1
Introduction
Society relies on biomedical research supported by the National Institutes of Health (NIH) to mitigate disease, prevent the spread of infectious agents, advance technologies to help those with disabilities, and promote health and wellness, among other objectives. Studies aimed at accomplishing these objectives often rely on animal, cellular, and in silico systems to model complex human biological systems and disease processes, with the appropriate choice of a model system being dictated by the question(s) being asked.
Nonhuman primates (NHPs) represent a small proportion—an estimated one-half of 1 percent—of animals used in biomedical research in the United States (Friedman et al., 2017). They are useful because their similarities to humans with respect to genetic makeup, anatomy, physiology, and behavior make it possible to approximate the human condition. Indeed, remarkable biomedical breakthroughs—including successful treatments for Parkinson’s and sickle cell disease, drugs to prevent transplant rejection, and vaccines for polio and COVID-19, as well as fundamental discoveries related to vision, motor control, decision making, and memory—have been enabled by research using NHP models. Nonetheless, the use of NHP models is not without controversy or challenge. Policy makers, animal advocates, researchers, and the public continue to raise questions as to whether and how nonanimal models can be used to answer scientific questions for which NHPs have historically been regarded as fit for purpose, questions that apply as well to animal models more broadly. Additionally, limitations in the availability of NHPs, exacerbated by the COVID-19 pandemic and recent restrictions on their exportation and transportation, have had negative impacts on NIH-funded research necessary for both public health and national security (Subbaraman, 2021).
In this context, and at the direction of the U.S. Congress, NIH asked the National Academies of Sciences, Engineering, and Medicine to convene an ad hoc committee of relevant experts to conduct a landscape analysis focused on describing the state of the science of NHP model systems and exploring their current and future role in NIH-funded biomedical research. The committee was also asked to examine opportunities for new approach methodologies to complement or reduce reliance on NIH-supported research using NHPs. The committee’s full Statement of Task is presented in Box 1-1.
STUDY ORIGIN AND SCOPE
In its Consolidated Appropriations Act of 2021,1 the U.S. Congress directed NIH to commission an independent National Academies study to explore the current and future use of NHPs in intramural NIH research, as well as existing and anticipated future opportunities for alternatives to reduce NIH’s reliance on NHP models. As directed by NIH, the committee’s Statement of Task (Box 1-1) expanded the scope of the study beyond that described in
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1 The complete congressional language requesting this consensus study can be found in Division H of the Joint Explanatory Statement that accompanied H.R. 133, the Consolidated Appropriations Act, 2021 (P.L. 116-260) on PDF page 69 here: https://www.appropriations.senate.gov/imo/media/doc/Division%20H%20-%20Labor%20H%20Statement%20FY21.pdf (accessed September 13, 2022).
the congressional language to include both intramural and extramural2 biomedical research using NHPs. While there are differences between the intramural and extramural programs (e.g., scale, funding), many of the elements of the research landscape examined by the committee, including domains of NHP research and NHP availability challenges, are similar across the two programs. Aspects of the study and findings that are specific to NIH’s intramural research program are called out as such in the relevant chapters.
Acknowledging that NHPs are used in research in the United States in a broad range of contexts and that such research is supported by federal agencies such as the U.S. Department of Defense and the Food and Drug Administration (FDA), nonprofit organizations, and private industry, NHP research funded by entities other than NIH is beyond the scope of this study. Consequently, this study does not include an in-depth analysis of the use of NHPs in industry-sponsored research, including pharmaceutical safety and efficacy testing as part of regulatory approval processes. At the same time, however, drug and vaccine development builds on a foundation of knowledge derived from fundamental basic, translational, and clinical research (see Chapter 2), and the indirect contributions of NIH-funded research to advances in available vaccines and treatments, though difficult to quantify, were considered to be within the study scope. Additionally, the committee was charged with assessing gaps in NHP availability, and such an assessment cannot ignore the constraints on the system imposed by competing demands from other sponsors of NHP research. Moreover, research supported by different sponsors, both federal and nonfederal, is often complementary. For example, both NIH and the Biomedical Advanced Research and Development Authority may fund research on vaccines and other medical countermeasures in support of eventual product approvals by the FDA (NIH, 2022). NIH provides such support in part through the Small Business Innovation Research and Small Business Technology Transfer award mechanisms (NIGMS, 2023). Thus in some specific contexts, the committee examined how NIH-supported NHP research affects and is affected by NHP research funded by other organizations.
The supply of NHPs for biomedical research in the United States relies in part on the importation of animals from other countries, as discussed in more detail in Chapter 3. Imported NHPs may be bred in other countries and exported for research purposes, or they may be captured from wild populations. The committee was not charged with examining the impacts of biomedical research on wild NHP populations, so no analysis of such impacts is included in this report. Additionally, as of 2015, NIH no longer supports biomedical research with chimpanzees (Collins, 2015). Accordingly, this report does not include consideration of the use of chimpanzees, or other great apes, as research models. Furthermore, approaches that employ non-NHP animal species as alternatives to NHP models were considered to be beyond the scope of this study, although the potential for other animal models (e.g., transgenic animals) to reduce reliance on NHPs is briefly acknowledged in the report where appropriate. A comprehensive assessment of such opportunities would have expanded the study beyond what was feasible given the available time and resources. This represents an important area for future consideration.
The committee recognizes that research utilizing NHPs, like all scientific animal research, must be conducted for ethically appropriate reasons and in ethically appropriate ways. However, as clarified by the sponsor of the study during the committee’s first meeting, the charge did not include specific examination of ethical standards and principles that underlie NHP research, or current ethical issues and disputes relevant to this research. This report rests on
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2 Intramural research at NIH is carried out by researchers employed by the federal government, whereas extramural research is carried out by researchers at institutions across the United States and in some foreign countries who have received funding from NIH institutes, centers, and offices (NHGRI, 2015).
the foundational assumption that biomedical research with NHPs can be conducted ethically when an NHP is the appropriate research model to address the aims of the research (a non-NHP model would not achieve the stated aims); when studies are well designed and conducted; and when the research and the housing and care of the animals afford requisite attention to their welfare, including minimization of pain, distress, and discomfort, and appropriate environmental enrichment.
In accordance with the Statement of Task, this report presents the committee’s findings and conclusions based on a landscape analysis. As emphasized by NIH during the committee’s first public meeting, the analysis was intended to survey the various scientific disciplines in which NHPs are currently used and may be used in the future, considering the scientific opportunities, public health needs, and development status of alternative and complementary model systems. It is important to note that the committee was not asked to prioritize research disciplines in terms of their relative importance or the value of NHP models to each field of research.
Finally, in contrast with other reports of the National Academies on the use of large-animal models—specifically, chimpanzees (IOM, 2011) and dogs (NASEM, 2020)—the committee’s charge did not include the provision of conclusions related to parameters intended to guide how and when to use NHPs for biomedical research. Thus, unlike previous reports, the present report does not provide criteria for determining when it is scientifically necessary to use NHPs, a task that would have substantially altered the committee’s composition and approach.
KEY TERMINOLOGY
A number of key terms related to research models are used throughout this report. These terms are defined in Box 1-2.
STUDY CONTEXT
NHP Models in the Broader Context of Biomedical and Animal Research
Humankind is plagued by a multitude of diseases, illnesses, and forms of infirmity and disability that shorten or end lives; cause significant pain, distress, fear, anxiety, and sorrow; impair quality of life; and impose substantial economic costs on sufferers and society at large. The steady annual growth in federal expenditures on biomedical research in recent years—the vast majority of which represent investments by NIH (Research!America, 2022)—reflects recognition of the need to address the significant burden on Americans of premature death and disability due to such public health threats as cancer, diabetes, infectious disease, and neurological disorders (see Figure 1-1). For many conditions that threaten the health and quality of life of an aging population, such as Alzheimer’s disease, there remains no cure and little understanding of how to prevent or slow their onset or progression (AA, 2022; Eaton and Wishart, 2017). Accordingly, it is incumbent on a society with sufficient resources and scientific expertise to strive to make significant progress in preventing, alleviating, and curing these conditions that are responsible for so much human suffering.
The 21st century has seen numerous technological advances—including high-throughput sequencing, CRISPR-Cas gene editing methodologies, induced pluripotent stem cells, and artificial intelligence—that have revolutionized many areas of biomedical research. Despite this progress, however, some scientific questions cannot be answered outside the context of a living organism (Anderson, 2008; Eaton and Wishart, 2017; Friedman et al., 2017). For many applications, complete biological systems in the form of animal models are needed to study complex biological systems and disease processes and evaluate novel approaches for prevention or treatment when research in humans is unethical or otherwise infeasible. In the study of viral infection, for example, investigation of the interaction between the virus and the cells it infects may be possible in vitro (Rijsbergen et al., 2021), but understanding the body’s full immune response requires a living model organism that accurately models the human condition (Baxter and Griffin, 2016; Veenhuis and Zeiss, 2021).
SOURCE: CDC, 2021
As noted earlier, NHPs have been estimated to account for only one-half of 1 percent of all animals used in biomedical research in the United States (Friedman et al., 2017). However, accurate estimation of this figure in the United States is hindered by the absence of requirements to report on subsets of commonly used vertebrate animal models, including rodents and fish, under the Animal Welfare Act of 1966 (AWA),3 discussed in the section that follows. NHPs, common species of which are listed in Table 1-1, represent approximately 8.6 percent of the nearly 800,000 animals used in research for which the AWA requires reporting to the U.S. Department of Agriculture (USDA) (APHIS, 2021).4 In the European Union (EU), 93 percent of research is conducted on species not counted under the AWA, with mice accounting for roughly half of the 10.4 million animals used for research in EU member states in 2019 (European Commission, 2022). These EU data have been used to estimate that 14 million vertebrates are used each year in research in the United States (Taylor and Alvarez, 2019),
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3 7 U.S.C. §§ 2131–2159 (P. L. 89-544), with implementing regulations: 9 C.F.R. § 1(A).
4 Laboratory mice and rats, fish, and certain other species used in laboratory research are not covered by the AWA and accordingly, their numbers are not reported to USDA; therefore, the relative proportion of NHPs among all laboratory animals is much lower than 8.6 percent (APHIS, 2021).
TABLE 1-1 Nonhuman Primate Species Used in Biomedical Studies
| Scientific Name | Common Name | Examples of Applications | |
|---|---|---|---|
| Chlorocebus sabaeus | African green monkey | Infectious disease (e.g., COVID-19,d HIV/AIDS), neuroscience | |
| Papio spp. | Baboon | Reproduction, neuroscience, hematology, transplantation, COVID-19d | |
| Cebus/cebinae | Capuchin | Aging,b cognitione | |
| Callithrix jacchus | Common marmoset | Reproduction, endocrinology, vision, behavior, COVID-19d | |
| Macaca fascicularis | Cynomolgus macaque | Infectious disease (COVID-19,d tuberculosis, HIV/AIDS), neuroscience | |
| Macaca fuscata | Japanese macaque | Batten disease,a obesityc | |
| Aotus spp. | Owl monkey | Vaccine development (e.g., dengue, malaria), behavior, endocrinology, vision | |
| Macaca nemestrina | Pig-tailed macaque | Infectious disease (e.g., COVID-19,d HIV/AIDS), reproduction, growth and development, behavior, neuroscience | |
| Macaca mulatta | Rhesus macaque | Infectious disease (e.g., COVID-19,d HIV/AIDS, tuberculosis,g Ebola,f measlesh), reproduction, growth and development, behavior, neuroscience | |
| Cercocebus atys | Sooty mangabey | HIV/AIDS, leprosy | |
| Saimiri sciureus | Squirrel monkey | Malaria, neuroscience | |
| Callicebinae spp. | Titi monkey | Neuroscience,i behaviorj | |
| Chlorocebus pygerythrus | Vervet | HIV/AIDS, neuroscience | |
NOTE: AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.
SOURCE: Table adapted with permission from Anderson, D.M. 2008. The nonhuman primate as a model for biomedical research. In Sourcebook of models for biomedical research. Pp. 251–258. Springer Nature. Additional sources are noted below.
with NHPs representing approximately 72,000, or 0.5 percent, of those animals in fiscal year (FY) 2021 (APHIS, 2022a). Private industry accounts for just under half of all NHPs reported to USDA (see Appendix B for USDA-reported listings of all research facilities holding and using NHPs in FY2021).
Models are just that—simplified representations of complex systems used to answer specific questions of interest (Denayer et al., 2014; Ferreira et al., 2020). No model, animal or otherwise, can fully recapitulate the unique complexities of the human body and the disease processes that afflict it (even a human is not a perfect model of the health and biology of another human given natural heterogeneity), but that does not negate their usefulness for studying specific aspects of a disease. Given the limitations inherent in all models, the selection of a model depends on the precise question being asked to ensure that the model is fit for purpose. In many cases, a combination of models, each used to address different scientific questions, may better recapitulate the clinical process being studied (Denayer et al., 2014).
The primary determinant of whether NHPs are appropriate and uniquely suited as a model system for answering a specific scientific question is translational relevance (the degree to which findings from research using NHPs applies to humans) and the inability to study the process of interest in other models in a way that is translationally relevant to people. Factors contributing to the translational relevance of NHP models include similarities between the biological (e.g., anatomy and physiology, genetics, epigenetics) and behavioral characteristics of NHPs and humans and the extent to which human diseases are mirrored in NHPs. Also important is predictive validity, or the ability to predict the effect of an intervention (e.g., vaccine, therapeutic) in humans based on the effect observed in the NHP model (Denayer et al., 2014), in terms of both clinical efficacy and safety. A number of factors may affect translational relevance, including the similarity of a given target in disease processes in humans and the animal model. For this reason, limitations in understanding of the underlying biology can pose barriers to selecting an appropriate model.
The use of large-animal models (e.g., NHPs, dogs, pigs) in nonclinical research is generally premised on the greater translational relevance of those models to humans as compared with rodents. The translational relevance of animal models depends to some degree on the evolutionary conservation of biological structures and processes under study. For highly conserved pathways and structures, animals that are more phylogenetically distant from humans (e.g., zebrafish, nematodes, mice) may serve as valuable model systems for the study of human anatomy, physiology, and disease (Bradford et al., 2017; Markaki and Tavernarakis, 2010). Cost, logistics, and ethics are among the considerations that may guide researchers in the decision to use so-called lower-order animals when they can adequately model the system or disease of interest. Yet while mice and other animals that are evolutionarily more distant than NHPs from humans have been invaluable models in biomedical research, they lack certain features unique to primates and may not recapitulate key aspects of human diseases. For example, because of differences in anatomy (especially brain structure) and physiology, rodent models do not represent with fidelity the complete response of human immune and neurological systems across the lifespan (Buffalo et al., 2019; Hutchison and Everling, 2012; Wagar et al., 2018). Concerns regarding a poor rate of translation from bench to bedside have been attributed to such differences (Deutsch et al., 2012; Perlman, 2016). Indeed, one can point to numerous examples of the potential discovery of “cures” for human disease (e.g., cancer) in rodent models that were found not to be clinically relevant in humans (Kerbel, 1998; Mak et al., 2014). Whatever type of model is used, it must sufficiently recapitulate the human disease of interest to increase the likelihood that the data it yields will translate to humans at the clinical trial stage (Ferreira et al., 2020). For biological processes that are unique to primates, NHPs may be the best available model when research cannot be conducted in humans or with human cells or tissues.
That being said, the translatability of even the best available model is not perfect, an observation that has led to questions of whether animal models should be used at all (Pound and Ritskes-Hoitinga, 2018). While NHPs are generally more similar to humans than are mice, species-specific differences still contribute to limitations in predictive validity. For example, the CD28-specific monoclonal antibody TGN1412, which was found to be safe in nonclinical toxicity testing using NHPs, in combination with other animal models, caused unexpected morbidity during first-in-human clinical trials (Pallardy and Hünig, 2010; Suntharalingam et al., 2006) owing to human-specific T cell subtype expression of CD28 unknown at the time. This experience highlights the nature of scientific inquiry, in which the process of reconciling results leads to new understanding and medical breakthroughs. Yet despite examples in which predictive validity has been imperfect, there are numerous examples in which NHP models have proven essential when the necessary testing could not be performed
otherwise. Examples of research in which NHP models have provided critical insights into the human condition and contributed to health advances are highlighted in Chapter 2.
Translational relevance, and thus the suitability of NHPs as model systems, varies across different NHP species for different applications (Cauvin et al., 2015). Moreover, it is worth emphasizing that NHPs are not the most appropriate or only large-animal models for studying all human diseases, including some that contribute substantially to the public health burden in the United States. For example, similarities in the anatomy of pigs and humans make pigs suitable large-animal models for studying atherosclerosis (heart disease) (Hamamdzic and Wilensky, 2013), gastrointestinal disease (Sangild et al., 2014), and some aspects of the renal system (Dalgaard, 2015; Gutierrez et al., 2015).
Other factors beyond translational relevance may make an animal model more or less suitable for use in research. For example, experience with a given species may also be a consideration, as the ability to compare data with findings of past studies may add value to the use of a particular model (Singh and Olabisi, 2017). Moreover, the transition to a different species may initially require adjusting the number of animals to meet the need for a fully characterized new model (Golding et al., 2018). At the same time, however, it is important to guard against letting the availability of historical data alone justify the continued use of any animal model (NASEM, 2020).
Aside from suitability, feasibility may be a consideration in the use of a particular model. Feasibility may be affected by such factors as access, cost, and the ability to meet the care needs of the animal (e.g., housing and veterinary services). Such factors are not to be used to justify the use of a less appropriate model. Ultimately, it is important to use the best model or combination of models, whether animal or not, to answer the question at hand.
Oversight of Care and Use of NHPs in Research
When the best model for a given scientific study is an NHP model, the welfare of the animals and the scientific need to use them are addressed by a robust body of laws, regulations, and policies that guide oversight practices from the federal to the local level, as depicted in Figure 1-2.
Evaluation of Scientific Merit
Like all research proposals submitted to NIH, research proposals involving NHP models receive careful and comprehensive evaluation. The process of obtaining NIH funding is highly competitive. Only a small proportion of proposals receive funding following a peer review process that evaluates the project’s scientific merit, experimental design, and potential for impact to the field. This process is conducted for intramural proposals by scientific merit committees (Denny, 2022) and for extramural proposals by NIH scientific review groups (also known as study sections) composed of researchers with expertise in the areas under study (NIH, 2021c). Most NIH institutes fund proposals judged to be within the top 20 percent of those submitted, although specific percentile cutoff points vary by institute and year (Fang et al., 2016).
For proposals involving the use of NHPs, Principal Investigators (PIs) are required in a separate “vertebrate animals section” of the grant application to justify their need for an NHP model and the number of NHPs required for the work (NIH, 2021a). They must also specify how any potential animal pain and distress will be minimized throughout the study. Review of this section of the grant application is part of the rigorous scientific and technical merit review conducted by the study section. Given that all animal research projects funded by
*Grant versus protocol review is a process whereby an institution’s Research Administration Services reviews the grant and the protocol side-by-side (often together with IACUC staff) and confirms that everything funded by the grant is approved in the IACUC protocol.
NOTES: ACP = animal care policy; AWAR = Animal Welfare Act and Animal Welfare Regulations; HREA = Health Research Extension Act; IACUC = institutional animal care and use committee; NIH = National Institutes of Health; OLAW = Office of Laboratory Animal Welfare; PHS Policy = Public Health Service Policy on Humane Care and Use of Laboratory Animals; the Guide = the National Research Council’s Guide for the Care and Use of Laboratory Animals; USDA = U.S. Department of Agriculture. Accreditation from AAALAC International, an independent international accrediting agency for animal research facilities, is voluntary.
NIH must be judged by peer reviewers to have strong scientific and technical merit, NIH’s funding of a study using NHPs constitutes strong evidence of the likelihood that it will add significant scientific value.
Protection of NHP Welfare
High standards of animal welfare are integral to high-quality science, and multiple layers of oversight are built into the process of ensuring appropriate care and use of NHPs in research. Researchers carrying out work with NHPs, along with animal care staff employed by investigators and research facilities and veterinarians in these facilities, seek to protect and promote the maximum welfare of NHPs.
Before beginning any work involving NHPs (and independently of the project’s source of funding), a PI must receive approval from the institution’s institutional animal care and use committee (IACUC). IACUCs are legally obligated to apply all relevant laws, regulations, and policies aimed at ensuring that research animals are not subjected to unnecessary pain, distress, or discomfort and are afforded care and housing that is conducive to their comfort
and well-being (NIH, 2021b). IACUC review occurs concurrently with or following input from a veterinarian with experience in the use of NHPs in research, who works closely with the researchers to optimize their protocol so that the animals are handled appropriately, and procedures that may cause pain or distress are minimized and managed effectively. In reviewing research projects involving NHPs and their potential impact on the animals’ welfare, IACUCs receive input from all their members, including scientist and veterinarian members, nonscientist members, and members who represent community interests in the proper care and treatment of animals. This review includes application of the 3Rs, described in Box 1-3. In any proposed project involving NHPs funded by NIH, the IACUC must also determine that an NHP model is required to address the questions posed by the project; that no more NHPs will be used than is necessary for addressing these questions; and that all animals receive appropriate housing, care, and environmental enrichment that fosters species-typical behaviors and well-being.
IACUCs receive their authority from federal law, specifically from the AWA and the Health Research Extension Act (HREA) of 1985.5 Protection of NHP welfare by institutions and investigators is overseen by USDA (pursuant to the AWA); NIH’s Office of Laboratory Animal Welfare (OLAW) (pursuant to the HREA); and for a number of research institutions, AAALAC International (AAALAC), an independent international accrediting agency for animal research facilities (AAALAC, n.d.). Institutions can seek accreditation from AAALAC, whose standards of animal care exceed even those of USDA and OLAW. AAALAC accreditation is not compulsory, but OLAW regards it as evidence of the highest standards of care (Na and Diggs, 2021; Newcomer, 2012).
The AWA authorizes and directs USDA to issue and enforce regulations to implement its provisions. These regulations include standards for humane handling, housing, husbandry, veterinary care, and transportation of NHPs and other species covered by the Act. In accordance with the AWA and its associated Animal Welfare Regulations (AWAR) (APHIS, 2022b), all registered institutions must report annually to USDA the number of NHPs being held or used for research purposes. Institutions must also report the number of animals used in research that experienced no pain or distress; the number that received anesthetics, analgesics, or tranquilizers to prevent or relieve potential pain or distress; and the number that experienced unrelieved pain or distress. An explanation of any procedures that cause pain or distress and the reasons such drugs were or were not used must be provided with the report. The AWA and its associated regulations require investigators to prevent or minimize pain and distress whenever possible and to consider alternative procedures to avoid pain and distress. In addition to requiring yearly written updates from the research institution, USDA conducts unannounced inspections of all research facilities at least once yearly, during which inspectors examine the animals’ housing environment, the locations where research with the animals is conducted, and the IACUC’s processes for providing oversight to ensure that they accord with the AWAR.
Section 495 of the HREA covers all extramural research on vertebrate animals that is funded by NIH or the Public Health Service. Like the AWA, the HREA requires the humane care and treatment of animals used in research that are covered by the Act. The HREA authorizes and directs NIH to issue and enforce standards pursuant to the Act, a mandate that has been delegated to OLAW. OLAW has incorporated into its animal use and care standards the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (U.S. Principles) (Office of Science and Technology Policy, 1985; OLAW, 2018), which were originally adopted by NIH and other federal agencies for
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5 P.L. 99-158.
animal research they conduct or require to be conducted by others. OLAW has also incorporated into its animal care standards the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy) (OLAW, 2015) and the National Research Council’s Guide for the Care and Use of Laboratory Animals (the Guide) (NRC, 2011). Although the HREA does not cover research conducted intramurally within NIH itself, NIH has adopted the U.S. Principles, the PHS Policy, and the Guide for its use of NHPs and other vertebrates in intramural research.
Guidance regarding the role of the IACUC, the protocol review process, and how IACUCs should determine whether animal welfare is being protected in a research setting is provided by the AWAR, USDA animal care policies,6 the U.S. Principles, the PHS Policy, and the Guide, among other documents. Significant deviations from policies and requirements of the HREA and OLAW or from procedures and care and treatment of animals approved by the IACUC must be reported promptly to OLAW, which is authorized to take remedial action, which may include withdrawing funding from a particular research project or prohibiting an investigator or institution from conducting further research using NHPs.
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6 The USDA Animal Care Policy Manual is available at https://naldc.nal.usda.gov/catalog/7219640 (accessed January 15, 2023).
The Critical Need for a New Look at the Landscape for NHP Research
In conducting its landscape analysis, the committee benefited from previous efforts to characterize the landscape of NIH-supported research using NHPs; those prior reports (see Box 1-4) provided an invaluable foundation for the committee’s work. However, this report differs from past efforts in that it focuses not only on the current and future use of NHPs in biomedical research but also on the opportunities for emerging technologies and innovative approaches to complement such research and/or reduce future reliance on NHPs as model
systems. Moreover, supply and demand for NHPs for biomedical research have changed dramatically in the past few years, driving a need for a critical evaluation of the state of NHP resources and their ability to support current and future priorities for NIH-funded research.
In 2020, two major related events occurred in rapid succession that drastically altered the landscape for NHP research in the United States and globally. The emergence of SARS-CoV-2 and the subsequent elevation of COVID-19 to pandemic status in early 2020 spurred a significant increase in demand for NHPs as scientists across the globe raced to understand the pathogenesis of the novel coronavirus and to develop treatments and vaccines. Shortly after the emergence of SARS-CoV-2, China, previously the largest supplier of monkeys for research to the United States,7 banned the export of all NHPs. The export ban, along with existing policies of major airlines prohibiting the transport of NHPs (Grimm, 2018; Wadman, 2012), exacerbated supply issues at a time of heightened demand and necessitated the prioritization of NHPs from other sources for COVID-19 research. As discussed in Chapter 3, these events have impacted the ability of researchers in scientific disciplines apart from COVID-19 research to access NHPs and conduct studies requiring them as models. In this context of increasing external pressures and demand for highly valuable NHP research resources, the present report provides a timely update of previous assessments of the landscape for NHP research, including the status of NHP availability for use in NIH-supported biomedical research.
STUDY APPROACH
Committee Formation
The necessary expertise for a National Academies consensus committee is guided by the study’s Statement of Task. To respond to its charge (Box 1-1), the National Academies convened a 16-member committee with expertise in NHP research (including primatology and primate behavior/psychology/welfare in wild and captive contexts), veterinary medicine, pathology, in vitro and in silico models, clinical research, and ethics. Because the committee was charged with analyzing the current and future landscape of continued NHP use, researchers who have used NHPs in their research and are knowledgeable regarding the opportunities and challenges associated with and alternatives to using NHP model systems represented critical areas of expertise for the committee. While it was not feasible to represent every field in which NHPs are used in biomedical research, efforts were made to ensure representation across multiple scientific disciplines (e.g., neuroscience and psychology, infectious disease, reproductive health), phases of the research pipeline (e.g., basic, translational, clinical), and NHP model systems (e.g., macaques, marmosets, baboons, capuchins). Similarly, researchers using different nonanimal models that may be classified as new approach methodologies (e.g., microphysiological systems, organoids, artificial intelligence/machine learning) were sought. Biographical sketches of the committee members can be found in Appendix C.
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7 In 2019, more than 30,000 NHPs were imported into the United States, and approximately 60 percent of those animals were imported from China (based on NHP importation data provided to the committee on February 10, 2023; available by request through the National Academies’ Public Access Records Office).
Information Gathering and Public Input
Public Meetings
The committee met and deliberated over a roughly 1-year period (April 2022–April 2023). During this time, the committee held three public information-gathering meetings (April, August, and November 2022). The committee’s first public meeting, in April 2022, provided an opportunity to hear the study charge from NIH and to clarify any issues of scope. A public workshop held in conjunction with the August 2022 meeting included sessions on NHP research from the perspective of funders, domestic breeding resources, and investigators. It also included a session on emerging technologies and innovative methodologies with the potential to refine, reduce, and replace the use of NHPs in NIH-supported biomedical research. A public meeting held in November 2022 provided further opportunity for the committee to hear from the NIH Office of Research Infrastructure Programs and representatives of individual NIH institutes, centers, and offices that support NHP research. This meeting also included a session with researchers involved with or having insights on the use of new approach methodologies to complement or reduce reliance on NHP research.
Literature Review
Multiple literature reviews were conducted throughout this study using PubMed and Scopus. These searches guided and provided references for content in this report describing current uses of NHPs in biomedical research and the current state of new approach methodologies. More information on the committee’s literature review strategy, including search terms, can be found in Appendix A.
Information Requests and Survey
To supplement the evidence available from the published literature, the committee gathered additional information from stakeholders who support or are engaged in NHP research (detail is provided in Appendix A). Information requests were sent to NIH, FDA, the Centers for Disease Control and Prevention, the National Primate Research Centers (NPRCs), National Resources,8 and other selected institutions with NIH-supported breeding colonies. Experiences and perspectives of individual investigators with NIH awards supporting NHP research were solicited through an online survey (details on the survey methodology can be found in Appendix A, while a presentation of analyses of data collected by the committee can be found in Appendix B and a copy of the survey with frequency tables can be found in Appendix E).
Public Comments
Members of the public were given an opportunity to submit questions and comments during the committee’s first meeting in April 2022 and could also submit comments and documents for the committee’s consideration through the project website at any time during the course of the study. The committee received and reviewed more than 4,500 public comments related to its task.
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8 For the purposes of this report, “National Resources” include the four non-NPRC institutions with NHP breeding colonies identified by ORIP: the Michale E. Keeling Center for Comparative Medicine and Research (MD Anderson Cancer Center), The Johns Hopkins University, Wake Forest University, and the Caribbean Primate Research Center (see Chapter 3).
Data Limitations and Challenges Related to Information Gathering
Despite efforts to conduct a comprehensive assessment of the landscape of NHP use in NIH-supported biomedical research, the committee experienced difficulties related to data access. In contrast to the publicly available data systems in the EU for tracking numbers and uses of research animals, centralized data collection on NHPs in the United States is limited to data compiled by USDA, which do not include species-level data or information on specific research applications. While the NIH RePORTER tool9 provides a mechanism for searching active NIH awards for projects in which NHPs are referenced, limited information is included in the public project descriptions, and not all projects that include references to NHPs involve use of the animals (some may refer to past NHP research, for example). In contrast to the analysis undertaken for the NIH report on NHP supply and demand (ORIP, 2018a), the committee lacked access to internal NIH data systems containing detailed information from NIH award applications (e.g., information on research domain, NHP species, quantity of NHPs planned for use, justification for the choice of model). Much of that information is contained in the vertebrate animals section of the application, which is not included in the information publicly available on NIH RePORTER.
Given the above challenges, an accurate, detailed, quantitative accounting of the use and availability of NHPs in NIH-supported research was not feasible for this study. As a result, the committee included quantitative information in its description of the NHP research landscape only when such data were available and when confidence in the validity of the data was warranted.
ORGANIZATION OF THE REPORT
This report is organized into five chapters. Following this introductory chapter, Chapter 2 provides an overview of the contribution of NHP research to advances in human health. Chapter 3 presents the current landscape of NHP use and availability for NIH-supported intramural and extramural biomedical research. In Chapter 4, the committee examines the status of new approach methodologies with the potential to complement NHP research or reduce reliance on NHP models. Chapter 5 describes the future needs and opportunities for NHPs in NIH-funded biomedical research. Appendix A details the methods used by the committee in conducting this study, while Appendix B provides additional supporting data for the landscape analysis presented in Chapter 3. Biographical sketches of the committee members and disclosures regarding the members’ conflicts of interest can be found in Appendixes C and D, respectively. Appendix E includes a copy of the survey provided to NIH-supported NHP researchers and frequency tables of responses.
REFERENCES
AA (Alzheimer’s Association). 2022. 2022 Alzheimer’s disease facts and figures: Special report more than normal aging: Understanding mild cognitive impairment. Chicago, IL: Alzheimer’s Association.
Alfson, K. J., Y. Goez-Gazi, M. Gazi, H. Staples, M. Mattix, A. Ticer, B. Klaffke, K. Stanfield, P. Escareno, P. Keiser, A. Griffiths, Y. L. Chou, N. Niemuth, G. T. Meister, C. M. Cirimotich, and R. Carrion, Jr. 2021. Development of a well-characterized rhesus macaque model of Ebola virus disease for support of product development. Microorganisms 9(3).
___________________
9 RePORTER stands for Research Portfolio Online Reporting Tools (see https://reporter.nih.gov [accessed December 12, 2022]).
Anderson, D. M. 2008. The nonhuman primate as a model for biomedical research. In Sourcebook of models for biomedical research, edited by P. M. Conn. Totowa, NJ: Humana Press. Pp. 251-258.
APHIS (Animal and Plant Health Inspection Service). 2021. Annual report: Animal usage by fiscal year 2019. United States Department of Agriculture. Washington, DC: U.S. Department of Agriculture.
APHIS. 2022a. Research facility annual usage summary report (FY2019-FY2021). https://www.aphis.usda.gov/aphis/ourfocus/animalwelfare/sa_obtain_research_facility_annual_report/ct_research_facility_annual_summary_reports (accessed January 24, 2023).
APHIS. 2022b. USDA animal care: Animal Welfare Act and Animal Welfare Regulations. APHIS 41-35-076. Washington, DC: U.S. Department of Agriculture.
AALAC. n.d. About aaalac. https://www.aaalac.org/about/what-is-aaalac/ (accessed January 24, 2023).
Bales, K. L., R. Arias Del Razo, Q. A. Conklin, S. Hartman, H. S. Mayer, F. D. Rogers, T. C. Simmons, L. K. Smith, A. Williams, D. R. Williams, L. R. Witczak, and E. C. Wright. 2017. Titi monkeys as a novel non-human primate model for the neurobiology of pair bonding Yale Journal of Biology and Medicine 90(3):373-387.
Baxter, V. K., and D. E. Griffin. (2016). Animal models: No Model is perfect, but many are useful. In Viral pathogenesis, 3rd ed., edited by M. G. Katze, M. J. Korth, G. L. Law, and N. Nathanson. Boston, MA: Academic Press. Pp. 125-138.
Bradford, Y. M., S. Toro, S. Ramachandran, L. Ruzicka, D. Howe, A. Eagle, P. Kalita, R. Martin, S. Taylor Moxon, K. Schaper, and M. Westerfield. 2017. Zebrafish models of human disease: Gaining insight into human disease at ZFIN. Institute for Laboratory Animal Research 58(1):4-16.
Buffalo, E. A., J. A. Movshon, and R. H. Wurtz. 2019. From basic brain research to treating human brain disorders. Proceedings of the National Academy of Sciences 116(52):26167-26172.
CDC (Centers for Disease Control and Prevention). 2021. Leading causes of death. https://www.cdc.gov/nchs/nvss/leading-causes-of-death.htm#publications (accessed March 3, 2023).
Collins, F. S. 2015. NIH will no longer support biomedical research on chimpanzees. National Institutes of Health, November 17. https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-will-no-longer-supportbiomedical-research-chimpanzees (accessed March 3, 2023).
Dalgaard, L. 2015. Comparison of minipig, dog, monkey and human drug metabolism and disposition. Journal of Pharmacological and Toxicological Methods 74:80-92.
de Swart, R. L. 2009. Measles studies in the macaque model. Current Topics in Microbiology and Immunology 330:55-72.
Denayer, T., T. Stöhr, and M. Van Roy. 2014. Animal models in translational medicine: Validation and prediction. New Horizons in Translational Medicine 2(1):5-11.
Denny, S. 2022. Intramural Research Program. Presentation at Committee on the State of the Science and Future Needs for Nonhuman Primate Model Systems Meeting #3, Washington, DC, August 25.
Deutsch, S. I., M. R. Urbano, and C. Zemlin. 2012. Mouse models have limitations for development of medications for autism spectrum disorders, but also show much promise. Future Neurology 7(1):1-4.
Eaton, S. L., and T. M. Wishart. 2017. Bridging the gap: Large animal models in neurodegenerative research. Mammalian Genome 28(7):324-337.
European Commission. 2022. Summary report on the statistics on the use of animals for scientific purposes in the member states of the European Union and Norway in 2019. Brussels, Belgium: European Commission.
Fang, F. C., A. Bowen, and A. Casadevall. 2016. NIH peer review percentile scores are poorly predictive of grant productivity. eLife 5:e13323. https://doi.org/10.7554/elife.13323
FDA (U.S. Food and Drug Administration). 2017. FDA’S predictive toxicology roadmap. https://www.fda.gov/media/109634/download (accessed March 3, 2023).
Ferreira, G. S., D. H. Veening-Griffioen, W. P. C. Boon, E. H. M. Moors, and P. J. K. van Meer. 2020. Levelling the translational gap for animal to human efficacy data. Animals (Basel) 10(7).
Friedman, H., N. Ator, N. Haigwood, W. Newsome, J. S. Allan, T. G. Golos, J. H. Kordower, R. E. Shade, M. E. Goldberg, M. R. Bailey, and P. Bianchi. 2017. The critical role of nonhuman primates in medical research. Pathogens & Immunity 2(3):352-365.
Golding, H., S. Khurana, and M. Zaitseva. 2018. What is the predictive value of animal models for vaccine efficacy in humans? The importance of bridging studies and species-independent correlates of protection. Cold Spring Harbor Perspectives in Biology 10(4).
Grimm, D. 2018. Airlines fight effort to force them to carry lab animals. Science, October 2. https://www.science.org/content/article/airlines-fight-effort-force-them-carry-lab-animals (accessed March 3, 2023).
Gutierrez, K., N. Dicks, W. Glanzner, L. Agellon, and V. Bordignon. 2015. Efficacy of the porcine species in biomedical research. Frontiers in Genetics 6.
Hamamdzic, D., and R. L. Wilensky. 2013. Porcine models of accelerated coronary atherosclerosis: Role of diabetes mellitus and hypercholesterolemia. Journal of Diabetes Research 761415.
Hutchison, R. M., and S. Everling. 2012. Monkey in the middle: Why non-human primates are needed to bridge the gap in resting-state investigations. Frontiers in Neuroanatomy 6:29. https://doi.org/10.3389/fnana.2012.00029
IOM (Institute of Medicine). 2011. Chimpanzees in biomedical and behavioral research: Assessing the necessity. Edited by B. M. Altevogt, D. E. Pankevich, M. K. Shelton-Davenport, and J. P. Kahn. Washington, DC: The National Academies Press.
Kerbel, R. S. 1998. What is the optimal rodent model for anti-tumor drug testing? Cancer Metastasis Review 17(3):301-304.
Mak, I. W., N. Evaniew, and M. Ghert. 2014. Lost in translation: Animal models and clinical trials in cancer treatment. American Journal of Translational Research 6(2):114-118.
Markaki, M., and N. Tavernarakis. 2010. Modeling human diseases in Caenorhabditis elegans. Biotechnology Journal 5(12):1261-1276.
McBride, J. L., M. Neuringer, B. Ferguson, S. G. Kohama, I. J. Tagge, R. C. Zweig, L. M. Renner, T. J. McGill, J. Stoddard, S. Peterson, W. Su, L. S. Sherman, J. S. Domire, R. M. Ducore, L. M. Colgin, and A. D. Lewis. 2018. Discovery of a CLN7 model of Batten disease in non-human primates. Neurobiology of Disease 119:65-78.
Mercier, F., L. R. Witczak, and K. L. Bales. 2020. Coppery titi monkey (Plecturocebus cupreus) pairs display coordinated behaviors in response to a simulated intruder. American Journal of Primatology 82(7):e23141.
Na, J., and H. Diggs. 2021. What every IACUC should know about AAALAC International. OLAW Webinar, September 9. [Slide deck]. https://olaw.nih.gov/sites/default/files/Webinar%20Slides%20What%20Every%20IACUC%20Should%20Know%20About%20AAALAC%20International.pdf (accessed March 21, 2023).
NASEM (National Academies of Sciences, Engineering, and Medicine). 2020. Necessity, use, and care of laboratory dogs at the U.S. Department of Veterans Affairs. Washington, DC: The National Academies Press.
Newcomer, C. E. 2012. The evolution and adoption of standards used by AAALAC. Journal of the American Association for Laboratory Animal Science 51(3):293-297.
NHGRI (National Human Genome Research Institute). 2015. Frequently asked questions about NHGRI research. https://www.genome.gov/12011002/about-nhgri-research-fact-sheet (accessed January 13, 2023).
NIGMS (National Institute of General Medical Sciences). 2023. Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR). https://nigms.nih.gov/grants-and-funding/research-funding/small-business-research (accessed March 1, 2023).
NIH (National Institutes of Health). 2016. NIH workshop on ensuring the continued responsible oversight of research with non-human primates: Final report. https://osp.od.nih.gov/wp-content/uploads/NHP_NIH_Workshop_Report_01_18_2017.pdf (accessed March 3, 2023).
NIH. 2020. Fostering rigorous research: Lessons learned from nonhuman primate models and charting the path forward. February 18-19, 2020, Bethesda, MD. https://osp.od.nih.gov/wp-content/uploads/NHP_Workshop_Report_FINAL_20200218.pdf (accessed March 3, 2023).
NIH. 2021a. Vertebrate animals section. https://olaw.nih.gov/guidance/vertebrate-animal-section.htm (accessed January 27, 2023).
NIH. 2021b. The IACUC. https://olaw.nih.gov/resources/tutorial/iacuc.htm (accessed January 27, 2023).
NIH. 2021c. Peer review. https://grants.nih.gov/grants/peer-review.htm (accessed January 27, 2023).
NIH. 2022. Statement from NIH and BARDA on the Novavax COVID-19 vaccine. https://www.nih.gov/news-events/news-releases/statement-nih-barda-novavax-covid-19-vaccine (accessed March 1, 2023).
NRC (National Research Council). 2011. Guide for the care and use of laboratory animals, 8th ed. Washington, DC: The National Academies Press.
OECD (Organisation for Economic Co-operation and Development). 2005. Joint meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides, and Biotechnology. https://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd-gd34.pdf (accessed March 3, 2023).
Office of Science and Technology Policy. 1985. U.S. government principles for utilization and care of vertebrate animals used in testing, research, and training. Federal Register 50(97):20864-20865.
OLAW (Office of Laboratory Animal Welfare). 2015. PHS policy on humane care and use of laboratory animals. https://olaw.nih.gov/policies-laws/phs-policy.htm (accessed January 13, 2023).
OLAW. 2018. U.S. government principles for the utilization and care of vertebrate animals used in testing, research, and training. https://olaw.nih.gov/policies-laws/gov-principles.htm (accessed January 13, 2023).
ORIP (Office of Research Infrastructure Programs). 2018a. Nonhuman primate evaluation and analysis Part 1: Analysis of future demand and suppy. National Institutes of Health. https://orip.nih.gov/about-orip/research-highlights/nonhuman-primate-evaluation-and-analysis-part-1-analysis-future (accessed March 21, 2023).
ORIP. 2018b. Nonhuman primate evaluation and analysis Part 2: Report of the expert panel forum on challenges in asssessing the nonhuman primate needs and resources for biomedical research. National Institutes of Health. https://orip.nih.gov/sites/default/files/NHP%20Evaluation%20and%20Analysis%20Final%20%20Report%20-%20Part%202%20Final%20508%2021Dec2018_002.pdf (accessed March 3, 2023).
Orkin, J. D., M. J. Montague, D. Tejada-Martinez, M. de Manuel, J. del Campo, S. Cheves Hernandez, A. Di Fiore, C. Fontsere, J. A. Hodgson, M. C. Janiak, L. F. K. Kuderna, E. Lizano, M. P. Martin, Y. Niimura, G. H. Perry, C. S. Valverde, J. Tang, W. C. Warren, J. P. de Magalhães, S. Kawamura, T. Marquès-Bonet, R. Krawetz, and A. D. Melin. 2021. The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS. Proceedings of the National Academy of Sciences 118(7):e2010632118.
Pallardy, M., and T. Hünig. 2010. Primate testing of TGN1412: Right target, wrong cell. British Journal of Pharmacology 161(3):509-511.
Peña Juliet, C., and W. Z. Ho. 2015. Monkey models of tuberculosis: Lessons learned. Infection and Immunity 83(3):852-862.
Perlman, R. L. 2016. Mouse models of human disease: An evolutionary perspective. Evolution, Medicine, and Public Health 2016(1):170-176.
Pound, P., and M. Ritskes-Hoitinga. 2018. Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. Journal of Translational Medicine 16(1):304.
Research!America. 2022. U.S. investments in medical and health research and development 2016-2020. Arlington, VA: Research!America.
Rijsbergen, L. C., L. L. A. van Dijk, M. F. M. Engel, R. D. de Vries, and R. L. de Swart. 2021. In vitro modelling of respiratory virus infections in human airway epithelial cells—A systematic review. Frontiers in Immunology 12:683002.
Russell, W. M. S., and R. L. Burch. 1959. The principles of humane experimental technique. North Yorkshire, UK: Methuen.
Sangild, P. T., D. M. Ney, D. L. Sigalet, A. Vegge, and D. Burrin. 2014. Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: Translational relevance and challenges. American Journal of Physiology-Gastrointestinal and Liver Physiology 307(12):G1147-G1168.
Singh, V. K., and A. O. Olabisi. 2017. Nonhuman primates as models for the discovery and development of radiation countermeasures. Expert Opinion on Drug Discovery 12(7):695-709.
Subbaraman, N. 2021. The US is boosting funding for research monkeys in the wake of COVID. https://www.nature.com/articles/d41586-021-01894-z (accessed March 17, 2023).
Suntharalingam, G., M. R. Perry, S. Ward, S. J. Brett, A. Castello-Cortes, M. D. Brunner, and N. Panoskaltsis. 2006. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. New England Journal of Medicine 355(10):1018-1028.
t’ Hart, B. A., J. D. Laman, and Y. S. Kap. 2018. Reverse translation for assessment of confidence in animal models of multiple sclerosis for drug discovery. Clinical Pharmacology and Therapeutics 103(2):262-270.
Takahashi, T., A. Higashino, K. Takagi, Y. Kamanaka, M. Abe, M. Morimoto, K. H. Kang, S. Goto, J. Suzuki, Y. Hamada, and T. Kageyama. 2006. Characterization of obesity in Japanese monkeys (Macaca fuscata) in a pedigreed colony. Journal of Medical Primatology 35(1):30-37.
Tannenbaum, J., and B. T. Bennett. 2015. Russell and Burch’s 3 Rs then and now: The need for clarity in definition and purpose. Journal of the American Association for Laboratory Animal Science 54(2):120-132.
Taylor, K., and L. R. Alvarez. 2019. An estimate of the number of animals used for scientific purposes worldwide in 2015. Alternatives to Laboratory Animals 47(5-6):196-213.
Trichel, A. M. 2021. Overview of nonhuman primate models of SARS-CoV-2 infection. Comparitive Medicine 71(5):411-432.
Varga, O. E., A. K. Hansen, P. Sandøe, and I. A. Olsson. 2010. Validating animal models for preclinical research: A scientific and ethical discussion. Alternatives to Laboratory Animals 38(3):245-248.
Veenhuis, R. T., and C. J. Zeiss. 2021. Animal models of COVID-19 II: Comparative immunology. Institute for Laboratory Animal Research Journal 62(1-2):17-34.
Wadman, M. 2012. Activists ground flying monkeys. Scientific American, March 20. https://www.scientificamerican.com/article/activists-ground-flying-monkey (accessed March 3, 2023).
Wagar, L. E., R. M. DiFazio, and M. M. Davis. 2018. Advanced model systems and tools for basic and translational human immunology. Genome Medicine 10(1):73.
Williams, L. 2008. Aging cebidae. In Primate reproductive aging, Vol. 36, edited by M. S. Atsalis and P. R. Hof. Basel, Switzerland: Karger. Pp. 49-61.
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