NIH Intramural Research Facilities

NIH ICOs are actively involved in both supporting the supply of NHPs for intramural research activities and the use of NHPs in research. USDA data from FY2021 show that 7,328 NHPs were reportedly held or used for research purposes at NIH ICO facilities supporting intramural programs (USDA, 2021) (see Table B-2 in Appendix B). ⁷ NIH support for intramural NHP resources involves several different acquisition pathways, although publicly available details are limited and complicated by complex funding and contracting processes. Several ICOs own breeding colonies for intramural research use, some of which are managed by third parties (Florence, 2022). ICOs may also have agreements with other ICOs to provide animals for use in intramural research. In addition, ICOs may access NHPs from NPRCs and National Resources, other academic centers with breeding colonies, or international and domestic suppliers. It should be noted that these suppliers do not contract exclusively with NIH ICOs and may also supply NHPs for their own use or for sale to other research institutions.

National Primate Research Centers

First established in the 1960s as regional primate research centers (Gibson, 1994), NPRCs are awarded competitively by NIH and hosted at research universities and institutions throughout the United States (see Figure 3-1). NPRCs complement and enable the missions of NIH ICOs by maintaining NHP breeding colonies and providing investigators with centralized expertise and resources (e.g., clinical laboratories, staffed cores for collecting samples, development of NHP models). Thus, these facilities fulfill essential functions for the domestic production of NHPs in addition to being active in the conduct of specialized research programs using NHPs. NPRCs receive funding from the Division of Comparative Medicine within ORIP via P51 Primate Research Center Grants (NIH, 2020), along with supplemental awards, to perform their dual functions of NHP resource production and research.

FIGURE 3-1

National Primate Research Centers and other nonhuman primate research resources supported by the Office of Research Infrastructure Programs (ORIP) at the National Institutes of Health. NOTES: In addition to the seven National Primate Research Centers, (more...)

While much of the work of NPRCs is focused on NIH-supported research projects carried out by investigators internal and external to the center, NRPCs do not supply NHPs exclusively to NIH-supported investigators or carry out only NIH-supported research. The seven NIH-supported NPRCs accounted for nearly 24 percent (27,067) of all NHPs reported to USDA in FY2021 (USDA, 2021); however, the exact number of NHPs used by the NPRCs for NIH-supported research projects is unknown because of the aforementioned data limitations.

Individual NPRCs establish their own administrative processes for reviewing investigator requests for animals and services. However, these requests are generally prioritized in the following order based on funding source, as specified by NIH (NIH, 2020): (1) NIH extramural grants, (2) NIH intramural funding, (3) other federal agency funding, (4) not-for-profit funding, and (5) for-profit funding. Other factors considered within the context of this prioritization structure include primary research domain, funding mechanism, scientific justification, and logistical issues such as transportation (NPRC Information Request, 2022⁸).

The seven NPRCs carry out coordinated activities under the auspices of the NPRC Consortium, an important component of the NIH-supported NHP research infrastructure. These Consortium-based activities are NPRC-driven and include the sharing of best practices, protocols, and data to “enhance the resources of the program and promote cost savings by standardizing common activities across all of the NPRCs” (NIH, 2020). Working groups within the Consortium (e.g., Breeding Colony Management, Genetics and Genomics, Behavioral Management, Occupational Health and Safety, Pathology) are formed in consultation with ORIP staff, and their members are appointed by NPRC directors.

Non-NPRC National Resources

Four institutions receive ORIP support to serve as National Resources for domestic breeding colonies of NHPs (see Figure 3-1).⁹ NHPs reported by these four National Resources accounted for just over 7 percent (8,112) of all NHPs reported to USDA as held or used for research purposes in FY2021 (USDA, 2021). As with NPRCs and other stakeholders, however, the proportion of this population that was associated with NIH-supported research is unknown, as National Resources may receive funds from other federal and private entities to breed and supply NHPs (e.g., NIH directly supports the maintenance of a squirrel monkey colony at the MD Anderson Cancer Center but not the rhesus macaque colony at the same site, even though all of these animals may be used for NIH-supported research projects). Investigators at National Resources also actively conduct NHP research, some of which may be funded by NIH, and may purchase supplemental animals from the commercial market to meet their research needs. In addition to National Resources supplying NHPs for research use, ORIP supports three Reagent Resources (Figure 3-1) that do not maintain ORIP-funded NHP breeding colonies but serve as resources for primate-specific immune reagents (Grieder, 2023; ORIP, 2022). In contrast with the loosely centralized coordination efforts of the NPRC Consortium, the National Resources set priorities and operate independently, with no formal or informal coordinating structure, although they are often invited to participate in NPRC working groups.

Contract Research Organizations and Other Commercial NHP Suppliers

CROs provide an array of contracted research services within their facilities, often using CRO-owned NHP colonies for drug and product development activities. Some CROs and other commercial organizations also act as suppliers of NHPs and make animals from their onsite populations available for purchase; they also may arrange for importation of NHPs (Harding, 2017; ORIP, 2018a). Cumulatively, NHPs reported by these entities accounted for greater than 42 percent (approximately 48,400) of all NHPs reported to USDA as held or used for research purposes in FY2021 (see the listing of research facilities in Tables B-2 and B-3 in Appendix B) (USDA, 2021). It is not known what proportion of these NHPs were supplied for or used in NIH-supported research.

Several CROs and commercial suppliers have relationships with NIH ICOs through cooperative agreements and contracts to manage NIH-owned breeding colonies or to supply animals for extramural or intramural research purposes from colonies owned and/or managed by third parties. The NHP breeding colony on Morgan Island, South Carolina, for example, is owned by NIH for intramural research purposes but is managed by the CRO Charles River Laboratories, which in turn leases the land from the State of South Carolina (GovTribe, 2022; McCombs, 2021).

Private Pharmaceutical and Biotechnology Companies

Pharmaceutical and biotechnology companies also use NHPs to support their research programs in the United States, accounting for 2.7 percent of NHPs reported to USDA in 2021 (see the listing of pharmaceutical and biotechnology companies in Tables B-2 and B-3 in Appendix B) (USDA, 2021). This small percentage does not represent the totality of industry-sponsored NHP research, as these companies frequently use CROs to carry out research activities offsite (Harding, 2017). These companies may manage their own NHP colonies, procure NHPs from international or domestic suppliers, or contract with CROs to carry out NHP research activities. While rarely associated directly with NIH-supported research using NHPs, industry-sponsored NHP research activities can impact the balance of supply, demand, and prices for NHP resources across the broader research landscape. Increases in NHP demand by pharmaceutical and biotechnology companies that cannot be met by importation or industry-owned colonies—a situation experienced during the COVID-19 pandemic—can result in increased competition and cost increases for the limited domestic NHP resources sought after by other stakeholders (Zhang, 2020).

NHP Investigators at Non-NPRC and Non–National Resource Academic Institutions

An assessment of USDA NHP use data shows that academic institutions—outside of NPRCs and National Resources—reported using more than 16,000 NHPs in FY2021, with 31 percent of these facilities reporting use of fewer than 20 NHPs (USDA, 2021). In total, these academic institutions account for just over 14 percent of all NHPs reported to USDA in 2021, but nearly 47 percent of all research facilities conducting research using NHPs. NIH RePORTER records indicate that many of these institutions hold active awards from NIH to carry out research using NHP models. The finding that many institutions report the use of small numbers of NHPs suggests that much of the NIH-supported, investigator-initiated research in the United States may involve small numbers of NHPs used by individual NIH grantees. These findings have implications for the tracking of investigator demand and strategies for ensuring access to NHP resources.

NHP Trends in the United States

Analysis of USDA-reported data on NHPs held and used in all research facilities in the United States over the last decade suggests that usage is outpacing the supply of NHPs held but not used for research purposes (e.g., animals reserved for breeding and held while maturing to ages suitable for use in research). As shown in Figure 3-2, the total number of NHPs actively used for research protocols in the United States annually—not just those used in NIH-supported research—has fluctuated over time, but was roughly the same in FY2021 as FY2008 (just over 70,000). However, the number of NHPs held or bred but not yet used for research purposes has declined overall. As a result, the absolute number of NHPs—those held but not used in research and those actively used—has decreased over the past decade (2011–2021) by more than 2,100 and has shown only minor year-to-year fluctuations (USDA, 2021, 2022). The decline in animals reserved for domestic breeding, if not addressed through targeted action, has implications for the future availability of NHPs to meet research needs.

FIGURE 3-2

Nonhuman primates (NHPs) held or used for research purposes annually in the United States for fiscal years 2008–2021, based on data collected by the U.S. Department of Agriculture. NOTES: These data include all NHPs held and used in the United (more...)

NHP Importation

Based on information gathered by the committee on the species of NHPs used by NIH-supported investigators and the predominant NHP species imported into the United States (discussed below), it is likely that the majority of imported NHPs are intended for use by private industry, while a lesser proportion is used for NIH-supported research purposes. However, the Centers for Disease Control and Prevention (CDC), which tracks the importation of NHPs into the United States, does not collect data on the ultimate destination and use of NHPs after their arrival (CDC, 2022); therefore, the number of imported NHPs eventually used in NIH-funded research cannot be accurately determined. These data issues limited the committee’s ability to assess the role of imported NHPs in NIH-supported research.

Between FY2012 and FY2017, more than 90 percent of the NHPs imported into the United States were cynomolgus macaques (ORIP, 2018a); from FY2019 to FY2022, this species accounted for a yearly average of 95 percent of all NHP imports (CDC, 2023). Data collected by the committee show that low numbers of cynomolgus macaques are held and used by NPRCs and National Resources, which instead report high levels of use of rhesus macaques (National Resources Information Request, 2022¹²; NPRC Information Request, 2022). Similarly, data collected from the committee’s survey of NIH-supported NHP investigators found high levels of use of rhesus compared with cynomolgus macaques (see Table B-16 in Appendix B) (NHP Investigators Survey, 2022). These data suggest that imported cynomolgus macaques are used largely by private industry (e.g., CROs and pharmaceutical and biotechnology companies), a finding consistent with previous accounts (Grimm, 2022). Domestic resources of cynomolgus macaques have been slow to develop because importing the NHPs (primarily from China) has been deemed more cost-effective than developing U.S. breeding colonies (ORIP, 2018b).

As discussed previously, unexpected and rapidly implemented export restrictions established by China in early 2020 included a total ban on exports of NHPs. This restriction had the effect of reducing the total number of NHPs imported into the United States in FY2020 by more than 20 percent compared with FY2019 and increasing demand for domestic NHP resources (CDC, 2023). Such dramatic shifts in importation create secondary demand for commercially available domestic populations of NHPs, which are also used by NIH-supported investigators, and place further pressure on NPRCs and National Resources to fulfill the needs of these investigators.

As shown in Table 3-2, the total number of NHPs imported into the United States had recovered by FY2021, largely through increased importation of cynomolgus macaques from Asian countries other than China—primarily Cambodia, Vietnam, and Mauritius (see Appendix B for importation data by country of origin). These alternative sources of imported NHPs are not assured, however, as these nations could choose to end exportation of NHPs at any time (see the discussion of Indian NHP exportation below). Additionally, anecdotal reports indicate that China is competing with the United States for the purchase of NHPs from Southeast Asian countries—over which China holds significant geopolitical influence—as it endeavors to expand its own domestic NHP research programs (see Box 3-2) (Einhorn and Lew, 2022).

TABLE 3-2

Number of Nonhuman Primates Imported to the United States, by Species and Fiscal Year (FY).

BOX 3-2

IMPLICATIONS OF CHINESE EXPANSION OF NHP RESEARCH.

In 2022, a further threat to importation of NHPs was highlighted following the apparent illegal exportation of wild-caught cynomolgus macaques from Cambodia that were falsely labeled as captive bred, drawing international concern (Grimm, 2022) and scrutiny of exports by both Cambodia and the United States. Relatedly, the importation of NHPs also raises concerns about the conditions in which NHPs are bred and housed in nations with less stringent animal welfare regulations prior to their export (Mitchell et al., 2021). Beyond serious animal welfare considerations, poor conditions prior to export could impact the future suitability of the animals for research. Having purpose-bred, self-sustaining domestic populations of NHPs would likely allow for a greater degree of regulatory control over the health and well-being of NHPs used in research, as well as tracing of their social and genetic backgrounds, which in turn would support improved experimental rigor and the quality of the data generated.

The above recent experiences, together with the possible future risk of additional export restrictions instituted by countries attempting to prevent the exportation of wild-caught animals, suggest that importation is not an assured long-term solution for sourcing of cynomolgus macaques and other NHPs for research use in the United States. Failure to reduce reliance on foreign sources for these critical research resources exposes U.S. biomedical research programs to preventable supply chain vulnerabilities and impedes the nation’s ability to prepare for future public health threats.

The vulnerabilities associated with reliance on China for the majority of imported NHPs, specifically cynomolgus macaques, are highlighted in the 2018 ORIP report, which notes that between FY2013 and FY2017, the majority of cynomolgus macaques imported to the United States were supplied by China (ORIP, 2018a). The report further emphasizes that a disruption in this supply—upon which the device and therapeutics development industry relies—would likely result in increased demand for domestic macaque populations by industry and a reduction in the number of domestic animals available for use by academic investigators supported by NIH grants, as well as dramatically increased costs of animals for all stakeholders (ORIP, 2018a,b). As described previously, these vulnerabilities associated with dependence on foreign sources of NHPs were realized in 2020 with China’s export ban and were further intensified by NIH’s prioritization of domestic populations of NHPs for COVID-19 research.

It is unclear how far into the future the United States will be able to continue importing NHPs for research purposes. The elimination of NHP exportation by foreign nations is not a novel occurrence, and the expectation of a reversal of exportation policy at some point in the future is not an appropriate strategy for ensuring a sustainable supply of NHPs for biomedical research. India, for example, reduced its NHP exportations over a 5-year period before instituting a complete ban (NIH, 1978), which allowed the United States time to procure Indian-origin rhesus macaques and establish domestic breeding populations. India has not reversed this policy in the decades since. The recent experience with China serves as a stark reminder that access to imported NHP species could be cut off with no advance notice in the future.

There now exists a critical window of opportunity 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 ethically sourced breeding stocks. The development of purpose-bred, self-sustaining, and diverse U.S. populations of NHPs also would provide a greater degree of regulatory control over the health and well-being of the animals; prevent misrepresentation of animal origin, age, or prior use; and reduce the impact on wild populations of NHPs in their countries of origin. The latter benefit is particularly important given how classification of NHP species as endangered will drastically impact research using those species, leading to lost opportunities for scientific and medical breakthrough discoveries (discussed in Box 3-3).

BOX 3-3

POTENTIAL IMPACT OF CHANGES IN WILD MACAQUE POPULATIONS ON BIOMEDICAL RESEARCH.

Domestic Breeding of NHP Resources

The seven NPRCs and four National Resources together constitute a long-established network of highly specialized research facilities that are responsible for providing domestically produced NHPs for NIH-supported extramural research purposes (see Table 3-3 for a listing of the species bred as reported by NPRCs and National Resources). In FY2021, these resource programs reported producing approximately 5,000 NHPs across 11 different species (see Tables B-11 and B-12 in Appendix B); the lack of historical data on domestic breeding levels makes it impossible to know whether this reported production represents an increase over recent years. As discussed previously, other academic research facilities (such as the New Iberia Research Center) and commercial entities (such as Alpha Genesis, Inc.) also breed NHPs domestically under contracts and cooperative agreements with federal agencies and others. In some cases, academic and other institutions with breeding colonies (e.g., the Keeling Center at the MD Anderson Cancer Center and Wake Forest University) may maintain colonies supported by both NIH and other sources.

TABLE 3-3

Species of Nonhuman Primates Bred by Domestic National Institutes of Health (NIH)–Supported National Primate Research Centers (NPRCs) and National Resources, Fiscal Year (FY) 2017 versus FY2021.

Rhesus macaques continue to be the most commonly bred species at NPRCs and National Resources (more than 4,000 bred in FY2021), and nearly all NIH-supported stakeholders engaged by the committee predicted increases in demand for this species given its widespread use as a model. Of the 517 active NIH awards using NHPs reported by investigators surveyed by the committee, and for which data on NHP species were provided, nearly 71 percent involve the use of rhesus macaques (NHP Investigators Survey, 2022). In contrast with other NHP species, for which only a few institutions maintain breeding colonies, most NPRCs and National Resources report breeding rhesus macaques, as do other stakeholders with NIH agreements for breeding services (National Resources Information Request, 2022; NPRC Information Request, 2022). Still, the current production of rhesus macaques at these domestic facilities remains insufficient to meet the demand of investigators (as discussed further in the section below on investigator demand).

The 2018 ORIP report also cites marmosets as a high-demand species for biomedical research (ORIP 2018a,b), and interest in using this model continues to grow among both extramural and intramural investigators, particularly in the areas of behavioral and systems neuroscience, molecular neuroscience, neurodegenerative disorders, and visual systems research. Just 6 percent of active awards captured in the committee’s survey of NIH-supported NHP researchers for which species data were provided involved the use of marmosets. However, more than 11 percent of responding investigators indicated that they planned to use marmosets for future research (see Table B-28 in Appendix B) (NHP Investigators Survey, 2022). The potential of transgenic marmoset models to advance research on neurodevelopmental conditions, such as autism (Zhao et al., 2018), and neurodegenerative disorders, such as Alzheimer’s disease (Rizzo et al., 2021), is further increasing interest in this species.

In FY2021, 194 marmosets were produced at NPRCs and National Resources (National Resources Information Request, 2022; NPRC Information Request, 2022). In 2019, concerns related to extramural investigators’ increasingly limited access to marmosets for neuroscience research spurred several ICOs to cofund a request for applications (RFA) through the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative to support the creation of a Marmoset Coordinating Center to facilitate data sharing and coordination of marmoset distribution and breeding efforts (NIH, 2019). This U24 cooperative agreement was eventually awarded to the Oregon Health & Sciences University in collaboration with the Wisconsin NPRC and Southwest NPRC for oversight of the Coordinating Center’s functions (OHSU, 2021; Robinson, 2020). Additionally, in 2020, a U24 grant was awarded to The Johns Hopkins University, in collaboration with the University of California, San Diego, to establish the Bicoastal Marmoset Breeding Center (NIH RePORTER, 2022), which will support two breeding colonies to supply research programs with marmosets. Information provided to the committee by NIH-funded investigators and NIH ICOs indicates that these current breeding colonies remain small and continue to be outpaced by demand, although it should be noted that the shorter biological development periods of marmosets versus other NHPs, especially sexual maturity and gestation period, do provide advantages with respect to the time required to expand breeding colonies (NASEM, 2019).

Although, as discussed above, cynomolgus macaques are less commonly used than rhesus macaques in NIH-supported extramural research, they are critical resources frequently used in research sponsored by the pharmaceutical industry¹³ and increasingly in some areas of NIH extramural research (ORIP, 2018a). Responses of investigators surveyed both by ORIP for the 2018 report and by this committee indicate that demand for this model has remained stable since 2018—just over 20 percent of responding investigators reported planned future use of cynomolgus macaques in both 2018 and in 2022 (NHP Investigators Survey, 2022; ORIP, 2018a). As mentioned earlier, the ease of importing cynomolgus macaques in the past has served as a disincentive for the creation of domestic breeding colonies (ORIP, 2018a). However, establishment of such colonies is a key recommendation of the 2018 ORIP report, and efforts were subsequently undertaken to establish a breeding population at the Wisconsin NPRC (NPRC Information Request, 2022). A breeding colony at the New Iberia Research Center was also established under an NIH cooperative agreement (HHS, 2021). However, the annual production of animals at these domestic facilities remains low (e.g., 102 reported bred at the Wisconsin NPRC in FY2021), numbers that are insufficient to meet the current demands of NIH-supported investigators.

Given the predictions of NPRCs and National Resources that investigator demand for NHPs for use in NIH-supported research—specifically for rhesus and cynomolgus macaques and marmosets—will increase, efforts and investment to further expand existing breeding programs at NPRCs and National Resources are needed. Among the 258 NIH-supported investigators who responded to the committee’s survey question about future demand for NHPs and reported expected NHP species needs for future NIH awards, rhesus macaques were overwhelmingly identified as the preferred NHP species (82 percent), followed by cynomolgus macaques (22 percent), common marmosets (11 percent), and baboons (11 percent) (see Table B-28 in Appendix B) (NHP Investigators Survey, 2022).

Meeting the anticipated future demand for NHPs is possible given the nation’s past investment in establishing a strong network of research infrastructure and expertise at NPRCs and National Resources, which currently support much of NIH-funded NHP research. However, ensuring that these essential stakeholders have the capacity to meet the demands of the U.S. biomedical research enterprise, particularly if the nation seeks to move away from its reliance on foreign sources of NHPs, will require dedicated, long-term investments. These investments include dedicated funds to support the update and expansion of physical infrastructure for breeding facilities; their maintenance to remain in regulatory compliance; and their operation, since the process of expanding domestic breeding colonies is inherently lengthy (see the section below on research infrastructure). Additionally, meeting anticipated demand will likely require an up-front decrease in the number of animals allocated by NPRCs and National Resources for use in study protocols, as more animals will need to be held for breeding purposes. Both the 2018 ORIP report and testimony given to the committee described these facilities as being close to or at capacity, and highlighted the need to accommodate more animals and acquire additional personnel to provide for their care (NPRC Information Request, 2022; ORIP, 2018b). In establishing breeding programs to secure the domestic NHP supply, it will be important to consider geographic separation of breeding sites, in much the same way as the NPRCs were separated across the United States, which will help mitigate risks from the collapse of a single colony as the result of a natural disaster (Hutchinson, 2022). Also important is providing a means of enhancing genetic diversity (which can improve colony health and help avoid genetic confounding in population studies) (ORIP, 2018b).

Availability of NHP Resources for Intramural Research Programs

NHPs used for NIH intramural research are procured from several different sources, including ICO-owned colonies and facilities contracted to provide the animals. Whereas multiple ICOs reported concerns in 2021 with respect to the availability of NHPs for intramural research, NIAID, which holds its own established breeding colonies, reported minimal issues with acquiring rhesus macaques, highlighting the value of these long-term investments in securing a stable supply of NHPs (NIH, 2022a).

NPRCs and National Resources are not major providers of NHPs for intramural research but do supply some specific species (ORIP, 2018a,b). At the committee’s August 2022 public workshop, representatives of the NIH intramural research program reported that approximately 66 percent of the roughly 800 animals acquired for use in intramural research in each year had come from NIH-owned colonies, such as the rhesus macaque colony on Morgan Island in South Carolina, while 33 percent had been purchased from private-sector suppliers (Denny, 2022). The remaining animals had been obtained from other outside sources.¹⁴

Investigator Demand and Access Challenges

Timely access to NHP models is a concern widely reported by NIH-supported investigators and the ICOs for both extramural and intramural research (NIH, 2022a; NHP Investigators Survey, 2022). Among the NIH-supported NHP investigators responding to the committee’s survey (n = 273), about 64 percent reported issues with obtaining NHPs for their current awards, regardless of the source of the animals (e.g., NPRC, importer, other domestic supplier) or the type of research facility in which the research was being conducted (NHP Investigators Survey, 2022). This percentage represents an increase since the ORIP report was published in 2018; 50 percent of the extramural investigators surveyed at that time reported issues related to access to NHPs or related research services (ORIP, 2018a).

Additionally, three of the seven NPRCs reported being unable to fulfill on average 10 to 25 percent of investigator requests for NHPs between 2018 and 2021, and one NPRC was unable to fulfill more than half of requests during that time (see Table 3-4) (NPRC Information Request, 2022). NIH-supported investigators’ access to NHPs from NPRCs varies relative to the intended research location. Overall, the provision of NHPs to investigators who planned to carry out the research at an external institution (e.g., researchers not employed by an NPRC who wished to conduct research at their home institution using animals sourced from NPRCs) declined by more than half in FY2020 and FY2021 relative to FY2019, although individual NPRCs varied substantially in the number of NHPs provided for research at external facilities during FY2018–2021. The number of animals provided to external investigators for research being carried out at the NPRCs increased in FY2021 following declines the previous 2 years (NPRC Information Request, 2022) (see Tables B-18 and B-19 in Appendix B). These shifts may be related to prioritization of NPRC research efforts carried out during the COVID-19 pandemic or to other logistical barriers limiting access to these resources.

TABLE 3-4

Proportion of National Institutes of Health–Supported Investigator Requests Not Met by National Primate Research Centers (NPRCs), Fiscal Years 2018–2021.

Challenges in securing NHP resources for intramural research activities were reported by the National Institute of Mental Health (NIMH); the National Eye Institute (NEI); the National Institute on Drug Abuse (NIDA); the National Heart, Lung, and Blood Institute (NHLBI); the National Cancer Institute (NCI); and NIAID (NIH, 2022a). Difficulties with timely access to NHPs, particularly macaques and animals of a specific sex or age, on the commercial market were emphasized as barriers to conducting research (NIH, 2022b). As with NIH-supported extramural research, intramural research has faced project delays, long wait times for animals, and modifications to study designs to accommodate reduced numbers of NHPs (NIH, 2022a).

Among investigators who responded to the committee’s survey and reported specific challenges with accessing NHPs for any of their NIH awards, the factors associated with these access challenges included a lack of animals that met specific demographic criteria required for the research (e.g., age, sex) (72 percent of respondents), the increasingly high cost of animals (43 percent of respondents), and the unavailability of NHPs with specific genotypes or genetic diversity (15 percent of respondents) (see Table B-24 in Appendix B) (NHP Investigators Survey, 2022). These findings indicate not only that there are insufficient supplies of NHPs, but also that those animals that are available do not necessarily have characteristics that align with the needs of investigators. For example, investigators may be unable to access female NHPs that would be needed to study sex differences as part of their study design because females may be held for use in breeding colonies.

High demand for and limited supplies of NHPs have also resulted in research projects enrolling fewer animals than originally planned. A description of the number of animals planned for use in a study is recorded in the NIH award application and reviewed to confirm that studies are sufficiently powered and properly designed. Reducing the number of animals enrolled in a study may negatively impact the quality of the research and the conclusions drawn from it. Thus, initiation of studies for which funding has been received may need to be delayed until adequate numbers of NHPs become available. More than 57 percent of active NIH awards reported by survey respondents ultimately enrolled fewer NHPs than originally planned (see Table 3-5). The most common factor reportedly contributing to lower-than-planned enrollment of NHPs for awards was lack of access to NHPs (57 percent of awards for which fewer NHPs were used than planned) (see Table 3-6) (NHP Investigators Survey, 2022). NIH ICOs also have recently raised concerns about lower-than-planned enrollment by extramural projects. In a case reported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the project in question was able to obtain only 8 of the 12 requested macaques because of severe shortages (NIH, 2022a).

TABLE 3-5

Nonhuman Primates (NHPs) Planned versus Used, by Source.

TABLE 3-6

Factors Contributing to Decreased Enrollment of Nonhuman Primates (NHPs), by Source.

Related to challenges in obtaining the requested number of NHPs to carry out studies funded by NIH awards, both NIH ICOs and committee-surveyed investigators reported long wait times for receipt of animals, a pattern identified as a barrier to the conduct of high-quality research. Because animals at NPRCs and National Resources are often committed several years in advance, investigators must wait for existing animals to become ready for use in their respective protocols. For example, the committee learned that specific-pathogen-free (SPF) baboons at the MD Anderson Cancer Center have already been committed for the next 2 years (Hopkins, 2022). Of the 475 awards reported by investigators responding to the committee survey question on enrollment times, 41 percent received NHPs after the desired date of enrollment. For awards reporting the use of rhesus macaques (n = 351), late enrollment increased to 44 percent of all awards (see Table 3-7) (NHP Investigators Survey, 2022). While it is impossible to compare changes in wait times since 2018 because of a lack of historical data on this variable, five of the seven NPRCs reported an average wait time of more than 3 but less than 6 months for fulfilling a given NHP request (not species specific) (see Table 3-8). Extended wait times for access to NHPs can have significant effects on the success as well as the timeliness of a research project, depending on the nature of the study and its funding requirements (e.g., need for a no-cost extension or return of funds) and on the advancement of biomedical research in general. Such delays can be extremely costly given the urgency of emergent needs at times of crisis. Moreover, delays in nonclinical studies can prolong the time to initiate clinical trials for potential disease treatments, delays that are particularly significant for rapidly progressing, terminal conditions such as amyotrophic lateral sclerosis (ALS).

TABLE 3-7

Wait Times for Nonhuman Primates (NHPs) Reported by National Institutes of Health–Supported Survey Respondents.

TABLE 3-8

Average Wait Times for Nonhuman Primates (NHPs), Fiscal Years 2018–2021.

NPRCs reported that species, age, genotype, and sex are common factors likely to cause delays for those requests that can be fulfilled, corroborating experiences with unmet demand reported by NHP investigators and NIH ICOs (see Table B-22 in Appendix B) (NPRC Information Request, 2022). For this reason, requests for certain high-demand species, such as rhesus macaques, are more likely not to be fulfilled or to require longer wait times. For example, NPRCs were able to fulfill only one-third of the 5,300 investigator requests received in FY2021 for research-naïve macaques (including pig-tailed, cynomolgus, and rhesus macaques) (Johnson, 2022). In another example provided to the committee, Wake Forest University, which is a National Resource, reported that it was able to fulfill just one-third of requests for African green monkeys during the height of the COVID-19 pandemic (Jorgensen, 2022).

These recent data indicate that barriers to NHP access have persisted and in fact have worsened since publication of the 2018 ORIP report, which at that time acknowledged similar investigator challenges related to meeting demand for NHPs, increased wait times, and the need to stagger delivery of animals over the course of studies. In summary, although NHP models continue to be necessary to carry out NIH-supported research, data collected from NPRCs, National Resources, and NIH-supported investigators indicate that demand for NHPs (rhesus and cynomolgus macaques and marmosets in particular) cannot be met by the existing supply chain.

Demand for NHP Resources by Research Domain: Extramural Research

Data collected from NPRCs, National Resources, ICOs, and NIH-supported investigators demonstrate several overlapping areas of NHP use across the current biomedical research landscape. Stakeholders cited research in neuroscience and neurological disorders as well as in infectious diseases and immunology (including human immunodeficiency virus [HIV]/acquired immune deficiency syndrome [AIDS]) as priority areas for current NHP research (National Resources Information Request, 2022; NIH, 2022b; NHP Investigators Survey, 2022; NPRC Information Request, 2022). These same priority NHP research areas are identified in the ORIP report (ORIP, 2018a). Emerging trends include the use of NHPs in developing and testing gene therapies (see Appendix B for data on current research priorities across different stakeholders).

ICOs widely reported infectious disease and immunology research as a priority for NHP use in extramural research for FY2021 (Eisinger, 2022). Figures on the number of NHPs reprioritized for research on the pathogenesis of COVID-19 and for supporting the development and testing of vaccines and therapeutics are not available. Nonetheless, stakeholders described the impacts of this prioritization as a factor exacerbating the inadequate supply of NHPs for use in other areas of infectious disease research, as well as increasing costs of the limited pool of available animals (NIH, 2022a; Ross, 2022).

Information on active extramural research provided by multiple ICOs, including NIAID, NIDA, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Office of AIDS Research (OAR), indicates that the demand for NHPs for research in the area of HIV/AIDS has remained high in recent years. ICOs described HIV/AIDS research as encompassing a broad range of activities, from the development of treatments and cures to the exploration of other body systems and associated complications in the context of HIV infection (NIH, 2022a). Surveyed investigators likewise cited HIV/AIDS as a highly active area of NHP research, accounting for 36 percent of all NHPs reported as being used by responding investigators (see Table B-27 in Appendix B for information on priority research domains for NIH-supported researchers) (NHP Investigators Survey, 2022).

Multiple stakeholders identified research in neuroscience and neurological disorders as continuing to represent a major priority for NHP research. Respondents to the committee’s survey highlighted projects in behavioral and systems neuroscience in particular as a major domain for current NHP use, accounting for the highest number of individual awards reported for a single domain—155 of 482 unique awards (note that respondents were able to select more than one research domain to describe the focus of an active NIH award) (see Figure B-1 in Appendix B) (NHP Investigators Survey, 2022). ICOs provided several examples of active extramural research projects in this domain, providing a sense of the scope of neuroscience research conducted using NHPs. Among these examples are collaborative research on neural circuitry through the BRAIN Initiative, the development of therapies for neurodegenerative diseases, and exploration of the brain–computer interface (NIH, 2022a).

The data collected by the committee on current demand for NHPs indicate that priority areas for NHP research remain similar to those identified in the 2018 ORIP report. However, data provided by ICOs regarding their current priority investment areas for extramural research show an increasing focus on NHP use for studies of genetic disorders and for the development and testing of gene therapies (NIH, 2022a)—research areas also reported by NPRCs and National Resources (National Resources Information Request, 2022; NPRC Information Request, 2022).

Demand for NHP Resources by Research Domain and Species: Intramural Research

Information on demand for NHP models within the NIH intramural research program, based on current intramural research activities, shows overall concordance with high-demand domains in extramural research—including neuroscience and neurological disorders, and infectious disease and immunology (Denny, 2022). These domains for the intramural program also align with past trends described in the 2018 ORIP report (ORIP, 2018a).

ICOs provided several examples of intramural research activities requiring the use of NHPs within these high-priority research domains. In the domain of neuroscience and neurological disorders, the National Institute of Neurological Disorders and Stroke (NINDS) highlighted investment in research using NHPs to better understand the pathogenesis of such neurodegenerative diseases as multiple sclerosis, Alzheimer’s disease, and ALS. NIMH cited the need for NHPs to study brain–behavior relationships to better understand the dysregulation of cognition and emotion in psychiatric disease and how neural circuit manipulations can ameliorate such dysfunction. The National Institute on Deafness and Other Communication Disorders (NIDCD) highlighted the use of NHPs for gene therapy work to advance its efforts to develop treatments for hearing loss and balance issues (NIH, 2022a).

There is significant demand for NHPs in intramural research in the domain of infectious disease and immunology, with much of this research being carried out by NIAID. This work focuses on the development and testing of therapeutics and vaccines for such high-consequence microbial threats as Ebola, Nipah, Hendra, Marburg, Lassa, and other viral agents (NIH, 2022a).

Additionally, the National Institute on Aging (NIA) reported active NHP use for research in the domain of aging and age-related disease. Specifically, this work is focused on understanding the pathogenesis of and the development of translational models of aging and age-related disease. The provision of NHP resources for investigators was noted as a priority for NIA’s intramural program (NIH, 2022a).

As with extramural research, multiple ICOs with intramural research programs noted that COVID-19 research efforts significantly altered use patterns for NHPs and resulted in unmet demand for NHPs for some research activities within these programs (NIH, 2022a). NINDS, for example, reported a 3-year hiatus from macaque use, while NHLBI had to delay promising studies on stem cell transplantation and gene therapy (NIH, 2022a).

Compared with the extramural research program, the NIH intramural research program relies on fewer NHP species. Data provided by ICOs that carry out intramural research using NHPs show that macaques account for 75 percent of all NHPs used (Denny, 2022), a proportion consistent with that described in the 2018 ORIP report. Marmosets account for much of the remainder of NHP use, with squirrel and African green monkeys being used in some limited instances for neuroscience and infectious disease research (NIH, 2022a).

Costs of NHPs

The increased demand for NHPs caused by the COVID-19 pandemic exacerbated the existing shortage of NHPs described in the 2018 ORIP report, which in turn resulted in a rapid and substantial rise in the cost of NHPs. These skyrocketing costs have had direct implications for the conduct of both extramural and intramural NIH-supported biomedical research by limiting the number of NHPs that can be procured and the number of NHP studies that can be performed. Increases in the average price of NHPs—not species specific—since 2019 as reported by individual NPRCs range from 10 percent to 22 percent (NPRC Information Request, 2022).¹⁶ National Resources reported that the price of animals increased by 25–35 percent during the same period (National Resources Information Request, 2022).

The costs of animals from other sources, such as commercial suppliers, have been reported as vastly surpassing cost increases at NIH-supported resources, and the price increases for high-demand species, such as rhesus and cynomolgus macaques, have been especially steep. NINDS conveyed to the committee the concerns raised by its awardees with respect to the costs of rhesus macaques, which had risen from $8,000 to $24,000—a 200 percent increase (NIH, 2022a). Compounding these difficulties related to NHP costs, rising inflation has resulted in increased costs for personnel and husbandry programs associated with NHP care (NIH, 2022b).

Intramural research programs have experienced similar cost pressures. ICOs reported that since 2018, all costs related to intramural NHP research infrastructure, procurement, and care have increased dramatically, primarily as a result of the scarcity of NHPs, the Chinese export ban, and rising inflation (NIH, 2022b). NEI and others reported that the cost of NHPs has increased two to five times compared with recent years. NIAID indicated that the price of cynomolgus macaques, the supply of which was strongly impacted by the Chinese export ban, had increased by 500 percent. Cost increases apply to all NHP species used in intramural research, even those for which demand is not typically high and whose supply was largely unaffected by the knock-on effects of shortages of macaques, as seen with the doubling in price of African green monkeys. NCI reported that the severe shortage of NHPs has resulted in the need to procure young animals and house them until they are mature enough to be used in NCI research protocols, a process that incurs a substantial additional cost over the life of the animals for their housing and care and limits the physical capacity of the institute to carry out research at its anticipated pace (NIH, 2022a).

These cost increases have a particularly detrimental impact on NIH-supported extramural NHP research because of the inflexibility of NIH direct funding caps, which the 2018 ORIP report cites as a challenge for investigators (ORIP, 2018b). These funding caps have not been raised for many years and currently are fixed at $500,000 per year for direct costs (ORIP, 2018a). ICOs described approaches used to address the increased costs, including provision of supplemental funding for the purchase of animals from alternative suppliers, reallocation of contract funds, and recycling of animals where possible (NIH, 2022a). However, these approaches are not always available and do not adequately address the rapidly rising costs of NHPs and overall increases in the cost of conducting NHP research. How frequently exemptions to funding caps are granted and other approaches are used to address the rising costs of NHPs remain unknown.

Transportation and NHP Accessibility

Importation challenges resulting from recent changes in international export policy (discussed earlier) have been compounded by increasingly strict transportation policies that affect NHP availability. In addition to the international and domestic regulations for NHP transport (NRC, 2006), commercial transporters have enacted their own policies that have resulted in operational and logistical barriers to the transportation of NHPs for biomedical research purposes, both internationally and within the borders of the United States (ORIP, 2018a,b). The most significant of these corporate policy decisions is the cessation of air transportation of NHPs by major commercial air carriers, with most noncharter carriers being influenced by public pressure to restrict NHP transport (Abbott, 2014; AviationPros, 2013; Grimm, 2018; Wadman, 2012). Added in 2022 to this list of carriers were Egypt Air; Kenya Airways; and Air France, the last major carrier to provide international air transport for NHPs (Daley, 2022; O’Grady, 2022; Roscoe, 2022). Alternative international transportation options, such as transit by sea, are not permitted because of the deleterious effects of the long journey on the animals’ health (Wadman, 2012).

These changes in policies have impacted the availability of and access to NHPs by U.S.-based investigators both directly, with investigators increasingly being unable to import animals because of transportation barriers, and indirectly, because of increased demand and cost for domestically produced primates. Four of seven NPRCs reported that transportation issues limit their ability to meet investigator demand; transportation issues were also cited as a barrier by National Resources (National Resources Information Request, 2022; NPRC Information Request, 2022). Among NHP investigators who responded to the committee’s survey noting specific challenges with accessing NHPs for their research (n = 175), 18 percent attributed these challenges to transportation issues (see Table B-24 in Appendix B) (NHP Investigators Survey, 2022).

Domestically, U.S.-based NHP research is increasingly relying on ground transportation in response to the lack of air travel options. This shift in transportation mode has various implications for both investigators’ access to animals and the animals’ health and safety (Prescott and Jennings, 2004), as well as that of the public (Elmore, 2008), during transport. For example, the vast majority of the NPRCs and National Resources are located along a coastline and investigators requiring animals may experience difficulties in transporting animals to their home institutions or in traveling to an NPRC to carry out their research. One significant concern with long-duration transportation of NHPs is the increased risk of accidents. In 2020, for example, a truck transporting NHPs caught on fire in New Jersey (Tarrazi, 2020), and in 2022, a collision between a dump truck and a truck carrying a trailer with NHPs in Pennsylvania resulted in the euthanasia of multiple animals (AP, 2022). Increased travel times increase the risk of illness in the animals, as well as their degree of stress (Elmore, 2008; Prescott and Jennings, 2004), as indicated by elevated levels of cortisol (Nehete et al., 2017) and weight loss (Málaga et al., 1991). Some animals may be unable to stabilize once resettled in their new locations. Outwardly sick and/or injured NHPs cannot be used in research, compounding an already limited and insufficient NHP supply.

Short-Term Efforts by Stakeholders to Address Impacts of Unmet Investigator Demand

Both NIH and NPRCs have actively undertaken measures to ameliorate the impacts of limited NHP supply on biomedical research (Eisinger, 2022), although the NPRCs emphasized that these efforts, while beneficial, are only short-term measures, and that long-term solutions are needed to address the persistent shortfall in supply, including increased and continued investment in domestic breeding of animals, infrastructure, and personnel (Morrison et al., 2022). Recent measures to address NHP supply constraints have involved coordinated action around specific public health threats to prevent duplication of research across multiple centers and enhance complementary work, thereby reducing the total number of NHPs needed to carry out the proposed research. Additionally, the reuse of animals is prioritized where possible (NIH, 2022a), although not all NHPs will be fit for reuse based on prior research interventions.

There have been strategic efforts to maximize the usefulness of the NHPs that are available. In response to the exacerbation of the shortage of animals during the COVID-19 pandemic, for example, NIH provided funding to build a partnership across the seven NPRCs called the Coronavirus Vaccine and Therapeutic Evaluation Network (CoVTEN). This coordinated NPRC effort, led by the Tulane NPRC, was aimed at standardizing research protocols and methods, collecting and disseminating preliminary data, and reducing numbers of NHPs needed by using a single control group across multiple studies (NASEM, 2021; Rappaport, 2022; Tate, 2021). Other efforts undertaken to maximize the limited supply of NHPs included policy changes by NIH that allowed for SPF colony repurposing, as well as ORIP’s publication of a notice of limited availability of research NHPs in March 2021 (Eisinger, 2022). This notice formalized the prioritization of NHPs at NPRCs and National Resources to conserve their use for research that is “urgently required to save human lives or shorten the COVID-19 pandemic” (HHS, 2021).