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Research Modernization NOW

Plan of Action: Recommendations for Modernizing U.S. Biomedical Research

1. End animal use in research areas in which animals have been demonstrated to be poor “models” of humans and their use has impeded scientific and medical progress.

Multiple reviews have documented the overwhelming failure of animal use to benefit human health in specific areas, including cancer, cardiovascular disease, diabetes, gastrointestinal disorders, inflammation, infectious disease, sepsis, nerve regeneration, neurodegenerative diseases, neuropsychiatric conditions, stroke, and women’s health. Since these experiments are generating results that are, at best, useless and, at worst, harmful, experiments on animals in these research areas should be ended as soon as possible and replaced with more effective and efficient non-animal methods. Please find further elaboration on and recommendations for these areas in the appendices.

2. Conduct systematic reviews of the efficacy of animal use to identify additional areas in which non-animal methods are available or animal use has failed to protect human health and the environment and can, therefore, be ended.

For research areas in which there is still some question as to whether the use of animals is beneficial, a thorough systematic review should be conducted to determine the efficacy of using animals. Systematic reviews, which critically analyze multiple research studies, are a crucial first step in assessing the effectiveness of animal use. Such systematic reviews should include information about the return on investment received by the public from the results of animal studies, particularly when publicly funded.

Several U.S. funding entities, including NIH, the Department of Veterans Affairs, and the Department of Defense, are members of the Ensuring Value in Research Funders’ Forum (EViR), a collection of prominent international funding bodies formed to address waste in clinical and preclinical research. EViR states as its second guiding principle, “[r]esearch should only be funded if set in the context of one or more existing systematic reviews of what is already known or an otherwise robust demonstration of a research gap.”1 It explains, “[t]his is important because new research not set in the context of what is already known leads to unnecessary duplication, studies that cannot change decision making (e.g., will not change the meta analysis), or inappropriate design (e.g., inappropriate outcome measures, incorrect prevalence assumptions, failure to learn from past previous studies).”2 To apply this principle, EViR says that funders must “[r]outinely assess whether an adequate review has been done and whether the results of that review support the case for further clinical or preclinical research.”3

The recommendation to conduct systematic reviews of the efficacy of procedures is, therefore, already one that the largest funding bodies in the world agree is a necessary principle for guiding valuable research and reducing waste in research funding, yet there is no concerted effort within the U.S. to put this recommendation into action.

When the National Academy of Medicine, formerly the Institute of Medicine, completed an examination of the scientific necessity of using chimpanzees in behavioral and biomedical research,4 the effort revealed that harmful studies had been approved, funded, and conducted for years, even though there were alternative methods in virtually every area in which chimpanzees were being used. Institutional oversight bodies and funding agencies had given their stamp of approval to these protocols. However, as we now know, the review processes in place were inadequate. Wherever thorough and objective systematic reviews of animal use for various areas of inquiry have not been conducted, they should be undertaken.

A number of resources exist for facilitating systematic reviews, including software for each step of the review process, tools for assessing study quality, reporting standards, workshops, tutorials, and opportunities to commission systematic reviews from trained researchers.567

3. Redirect funds from animal studies to reliable, non-animal methods.

The poor predictivity of preclinical experiments on animals has led to high attrition rates in the development of new therapies. As long as billions of NIH’s funding budget goes to experiments on animals, the U.S. will be stalled in the development of effective treatments for human disease. Forward-thinking scientists are developing and implementing methods for studying and treating diseases and testing products that do not entail the use of animals and are relevant to human health. Researchers have created human cell–derived models, “organs-on-chips,” in silico models, and other methodologies that can replicate human physiology, diseases, and drug responses more accurately than experiments on animals do.

Studies have repeatedly shown that these new methodologies are better at modeling human diseases than crude experiments on animals are, yet funding for these tools pales in comparison to funding for poorly translatable animal methods.

NIH and other federal agencies must now take the next step by ending the funding of experiments on animals that have failed to provide effective treatments and cures. This will free up immense resources that when reinvested in exciting and innovative non-animal methods, career tracks, and institutes—together with bold policy initiatives—will boost the development of far more promising cures and treatments for humans. This will also alleviate the almost unimaginable suffering of millions of animals and help protect human health.

4. Implement a harm-benefit analysis system for animal studies that includes an ethical perspective and consideration of lifelong harm inflicted on animals.

For the benefit of animal welfare and human health, researchers should focus their considerable talent, time, money, and energy on moving away from archaic animal use—prioritizing areas in which the harm inflicted on animals is so great that no benefit could ever justify the experiment. Examples of such studies would include the following: maternal deprivation experiments (tearing infants away from their mothers); psychology experiments that cause fear, anxiety, or depression; drug, alcohol, and food addiction experiments; and painful experiments during which analgesia is withheld. Until all experiments on animals have ended, a system of analysis for a “risk threshold” or “upper limit,” similar to that employed in research on humans, should be implemented. Examples of frameworks by which to conduct harm-benefit analyses of animal experimentation can be found in the reports of the U.K. Animals in Science Committee Harm-Benefit Analysis Sub-Group,8 the report of the Working Group on the Use of Chimpanzees in NIH-Supported Research,9 and the research of Pandora Pound.10

The harm to animals that is considered should not be restricted to that resulting from specific procedures but should also include the inherent harm caused by life in a laboratory, where animals are denied the opportunity to meet their species-specific needs. Currently, the system does not adequately determine the extent to which animals are suffering in these experiments. Until researchers make this critical assessment, they cannot reasonably measure whether the results are worth the pain and suffering.

5. Work with organizations and agencies globally to harmonize and promote international acceptance of non-animal testing methods for regulatory testing requirements.

As described above, the regulatory acceptance of non-animal techniques in one region or country is an open door to international modernization of testing requirements. Therefore, we advocate that national and international regulatory bodies and standards organizations liaise with industry, research agencies, and relevant non-governmental organizations worldwide to establish and promote clear paths to and streamlined frameworks for the validation and harmonization of non-animal techniques for regulatory testing requirements.

Scientific confidence can be gained through transparent, peer-reviewed assessments of the fitness for purpose, technical reliability, and relevance of a new method. Implementing a streamlined framework for evaluating new toxicity testing methods that incorporate these key elements—and which is based on how well the methods reflect human biology rather than how well they align with traditional in vivo results—would allow for faster implementation of the best science and replace the use of flawed animal tests.11

To implement the vision of a more sophisticated approach to toxicity testing that would more adequately provide safety information on all chemicals in commerce, we further recommend that regulatory and government agencies enforce the existing EU legal requirement that a scientifically satisfactory method or testing strategy not entailing the use of live animals be adopted instead of a procedure involving animals wherever possible. In addition, we recommend that a public-private center for predictive animal-free toxicology be coordinated through the European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM). Such a center would help transform the science of safety assessment, with new tools to guide industry, government, consumers, and international trade partners to adopt best practices.

6. Educate the scientific and regulatory communities about the benefits of non-animal approaches and train scientists to use them.

As the fields of animal-free research and testing continue to expand, increased education and hands-on training will accelerate the transition to these methods. In deploying such initiatives, it is important to simultaneously remove the barriers to adopting new technology and build confidence in it. For example, Innovate UK has recognized that overcoming skepticism about the ability of non-animal methods to model biological processes will help remove a major barrier to the use of these methods. Furthermore, conservatism and inertia obstructing the move away from animal-based methods can be overcome by encouraging scientists “to think beyond their immediate research areas to how their skills, technology and ‘know-how’ can be leveraged and exploited to accelerate the development and adoption of”12 advanced non-animal methods. Such educational initiatives must be adopted and given ample financial support across the whole research sector, including academia, scientific and funding communities, and industry, from future scientists to established professionals.

There is a need for additional education and hands-on training in non-animal methods. Students and early-career scientists must be provided with opportunities to develop the skills necessary to contribute to this research field so that the U.S. can compete with international developments. Because many study programs lack sufficient courses about animal-free methods, supplemental training programs have been developed. For example, the European Commission’s Joint Research Centre hosts a summer school on non-animal approaches.13 Similar programs could be replicated in the U.S. at a federal level. Many online resources by experts in the field also exist, including those offered by PETA Science Consortium International e.V.14 and the Early-Career Researchers Advancing 21st Century Science program by the Physicians Committee for Responsible Medicine.15 Thus, information about animal-free research and testing is available and should be a component of all biomedical education.

Established researchers using animal-based methods should also be provided with retraining opportunities and encouraged to forge multidisciplinary collaborations to evolve their skills. These collaborations can help them develop new and innovative ways of asking research questions and finding methods for answering them. For example, the Dutch Transition Programme for Innovation without the use of animals created a series of “helpathons,” action-orientated workshops centered around a specific question that encourages researchers to think creatively about non-animal approaches through a community forum.16

Awareness among scientists of animal-free methods may be increased through the creation of a national center for animal-free research and testing, tenure tracks and professorships based on non-animal methods, and animal-free research leadership positions to advise professors, staff, and students. Universities and other institutions should also be encouraged to develop a departmental body for the transition to animal-free research that can work and advise across different departments. Such bodies could help organize undergraduate, graduate, and postdoctoral programs that use only non-animal methods as well as workshops, seminars, and summer schools on in vitro and in silico methods.

Funders also need training to identify the most promising advanced animal-free methods with translational potential in order to develop new funding streams. The same applies to grant reviewers to ensure that non-animal methods are not subjected to animal methods bias (the preference for animal-based research methods or the lack of expertise to adequately evaluate non-animal methods).17 An analysis of the expertise of members on NIH funding panels for basic, translational, and preclinical neuroscience research revealed that the committees were disproportionately biased toward experiments on animals. This bias was correlated with lower funding rates for non-animal research projects. The researchers wrote:

The implication of these data is that review bodies without sufficient expertise in non-animal methods may not be providing fair review and consideration to research proposals that propose to use non-animal methods. We expect this research to demonstrate the necessity for systemic and cultural change in the biomedical research community and be used to advocate for policies that raise the bar on ethical and effective research.18

As the field of animal-free testing methods continues to expand, the scientific and science policy communities must keep pace with these pivotal developments. Increased education and training initiatives are urgently required to build confidence in reliable and relevant non-animal methods that can best protect human health and the environment.

Conclusion

The current waste of resources, time, and animals’ lives has a direct and disastrous effect on human health and the environment. Experiments on animals are not reliably generating the safe and effective treatments and cures they were promised to produce. Existing oversight of U.S. biomedical research and testing is failing to ensure that animals aren’t being used unnecessarily, that their welfare is protected when they are, or that human-relevant methods are being adequately supported. Research Modernization NOW provides a roadmap for revitalizing the U.S. research and testing enterprise. Until this plan is implemented, the research funded by U.S. taxpayers will fail to provide the basic and applied research and testing needed to protect human health and the environment.

Detailed information on 42 areas of research, medical education, toxicity assessment, and laboratory production methods as well as the astonishing failure of animal use to protect human health and the environment is included in the appendices.

References
  1. Ensuring Value in Research. Our principles. EViR. 2022. Accessed November 1, 2024. https://evir.org/our-principles/ ↩︎
  2. Ensuring Value in Research. Our principles. EViR. 2022. Accessed November 1, 2024. https://evir.org/our-principles/ ↩︎
  3. Ensuring Value in Research. Applying the principles. EViR. 2022. Accessed November 1, 2024. https://evir.org/our-principles/applying-the-principles/ ↩︎
  4. National Research Council, Institute of Medicine, Division on Earth and Life Studies, Board on Health Sciences Policy, Board on Life Sciences, Committee on the Use of Chimpanzees in Biomedical and Behavioral Research. Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity. National Academies Press; 2011. doi:10.17226/13257 ↩︎
  5. Cochrane. Our products and services. Cochrane.org. 2024. Accessed November 13, 2024. https://www.cochrane.org/about-us/our-products-and-services ↩︎
  6. NIH Library. Systematic review standards & organizations. NIH.gov. Accessed November 13, 2024. https://www.nihlibrary.nih.gov/services/systematic-review-service/systematic-review-standards-organizations ↩︎
  7. NIH Library. Tools & resources. NIH.gov. Accessed November 13, 2024. https://www.nihlibrary.nih.gov/services/systematic-review-service/tools-resources ↩︎
  8. The Animals in Science Committee. Review of Harm-Benefit Analysis in the Use of Animals in Research. Home Office; 2017:88. https://assets.publishing.service.gov.uk/media/5a81edade5274a2e8ab5695b/Review_of_harm_benefit_analysis_in_use_of_animals_18Jan18.pdf ↩︎
  9. National Research Council, Institute of Medicine, Division on Earth and Life Studies, Board on Health Sciences Policy, Board on Life Sciences, Committee on the Use of Chimpanzees in Biomedical and Behavioral Research. Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity. National Academies Press; 2011. doi:10.17226/13257 ↩︎
  10. Pound P, Nicol CJ. Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions. PLoS One. 2018;13(3):e0193758. doi:10.1371/journal.pone.0193758 ↩︎
  11. van der Zalm AJ, Barroso J, Browne P, et al. A framework for establishing scientific confidence in new approach methodologies. Arch Toxicol. 2022;96(11):2865-2879. doi:10.1007/s00204-022-03365-4. ↩︎
  12. Innovate UK, National Centre for the Replacement, Refinement and Reduction of Animals in Research, Biotechnology and Biological Sciences Research Council, Defence, Science and Technology Laboratory, Engineering and Physical Sciences Research Council, Medical Research Council. A Non-Animal Technologies Roadmap for the UK. 2015:20. https://www.ukri.org/wp-content/uploads/2015/11/IUK-071221-RoadmapNonAnimalTech.pdf ↩︎
  13. Joint Research Centre (European Commission). EU Reference Laboratory for alternatives to animal testing (EURL ECVAM)—European Commission. 2024. Accessed November 2, 2024. https://joint-research-centre.ec.europa.eu/reference-measurement/european-union-reference-laboratories/eu-reference-laboratory-alternatives-animal-testing-eurl-ecvam_en ↩︎
  14. PETA Science Consortium International e.V. Opportunities for Early-Career Scientists. 2024. Accessed November 2, 2024. https://www.thepsci.eu/early-career-scientists/ ↩︎
  15. Physicians Committee for Responsible Medicine. Early-career researchers advancing 21st century science. PCRM.org. 2024. Accessed November 2, 2024. https://www.pcrm.org/ethical-science/ethical-education-and-training/ERA21 ↩︎
  16. TPI. Helpathons. TPI TV. 2024. Accessed November 2, 2024. https://tpi.tv ↩︎
  17. Coalition to Illuminate and Address Animal Methods Bias. Home | COLAAB. 2024. Accessed November 1, 2024. https://www.animalmethodsbias.org/ ↩︎
  18. Trunnell ER, Roe KV. Predominance of animal-based expertise may bias NIH neuroscience grant review: a pilot study with implications for non-animal methodologies. bioRxiv. Preprint posed online March 2, 2025. doi:10.1101/2025.02.28.640877 ↩︎