Collaboration between Human and Veterinary Research and Medical Experts Could Provide a Balanced Discussion on the Ethics of Using Animals in Research

Abstract

Animal use in biomedical research continues to present ethical issues regarding justification, care, and welfare. There are differing viewpoints for the continued use of animals in research, testing, and training, and the public can easily search for viewpoints that support a single perspective but rarely are provided with a balanced discussion. An issue of the American Medical Association Journal of Ethics (September 2024, vol. 26, no. 9) exemplifies this problem by providing many views opposing the continued use of animals in research without allowing or providing input from those in the laboratory animal science profession. As a result, many of the views represented in the journal misrepresent important considerations that currently exist when considering the ethical use of animals in research. If a more diverse set of experts, including those with knowledge of laboratory animal medicine, governance, application of the 3Rs, and nonanimal alternatives, were invited into the discussion, we believe that a more accurate perspective of this issue could have been presented. Such diverse viewpoints would have fostered a better atmosphere that more accurately reflects the current reality of how animal use in research is considered by IACUCs. A better understanding of differing perspectives, and with further opportunity for respectful dialogue, could more effectively move this issue forward.

The September 2024 issue of the American Medical Association Journal of Ethics (AMA JE; 26(9):E665-E744) was a missed opportunity for medical professionals to collaborate on a subject of mutual interest—the welfare and appropriate use of animals in biomedical research. This issue covered subjects related to animal research, which could have benefited from input from diverse experts including those using animals in research, regulation, animal biology, bioengineering, and scientists who have considered alternatives but continue to use animals in their research. Indeed, there is a specialty college, the American College of Animal Welfare, that also could have contributed to the subject. Factual errors and misinformation could have been avoided, creating a stronger, more accurate, and more collaborative publication presenting the diverse opinions of this complex issue, which would have helped to encourage public dialogue on a controversial ethical issue in which stakeholders often hold strong opinions.

We applaud the AMA JE editors for devoting an entire journal to the topic of the ethics of animal research to help readers gain a deeper understanding of the issues behind this topic. Individual articles covered a wide range of topics including animal personhood, IACUCs, and replacement of animal models. A thorough reading by veterinarians certified by the American College of Laboratory Animal Medicine noted multiple factual errors, omissions, and misinterpretations of regulation and practices. While the AMA JE authors possess expertise within their own discipline, partnering with veterinary specialists, IACUC staff or compliance specialists, and researchers would have created a balanced publication and enhanced the public discussion regarding the ethical use of animal models for human-centric research.

Throughout the AMA JE, there are several important, and appropriate, references to the Animal Welfare Act,¹ which is the seminal law first passed by the United States Congress in 1966 to protect research animals. However, the journal fails to give adequate acknowledgment to other critical laws, policies, and guidance documents published in the United States that affect animal research and provide interpretation of various regulations, policies, and guidance, including those related to the ethical use of animals in research, testing, and training. These include, but are not limited to, the following: Public Health Service policy on humane care and use of laboratory animals,² Health Research and Extension Act of 1985,³ US government principles for the utilization and care of vertebrate animals used in testing, research, and training,⁴ Guide for the Care and Use of Laboratory Animals, 8th ed. (the Guide),⁵ AVMA Guidelines for the Euthanasia of Animals: 2020 Edition,⁶ the Lacey Act,⁷ NIH’s Office of Laboratory Animal Welfare (OLAW),⁸ and AAALAC International.⁹ Such regulations, policies, principles, guidelines, publications, and reference documents exist in the United States, although AAALAC accreditation, which uses existing laws and the Guide as a primary reference document, extends to an international scope.

While the use of animals in research is a controversial topic for some, AAALAC supports the use of animals in research, teaching, and training when there are no nonanimal alternatives, and when it is done ethically and humanely. Seeking AAALAC accreditation is a voluntary process. AAALAC has accredited more than 1,140 companies, universities, hospitals, government agencies, and other research institutions in 52 countries/regions. Regulations and guidelines governing animal use ethical considerations also exist in other countries, and may be more restrictive than those developed and in use in the United States.

The case study basis for the articles presented by Walker¹⁰ and John¹¹ failed to discuss the importance of the Guide or AAALAC accreditation on the oversight of animal use, care, welfare, and research. The authors do not mention the funding source for the research upon which their discussions are focused, although it was assumed to be United States based. Most animal research in the United States is funded by the National Science Foundation or the NIH. As a condition for receiving this funding, the research institutions must provide assurance to the National Science Foundation or NIH that they follow the Guide.¹² In the United States, most academics and the pharmaceutical industry demonstrate compliance with the Guide by being AAALAC accredited. AAALAC uses the Guide as a primary standard upon which to grant accreditation. Such an omission from the AMA JE case study undermines the actual regulatory framework that currently exists for consideration of research using animals in this country.

The AMA JE presents many open-ended ethical concerns suggesting that such ethical issues have not previously been considered. The Guide, OLAW, and AAALAC include substantial guidance on ethical principles associated with animal research including harm/benefit analysis, humane endpoints, conflicts of interest, breeding and transportation, experimental strength and validity, and justification for the use of animals in research. Omitting such references does not give justness to the animal research community’s own efforts to understand and tackle ethical principles around this topic. Letters to the editors and alternative viewpoints were submitted to the AMA JE expressing our concerns but were rejected.

One cannot understand the ethical framework upon which animals are used in research without thoroughly reviewing the guidance provided by OLAW and AAALAC. OLAW and AAALAC provide position statements and guidance statements, for example on the 3Rs and Culture of Care that address ethical and welfare concerns. Furthermore, OLAW and AAALAC collaborate with the USDA to develop instructive materials that have profound impacts on the care and use of animals in research, much through frequently asked questions (FAQs). OLAW provides some 75 FAQs¹³ on a broad range of topics including IACUC protocol review (24 FAQs), program review and inspection, animal use, and management (19 FAQs), institutional disaster, and emergency response requirements. AAALAC provides 64 FAQs.¹⁴ Such FAQs, when considered together with other position statements and guidance statements, provide specific interpretation of the requirements set forth in the Animal Welfare Regulations, PHS policy, and the Guide.

Misinterpretations are also found throughout this edition. One example includes points made in the section titled “From the Editor”.¹⁵ While this is not the only section with items of concern, it established a tone for the edition. One particular point is worth mentioning:

• The author drew a false conclusion from the references provided and overgeneralized that the COVID-19 pandemic led to a vaccine development process that was accelerated while using fewer animals. In fact, the supporting references note that animals are required; that speed was largely due to simultaneous, rather than sequential steps, and other events; and that it was nearly impossible to determine numbers of animals used. The numbers discussed were focused on reports from Germany alone, which may not be representative of research conducted regionally or across the globe.

Another is the article on microphysiologic systems (MPS) by Sharoni.¹⁶ It provides an excellent example of how different conclusions might be reached had the voices of additional scientists been included. Sharoni claims that scientists are uneducated about MPS, or that its slow advance is from lack of knowledge, resistance, or lack of publishers and funding agency coercion. Scientists and research veterinarians are fully aware of progress in this area and have been strong advocates for its progress from the earliest stages of development. The author could have included voices of researchers using MPS. A dialog on its effectiveness as an adjunct methodology, and its limitations, could lead us toward growing a more complete knowledge database on the strengths and limitations of the developing field of MPS.

Sharoni is an advocate for the promising field of MPS and its future in biomedical research but failed to support assertions that MPS more accurately models human physiology, reduces the failure rate of drugs in clinical trials, and limits ‘unnecessary’ animal use:

• References provided by Sharoni¹⁶ include discussion of the importance of animals in research while noting the potential usefulness of MPS.¹⁷ The cited references also note that MPS cannot completely replicate the many known and yet unidentified chemical interactions and signaling processes of in vivo systems.

Other references cited by Sharoni¹⁶ do not mention animal use as being part of reproducibility failure or as an issue in clinical trial outcomes:

• At least one citation used to support a case for animal models hindering scientific progress is actually a small survey of scientists asked to self-report as to whether they felt a reviewer request for animal data was justified (this article was produced by the animal rights groups Physicians Committee for Responsible Medicine and the Humane Society International).¹⁸

Absent from this edition was any acknowledgment of the important contributions of animals to research. Some of the worst tragedies in drug development were due to insufficient animal testing such as the thalidomide tragedy of the mid-1900s, where thousands of children suffered devastating birth defects.¹⁹ Since then, an enhanced regulatory framework has been in place to require more robust animal testing of new pharmaceutical products, including the use of more than one species in reproductive toxicology. Another tragedy resulted in several human deaths in 1995, where hepatitis B–positive subjects in a clinical trial suffered major liver damage following failure to detect toxicity potential in preclinical testing and early testing in healthy human subjects.²⁰ Determining species-specific COX-2 inhibitor toxicity is another example of modern era, beneficial animal testing.²¹ Indeed, while respecting the advance of nonanimal methods, toxicology experts largely agree that animal testing has proven invaluable in drug safety, and will continue to be part of safety assessment for the foreseeable future. Currently, the Foundation for Biomedical Research website²² indicates that the 25 most prescribed medications in the United States were all developed using animal models. There may come a time when animals are no longer necessary to advance our understanding of biology, develop drugs, or assure product and drug safety. Until then, we must acknowledge the limits of nonanimal methods as we seek a future without animal-based research.

The use of animals in research, testing, and teaching can evoke strong emotions and responses from the public, both pro and con, in part because the information they receive is not balanced or complete. Medical professionals, especially, have a heightened responsibility to provide impartial information because they are trained in the scientific method to present all sides of an issue and then engage in active debate in search of the truth. We think that the September 2024 AMA JE represented a missed opportunity to provide its readership with an accurate understanding of the full and complex environment in which animals are considered for their use in research. Additional commentary and input from those using animals in research, regulatory experts, experts in animal biology, bioengineering, and scientists who have considered alternatives but continue to use animals in their research could have greatly expanded the perspectives represented. Such additional perspectives would have allowed the reader a more complete understanding of the current ecosystem and hopefully stimulated more robust understanding and dialogue within this complex issue. In the future, we encourage professionals across the medical community to work together for the advancement of biomedical research and the creation of valid alternatives to the use of animals.

Conflict of Interest

The authors have no conflicts of interest to declare.

Funding

This work was internally funded.