The Association of Primate Veterinarians and the European Primate Veterinarians Position Statement on the Value of Nonhuman Primates in Research

Introduction

The Association of Primate Veterinarians (APV) and the European Primate Veterinarians (EPV) recognize the vital role of nonhuman primates (NHPs) in basic and applied research to improve the understanding of diseases affecting both human and NHP health. The APV and EPV are committed to using evidence-based approaches to advance the medical and behavioral care of NHPs and maximize their well-being by facilitating the implementation of the 3Rs (reduction, refinement, and replacement) for humane research.¹ The intent of this document is to provide guidance to veterinarians, research staff, and regulatory agencies on the scientific evidence for the continued need for NHPs in research and outline expectations for considerations for their ethical use, and it has been reviewed and approved by boards of both organizations. Funding agencies and biomedical research institutions around the world demand rigor and reproducibility in scientific applications, and these attributes are considered critical in maximizing information gained from NHP studies (US NIH: https://grants.nih.gov/policy/reproducibility/index.htm; UK Academy of Medical Sciences: https://acmedsci.ac.uk/policy/policy-projects/reproducibility-and-reliability-of-biomedical-research).² The importance of NHP models in biomedical research is at the forefront of recent policy discussions by representative groups of scientific and medical experts.^3–5 In 2023, the National Academies of Sciences, Engineering, and Medicine highlighted the critical nature of NHP research for supporting the advancement of medical knowledge and care.⁶ The crucial role of NHPs in biomedical research is in part due to their genetic and physiologic similarities to humans, which conveys the unique ability to model complex diseases and/or disorders. Many recent articles highlight the contemporary importance of NHP research for continued progress in scientific and medical fields and reinforce the positions of other international experts and organizations.^6–8 Additional online resources provided by research advocacy organizations provide compelling evidence for the historical and current importance of NHP research (Understanding Animal Research: http://www.understandinganimalresearch.org.uk/; Foundation for Biomedical Research: https://fbresearch.org/; Americans for Medical Progress: https://www.amprogress.org/).

Medical Breakthroughs with NHP Models

The World Health Organization/World Bank “World Report on Disability” lists the diseases that are thought to trigger the highest levels of pain and discomfort and negatively impact the quality of life of millions of people. This report highlights that 15% of the world’s population lives with some disability, with 2%-4% significantly affecting function (World Health Organization, 2011). NHP models have, and continue to be, fundamental for scientific discoveries for both human and animal health for many of the diseases on the list, which include arthritis,⁹ cardiac disease and stroke,^10,11 diabetes,¹² endometriosis,^13–15 neurodegenerative diseases,^16–19 and infectious diseases.^20–24

Remarkable scientific and medical progress has been achieved that would not have been possible without the contributions of NHPs.^3,6 NHPs remain unique translational models for understanding complex biologic mechanisms in humans under normal and pathologic conditions and for evaluating efficacy and safety of new drugs, treatments, vaccines,^25,26 and diagnostic tools.²⁷ NHPs are the only pharmacologically relevant animal species for human-specific monoclonal antibody research, making them vital in this area.^28,29 Despite advances in in vitro assays, transgenic mouse models, and other alternatives, these only limit but do not eliminate the need for NHPs in this area.³⁰ In the field of neuroscience, NHP models are required due to their cognitive complexity to study advanced cognition, neurodegeneration, and treatments for these conditions.^31–35

The criticality of NHPs in research is only increasing. This was highlighted during the COVID-19 pandemic, when NHP research facilitated the rapid development of a vaccine that prevented more than a million related deaths and 10 million hospitalizations.^7,36 This vital life-saving research must continue if human and animal medicine are to meet existing health challenges (for example, tuberculosis, malaria, HIV/AIDS, cancer, retinal degeneration, autoimmune diseases) as well as understand, prevent, and treat contemporary health issues such as neurodegenerative diseases,^16–19 neuronal trauma,³⁷ aging-related diseases,³⁸ reproductive health,^13–15 regenerative medicine,³⁹ lifestyle-related diseases, and emerging, and reemerging, infectious diseases such as Zika⁴⁰ or influenza.²⁶

In addition to the sources cited above, which outline advances in medical research where NHP research has proved critical, some recent examples that highlight medical breakthroughs are as follows:

• Macaques were instrumental in the rapid evaluation of treatments for SARS-CoV-2 infections, including convalescent plasma, monoclonal antibody therapies, and vaccination against COVID-19. The macaque models facilitated rapid approval of monoclonal antibody therapies and vaccines around the world in the face of a pandemic.^41–50

• Macaques served a critical role in the development of a vaccine for Mpox, previously known as monkeypox.^51,52

• Respiratory syncytial virus vaccines for older adults and pregnant women were recently released along with monoclonal antibody therapies for at-risk infants. Macaques were instrumental in the development of these therapies.^53–55

• A genetic therapy for Parkinson disease (ProSavin) has produced outstanding recoveries in NHP models of the disease.^56,57 It has also been successfully administered to human patients and showed significant improvement in motor symptoms for up to 4 years post-treatment.^56,58,59

• Developments in the field of neuroscience and bioengineering are offering new options for patients affected with paralysis or paresis through exoskeleton prosthetics or the direct operation of other robotics through brain/computer interfaces.^60–62

• Retinal prosthesis to restore vision in blind patients⁶³ was made possible with macaque preclinical trials,⁶⁴ and continual improvements are being explored.⁶⁵

• Stem cell therapy^66,67 and transgenic primate models have been used for complex diseases such as autism.⁶⁸

Availability of NHPs for Research

For many diseases targeted by the World Health Organization, NHPs are the primary or only model available.^5,69 The 2023 National Academies of Sciences, Engineering, and Medicine report underlined the critical need for a steady resource of NHPs to support research advancements, as well as serving as a validation system for nonanimal models as new options become available. Ready domestic availability of NHP animal models prevents scientific bottlenecks and facilitates rapid scientific responses in the face of urgent medical crises.⁶

Supporting Ethical Research Using NHPs

Despite advances of alternative methods that aim to decrease reliance on animal research, there are no reliable alternatives that replicate a whole animal model and the underlying systemic body interactions. The APV and EPV both recognize that NHP research can be associated with societal concerns. Working with NHP models is a privilege subject to rigorous ethical and scientific scrutiny and conducted in compliance with applicable regulations, including the UK Animals (Scientific Procedures) Act 1986,⁷⁰ the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (ETS no. 123),⁷¹ the US Animal Welfare Act and associated regulations,⁷² the US Public Health Service Policy on Humane Care and Use of Laboratory Animals,⁷³ and the Guide for the Care and Use of Laboratory Animals.⁷⁴ Voluntary assessment and accreditation by nongovernmental bodies such as AAALAC is encouraged in the spirit of continuous improvement to ensure implementation of the highest standards of humane NHP care and use in research. Finally, IACUCs, University Animal Care Committees, Animal Welfare and Ethical Review Bodies, and similar institutional bodies provide local oversight for animal care and research programs.⁷

The APV and EPV support the responsible stewardship of NHPs in research. All NHP studies require strong scientific justification that clarifies the expected advances in understanding NHP biology and potential benefits to human and animal health. All NHP research should be conducted only by those appropriately trained and competent to use the current best practices of animal care, in accordance with aforementioned national, regional, and industry regulating bodies and laws.^70–75 Given the proven importance and validity of NHP research, the APV and EPV support the continued, responsible involvement of NHPs in studies where the research is subject to ethical scrutiny such as application of a harm/benefit analysis and evaluation of the 3Rs. While we conclude that NHP involvement in biomedical research is scientifically necessary, we agree with other published experts that each case should be evaluated individually and in real time to determine whether advancements to alternatives exist given rapid progression in the field of biomedicine.^76,77 Many countries and organizations have produced online resources for alternatives to animal testing that should be reviewed regularly (https://www.niehs.nih.gov/health/topics/science/sya-iccvam; https://norecopa.no/; https://nc3rs.org.uk/; https://www.nal.usda.gov/programs/awic). When it is determined that NHP models are necessary, refinements to existing policies and practices to reduce the potential for pain or distress should be pursued.⁷⁸

Veterinarians, veterinary technicians, animal care technicians, IACUCs and ethics committees, behaviorists/ethologists, physicians, and the scientists who work with NHPs in research play key roles in the improvement and application of best practices for housing, care, husbandry, and experimental procedures. The continued development of improved research techniques and equipment designed to reduce or eliminate animal pain and distress is promoted throughout the laboratory animal community using objective scientific assessment. Examples include utilization of state-of-the-art anesthesia, analgesia, and perioperative care, behavioral training to facilitate cooperative care,⁷⁹ evidence-based pain assessment,^80,81 the development of minimally invasive surgery practices using ultrasound or endoscopic technology for visualization,⁸² and the substitution of detailed imaging procedures to reduce or replace more invasive procedures.⁸³ Comprehensive primate behavioral management programs informed by evidence-based data including social housing, positive reinforcement training, human–animal interaction, food-related enrichment, and provision of manipulanda to encourage species-specific behaviors are standard practices in current NHP research and breeding facilities. These approaches in combination contribute to the improved well-being and health of the animals and produce more reliable and consistent research results when NHP studies are performed. The members of the APV and EPV are committed to maximizing the welfare of the animals under their care and ensuring the most valuable research outcomes.

Disclaimer

The position statements and/or guidelines produced by the APV are intended to be recommendations and offer guidance and are not a regulatory requirement. The Scientific Advisory Committee within the APV is tasked with the generation and revision of guidance documents for use by the membership and primate specialists worldwide. A subcommittee of current APV members and subject matter experts that have expertise in the area of interest are recruited to draft a document that is then sent out for comment and input from the Scientific Advisory Committee, the APV Board of Directors, and the APV membership. The final version was approved by the Board of Directors of both the APV and EPV before being published.

We extend special thanks to the committee members who worked on and contributed to this document: Dalis Collins, DVM, DACLAM (University of Michigan), Andrew Haertel, DVM, MPH, DACLAM (Oregon National Primate Research Center), Sherrie Jean, DVM, DACLAM, Elizabeth Magden, DVM, MS, DACLAM (UT MD Anderson Cancer Center–Michale E. Keeling Center), Devon Owens, DVM (Tulane National Biomedical Research Center), Rebecca Sammak, DVM, DACLAM (California National Primate Research Center), and Heather Sidener, DVM, DACLAM (Veteran’s Health Administration Portland). Committee members received no financial support for the research, authorship, and/or publication of this article.