of the published literature and publicly available data; and (3) a review of public comments received over the course of the committee’s deliberations. These are discussed further in the sections below.

RESEARCH METHODS

The committee gathered data from many different sources to address its charge and to inform its findings and conclusions. Building upon the 2018 report published by ORIP on NHP supply and demand,¹ the committee sought to mirror some of the data-collection methods used in that report to evaluate current use of and future priorities for the use of NHPs. These efforts included the collection and analysis of publicly available data from the U.S. Department of Agriculture’s (USDA’s) Animal and Plant Health Inspection Service (APHIS) and NIH; a survey of experiences and perspectives of NIH-supported principal investigators (PIs) using NHPs in their research; and information requests to federal agencies (NIH, Food and Drug Administration [FDA], Centers for Disease Control and Prevention [CDC]), the National Primate Research Centers (NPRCs), and seven institutions that receive NIH support for breeding colonies or colony management. In addition to these data-collection efforts, the committee conducted a series of literature searches of peer-reviewed and gray literature (e.g., federal agency reports, working papers). This section describes each of these activities and how the resulting data were used in the report.

Information Requests

The committee sent formal information requests to several federal agencies and other stakeholder organizations to collect information that was not publicly available (see Table A-1). Copies of these written requests and their complete responses can be requested from the committee’s public access file. The nature of these requests and descriptions of how the resulting information was used in this report are included below.

CDC

The committee requested up-to-date information from the CDC Quarantine and Border Health Services branch on NHP importation from 2019 to 2022 to assess changes in recent NHP importation levels. Data requested included number of NHPs imported, countries of origin, and species. These data were used in the report to assess importation trends from 2018 to 2022, including species imported and country of origin.

FDA

The committee requested data from FDA on the use of NHPs, as well as in vitro and in silico methods that have been used as alternatives to animal-based models, in regulatory approval processes. While quantitative data were unavailable, examples provided by FDA

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¹ ORIP. 2018. Nonhuman primate evaluation and analysis Part 1: Analysis of future demand and supply. National Institutes of Health. https://orip.nih.gov/about-orip/research-highlights/nonhuman-primate-evaluation-and-analysis-part-1-analysis-future (accessed March 21, 2023); ORIP. 2018b. Nonhuman primate evaluation and analysis Part 2: Report of the expert panel forum on challenges in asssessing the nonhuman primate needs and resources for biomedical research. National Institutes of Health. https://orip.nih.gov/sites/default/files/NHP%20Evaluation%20and%20Analysis%20Final%20%20Report%20-%20Part%202%20Final%20508%2021Dec2018_002.pdf (accessed March 3, 2023).

TABLE A-1 Overview of Committee Information Requests to Federal Agencies and Other Stakeholder Organizations

*In some cases, more than one information request was submitted as additional data needs were identified by the committee.

informed the committee’s evaluation of the landscape of NHP research and new approach methodologies.

NPRCs

Information requests were sent to the center directors at each of the seven NPRCs through an Alchemer survey form. Information requested to characterize current use trends and experiences included (1) species bred and used, (2) number of NHPs on-site, (3) annual production from breeding colonies, (4) number of NHPs enrolled in active research protocols, (5) capacity to meet recent investigator requests, and (6) current challenges experienced in meeting demand for NHPs. Additionally, to describe predictions of future needs for NHP models, NPRCs were asked to provide their predictions for future priority research areas, changes in demand for NHP models, and their ability to meet future demand for NHPs. All seven NPRCs completed the written information request, and these data were used to describe trends in NHP use by species, capacity to meet research needs, research priorities, and future challenges and opportunities for these institutions.

National Resources and Selected NIH-Supported Research Facilities

Information requests were sent to points of contact at select research facilities receiving NIH support to maintain breeding colonies. These included ORIP-supported National Resources—MD Anderson Cancer Center (Keeling Center), The Johns Hopkins University, Caribbean Primate Research Center, and Wake Forest University.² Additionally, identical information requests were sent to institutions with NIH P40 and N01 awards used to support breeding colonies but not identified by ORIP as National Resources. These included the University of Pittsburgh; University of Louisiana at Lafayette (New Iberia Research Center);

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² The three national NHP reagent resources supported by ORIP—University of Massachusetts, University of Louisiana at Lafayette, and Trinity University—were not asked to complete this information request because they do not host National Resource NHP breeding colonies.

and Alpha Genesis, Inc. Requested information included (1) species currently bred and used, (2) number of NHPs on-site, (3) annual production from breeding colonies, (4) number of NHPs enrolled in active research protocols, (5) recent capacity to meet investigator requests, and (6) current challenges experienced. The form also asked the research facilities to provide predictions for future priority research areas, changes in demand for NHP models, and their ability to meet future demand for NHPs. All seven facilities completed the written request, and these data were used to describe trends in NHP use by species, capacity to meet research needs, current NHP use in research, and future priorities and needs for these facilities.

NIH

In addition to the participation of NIH ICOs in the committee’s public information-gathering sessions, the committee sent several information requests to NIH in efforts to gather quantitative and qualitative data on NHP use in extramural and intramural research projects, challenges related to supply and demand, and NIH-supported and -owned breeding colonies. Quantitative data from internal NIH data systems were not available to the committee because of privacy concerns by NIH about accessing internal records, and because no automated methods are in place for collecting the requested data. Thus, this lack of quantitative data on NHP use in NIH-supported research limited the committee’s ability to evaluate the NHP research landscape quantitatively. However, 21 ICOs provided brief summaries of current extramural and intramural research priorities for NHP research, NHP availability concerns, and areas of investment, as applicable. Additionally, NIH provided written responses to committee questions in advance of the November 2022 public meeting. These responses provided additional details about NHP research funding, priorities, and collaboration efforts.

Literature Reviews and Publication Analysis

Multiple literature searches, carried out in PubMed and Scopus, were conducted throughout the study as research needs evolved. These searches were used to guide and provide references for report content describing current uses of NHPs in biomedical research and the current state of new approach methodologies.

Scopus Publication Analysis

In addition to literature searches, the committee commissioned the National Academies Research Center to conduct a literature review and series of publication analyses in Scopus, which provided additional context and evidentiary support for the description of the current use of NHPs in NIH-funded biomedical research in Chapter 2. This review was restricted to research published since 2018 and supported by NIH funding. Because the intent of this effort was to understand the distribution of NHP research and, importantly, identify examples of NHP use and types of research, the committee targeted a nonrandom selection of highly cited articles. Relevant articles were used in the committee’s description of the landscape of NHP research and the contribution of NHPs to advances in human health (Chapter 2).

In addition to the Scopus publication analysis carried out for recent NHP research, two literature reviews were also conducted in Scopus for recently published reviews on in vitro and in silico approaches. These searches were not restricted to NIH-funded projects. The results were used to broadly evaluate the scope of impactful new approach methodologies. Additionally, the results of these two Scopus searches were narrowed to recently published reviews, the abstracts of which were assessed by a committee member to determine whether

these reviews provided detail on how new approach methodologies could complement or reduce reliance on NHP models in biomedical research. These review articles were used to contextualize the contents of Chapter 4.

Search Terms

KEY(monkey* or primate* or aotus or owl-monkey* or callithrix or marmoset or cebus-capuci-nus or cercocebus or mangabey or sabaeus or african-green or chlorocebus-pygerythrus or vervet or erythrocebus-patas or patas-monkey or macaca-mulatta or m-mulatta or macacafascicularis or m-fascicularis or macaca-nemestrina or m-nemestrina or rhesus-macaque or cynomolgus or pigtail-macque or papio or baboon* or saguinus or tamarin or saimiri or saimiri-boliviensis or saimiri-oerstedii or saimiri-sciureus or saimiri-ustus or saimiri-vanzolinii or squirrel-monkey) AND PUBYEAR > 2017 AND ( LIMIT-TO ( FUND-SPONSOR,”National Institutes of Health” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Allergy and Infectious Diseases” ) OR LIMIT-TO ( FUND-SPONSOR,”NIH Office of the Director” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Mental Health” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Neurological Disorders and Stroke” ) OR LIMIT-TO ( FUND-SPONSOR,”National Eye Institute” ) OR LIMIT-TO ( FUND-SPONSOR,”Eunice Kennedy Shriver National Institute of Child Health and Human Development” ) OR LIMIT-TO ( FUND-SPONSOR,”National Cancer Institute” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute on Aging” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute on Drug Abuse” ) OR LIMIT-TO ( FUND-SPONSOR,”National Heart, Lung, and Blood Institute” ) OR LIMIT-TO ( FUND-SPONSOR,”National Center for Advancing Translational Sciences” ) OR LIMIT-TO ( FUND-SPONSOR,”Office of Research Infrastructure Programs, National Institutes of Health” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Diabetes and Digestive and Kidney Diseases” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Child Health and Human Development” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Biomedical Imaging and Bioengineering” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute on Deafness and Other Communication Disorders” ) OR LIMIT-TO ( FUND-SPONSOR,”Division of Intramural Research, National Institute of Allergy and Infectious Diseases” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Dental and Craniofacial Research” ) OR LIMIT-TO ( FUND-SPONSOR,”National Institute of Environmental Health Sciences” ) OR LIMIT-TO ( FUND-SPONSOR,”National Human Genome Research Institute” ) OR LIMIT-TO ( FUND-SPONSOR,”Foundation for the National Institutes of Health” ) )

TITLE(2D-cell-culture-model* or 2D-cell-culture-system* OR 2-dimensional-cell-culture-model* OR 2-dimensional-cell-culture-system* or two-dimensional-cell-culture-model* or two-dimensional-cell-culture-system* or 2D-cellular-model* or 2D-cellular-system* or 3D-cell-culture-model* or 3D-cell-culture-system* or 3-dimensional-cell-culture-model* or 3-dimensional-cell-culture-system* or three-dimensional-cell-culture-system* or three-dimensional-cell-culture-model* or spheroid* or organotypic-culture* or tissue-slice* or explant-culture* or primary-culture* or microtissue* or 3D-bioprint* or stem-cell* or 3D-cellular-model* or 3D-cellular-system* or organoid* or organ-on-a-chip or human-on-a-chip or liver-on-a-chip or skin-on-a-chip or kidney-on-a-chip or microphysiological-system* or microphysiological-device* or new-approach-method* or new-approach-methodology or in-vitro-complex-model* or microfluidic-model* or biomechanical-cue*) OR KEY(2D-cell-culture-model* or 2D-cell-culture-system* OR 2-dimensional-cell-culture-model* OR 2-dimensional-cell-cul-ture-system* or two-dimensional-cell-culture-model* or two-dimensional-cell-culture-system* or 2D-cellular-model* or 2D-cellular-system* or 3D-cell-culture-model* or 3D-cell-culture-

system* or 3-dimensional-cell-culture-model* or 3-dimensional-cell-culture-system* or three-dimensional-cell-culture-system* or three-dimensional-cell-culture-model* or spheroid* or organotypic-culture* or tissue-slice* or explant-culture* or primary-culture* or microtissue* or 3D-bioprint* or stem-cell* or 3D-cellular-model* or 3D-cellular-system* or organoid* or organ-on-a-chip or human-on-a-chip or liver-on-a-chip or skin-on-a-chip or kidney-on-a-chip or microphysiological-system* or microphysiological-device* or new-approach-method* or new-approach-methodology or in-vitro-complex-model* or microfluidic-model* or biomechanical-cue*) AND PUBYEAR > 2017

TITLE(virtual-human* or digital-twin* or QSAR-model* or quantitative-structure-activity-relationship* or systems-toxicology-modeling or IVIVE-model* or in-vitro-to-in-vivo-extrapolation or PBPK-model* or physiologically-based-pharmokinetic-model* or human-patient-simulator* or avatar* or quantitative-systems-pharmacology or computational-model* or computational-model-systems or computational-method* or computational-approach* or artificial-intelligence* or machine-learning) OR KEY(virtual-human* or digital-twin* or QSAR-model* or quantitative-structure-activity-relationship* or systems-toxicology-modeling or IVIVE-model* or in-vitro-to-in-vivo-extrapolation or PBPK-model* or physiologically-based-pharmokinetic-model* or human-patient-simulator* or avatar* or quantitative-systems-pharmacology or computational-model* or computational-model-systems or computational-method* or computational-approach* or artificial-intelligence* or machine-learning) AND PUBYEAR > 2017

Data Collection from Federal Sources

NIH RePORTER

The committee mined NIH RePORTER, a publicly accessible database of NIH awards, to collect data on NIH funding for P51 and P40 award mechanisms from fiscal years 2012 to 2022. This included funding provided via the primary awards (often referred to as “base grants”), as well as via administrative and competitive supplemental awards to each P51 and P40.

While the NIH RePORTER database represents a comprehensive record of NIH-supported biomedical research, it does not feature a mechanism for identifying projects using NHP models (generally, or specific species) as part of their methodologies. Keyword searches using NHP terminology did not provide a complete listing of active awards using NHPs. Unlike the prior review of NHP supply and use published by ORIP in 2018, the committee did not have access to internal NIH data systems to provide detailed information on current NHP use (e.g., information on research domain, species, quantity of NHPs planned for use, justification for the choice of model). This lack of access to complete quantitative and descriptive data limited the detail that could be provided regarding the landscape of extramural and intramural NHP research.

USDA

Annual data on NHP use in research facilities was collected from USDA’s APHIS Animal Care Public Search Tool. This tool provides a listing of the number of animals held, bred, or used for research purposes by registered institutions in the United States as required by the Animal Welfare Act,³ and represents the most comprehensive listing of the number of NHPs used

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³ 7 U.S.C. §§ 2131–2159 (P.L. 89-544), with implementing regulations: 9 C.F.R. § 1(A)

in research by year. However, this tool reports at an institutional level and does not include detail on the species used, specifics on the research domain in which NHPs were used, or source of the animals (e.g., imported or domestically sourced). Additionally, these annual reports by facilities do not provide information on individual animals over time, which limits understanding of how NHPs are used in these facilities over multiple years. For example, some facilities may host several long-term studies or run breeding colonies where the same animals are recorded on-site over multiple years. Conversely, other facilities may have animals enrolled in termination studies or may transport many NHPs out to other facilities, which in turn may impact how numbers are reported to USDA or may result in duplicative counting of animals moved across facilities, respectively. While these data have limitations, these annual reports are the only quantitative sources of information about NHP use at research facilities in the United States. Annual reports by research facilities reporting NHP holdings and use⁴ to APHIS were collected by year, 2018–2021, and were used to analyze NHP holdings and use over time and to identify the types of stakeholders involved in NHP research.

Survey of NIH-Supported Researchers Using NHPs

Given the paucity of publicly available, detailed information on the experiences of investigators engaged in NIH-supported NHP research, original data collection was undertaken by the committee in the form of a survey of NIH-supported researchers using NHPs in active NIH awards. This survey sought to (1) describe the landscape of NIH-funded extramural research using NHP models and (2) capture researcher experiences with limitations and challenges related to the access and use of NHPs in biomedical research, and predictions on future areas of value and infrastructure needs in this space. The protocol for these data-collection efforts was submitted to the Committee to Review Human Subjects, which acts as the National Academies’ Institutional Review Board (IRB) (#IRB00000281), and received an exemption from IRB review, under category 2 (subcategory i) of the Common Rule.⁵ A copy of the survey sent to investigators, including frequency tables by survey question, can be found in Appendix E.

Participant Recruitment

Because the committee was unable to access a comprehensive list of active, NIH-supported projects using NHPs, the committee used NIH RePORTER to identify all active NIH-sponsored extramural research projects likely to involve the use of NHPs by searching project abstracts, titles, and keywords. This database search was carried out by National Academies staff using such generic keywords as “primate” and “monkey,” as well as the scientific and common names for NHPs currently used in biomedical research (see search terms in the section above on NIH RePORTER). No restrictions were made in terms of research type (e.g., fundamental basic, translational) or area (e.g., immunology, psychology, neuroscience). The search was restricted to active project-driven research grants as categorized on NIH RePORTER as funding mechanisms for “Research Projects.” It should be noted that this search of NIH RePORTER captured projects that did not use NHP models, such as those projects that used a search term in the abstract in reference to prior research using NHPs, and likely missed some projects that did use NHPs, such as those that did not include a keyword in

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⁴ APHIS annual reports from research facilities provide information on the number of animals held, bred, or conditioned for research use and the number used for research purposes.

⁵ 45 C.F.R. 46, Part A § 46.104

the abstract that allowed it to be captured by the search. Investigators who responded to the committee survey but who did not use NHP models for their active award(s) were excluded. Because all investigators in the population of interest were contacted, no random sample was generated.

Inclusion criteria:

1. Principal investigator on an active, research-driven, extramural NIH award
2. Research involving the likely planned use of NHP models as part of the research methodology

Exclusion criteria:

1. Principal investigators with infrastructure or resource awards only
2. Intramural NIH investigators
3. Studies that do not use NHP models as part of the planned research methodology
4. Contact information not publicly available

National Academies staff manually collected emails for all PIs identified via the NIH RePORTER search of awards. In cases where the award was a multi-investigator grant, only the contact PI was contacted. After collecting this contact information, invitations to participate in the survey were sent by email by National Academies staff to each investigator identified (1,431 investigators after deduplication) with a description of the National Academies committee, its Statement of Task, the purpose of the survey, and a link to the survey form. All participants were given 3 weeks to complete the survey. For those who had not completed the survey, reminder emails were sent after the first and second weeks.

Because of the lack of information available about those respondents who did not choose to respond to the survey, no analysis of the representativeness of the respondents or the awards for which they reported information could be performed. Therefore, it is not known whether a higher or lower portion of researchers from a specific research domain, for example, responded to the survey as compared with the entire population of NIH-supported investigators using NHPs. Summaries of the survey responses, along with information on response rate and demographics, can be found in Appendix B.

Survey Composition

Survey questions were developed by the committee—specifically, the committee chair and appropriate content experts, including those with expertise in survey methodology. Because this National Academies committee built upon the work of the previously published 2018 ORIP report, which included a survey of a similar population of participants, this survey adopted similar methods, structure, and wording of questions. Prior to sending the survey, five investigators were selected to complete the survey and asked to provide preliminary feedback on the wording and content of the questions as a pilot phase.

The online survey began with a description of the purpose of the National Academies study, the voluntary nature of participation, and a description of noncompensation. The page also described how answers provided through the survey would be used and presented in the committee’s report (e.g., data would be deidentified and only aggregate data would be reported), as well as a description of how the data would be stored and managed. Participants were required to confirm that they read this material and that they agreed (or disagreed) to participate before they could proceed to the survey questions. After submitting their answers to the survey, each participant was thanked for their input and redirected to the study webpage.

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⁶ R Core Team. 2022. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. See https://www.R-project.org.