Summary1
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 models, 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 the animals used in biomedical research. NHPs 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 COVID-19 vaccines—have been enabled by fundamental basic and translational 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, a worsening shortage of NHPs, exacerbated by the COVID-19 pandemic and recent restrictions on their exportation and transportation, has had negative impacts on NIH-funded research necessary for both public health and national security. 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 expert committee 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.
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1 This summary does not include references. Citations for the discussion presented in the summary appear in the subsequent report chapters.
STUDY ORIGIN, STATEMENT OF TASK, AND SCOPE
In its Consolidated Appropriations Act of 2021,2 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 S-1) expanded the scope of the study beyond that described in the congressional language to include both intramural and extramural biomedical research using NHPs. The Statement of Task also charged the committee with determining the status of research, development, and validation efforts for new approach methodologies. The term “new approach methodologies” is often used to refer specifically to potential alternatives to animal models. In this report, new approach methodologies are defined broadly to include in vitro and in silico technologies and approaches that can be used to complement NHP studies or reduce reliance on NHPs in biomedical research.3 Complementary approaches can be used to fill gaps by answering research questions not fully answered by NHP models, extend understanding of the research conducted using NHPs, or confirm results from that research. Complementary approaches may or may not reduce reliance on NHPs, which can be achieved by substituting alternative models or decreasing the numbers of NHPs used in biomedical research.
The following aspects of NHP research were beyond the scope of this study, as clarified as needed during discussions with NIH representatives at the committee’s first meeting:
- NHP research funded by sponsors other than NIH. Based on this exclusion, this report does not include an in-depth analysis of the use of NHPs in industry-sponsored pharmaceutical safety and efficacy testing conducted as part of regulatory approval processes; however, indirect contributions of NIH-funded research to advances in available vaccines and treatments were considered within the study scope. In its assessment of gaps in NHP availability, the committee also considered the constraints imposed on NIH-funded biomedical research using NHP models by competing demands from other sponsors of NHP research (federal and nonfederal).
- Evaluation of the impact of biomedical research on NHP populations in the wild.
- The use of chimpanzees, other great apes, and non-NHP animal species as research models.
- Examination of ethical standards and principles that underlie NHP research, or current ethical issues and disputes relevant to this research. This report rests on 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; 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.
- The development of recommendations with criteria for determining when it is scientifically necessary to use NHPs. Such a task would have substantially altered the committee’s composition and its approach, and its exclusion distinguishes the
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2 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).
3 Of note, approaches that employ other species of animals as models (e.g., transgenic animals) to replace NHPs were beyond the scope of the committee’s charge and are not included within the committee’s definition of new approach methodologies.
- present study from other studies of the National Academies on the use of large animals—specifically, chimpanzees and dogs—as models in biomedical research.
- Prioritization of research disciplines in terms of their relative importance or the value of NHP models to each field of research.
In accordance with its Statement of Task, the committee presents in this report its findings and conclusions based on a landscape analysis of NIH-supported biomedical research. The committee’s analysis included a survey of 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 with respect to alternative and complementary model systems.
CURRENT LANDSCAPE OF USE OF NONHUMAN PRIMATES FOR NIH-SUPPORTED BIOMEDICAL RESEARCH
Contribution of NHP Models to Advances in Human Health
NHPs serve as models across many biomedical research areas, including infectious disease; immunology; social, cognitive, and behavioral research; reproduction; regenerative medicine; aging; and neuroscience research. No model, animal or otherwise, can fully mimic the complexities of the human body; all have limitations, but that does not negate their usefulness. There remain research questions that currently cannot be answered outside of the context of a living organism, and in some cases, NHPs may be the most translationally relevant animal model available.
Although NHPs represent a small fraction of animals used in biomedical research, their critical importance is evident in the number of medical advances that have relied on their use as models of human disease and disability. Through an iterative combination of fundamental basic and translational biomedical research, NHPs have contributed to and continue to inform the development of numerous medical products, including vaccines, therapeutics, and other treatment strategies, that have improved and preserved the quality of life in the United States and beyond. While it is not feasible for this report to provide a complete cataloging of human health advances enabled through NHP research, illustrative examples include the development of deep brain stimulation as a treatment for Parkinson’s disease; vaccines for polio, measles, Ebola, and COVID-19; treatments for human immunodeficiency virus (HIV) and sickle cell disease; and monoclonal antibodies that reduce graft rejection in transplant patients. In each of these cases, NHPs played an essential role because
- vital elements of the research could not be conducted in humans for ethical or logistical reasons;
- nonanimal models (in vitro and in silico) could not fully recapitulate the integrative systems biology required in these specific contexts to demonstrate the effectiveness and safety of the preventive or therapeutic approach;
- other animal models lacked necessary anatomical, physiological, and/or biomolecular structures and processes required to model the human disease condition reliably; and
- the predictive validity of the NHP model was high because of its ability to recapitulate key aspects of the human disease.
Based on this assessment, the committee reached the following conclusions:
Conclusion 2-1: Nonhuman primates have contributed to numerous human health advances that have improved and preserved countless lives, demonstrating a track record of unique predictive relevance critical for supporting ongoing fundamental basic and translational research missions of the National Institutes of Health.
Conclusion 2-2: Nonhuman primate research resources continue to be vital to the nation’s ability to respond to public health emergencies, such as the recent COVID-19 pandemic.
Current Use and Availability of NHPs for NIH-Supported Biomedical Research
In examining the state of NHP use in NIH-supported biomedical research, the committee used as a starting point the 2018 report of the NIH Office of Research Infrastructure Programs (ORIP), Nonhuman Primate Evaluation and Analysis. The ORIP report provides a snapshot of NHP research priorities and NHP supply and demand from fiscal years 2013 to 2017. A key finding in that report is that the availability of NHPs at the time was insufficient to meet the projected demand for NIH-sponsored biomedical research. Those challenges related to NHP supply and demand have since been exacerbated by external events—the COVID-19 pandemic, which spurred a significant increase in demand for NHPs to support the development of vaccines and treatments for SARS-CoV-2, and a ban by China on all exports of NHPs.4 These challenges have been magnified by persistent inaction on addressing long-recognized NHP supply-and-demand issues. Consequently, this report addresses the need to reevaluate the state of NHP resources and their ability to support current and future priorities for NIH-funded research.
To inform its landscape analysis of current NHP use and availability, the committee collected information from NIH, the Centers for Disease Control and Prevention, the U.S. Department of Agriculture, the seven National Primate Research Centers (NPRCs), seven other institutions that receive NIH support for NHP breeding colonies,5 and more than 200 NIH-supported NHP investigators who responded to a committee-generated survey. Based on these data, the committee found that the NHP shortage projected in the 2018 ORIP report has been exceeded, and that its current severity limits not only immediate research capabilities but also the nation’s ability to conduct critical public health research years into the future. This threat is evidenced by the following findings from the committee’s assessment:
- The absolute numbers of NHPs held or used for research purposes have decreased over the past decade.
- A more than 20 percent reduction in cynomolgus macaque imports was reported in 2020 following China’s export ban, highlighting the vulnerability of NHP research caused by undue reliance on imported NHPs subject to geopolitical pressures and logistical constraints that jeopardize reliable access.
- Approximately 64 percent of respondents to the committee’s survey reported challenges with obtaining NHPs for their currently funded NIH awards. For greater than half of all active NIH awards reported by survey respondents, fewer NHPs were enrolled than originally planned.
- In 2021, two-thirds of investigator requests for research-naïve macaques could not be met by the NPRCs because of a shortage of these animals.
- Impacts of NHP shortages have included increased wait times for NHP enrollment in studies and skyrocketing costs of individual NHPs (a 10–200 percent increase depending on the species and source).
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4 In 2019, more than 30,000 NHPs were imported into the United States, and approximately 60 percent of those animals were imported from China (data from the Centers for Disease Control and Prevention, Quarantine and Border Health Services).
5 Data were collected from the seven NPRCs and the four ORIP-recognized National Resources (the Michale Keeling Center at MD Anderson Cancer Center, The Johns Hopkins University, Wake Forest University, and the Caribbean Primate Research Center). Information was also collected from three additional research facilities with NIH awards supporting NHP breeding (the New Iberia Research Center, Alpha Genesis Inc., and the University of Pittsburgh). Together, these NIH-supported institutions provide NHPs to the NIH extramural and intramural research community.
While NIH and the NPRCs have taken initial steps to ameliorate the impacts of a limited supply of NHPs on NIH-supported biomedical research, these incomplete efforts represent only stopgap measures, not the sustained commitment of resources to existing NHP research infrastructure that is warranted by the current shortage. NPRCs and other institutions with NIH resource grants are the primary sources of NHPs for NIH-supported researchers. Accounting for inflation, funding in the form of base grants (P51 and P40 awards) for these institutions has generally declined over time, and increased supplemental funding provided by ORIP following its 2018 report and in 2020 through the Coronavirus Aid, Relief, and Economic Security (CARES) Act have not been sufficient to compensate for the decline. As a result of these budgetary shortfalls, these institutions have limited ability to expand breeding programs and infrastructure to meet domestic needs.
Based on this evaluation, the committee reached the following conclusions:
Conclusion 3-1: The shortage of nonhuman primate resources for National Institutes of Health (NIH)–supported biomedical research has continued to worsen, extending beyond concerns raised in the 2018 report of the NIH Office of Research Infrastructure Programs. This resource shortage has been exacerbated by export and transportation restrictions and global public health emergencies.
Conclusion 3-2: Without decisive action and a national commitment to a comprehensive plan for nonhuman primate (NHP) availability, the ability of National Institutes of Health (NIH)–supported extramural program investigators to conduct studies requiring the use of an NHP model will become a function more of access to NHPs than of a concerted response to national public health priorities. The core tenet of NIH that the most meritorious research should receive the highest priority will thereby be threatened.
Conclusion 3-3: Inadequate nonhuman primate (NHP), physical, financial, and human resources, along with the high costs of NHPs, severely limit the ability of National Institutes of Health–supported research programs to respond adequately to public health emergencies, as well as to carry out high-impact biomedical research requiring NHP models.
Conclusion 3-4: Biomedical and public health research in the United States is threatened by dependence on imported nonhuman primates (NHPs). This reliance on external resources is unsustainable and undermines the security of the U.S. biomedical research enterprise. To ensure that NHP resources are available to respond to public health threats, the United States needs to prioritize expansion of domestic NHP breeding programs.
Conclusion 3-5: The National Institutes of Health (NIH) has no central data management or reporting structure across its intramural and extramural programs to provide accurate tracking of the numbers of nonhuman primates (NHPs) required to meet current and future research needs. NIH thus has no way to collect the quantitative data needed to implement a comprehensive strategic management plan for its NHP research and resource portfolio.
Conclusion 3-6: Inadequate coordination of nonhuman primate (NHP) resources and research programs at the national level contributes to missed opportunities and diminished opportunities for efficient use of limited NHP resources.
Conclusion 3-7: Although the 2018 report of the National Institutes of Health Office of Research Infrastructure Programs (ORIP) identified a serious shortage of nonhuman primate (NHP) resources that was likely to worsen in the future, support for the ORIP-funded national NHP resource infrastructure remains inadequate.
Conclusion 3-8: Inadequate support for national nonhuman primate (NHP) resources by the National Institutes of Health (NIH) Office of Research Infrastructure Programs represents a major threat to NIH-supported NHP research programs nationwide. Funding will have to address current and future needs and the infrastructure required to support them.
POTENTIAL OF NEW APPROACH METHODOLOGIES TO COMPLEMENT OR REDUCE RELIANCE ON NHP MODELS
Use of NHPs in research comes with many challenges, and investigators using them have been clear about their interest in replacing NHPs with other models as their ability to answer the scientific questions under study can be established. New approach methodologies have been used to answer diverse questions of biomedical relevance, and ongoing research efforts continue to explore their potential to
- improve the translatability of nonclinical research by providing data that optimally reproduce the human condition;
- extend current knowledge of human diseases and provide opportunities to gain additional insights, as well as identify knowledge gaps;
- address shortages in the supply of NHPs by reducing the numbers required for biomedical research; and
- replace the use of NHPs.
Translational relevance, the primary goal for any model system intended to improve understanding of the human condition, is demonstrated through widely accepted qualification and/or validation pathways that establish the reliability and reproducibility of a new technology or approach within a defined context of use.6 Even when data derived from a new approach methodology is used to address a fundamental research question, in contrast to explicit regulatory decision making, there should be confidence that the approach will produce data that can be reliably used for the intended purpose. The intended purpose will in turn determine the appropriate level of qualification or validation required to provide that confidence in the approach. Notably, the committee found evidence that the Food and Drug Administration is supportive of new approach methodologies and has developed guidance and programs to advance their use in regulatory decision making as in vitro and in silico models are qualified. In the absence of qualification or validation, enthusiasm for new technologies and approaches must be tempered to avoid overpromising their capabilities as valid replacements for necessary and proven experimental systems. It should be emphasized, however, that the value of in vitro and in silico models is not limited to their ability to reduce reliance on NHPs. These models are often used in ways that are complementary to NHP studies and that can help to answer different kinds of scientific questions, including questions that cannot be answered using NHP models.
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6 Context of use denotes the manner and purpose of use for a technology or approach (how and when it will be used).
In Vitro Models
The discovery of human induced pluripotent stem cells (iPSCs) has transformed cell systems and their use by scientists to answer critical human health questions. Under specific differentiation conditions, most human tissue and organ cell types can now be reliably generated from iPSCs. These tractable and renewable cell systems can be used to generate foundational knowledge regarding human gene functions, biochemistry, physiology, and molecular mechanisms. Additionally, iPSCs generated from patients provide unprecedented opportunities for revealing disease-related phenotypes; understanding pathology; identifying disease-specific biomarkers; and screening for potential treatments, including personalized treatment strategies.
Two-dimensional cell cultures are the most simplified cellular model systems. Recent advances in bioengineering have led to the generation of three-dimensional human tissue–specific organoids and microphysiological systems (MPS; commonly referred to as organ or tissue chips) that resemble human tissues/organs in cell-type composition; architecture; and, to a certain extent, function. As such, they represent physiologically relevant in vitro models.
The committee identified numerous ways in which in vitro models are being used to complement NHP research—for example, in the study of pathogen–host interactions—but few concrete examples of a demonstrated role in reducing reliance on NHPs. One of the best examples of reduced reliance is testing to predict cytokine-mediated toxicity associated with biological therapeutics, such as monoclonal antibodies, using in vitro immunoassays. Yet while organoids and MPS have successfully mimicked many aspects of the complex physiology of organs and even interactions among organ systems, they cannot in their current state be used to replicate the full complexity of in vivo systems or to study processes that require systemic regulation. Therefore, these in vitro systems cannot yet be used to answer human health and safety questions that require this level of complexity. Furthermore, certain outcomes, such as behavior, can reliably be studied only using living organisms. Results from studies using in vitro models can, however, be used to inform the design of experiments using NHPs so as to reduce reliance on these animal models. For example, initial drug screening conducted in vitro can identify promising candidates that can then be tested and validated in vivo, ultimately limiting the number of NHPs used to evaluate drug candidates and potentially reducing the likelihood that subsequent testing in NHPs will cause harm.
In Silico Models
Over the years, a wide array of quantitative and computational methods has been used in an attempt to model the properties of biological systems—with greater or lesser degrees of success. Machine learning (ML), a subset of artificial intelligence (AI), has been recognized as having the potential to overcome some of the limitations of other computational modeling tools. AI/ML methods are generally capable of finding patterns in large, complex data sets that can be used to draw inferences about the system being studied. Improvements in both AI/ML methodology and computational speed and power have led to dramatic increases in performance capabilities, enabling improvements in speed and efficiency for in silico drug development and other applications. AI/ML methods have shown their utility in prescreening of large compound libraries to identify high-priority candidates; although these candidates will still need to be tested in a model system such as NHPs, narrowing the field of drug candidates will naturally reduce the use of NHPs in validation experiments. Thus these and other applications of AI/ML have the potential to aid in designing new experimental approaches and in reducing reliance on NHP studies. At the same time, however, all in silico methods
are limited by the available input data, and these methods cannot fully obviate the need for in vitro or in vivo testing.
With adequate high-quality training and validation data and informed knowledge about the limitations of the technology, both AI/ML tools and more well-established computational modeling methods have the potential to learn from past NHP studies and provide additional insights. Through modeling using previously collected data, it may be possible to create virtual NHP control groups that could be used in place of NHPs receiving a placebo. In particular, AI/ML could provide opportunities to develop virtual NHP tissue and organ models to guide drug formulation, design, and dosing regimens and to predict toxicological and efficacy endpoints. In addition to informing NHP studies, these applications could potentially reduce the numbers of animals used in nonclinical studies—an outcome that would both increase the utility of NHP models and make better use of these models at a time when their availability is severely limited.
While such applications are currently aspirational for NHPs, efforts to develop virtual dog tissues are under way, and if successful, could guide similar approaches for NHPs. Implementation of such a strategy will require high-quality training and validation data, investment in education and training, and further methodologic development and validation. One key to the success of AI/ML methods (and indeed any computational methods) would be a commitment to open, reproducible research through a requirement that data, models, and code be shared without restriction in public data archives.
Need for Collaboration
The establishment of collaboration opportunities for investigators developing and using different model systems, including NHP researchers, bioengineers, and computational biologists, could reduce barriers to the adoption of new approach methodologies. Strategies pairing investigators with different ways of approaching the same problems can enhance the complementarity and translatability of the work. Yet the committee found few examples of interaction between research groups developing and using new approach methodologies and NHP researchers. Efforts to facilitate such interactions could enhance awareness among NHP researchers regarding the evolving capabilities of in vitro and in silico systems, and enable improvements in the design of in vitro systems such that they would be better positioned to answer research questions for which NHPs are currently used. Likewise, reciprocal interaction could educate investigators developing new approach methodologies about the needs and priorities of NHP researchers.
Based on its evaluation of the research and development status of new approach methodologies, the committee reached the following conclusions:
Conclusion 4-1: Based on the current state of the science, there are no alternative approaches that can replace nonhuman primate (NHP) models to answer research questions that require complete multiorgan interactions and integrated biology. Thus, NHPs continue to be essential for the conduct of National Institutes of Health–supported biomedical research.
Conclusion 4-2: Select new approach methodologies (in vitro and in silico models) can replicate certain complex cellular interactions and functions. As such, these new approach methodologies may be used to answer specific research questions that contribute to understanding human biology to prevent and treat human disease. Although there currently exist no alternatives that can fully replace nonhuman pri-
mates, it is reasonable to be optimistic that this may change in the years ahead as new approach methodologies continue to advance.
Conclusion 4-3: Furthering the adoption of new approach methodologies (including in vitro and in silico model systems and approaches) with the intent of reducing reliance on nonhuman primate models will require planning and support for studies that can demonstrate adequate performance for specific contexts of use or intended purposes. Expectations for qualification or validation of new approach methodologies depend on the decisions to be made using the data derived from their use and the potential human health consequences of those decisions.
Conclusion 4-4: While nonhuman primates have been regarded as preeminent models for the evaluation of human safety and efficacy, recent guidance demonstrates that the Food and Drug Administration and other regulatory agencies are supportive of the use of new technologies and approaches for regulatory decision making once they have been adequately qualified or validated.
Conclusion 4-5: Efforts to reduce reliance on nonhuman primates (NHPs) in biomedical research will require investment in opportunities to facilitate direct interaction and collaborative research among investigators using NHP models and those developing in vitro and in silico approaches to expand the applicability of new approach methodologies to research questions for which NHPs are currently needed. At present, however, few mechanisms for fostering such interaction and collaborative research are available.
FUTURE NEEDS AND OPPORTUNITIES FOR NHP MODELS IN NIH-SUPPORTED BIOMEDICAL RESEARCH
Pending advances in the capabilities of new approach methodologies to fully recapitulate the physiological and structural complexities of an in vivo system, the committee anticipates that NHPs will remain the best available model for answering many research questions that require access to integrated systems biology to mimic the human condition reliably and reproducibly. Prohibiting the continued use of NHPs in NIH-supported biomedical research or imposing insurmountable barriers to their use could result in significant delays in the discovery and development of effective treatment strategies and interventions for human diseases and increase the potential for harm.
The future needs and opportunities for NHP models in NIH-supported biomedical research will be driven by many of the same factors that have shaped the current landscape. These factors include pressing public health needs; the importance of preparedness for unknown future threats, such as global pandemics; the evolving state of science and public policy; and the availability of NHP research resources and infrastructure. As with any horizon-scanning exercise, however, future predictions need to be undertaken and interpreted with caution commensurate with the numerous scientific and policy uncertainties that will shape the future landscape.
Research Domains for Which the Need for NHPs Is Likely to Grow
Neuroscience and infectious disease are domains of NHP research likely to grow in the future, as reflected in the NIH priorities for NHP research. The complexity of the primate
brain is not adequately modeled by any in silico or in vitro system or other animal species, and the burden of neurologic disease continues to rise as the population ages. Likewise, certain infectious diseases have a pathogenic mechanism seen only in primate species, and the COVID-19 pandemic and Zika, Ebola, and recent epidemics have highlighted the importance of NHP models for understanding novel diseases and testing the safety and efficacy of vaccines and therapeutics.
Other domains of NIH-supported biomedical research using NHPs are likely to see future growth as well. Immunotherapy using cellular-, protein-, or nucleic acid–based therapeutics has emerged as a vital area of NHP research, and the molecular similarity between humans and NHPs is key to understanding the effectiveness of these novel therapies. Another area ripe for future growth is reproductive biology, some aspects of which are primate specific, and the public health, social, and economic burdens associated with infertility and diseases of the reproductive system will continue to drive needs for research using NHPs in this area. Finally, NHP research in the areas of aging and chronic inflammatory diseases is likely to increase given the enormous public health burden associated with such diseases in the United States and the opportunities arising from long-term care that increasingly is being provided to aging NHP research subjects.
Rhesus macaques are likely to remain the predominant NHP species required to support these areas of research, based on input received by the committee from multiple stakeholders, including NIH, the NPRCs and National Resources, and NIH-funded investigators. Marmosets are increasingly being used in NIH-supported research as well, particularly in the area of neuroscience, and in the development of transgenic NHP models.
Conclusion 5-1: Given the nation’s most pressing public health needs and the evolving state of the science, specific domains of research—including neuroscience and neurodegenerative disorders, preparedness for unanticipated communicable infectious threats, immunotherapy, reproduction, aging, and chronic inflammatory diseases—are likely to require increased use of nonhuman primates in the future. The species distribution of future need for such research is likely to remain weighted toward macaques (particularly rhesus and cynomolgus), with increased use of marmosets.
Meeting Future NHP Resource Needs
Adequate investment in NHP research resources is necessary to support key strategic priorities for the United States, including maintaining global leadership in biomedical science and safeguarding the nation against unexpected public health threats. It is presently unclear how far into the future the United States will be able to continue importing NHPs for research purposes, and continued reliance on external sources of NHPs is therefore unsustainable. A national commitment and commensurate investment are needed to ensure that NHP research infrastructure, including domestic breeding colonies, supports the projected NHP needs of NIH-funded investigators. A critical window of opportunity now exists during which domestic investments in NHP research resources can be made while NHP species such as cynomolgus macaques, marmosets, and African green monkeys remain accessible from other countries and can be imported to establish breeding stocks. The development of purpose-bred, self-sustaining domestic populations of NHPs also offers the benefits of reducing the impact of increasingly limited options for international transport of imported NHPs and providing assurance of the responsible sourcing of animals. Domestic NHP breeding
can also provide a greater degree of regulatory control over the health and well-being, as well as the social and genetic backgrounds, of NHPs used in research, which in turn can support improved experimental rigor and the quality of the data generated; help prevent misrepresentation of data related to animal origin, age, or prior use; and reduce the impact on wild populations of NHPs in their countries of origin.
Beyond domestic breeding programs, future NHP research will depend on investment in human resources and physical and data infrastructure. Ensuring a scientific workforce with the skills needed to conduct NHP research will require support for training for early-career investigators and the support staff needed for NHP care. Likewise, experience with shortages of laboratory space during the COVID-19 pandemic demonstrated the importance of adequate facilities for NHP research, including biocontainment spaces. Moreover, the expansion of physical infrastructure supporting NHP breeding programs will provide opportunities to ensure optimal housing and husbandry conditions that align with best practices based on the evolving science of animal welfare. Investment in data infrastructure, within NIH and nationally, will be necessary as well to improve tracking of NHP demand and use so as to better support planning and coordination, both of which are essential to guide effective and appropriate use and management of NHP resources going forward. Importantly, such data infrastructure investments will also be integral to future efforts to reduce reliance on NHPs by enabling accurate measurement of the impact of changes in policy and the implementation of nonanimal models.
Given that NHPs are likely to remain a limited and high-cost resource—even with the necessary further investment in domestic breeding to address current shortages—advances in new approach methodologies offer the additional potential benefits of helping to reduce costs and mitigate future NHP shortages. In anticipation of these advances, attention is needed to the development of a strategy on the use of new approach methodologies in conjunction with NHP models to optimize the application of NHP research in the future.
Conclusion 5-2: The 2018 report of the National Institutes of Health (NIH) Office of Research Infrastructure Programs, Nonhuman Primate Evaluation and Analysis, included recommendations for improving communication and collaboration within the nonhuman primate (NHP) research community, increasing domestic NHP supply capabilities, addressing limitations in NIH funding mechanisms, promoting training in NHP care and research, and enhancing the utility and value of existing NHP resources. These solutions and recommendations have not yet been fully implemented and remain critically important.
Conclusion 5-3: Addressing the challenges posed for the national research infrastructure by a persistent lack of nonhuman primates (NHPs) will require a commitment and comprehensive national effort focused on expanding domestic NHP resources.
Conclusion 5-4: The creation of a national plan for allocation and expansion of nonhuman primate resources is necessary to optimize the use of this critical scientific resource. Such a plan will require adequate monetary, physical, and personnel resources, as well as a centralized tracking system to match need to investment in a data-driven fashion.
Conclusion 5-5: Continued development and validation of new approach methodologies (in vitro and in silico model systems) is critically important to support further advances in biomedical research. This may reduce the need for nonhuman primate
(NHP) models in the future, and/or enhance their utility. Additionally, this may help to mitigate shortages in NHP supply and the high cost of NHP research.
Enhancing NIH-Supported NHP Research Going Forward
Given the need for continued use of NHPs in NIH-supported biomedical research, it is incumbent on those supporting and conducting such research to ensure that these animal models are used as effectively as possible. NHP resources demand strong stewardship and research conducted in a way that maximizes the knowledge and actionable insights obtained from each individual animal in every study. Technologies and approaches including noninvasive monitoring and imaging approaches (e.g., digital biomarkers such as in home enclosure neural recordings, magnetic resonance imaging), AI/ML, and minimally invasive research procedures (e.g., laparoscopy, positive reinforcement training for voluntary provision of samples) can be applied to increase the impact and rigor of NHP research and improve alignment with processes implemented in the clinical setting. Additional opportunities to enhance NIH-supported NHP research include implementing thoughtful approaches for sample collection and sharing, fostering openness and data sharing, expanding and implementing data-driven NHP care and management practices (e.g., social housing), further characterizing NHP models, and learning from natural variation and disease in NHPs, as well as incentivizing collaboration among NHP and non-NHP research groups.
Conclusion 5-6: Given the limited numbers of nonhuman primates (NHPs) available for research, it is incumbent upon investigators and the National Institutes of Health (NIH) to make the best use of each animal through cooperative efforts, data sharing, purposeful planning, and use of data-driven care and management methods for the long-term care and use of NHPs in research. Examples of successful cooperative efforts from the community of NIH-funded NHP researchers—including collaborative working groups; data-sharing resources for clinical and clinical pathology data, gene expression profiling, and genotype data; and biospecimen repositories—can serve as models for broader adoption.
Conclusion 5-7: A system for consistent reporting is needed to adequately capture the life, scientific, and medical history, including experimental treatments and procedures, of individual nonhuman primates (NHPs). The need for complete NHP life histories further supports the development of increased domestic breeding capacity in the United States to maximize the accurate and complete sharing of clinical and experimental data. Currently, the incentives, mandates, and infrastructure within the National Institutes of Health research enterprise are insufficient to support uniform data management and reporting across all NHP research programs.
Conclusion 5-8: Recent advances in genomics, bioinformatics, imaging, digital biomarkers (e.g., noninvasive home enclosure neural and behavioral recordings), extended reality, and artificial intelligence/machine learning have revealed opportunities to understand normal biology and the mechanisms of disease. Such technologies and approaches have the potential to augment the scientific knowledge that can be gained from individual nonhuman primate (NHP) studies and, in some cases, enable less invasive use of NHPs. Leveraging these opportunities for NHP research will require tracking the genotype, phenotype, and history of each animal used, as well as transdisciplinary interactions.
Conclusion 5-9: Additional investments will be needed to implement, maintain, train, and use current and emerging technologies (such as digital biomarkers, artificial intelligence/machine learning, imaging, extended reality, and laparoscopy), as well as data-driven husbandry practices, with the potential to enhance nonhuman primate research funded by the National Institutes of Health.
