thought to have evolved from a lateralized manual communication system present in the common ancestor of humans and chimpanzees (Corballis, 2002; Kingstone et al., 2000). Chosen here for case evaluation is a PET study designed to determine whether chimpan- zees possess a gesture and vocalization-activated brain region homolo- gous with the IFG (Broca’s area), which in humans is most often enlarged on the left side to indicate significant left-lateralized patterns of activation during communication (Taglialatela et al., 2008). While it has been previously shown that chimpanzees engage in joint communication and exhibit structural asymmetry in the brain, it had not been demon- strated that the brain regions underlying joint attention were the same as those underlying homologous communicative behaviors in humans. In particular, it was not known whether the IFG and related cortical and subcortical areas were preferentially activated during gestural or vocal communication in the chimpanzee. The presence of similarly activated underlying brain structures would suggest that chimpanzees could be used to model human communication development. 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 chim- panzee and humans both uniquely share a highly convoluted and lateral-

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63 ASSESSING THE NECESSITY OF THE CHIMPANZEE ized cerebral cortex and the ability to engage in joint attention, it is likely to provide otherwise unattainable insight into the neurodevelopment of communication and, by implication, communicative disorders. Further- more, while the modern imaging modalities necessary to map neurode- velopment can be applied to both chimpanzees and adult human beings, the application of these techniques to children is often limited by logisti- cal and ethical considerations. Finally, even if all imaging techniques (even those involving unacceptably high radiation exposure) could be applied to children, the study of neurodevelopment would be arguably en- hanced by the availability of a comparative model like the chimpanzee. This study provided the first direct evidence that the neuroanatomical structures underlying communicative signals in chimpanzees are homol- ogous with those present in humans. Furthermore, chimpanzees engaging in communicative gestures—like human beings—activated the left IFG (Broca’s area) 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 main- tained within their home enclosure. The animals were then provided with a sweetened drink that contained the radioligand 18F-fluorodeoxyglucose (18F-FDG), which initiated a 40-minute uptake period, during which the radioligand would bind to parts of the brain that were being activated by the chimpanzee’s behavior. During the uptake period, the investigator sitting outside the enclosure placed a favored food item just beyond reach, a situation that predictably elicited both gestural and vocal signal- ing from subjects. Experimenters would periodically respond to subjects with both vocal communication and small food rewards. At the end of the 40-minute uptake period, chimpanzees received an intramuscular injection of an anesthetic agent and were transported to the PET facility. All animals had been previously trained with positive reinforcement to present for such anesthesia. Following scanning, animals were allowed to fully recover before being reintroduced to their social groups. It should be noted that three chimpanzees were used in the study, and each animal was scanned on two occasions—once following the gesture and vocaliza-

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64 ASSESSING THE NECESSITY OF THE CHIMPANZEE tion task and separately following a control task that did not require communicative interaction. Review of the study indicates that it was conducted in a manner con- sistent with acquiescence. Animals voluntarily engaged in behavioral testing during the awake part of the procedure (i.e., uptake) and, further- more, were trained to present for anesthesia. As described in the study, anesthesia persisted for about 50 minutes (transport to and from the PET facility, PET scanning). Animals were allowed to recover (and radioligands allowed to decay) for approximately 18 hours, after which they were returned to their social group. It is important to note that this study likely exposed the animals to more than “minimal” distress in that animals were fasted for 5 hours prior to the procedure, sedated for at least 50 minutes, and then were separated from their social groups to allow recovery. The total time required for the manipulation was proba- bly 28-32 hours. However, the effects of this amount of separation from the social group and handling must be judged against the unique contri- bution made by the study and the small number of acquiescent animals involved. It should be noted that a complete veterinary examination would involve a similar if not longer period of fasting, social group sepa- ration, and anesthesia. Finding In view of the scientific benefits compared to the temporary negative impacts on the animal subjects (separation and anesthesia), this study could potentially meet all criteria for approval if sufficient additional assurance were provided that the animals were maintained in species- appropriate housing and groupings and that the number and duration of procedures imposed on individual animals was minimized in a manner consistent with criteria described earlier in this report. FUTURE USE OF CHIMPANZEES IN BIOMEDICAL AND BEHAVIORAL RESEARCH As highlighted throughout this report, over many years scientific ad- vances that have led directly to the development of preventive and thera- peutic products for life-threatening or debilitating diseases and disorders have been dependent on scientific knowledge obtained through experi- ments using the chimpanzee. In addition, many preliminary proof-of-

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65 ASSESSING THE NECESSITY OF THE CHIMPANZEE concept experiments have been carried out in the chimpanzee; for exam- ple, development of human and humanized monoclonal antibody thera- pies have required preclinical testing in the chimpanzee (Iwarson et al., 1985). The same has been the case for early evaluation of therapeutic concepts based on RNAi, microRNA, and antisense RNA (e.g., for treat- ing chronic HCV infection), and for evaluation of TLR7 antagonists (e.g., for treating chronic HBV infection) (Lanford et al., 2011). The National Institute of Allergy and Infectious Diseases at the NIH has identified eight instances over the past two decades where research on new (or newly recognized), emerging, and reemerging infectious dis- eases has called for use of the chimpanzee to answer crucial questions pertaining to pathogenesis, prevention, control, or therapy. In five of these, the chimpanzee is still being used.11 At the same time, as has been the case rather often in the past, an important new, emerging, or reemerging disease may present treatment, prevention, and/or control problems that defy available alternative experimental approaches, including the most novel, innovative approaches, and therefore may require use of the chimpanzee—rare as this may be, this possibility cannot be discounted over the long term. The committee recognizes that the limited number of available animals and the potential need to perform experiments under conditions of biocontainment could potentially constrain the value of the chimpanzee during a public health emergency. The similarity in the neuroanatomy between the human and the chimpanzee may make it a model for neuropsychiatric disorders, for example, expressing human risk genes via viral vectors or from optogenetic methods that exploit the chimpanzee functional neuroanotomy. However, in this case the past is not necessarily prelude—great pro- gress is being made in developing alternatives to the chimpanzee; more studies are using other non-human primates (Ben-Yehudah et al., 2010; Couto and Kolykhalov, 2006; Pan et al., 2010; Suomi, 2006), genetically modified (knock-out, knock-in) mice (Chen et al., 2011a; de Jong et al., 2010; Dorner et al., 2011; Kneteman and Mercer, 2005; Lindenbach et al., 2005; Ma et al., 2010; Ploss and Rice, 2009), and even in silico tech- nologies (Hosea, 2011; Qiu et al., 2011; Valerio, 2011). In some instanc- es, “preclinical studies” in humans, that is, expanded studies carried out 11 Encephalitozoon cuniculi; Helicobacter pylori; Hepatitis C (ongoing); Hepatitis E (ongoing); Human herpesvirus 8 (ongoing); Human herpesvirus 6 (ongoing); Streptococ- cus, Group A; Staphylococcus aureus (ongoing) (NIAID, 2011).

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66 ASSESSING THE NECESSITY OF THE CHIMPANZEE in the field during disease outbreaks, have served as an alternative to the use of the chimpanzee. Finding The committee cannot predict or forecast future need of the chim- panzee animal model and encourages use of the criteria established in this report when assessing the potential necessity of chimpanzees for fu- ture research uses. CONCLUSIONS AND RECOMMENDATIONS Animal models serve as a critical research tool in facilitating the ad- vancement 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. As this report demonstrates, the committee’s conclusions and recommendations are predicated on the advances that have been made by the scientific community in developing and using alternative models to the chimpanzee, such as studies involving human subjects, other non-human primates, genetically modified mice, in vitro systems, and in silico technologies. Having reviewed and analyzed contemporary and anticipated biomedical and behavioral research, the committee offers the following three conclusions and two recommendations. Conclusion 1: Assessing the Necessity of the Chimpanzee for Biomedical Research Having explored and analyzed contemporary and anticipated bio- medical research questions, the committee concludes: • The chimpanzee has been a valuable animal model. • Based on a set of principles that ensure ethical treatment of chimpanzees, the committee established criteria to determine the necessity for the use of chimpanzees in current biomedical or behavioral research. • While the chimpanzee has been a valuable animal model in past research, most current use of chimpanzees for biomedical re-

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67 ASSESSING THE NECESSITY OF THE CHIMPANZEE 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. However, there may be a limited number of mono- clonal antibodies already in the developmental pipeline that may require the continued use of chimpanzees. 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. • The present trajectory indicates a decreasing scientific need for chimpanzee studies due to the emergence of non-chimpanzee models and technologies. • Development of non-chimpanzee models requires continued support by the NIH. • A new, emerging, or reemerging disease or disorder may present challenges to treatment, prevention, and/or control that defy non- chimpanzee models and technologies and therefore may require the future use of the chimpanzee. • Application of the committee’s criteria would provide a frame- work to assess scientific necessity to guide the future use of chimpanzees in biomedical research. Recommendation 1: The National Institutes of Health should limit the use of chimpanzees in biomedical research to those studies that meet the following three criteria: 1. There is no other suitable model available, such as in vitro, non- human in vivo, or other models, for the research in question; and 2. The research in question cannot be performed ethically on hu- man subjects; and

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68 ASSESSING THE NECESSITY OF THE CHIMPANZEE 3. Forgoing the use of chimpanzees for the research in question will significantly slow or prevent important advancements to prevent, control, and/or treat life-threatening or debilitating conditions. Animals used in the proposed research must be maintained either in ethologically appropriate physical and social environments or in nat- ural habitats. Biomedical research using stored samples is exempt from these criteria. Conclusion 2: Assessing the Necessity of the Chimpanzee for Comparative Genomics Research Having reviewed comparative genomics research, the committee concludes the chimpanzee may be necessary for understanding human development, disease mechanisms, and susceptibility because of the ge- netic proximity of the chimpanzee to humans. Furthermore, comparative genomics research poses minimal risk of pain and distress to the chim- panzee in instances where samples are collected from living animals and poses no risk when biological materials are derived from existing sam- ples. 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 liv- ing animals. Conclusion 3: Assessing the Necessity of the Chimpanzee for Behavioral Research Having explored and analyzed contemporary and anticipated behav- ioral research questions, the committee concludes that chimpanzees may be necessary for obtaining otherwise unattainable insights to support un- derstanding of social, neurological, and behavioral factors that include the development, prevention, or treatment of disease. Application of the committee’s criteria would provide a framework to assess scientific ne- cessity to guide the future use of chimpanzees in behavioral research.

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69 ASSESSING THE NECESSITY OF THE CHIMPANZEE Recommendation 2: The National Institutes of Health should limit the use of chimpanzees in comparative genomics and behavioral re- search to those studies that meet the following two criteria: 1. Studies provide otherwise unattainable insight into comparative genomics, normal and abnormal behavior, mental health, emo- tion, or cognition; and 2. All experiments are performed on acquiescent animals, using techniques that are minimally invasive, and in a manner that minimizes pain and distress. Animals used in the proposed research must be maintained either in ethologically appropriate physical and social environments or in nat- ural habitats. 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 cur- rent research policy, but also decisions regarding potential use of the chimpanzee model for future research. The committee acknowledges that imposing an outright and immediate prohibition of funding could cause unacceptable losses to research programs as well as have an impact on the animals. Therefore, although the committee was not asked to consid- er how its recommended policies should be implemented, it believes that the NIH should evaluate the necessity of the chimpanzee in all grant re- newals and future research projects using the chimpanzee model based on the committee’s criteria. In March 1989 the NIH chartered the Interagency Animal Model Committee (IAMC) “to provide oversight of all federally supported biomedical and behavioral research involving chimpanzees” (NIH, unpublished). As indicated in its charter: The IAMC review mechanism represents a commit- ment to the public and the U.S. Congress to promote the conservation and care of chimpanzees when this species is the best or possibly the only model for the conduct of research to advance scientific knowledge and to address questions that have significant impact on public health. The IAMC shall review all federally-supported re- search protocols involving the use of chimpanzees be- fore the initiation of the study. Prior to this review, the

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70 ASSESSING THE NECESSITY OF THE CHIMPANZEE project must be reviewed and approved by intramural scientific program staff or an extramural initial review group and by the appropriate Animal Care and Use Committee. The IAMC’s evaluation constitutes an addi- tional level of scientific review, focusing on such factors as the appropriateness of the animal model, appropriate- ness of the numbers of animals, the availability of the animals, the degree of invasiveness of the procedures, and any unnecessary duplication. (NIH, unpublished) Appointment of the IAMC is evidence that the NIH has determined that the conservation and care of chimpanzees requires additional over- sight. Membership on the Interagency Animal Model Committee is re- stricted 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. The committee believes that as- sessment of potential future use of the chimpanzee would be strength- ened and the process made more credible by establishing an independent oversight committee that uses the recommended criteria and includes public representatives as well as individuals with scientific expertise, both in the use of chimpanzees and alternative models, in areas of re- search that have the potential for chimpanzee use.