Nonhuman Primate Models in Biomedical Research State of the Science and Future Needs (2023) / Chapter Skim
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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.
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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.
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. To inform its exploration of the future role of nonhuman primates in NIH-funded research, the committee will: • Explore future needs, opportunities to improve human health, and challenges for biomedi cal research involving nonhuman primates, including identifying 0 Areas of emerging science that may benefit from nonhuman primate research models; 0 Opportunities for new approach methodologies to complement or reduce reliance on research with nonhuman primates; 0 Status of research, development, and validation efforts into new approach methodolo gies; and 0 Ways to increase coordination and collaboration between researchers who use nonhu man primates and those who use new approach methodologies to enhance the value of all methods and tools.
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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 biomolecu lar 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 recapitu late 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, demonstrat ing a track record of unique predictive relevance critical for supporting ongoing fundamental basic and translational research missions of the National Institutes of Health.
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, 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.
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, 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)
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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 bio medical 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.
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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.
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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.
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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.
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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)
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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.
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Conclusion 5-7: A system for consistent reporting is needed to adequately capture the life, scientific, and medical history, including experimental treatments and pro cedures, of individual nonhuman primates (NHPs)
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14 NONHUMAN PRIMATE MODELS IN BIOMEDICAL RESEARCH Conclusion 5-9: Additional investments will be needed to implement, maintain, train, and use current and emerging technologies (such as digital biomarkers, artifi cial 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.
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