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Animal Experimentation

There are many opinions about the pros and cons of using animals in scientific research. Read the overview below to gain a balanced understanding of the issue and explore the previews of opinion articles that highlight many perspectives on animal testing.

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Animal experimentation topic overview.

"Animal Experimentation." Opposing Viewpoints Online Collection , Gale, 2021.

Animal experimentation, also called animal testing , has contributed to many important scientific and medical discoveries. Breakthroughs include the development of many antibiotics, insulin therapy for diabetes, modern anesthesia, vaccines for whooping cough and other diseases, the use of lithium in mental health treatments, and the discovery of hormones. Studies using animals have also led to the development of new surgical techniques and medical devices. Scientists use animals for testing the safety of chemical products, known as toxicology testing , and for evaluating the effects of radiation and biological and chemical processes. Unlike field research, which involves observing animals in their natural habitats, animal experimentation takes place at laboratories in universities, medical schools, government facilities, and commercial facilities such as those run by pharmaceutical and cosmetics manufacturers. Experiments on animals can involve testing drugs and other substances as well as performing behavioral tests such as those conducted on dogs by Russian physiologist Ivan Pavlov in the early twentieth century.

Many people object to the use of animals in scientific studies because the animals are denied their freedom and often suffer serious injury and discomfort. Other people identify certain practices used in animal studies as cruel while still recognizing the benefits of using live animals when no alternative is available. Proponents of animal experimentation maintain that these studies provide benefits to humans that cannot be achieved through other means. Conversely, critics of using animals to learn more about humans contend that the differences between humans and nonhuman species are too great for such studies to produce meaningful results. In response, proponents note that humans are not the only beneficiaries of this type of research. Many experiments are carried out to further veterinary treatments and services, improve environmental protection efforts, and better understand diseases that affect nonhuman animals and plants.

  • Scientists have often used animals to learn about biology, test new surgical techniques, and observe the effects of different products on living things to determine the products' safety.
  • Because humans and other animals respond differently when exposed to different substances, critics of animal experimentation have questioned the scientific value of using animals to test products intended for humans.
  • Some opponents of animal experimentation contend that no scientific discovery can justify the conditions endured by animal test subjects.
  • Researchers in the United States have faced difficulty obtaining lab monkeys, as several countries that previously supplied to US labs have enacted bans on such exports. A worldwide decrease in the supply of primates used in research coincided with increased demand during research for a vaccine for COVID-19 .
  • The US Department of Agriculture enforces the Animal Welfare Act, which establishes regulations for the treatment of some animals used in research. While the law protects a range of species, it does not cover many of the species most commonly used in research, such as mice and fish.
  • Vivisection refers to surgical experiments performed on living specimens, while dissection refers to experiments performed on dead specimens. Many companies, research institutes, and schools are exploring alternatives to such practices.
  • Researchers have developed microdevices that use cell cultures to determine how different products would affect human physiology. In some cases, these devices can provide more useful and precise information than that gathered from experiments conducted on animals.

Regulations on Animal Test Subjects

Congress has enacted several pieces of legislation to regulate animal experimentation and prevent animal abuse, including the Animal Welfare Act (AWA), first passed as the Laboratory Animal Welfare Act in 1966; the Improved Standards for Laboratory Animals Act (ISLAA), passed as part of the Food Security Act of 1985; and the Health Research Extension Act of 1985, which tasks the National Institutes of Health (NIH) with establishing research standards. The AWA requires research facilities that use animals to establish an institutional committee, including at least one veterinarian and one person otherwise unaffiliated with the organization, to ensure compliance with the law. Established in 2000 as part of the NIH, the Office of Laboratory Animal Welfare (OLAW) implements federal policy and provides guidance to institutions receiving federal support.

As reported by the US Department of Agriculture (USDA), 780,070 animals were used in experiments at USDA-registered facilities in fiscal year 2018. The total includes only animals protected by the AWA and omits amphibians, birds, fish, mice, rats, and reptiles, which combined account for the majority of animals used in scientific studies. Of the animals monitored by the USDA, the most commonly used in laboratories is the guinea pig, which has been widely used for experimentation since the eighteenth century, leading it to become synonymous with a subject of any experiment. Guinea pigs, rabbits, and hamsters account for more than half of the animals in the totals reported by the USDA. The other reported test subjects include nonhuman primates, dogs, pigs, cats, and sheep.

Laboratories obtain animals for their experiments through three types of dealers: those licensed by the USDA as Class A dealers, those licensed as Class B dealers, or those not licensed at all. Class A dealers breed and raise animals for specific purposes in a closed, regulated environment. Class B dealers are less regulated and purchase or obtain animals to resell. The USDA excuses some breeders and dealers from licensing because of the type, amount, or intended use of the animals. Some states require research facilities to purchase solely from Class A dealers. Class B dealers often acquire animals from animal shelters and then sell them to research facilities.

Investigations in the 1990s revealed that some Class B dealers abducted family pets. This phenomenon led lawmakers to introduce the Pet Safety and Protection Act as an amendment to the AWA in 1996. The provision would have banned research facilities from using any dog or cat that was not obtained from a legal source. The amendment was not adopted, nor was it adopted when reintroduced in nearly every subsequent session of Congress, most recently in 2019. Despite the amendment repeatedly failing to become law, the National Institutes of Health (NIH) adopted rules in 2012 and 2014 that ended NIH funding for research involving cats and dogs from Class B or unlicensed dealers. Likewise, a provision to the Consolidated Appropriations Act of 2016 prevents the USDA from using any funds appropriated by the act to provide or renew licenses for Class B dealers. The law has effectively made it impossible for Class B dealers to obtain licenses to sell cats or dogs for research purposes. Some critics have questioned the need for the Pet Safety and Protection Act, noting that cats and dogs make up only a small portion of the animals used in experiments.

In 2017 Representative Martha McSally (R-AZ) introduced the Humane Cosmetics Act, which aims to phase out the use of animal testing in the cosmetics industry. In 2018 Representatives Mike Bishop (R-MI) and Jimmy Panetta (D-CA) followed by Senator Jeff Merkley (D-OR) introduced the Kittens in Traumatic Testing Ends Now (KITTEN) Act, which would ban the use of cats in any painful or stressful experiment, to their respective chambers of Congress. No action was taken on either the Humane Cosmetics Act or the KITTEN Act in 2019, so lawmakers reintroduced similar pieces of legislation in the subsequent session of Congress. Subsequently, in April 2019, USDA announced it would stop using cats in research. Also in 2019, lawmakers introduced the Humane and Existing Alternatives in Research and Testing Sciences (HEARTS) Act, which would prioritize federal funding for research that substituted animal subjects with alternatives. As of 2021, however, none of these bills had received a vote.

Scientists in certain fields have favored using nonhuman primates in experiments because they closely resemble humans in physiology. The National Aeronautics and Space Administration (NASA), for example, sent several nonhuman primates into space before sending astronaut Alan Shepard in 1961. Many laboratories worked with chimpanzees throughout the twentieth century. Animal behaviorists, noting the chimpanzee's intelligence and capacity for emotion, raised concerns that the use of chimpanzees in experiments amounted to torture. The Institute of Medicine deemed the use of chimpanzees in scientific research unnecessary in a 2011 report commissioned by the NIH. This report was followed by a proposal by the United States Fish and Wildlife Service (USFWS) to include captive chimpanzees, such as those used in research facilities, on the list of animals protected by the Endangered Species Act; chimpanzees in the wild had already been protected by the act since 1990. In 2013 the NIH announced its intentions to stop providing funding or granting research requests for experiments involving chimpanzees, and the USFWS proposal was finalized in 2015. Many NIH chimpanzees have since been moved to federal sanctuaries. However, scientists have chosen not to resettle many older research chimpanzees in sanctuaries because of concerns the move would worsen their health.

Though researchers have largely stopped using chimpanzees, other nonhuman primates continue to serve as research subjects. However, the policies of other countries have limited their availability. Since 2013, for example, India has banned foreign monkey exports, forcing several organizations to find new suppliers or limit their experiments. Obtaining research monkeys became increasingly difficult in 2020 when China, which had supplied more than 60 percent of research monkeys imported into the United States, instituted a ban on wildlife sales. The ban came in response to concerns that wildlife sales had contributed to the novel coronavirus disease (COVID-19) outbreak that originated in Wuhan, China, and was declared a worldwide pandemic in March 2020 by the World Health Organization (WHO). Though many animal rights activists and public health officials applauded China's decision, the ban had the unintended effect of reducing the supply of lab monkeys at a time when demand significantly increased as medical researchers and pharmaceutical companies sought to develop a vaccine for COVID-19. Like vaccines for other diseases, the COVID-19 vaccines available in the United States as of March 2021 were approved for emergency use based in part on results of experiments on animals including mice, rats, hamsters, and monkeys.

Alternatives to Animal Testing

Animal rights advocates and members of the scientific community have pushed for the use of alternatives to animal experimentation. The pursuit of alternatives has largely centered on concepts first introduced in 1959 by British zoologists W. M. S. Russell and R. L. Burch in The Principles of Humane Experimental Technique . Russell and Burch framed their proposal around three Rs. They suggested that experimentation should replace animal subjects with something else, such as nonsentient material or less sentient animals; reduce the number of animal subjects used experimentally while increasing the amount of data obtained; and refine living conditions and experimental procedures for animal subjects to reduce pain and discomfort.

The NIH established the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) in 2000 as part of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) to promote and regulate alternatives to animal testing. In addition to government programs, animal rights advocacy groups such as People for the Ethical Treatment of Animals (PETA) and the American Fund for Alternatives to Animal Research (AFAAR) also contribute funding to develop alternative research methods. AAALAC International, formerly known as the Association for Assessment and Accreditation of Laboratory Animal Care, distributes up to four $5,000 prizes each year to researchers that make significant contributions to improving the nature of animal research. The awards are a component of the organization's Global 3Rs Awards program, named for the principles put forth by Russell and Burch.

Companies and research facilities, however, can be slow to adopt alternatives. In 2009, for example, the Organisation for Economic Cooperation and Development (OECD) approved two alternatives to the Draize test, a research method that involves applying chemicals directly to the eyes or skin of animals, typically rabbits. The test is widely condemned by animal rights activists. In 2020 university researchers in the United Kingdom announced a method that they determined to be both cheaper and more ethical than the Draize test, as flatworms served as a substitute for rabbits. As of 2021, despite the availability of these alternatives, scientists continue to perform the Draize test, arguing that no single test has proven able to replicate the full benefits of the Draize test.

Technological advances have enabled scientists to perform many experiments without using live animals. Invasive animal experimentation that involves performing surgery on a living animal can be referred to as vivisection , as opposed to dissection , which is surgery performed on a deceased animal. The term vivisection, however, is typically used by opponents of animal experimentation and avoided by scientists. Researchers have developed ways to obtain data without using live specimens by experimenting on cells and tissues rather than the entire living organism; these procedures are referred to as in vitro experiments. In many in vitro experiments, human cells and tissues can be used. Proponents argue that this method produces data that is more relevant to human safety. Critics of in vitro methods argue that operating on a live animal provides more accurate data because the effects on the entire organism can be observed.

US schools began incorporating dissection into biology instruction in the 1920s, with the practice becoming widespread by the 1960s. A 2014 survey conducted by the National Association of Biology Teachers (NABT) found that 84 percent of biology teachers and 76 percent of biology students were using dissection in the classroom. Many of the responding teachers, however, reported that their schools were shifting away from dissection and pursuing alternatives such as virtual dissection programs, 3D models, and videos, largely in response to student requests. Educators also reported using these alternatives alongside traditional hands-on dissection. In 2019 the NABT reaffirmed its belief that students should have access to living and formerly living specimens and that nonanimal alternatives may not provide students with the most comprehensive understanding of life science. However, the NABT stresses the importance of teachers educating students about maintaining professional and ethical standards in animal research.

In the early 2000s, researchers began developing microdevices referred to as organs-on-a-chip (OOCs), which use cell cultures to imitate a human organ and determine how that organ would respond to different chemicals and other stimuli. OOCs are approximately the size of a deck of playing cards and have been developed to imitate lungs, hearts, kidneys, skin, eyes, and entire organ systems. In 2018 researchers successfully tested OOCs that imitated interconnected organ systems and could produce data for twenty-eight days, indicating that a microdevice could likely support an entire "human on a chip." In some cases, computer models can simulate the effects of diseases and medicines on the human body with greater accuracy than animal subjects. Research methods that substitute computer models for live animals are referred to as in silico experiments.

Critical Thinking Questions

  • In your opinion, why have federal lawmakers delayed holding votes on legislation introduced in the late 2010s that would have expanded protections for animals used in research?
  • Would you support a ban on the use of dissection in high school biology classrooms? Why or why not?
  • Under what conditions, if any, do you think scientists should be allowed to use animal subjects in their research? Explain your answer.

Extremist Activism

Despite efforts to reduce the number of animals used in scientific studies and minimize the pain and distress that animal subjects experience, some animal rights activists believe that the benefits of animal experimentation do not justify the cruelties involved. Some extremist groups of activists calling for an end to all animal testing have engaged in criminal activity to prevent animals from being used in experiments. In the late 1970s, radical animal rights groups began targeting companies and research facilities, using terrorist strategies to disrupt these industries and promote their extremist platform. These activists were sometimes called "ecoterrorists" by federal authorities and included members of radical groups such as the Animal Liberation Front (ALF) and Stop Huntingdon Animal Cruelty (SHAC).

To protect research companies and other commercial enterprises vulnerable to animal rights violence, Congress passed the Animal Enterprise Protection Act of 1992 and the Animal Enterprise Terrorism Act of 2006. Critics of these laws note that both bills received support from biomedical and agribusiness lobbying groups. Additionally, critics note that both laws include language that criminalizes activities protected by the First Amendment, such as picketing and leading boycotts, if they interfere with a company's ability to make money. In 2015 two animal rights activists, Kevin Johnson and Tyler Lang, challenged the constitutionality of the Animal Enterprise Terrorism Act after they were charged with violating the act for vandalizing a mink farm and setting hundreds of animals free in 2013. However, the United States Court of Appeals for the Seventh Circuit ruled that the law was constitutional in November 2017. By April 2021, this type of extreme action to stop animal experimentation has become rare, with no major events reported in the United States since 2013.

More Articles

Government regulations will encourage alternatives to animal experimentation.

“There was a time when dosing and contaminating animals with often toxic levels of chemicals was horrible for them but imperative for human health and safety.”

The Times Editorial Board determines the perspectives and positions of the news organization.

In the following viewpoint, the authors contend that the recent overhaul of the Toxic Substances Control Act will lead to a reduction in the number of animals subjected to experimentation. Revisions to the law, the authors maintain, will encourage companies to employ alternative methods for gathering data and work with other companies to reduce instances of duplicated experiments. The authors argue that advances in technology and a new willingness among companies to cooperate with one another have eliminated the need to test products on animals to ensure they are safe for humans to use.

Using Monkeys for Research Is Justified—It’s Enabling Treatments that Would Be Otherwise Impossible

“I am confident that the next 50 years will see wonderful progress in treatments for these terrible disorders and primate research will be central to this effort.”

Stuart Baker is a professor of movement neuroscience at Newcastle University in the United Kingdom.

In the following viewpoint, Baker argues that the expanded use of primates and other animals in experiments is necessary to find a cure to challenging diseases like neurological disorders among the elderly. Baker refutes the argument of critics that animals used in research are subjected to extreme suffering and contends that researchers follow state-of-the-art surgical procedures commonly used on humans. As a researcher himself, Baker maintains that the primates he used in his experiments willingly cooperated and did not exhibit any signs of stress. For the author, the use of animals in scientific pursuits is essential for alleviating suffering among human beings.

The Grim Good of Animal Research

"Experimenting with animals before testing on people is a crucial human rights protection required by the famous Nuremberg Code."

In the following viewpoint, Wesley J. Smith argues that research on animals has been indispensable in developing ways to treat human disease. No one likes the idea of experimenting on animals, he says, and efforts are being made to reduce it to a minimum; however, there is no other way to do the necessary research and check the safety of new drugs. Medical treatments have to be tested on living organisms; if not on animals, then on humans, which in Smith's opinion would be an atrocity. Smith is a senior fellow for the Discovery Institute's program on human exceptionalism. He also consults with the Patients Rights Council and the Center for Bioethics and Culture.

Results from Research on Animals Are Not Valid When Applied to Humans

"Animal advocates, as well as many scientists, are increasingly questioning the scientific validity and reliability of animal experimentation."

In the following viewpoint, the American Anti-Vivisection Society (AAVS) declares that experimentation on animals is not a valid means of testing treatments for human disease. The AAVS maintains that animal studies do not reliably predict human outcomes, that most drugs that appear promising in animal studies go on to fail in human clinical trials, and that reliance on animal experimentation can delay discovery. In the opinion of the AAVS, animals are used in medical research more from tradition than from evidence of scientific value. The AAVS is a nonprofit animal advocacy organization dedicated to ending experimentation on animals in research, testing, and education.

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Public perception of laboratory animal testing: Historical, philosophical, and ethical view

Affiliation.

  • 1 School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
  • PMID: 33331099
  • PMCID: PMC9252265
  • DOI: 10.1111/adb.12991

The use of laboratory animals in biomedical research is a matter of intense public debate. Recent statistics indicates that about half of the western population, sensitive to this discussion, would be in favor of animal testing while the other half would oppose it. Here, outlining scientific, historical, ethical, and philosophical aspects, we provide an integrated view explaining the reasons why biomedical research can hardly abandon laboratory animal testing. In this paper, we retrace the historical moments that mark the relationship between humans and other animal species. Then starting from Darwin's position on animal experimentation, we outline the steps that over time allowed the introduction of laws and rules that regulate animals' use in biomedical research. In our analysis, we present the perspectives of various authors, with the aim of delineating a theoretical framework within which to insert the ethical debate on laboratory animals research. Through the analysis of fundamental philosophical concepts and some practical examples, we propose a view according to which laboratory animals experimentation become ethically acceptable as far as it is guided by the goal of improving humans and other animal species (i.e., pets) life. Among the elements analyzed, there is the concept of responsibility that only active moral subjects (humans) have towards themselves and towards passive moral subjects (other animal species). We delineate the principle of cruelty that is useful to understand why research in laboratory animals should not be assimilated to a cruel act. Moreover, we touch upon the concepts of necessity and "good cause" to underline that, if biomedical research would have the possibility to avoid using animals, it would surely do that. To provide an example of the negative consequences occurring from not allowing laboratory animal research, we analyze the recent experience of Covid-19 epidemic. Finally, recalling the principle of "heuristics and biases" by Kahneman, we discuss why scientists should reconsider the way they are conveying information about their research to the general public.

Keywords: 3R principles; Covid-19; animal experimentation; animal rights; moral responsibility.

© 2020 Society for the Study of Addiction.

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animal testing research paper

Extending Animal Cruelty Protections to Scientific Research

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INTRODUCTION

On November 25, 2019, the federal law H.R. 724 – the Preventing Animal Cruelty and Torture Act (PACT) prohibiting the intentional harm of “living non-human mammals, birds, reptiles, or amphibians” was signed. [1] This law was a notable step in extending protections, rights, and respect to animals. While many similar state laws existed, the passing of a federal law signaled a new shift in public tone. PACT is a declaration of growing societal sentiments that uphold the necessity to shield our fellow creatures from undue harm. Protecting animals from the harm of citizens is undoubtedly important, but PACT does nothing to protect animals from state-sanctioned harm, particularly in the form of research, which causes death and cruelty. It is time to extend and expand protections for animals used in research.

There is a long history of animal experimentation in the US, but no meaningful ethical protections of animals emerged until the 20 th century. Proscription of human experimentation and dissection led to animals bearing the brunt of harm for scientific and medical progress. For instance, English physician William Harvey discovered the heart did not continuously produce blood but instead recirculated it; he made this discovery by dissecting and bleeding out living dogs without anesthesia. [2] Experiments like this were considered ethically tenable for hundreds of years. Philosophers like Immanuel Kant, Thomas Aquinas, and Rene Descartes held that humans have no primary moral obligations to animals and that one should be concerned about the treatment of an animal only because it could indicate how one would treat a human. [3] During the 20 th century, as agriculture became more industrialized and government funding for animal research increased, the social demand for ethical regulations finally began to shift. In 1966, the Animal Welfare Act (Public Law 89-544) marked the first American federal legislation to protect laboratory animals, setting standards for use of animals in research. [4]

There has been progress in the field of animal research ethics since Harvey’s experiments, but much work remains. In the US alone, there are an estimated 20 million mice, fish, birds, and invertebrates used for animal research each year that are not regulated by the Animal Welfare Act. [5] Instead, the “3Rs Alternatives” approach (“reduce, replace, and refine”) [6] is one framework used to guide ethical treatment of animals not covered by federal protections. Unfortunately, unpacking the meaning and details of this approach only leads to ambiguity and minimal actionable guidance. For instance, an experimenter could reduce the number of animals used in research but subsequently increase the number of experiments conducted on the remaining animals. Replace could be used in the context of replacing one species with another. Refining is creating “any decrease in the severity of inhumane procedures applied to those animals, which still have to be used.” [7] The vague “ any ” implies that even a negligible minimization would be ethically acceptable. [8] An experimenter could technically follow each of the “3Rs” with minimal to no reduction in harm to the animals. One must also consider whether it is coherent to refer to guidelines as ethical when they inevitably produce pain, suffering, and death as consequences of research participation.

Other ethical guides like Humane Endpoints for Laboratory Animals Used in Regulatory Testing [9] encourage researchers to euthanize animals that undergo intractable pain or distress. This is a fate that an estimated one million animals face yearly in the US. [10] However, to use the word “humane” in this context contradicts the traditional meaning and undermines the integrity of the word. Taking living creatures, forcing them to experience intractable pain and suffering for human benefit, and killing them is the antithesis of what it means to be humane. During one of my Animal Ethics classes as a graduate student, our cohort visited an animal research facility to help inform our opinions on animal research. We observed one of the euthanasia chambers for lab mice – an enclosed metal lab bench with a sign above describing methods for euthanasia if CO 2 asphyxiation were to fail. The methods included decapitation, removal of vital organs, opening of the chest cavity, incision of major blood vessels, and cervical dislocation. [11] Behind us were rows and rows of see-through shoebox-sized containers housing five mice in each little box. Thousands of mice were packed together in this room for the sole purpose of breeding. If the mice were not the correct “type” for research, then they were “humanely” euthanized. “Humane,” in this context, has been deprived of its true meaning.

One can acknowledge that animal research was historically necessary for scientific progress, but those that currently claim these practices are still required must show empirically and undoubtedly this is true. As of now, this is not a settled issue. In the scientific community, there is contention about whether current animal research is actually applicable to humans. [12] Many drug researchers even view animal testing as a tedious barrier to development as it may be wholly irrelevant to the drug or medical device being tested. Since 1962, the FDA has required preclinical testing in animals; it is time to question whether this is necessary or helpful for drug development.

The scientific community should stop viewing animal testing as an unavoidable evil in the search for medical and technological innovation. PACT should be amended and extended to all animals and the FDA should modify the requirement for preclinical animal testing of all drugs and medical devices. It is time to encourage the scientific community to find alternative research methods that do not sacrifice our fellow animals. We use animals as test subjects because, in some sense, they resemble humans. But, if they are indeed like humans, they should receive similar protections. Science builds a better world for humans, but perhaps it is time for science to be more inclusive and build a better world for all creatures.

[1] Theodore E. Deutch, “Text - H.R.724 - 116th Congress (2019-2020): Preventing Animal Cruelty and Torture Act,” legislation, November 25, 2019, 2019/2020, https://www.congress.gov/bill/116th-congress/house-bill/724/text.

[2] Anita Guerrini, “Experiments, Causation, and the Uses of Vivisection in the First Half of the Seventeenth Century,” Journal of the History of Biology 46, no. 2 (2013): 227–54.

[3] Bernard E. Rollin, “The Regulation of Animal Research and the Emergence of Animal Ethics: A Conceptual History,” Theoretical Medicine and Bioethics 27, no. 4 (September 28, 2006): 285–304, https://doi.org/10.1007/s11017-006-9007-8; Darian M Ibrahim, “A Return to Descartes: Property, Profit, and the Corporate Ownership of Animals,” LAW AND CONTEMPORARY PROBLEMS 70 (n.d.): 28.

[4] Benjamin Adams and Jean Larson, “Legislative History of the Animal Welfare Act: Introduction | Animal Welfare Information Center| NAL | USDA,” accessed November 3, 2021, https://www.nal.usda.gov/awic/legislative-history-animal-welfare-act-introduction.

[5] National Research Council (US) and Institute of Medicine (US) Committee on the Use of Laboratory Animals in Biomedical and Behavioral Research, Patterns of Animal Use , Use of Laboratory Animals in Biomedical and Behavioral Research (National Academies Press (US), 1988), https://www.ncbi.nlm.nih.gov/books/NBK218261/.

[6] Robert C. Hubrecht and Elizabeth Carter, “The 3Rs and Humane Experimental Technique: Implementing Change,” Animals: An Open Access Journal from MDPI 9, no. 10 (September 30, 2019): 754, https://doi.org/10.3390/ani9100754.

[7] Hubrecht and Carter.

[8] Hubrecht and Carter.                           

[9] William S. Stokes, “Humane Endpoints for Laboratory Animals Used in Regulatory Testing,” ILAR Journal 43, no. Suppl_1 (January 1, 2002): S31–38, https://doi.org/10.1093/ilar.43.Suppl_1.S31.

[10] Stokes.

[11] “Euthanasia of Research Animals,” accessed April 21, 2022, https://services-web.research.uci.edu/compliance/animalcare-use/research-policies-and-guidance/euthanasia.html.

[12] Neal D. Barnard and Stephen R. Kaufman, “Animal Research Is Wasteful and Misleading,” Scientific American 276, no. 2 (1997): 80–82.

Chad Childers

MS Bioethics Candidate Harvard Medical School Center for Bioethics

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Ethical care for research animals

WHY ANIMAL RESEARCH?

The use of animals in some forms of biomedical research remains essential to the discovery of the causes, diagnoses, and treatment of disease and suffering in humans and in animals., stanford shares the public's concern for laboratory research animals..

Many people have questions about animal testing ethics and the animal testing debate. We take our responsibility for the ethical treatment of animals in medical research very seriously. At Stanford, we emphasize that the humane care of laboratory animals is essential, both ethically and scientifically.  Poor animal care is not good science. If animals are not well-treated, the science and knowledge they produce is not trustworthy and cannot be replicated, an important hallmark of the scientific method .

There are several reasons why the use of animals is critical for biomedical research: 

••  Animals are biologically very similar to humans. In fact, mice share more than 98% DNA with us!

••  Animals are susceptible to many of the same health problems as humans – cancer, diabetes, heart disease, etc.

••  With a shorter life cycle than humans, animal models can be studied throughout their whole life span and across several generations, a critical element in understanding how a disease processes and how it interacts with a whole, living biological system.

The ethics of animal experimentation

Nothing so far has been discovered that can be a substitute for the complex functions of a living, breathing, whole-organ system with pulmonary and circulatory structures like those in humans. Until such a discovery, animals must continue to play a critical role in helping researchers test potential new drugs and medical treatments for effectiveness and safety, and in identifying any undesired or dangerous side effects, such as infertility, birth defects, liver damage, toxicity, or cancer-causing potential.

U.S. federal laws require that non-human animal research occur to show the safety and efficacy of new treatments before any human research will be allowed to be conducted.  Not only do we humans benefit from this research and testing, but hundreds of drugs and treatments developed for human use are now routinely used in veterinary clinics as well, helping animals live longer, healthier lives.

It is important to stress that 95% of all animals necessary for biomedical research in the United States are rodents – rats and mice especially bred for laboratory use – and that animals are only one part of the larger process of biomedical research.

Our researchers are strong supporters of animal welfare and view their work with animals in biomedical research as a privilege.

Stanford researchers are obligated to ensure the well-being of all animals in their care..

Stanford researchers are obligated to ensure the well-being of animals in their care, in strict adherence to the highest standards, and in accordance with federal and state laws, regulatory guidelines, and humane principles. They are also obligated to continuously update their animal-care practices based on the newest information and findings in the fields of laboratory animal care and husbandry.  

Researchers requesting use of animal models at Stanford must have their research proposals reviewed by a federally mandated committee that includes two independent community members.  It is only with this committee’s approval that research can begin. We at Stanford are dedicated to refining, reducing, and replacing animals in research whenever possible, and to using alternative methods (cell and tissue cultures, computer simulations, etc.) instead of or before animal studies are ever conducted.

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  • NATURE INDEX
  • 04 November 2022

US agency seeks to phase out animal testing

  • Rachel Nuwer 0

Rachel Nuwer is a freelance writer based in New York City.

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Close up of a white mouse emerging from the escape hole of a blue Barnes maze

Biomedical advances mean there might be sound alternatives to using animals such as mice for testing. Credit: Paul Chinn/The San Francisco Chronicle/Getty

The future of drug development might be animal-free — or, at least, involve far fewer animals than is currently the norm. Last June, the US Food and Drug Administration (FDA) set out proposals for the New Alternative Methods Program that will focus on replacing, reducing and refining the use of laboratory animals through the adoption of cutting-edge alternative methods. The aim is to produce findings that are more relevant to humans, streamline product development and reduce costs.

The shift, which has been years in the making, would be undertaken across all of the FDA’s centres, including ones that oversee the approval of new pharmaceuticals, medical devices, veterinary medicines, cosmetics and more. FDA scientists are conducting their own research in service of this goal and are collaborating extensively with colleagues in industry, academia and other sectors of the US government. Any methods eventually adopted in place of research involving animals would be rigorously vetted and “fully validated and based on the best science”, says Namandjé Bumpus, chief scientist at the FDA. Bumpus and her colleagues have not received any pushback from researchers about making this shift, she adds, or heard any concerns from the scientific community about cutting back on the use of animals.

Although there is no set timeline, FDA officials say the programme is a priority. It would be funded from US$5 million it has requested as part of its 2023 budget to develop a ‘comprehensive strategy’ on alternative testing methods. According to Paul Locke, an environmental-health scientist and lawyer at Johns Hopkins University in Baltimore, Maryland, who specializes in alternatives to animal testing, the FDA is taking a necessary step towards ensuring that the US government stays up to speed with the latest science. “I’m really excited about what the FDA’s doing here,” he says. “They’ve put a stake in the ground and said, ‘Hey, we want to be there using these tools, they’re consistent with our mission and they’re consistent with what twenty-first-century science looks like.’”

Biomedical advances fuel alternatives

Animal-based testing has been the gold standard for research for decades, and it remains an important requirement for establishing the safety and efficacy of products being brought to market today. But key differences exist between humans and the rodents, rabbits, non-human primates and other animals that researchers depend on for testing, and as biomedical understanding has advanced, scientists have begun to come up against the limitations of using other species as proxies for humans. “A mouse or a rat doesn’t always handle or process medicines and chemicals in the same way humans do,” Bumpus says. “Developing more in vitro systems that are based on human cells, human tissues and human models could, in some instances, be more predictive.”

The FDA’s interest in moving towards new approaches also reflects the current thinking of the biomedical community at large. In 2014, the United Kingdom, for example, announced plans to reduce the use of animal tests in scientific research, aiming to replace those tests with ‘scientifically valid alternatives’ where possible. In 2021, the European Parliament voted in favour of plans to phase out animal testing in research.

“A key for bringing about change is to do so among the multiple major regulatory agencies,” says David Strauss, director of the FDA’s Division of Applied Regulatory Science. “Drug-development programmes are global, and companies want to market their products in many countries around the world.”

That sentiment is echoed by Bumpus. “There’s a lot of energy around this across the globe,” she adds.

Animal-rights advocates have been calling for an end to animal testing for years; now, methods being developed in labs around the world have made this a realistic possibility for the future. “We think we’re at a potential tipping point,” says Strauss. The technologies include, for example, induced pluripotent stem cells — cells that scientists program to have the potential to turn into any cell type found in the body — and ‘organs-on-a-chip’, which are small devices containing living human tissues that mimic an organ, organ system or even an entire body 1 . Developments in artificial intelligence and machine learning are also allowing scientists to harness existing data to build computer models that can make predictions about a new drug’s safety and efficacy.

More funding needed

In addition to being more relevant to humans, says Locke, once these types of technology are qualified and validated for specific uses, they will probably be faster and cheaper than using animals, allowing products to be brought to market more rapidly and efficiently. These are still early days, however, and so far, the FDA has only a handful of successful animal-testing-replacement stories it can point to.

Funding for developing and validating alternative methods is also an issue, Locke adds — both internally at the FDA, and externally for scientists whose labs depend on federal funds to pioneer new approaches. The FDA is not primarily a funding agency, and the US National Institutes of Health, which is the largest public funder of biomedical research in the world, currently has no programme dedicated to developing alternatives to animal testing. “If we had a legitimate funding programme to push these technologies forward, it would accelerate their progress greatly,” Locke points out.

For now, despite the promising alternatives to animal testing, federal regulators have approved only a few cutting-edge methods, and such techniques will not completely replace animal testing any time soon. But they do hold great promise, Locke says, especially if other government agencies and countries join the FDA in its effort.

“There’s a lot of moving pieces here,” he says. “The FDA has started the ball rolling, but we need more work to make sure we can use these new methodologies appropriately.”

doi: https://doi.org/10.1038/d41586-022-03569-9

Sung, J. H. et al. Anal. Chem. 91 , 330–351 (2019).

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Meta-Research Articles feature data-driven examinations of the methods, reporting, verification, and evaluation of scientific research.

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Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications

Roles Conceptualization, Data curation, Formal analysis, Methodology, Visualization, Writing – original draft

* E-mail: [email protected]

Affiliations Centre for Reproducible Science, University of Zurich, Zurich, Switzerland, Clinical Neuroscience Center, University of Zurich, Zurich, Switzerland

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Roles Conceptualization, Data curation, Methodology, Writing – review & editing

Affiliation Centre for Reproducible Science, University of Zurich, Zurich, Switzerland

Affiliations Centre for Reproducible Science, University of Zurich, Zurich, Switzerland, Department of Mathematics, University of Zurich, Zurich, Switzerland

Roles Data curation, Writing – review & editing

Roles Conceptualization, Methodology, Supervision, Writing – original draft

Affiliation Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom

  • Benjamin V. Ineichen, 
  • Eva Furrer, 
  • Servan L. Grüninger, 
  • Wolfgang E. Zürrer, 
  • Malcolm R. Macleod

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  • Published: June 13, 2024
  • https://doi.org/10.1371/journal.pbio.3002667
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Table 1

There is an ongoing debate about the value of animal experiments to inform medical practice, yet there are limited data on how well therapies developed in animal studies translate to humans. We aimed to assess 2 measures of translation across various biomedical fields: (1) The proportion of therapies which transition from animal studies to human application, including involved timeframes; and (2) the consistency between animal and human study results. Thus, we conducted an umbrella review, including English systematic reviews that evaluated the translation of therapies from animals to humans. Medline, Embase, and Web of Science Core Collection were searched from inception until August 1, 2023. We assessed the proportion of therapeutic interventions advancing to any human study, a randomized controlled trial (RCT), and regulatory approval. We meta-analyzed the concordance between animal and human studies. The risk of bias was probed using a 10-item checklist for systematic reviews. We included 122 articles, describing 54 distinct human diseases and 367 therapeutic interventions. Neurological diseases were the focus of 32% of reviews. The overall proportion of therapies progressing from animal studies was 50% to human studies, 40% to RCTs, and 5% to regulatory approval. Notably, our meta-analysis showed an 86% concordance between positive results in animal and clinical studies. The median transition times from animal studies were 5, 7, and 10 years to reach any human study, an RCT, and regulatory approval, respectively. We conclude that, contrary to widespread assertions, the rate of successful animal-to-human translation may be higher than previously reported. Nonetheless, the low rate of final approval indicates potential deficiencies in the design of both animal studies and early clinical trials. To ameliorate the efficacy of translating therapies from bench to bedside, we advocate for enhanced study design robustness and the reinforcement of generalizability.

Citation: Ineichen BV, Furrer E, Grüninger SL, Zürrer WE, Macleod MR (2024) Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications. PLoS Biol 22(6): e3002667. https://doi.org/10.1371/journal.pbio.3002667

Academic Editor: Isabelle Boutron, University Paris Descartes, FRANCE

Received: November 26, 2023; Accepted: May 7, 2024; Published: June 13, 2024

Copyright: © 2024 Ineichen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data and code that support the findings of this study are available at https://osf.io/frjm4 (data including meta-data) and https://osf.io/9fgru (R code).

Funding: Swiss National Science Foundation (No. 407940_206504, to BVI) UZH Digital Entrepreneur Fellowship (No number, to BVI). UFAW (Universities Federation for Animal Welfare, to BVI). The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Animal studies remain foundational in basic research, accounting for a substantial share of global biomedical research investment. These experiments have provided insight on aspects of human diseases and have paved the way for therapeutic innovations. For example, mitoxantrone and glatiramer acetate, FDA-approved drugs for multiple sclerosis, owe their inception at least partly to animal studies [ 1 ]. Yet, in recent years, concerns have grown about the low translatability of findings from animal experiments to humans, a concern that certain drugs with beneficial findings in animal experiments did not show similar effects in humans [ 2 – 4 ]. For example, while NXY-059 showed substantial promise in animal stroke studies, it failed in human trials [ 5 ]. Natalizumab displayed considerable efficacy in both animal and human multiple sclerosis trials, but the animal studies did not detect a severe side effect caused by a virus not present in rodents [ 6 , 7 ]. Opicinumab demonstrated significant promise in multiple sclerosis animal studies but failed its primary endpoint in human trials for multiple sclerosis [ 8 , 9 ].

The concerns of low translatability of animal research are particularly relevant to the debate on the ethical use of animals in research because clinical translation is one of the primary justifications for such research [ 10 ]. Discussions around the usefulness of animal experiments persist, but much of the current debate relies on anecdotal findings from discrete research areas [ 11 ]. High-level evidence—spanning various biomedical sectors and assessing translational success rates—is scarce. Hence, here we aimed to (1) offer a quantitative perspective on animal-to-human translation across diverse biomedical fields; (2) scrutinize the agreement between findings in animal and human drug development studies; and (3) probe the time intervals separating animal and human trials during drug development.

Materials and methods

Study registration.

We registered the study protocol on the Open Science Framework platform (OSF, https://osf.io/jh2d8 ) and used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting [ 12 ].

Approach to identification of therapeutic interventions

Our method to identify therapeutic interventions assessed for bench-to-bedside translation was identified via a two-stage process: in a first step, we identified systematic/scoping reviews assessing animal-to-human translation of specific therapeutic interventions (described in the Methods section “Search strategy for systematic reviews”). In the second step, these therapeutic interventions were included in our analysis of translational proportions, consistency of animal and human findings, and development times (described in the Methods section “Assessment of translational proportions and development times”).

Search strategy for systematic reviews

We searched for studies published from inception up to August 01, 2023, in Medline (Ovid), Embase, and Web of Science Core Collection (Clarivate). We created the search string in Medline and translated to the other databases. The exact search strings are provided in the S1 Data . In brief, the search string comprised one block with terms for translation and one block for systematic/scoping reviews, and was limited to animal studies by employing the SYRCLE animal filter [ 13 ]. To probe the sensitivity of this approach, we also tested a broad search string comprising only the systematic review block and the SYRCLE animal filter (i.e., without the block for translation). Our protocol stated that we would use this broader strategy if we identified in a subgroup of search returns additional studies equivalent to 5% of the total. However, we did not identify any additional eligible studies using the broad search strategy (i.e., 0%) and so we used the narrower search string for this systematic review (see protocol for details). We deduplicated the references in Endnote using the Bramer method [ 14 ].

Inclusion and exclusion criteria

Inclusion criteria..

Systematic reviews or scoping reviews with or without meta-analysis which investigate translation of interventions in animal models of human diseases, i.e., the study must have the goal of assessing animal-to-human translation of therapies. Any type of intervention with the goal of improving at least 1 disease outcome was eligible (e.g., drugs, surgical interventions, neuromodulation, diets, behavioral therapy). The minimum requirement to be eligible as systematic review, scoping review, and/or meta-analysis was at abstract level: (1) Having at least 2 authors; (2) mentioning a systematic literature search; and (3) at full-text level having a paper section describing methodology of the systematic review.

Exclusion criteria.

Original studies and/or studies not assessing bench-to-bedside translation, non-English articles, and gray literature (conference abstracts, book chapters). We excluded non-systematic reviews but retained them to find potential additional references.

Study selection and data extraction

Three independent reviewers (BVI, SG, and EF) screened titles and abstracts of studies for their relevance in the web-based application SyRF (RRID: SCR_018907) in duplicate [ 15 ]. We resolved discrepancies by discussion. Subsequently to full-text screening, we extracted the following data: bibliographic data (author names, journal, title, publication year, digital object identifier), number of included animal studies and clinical trials, disease classes, any data related to translation, any provided definition on translation as well as data on year/outcome of clinical studies (see below). We extracted all data from text/tables if possible, and if not extracted from figures using Universal Desktop Ruler [ 16 ].

Critical appraisal of included studies

We assessed the quality of each included study against predefined criteria by 3 independent reviewers in duplicate (BVI, WEZ, and EF), based on a checklist proposed by Sena and colleagues [ 17 ], and extended with additional items for a more granular critical appraisal. Concretely: (1) Was an a priori study protocol defined? (2) Was a flowchart for study selection provided? (3) Was a conflict-of-interest statement provided? (4) Was screening and/or extraction conducted by 2 or more reviewers? (5) Was a clear research question defined? (6) Were in- and exclusion criteria reported? (7) Were 2 or more literature databases searched? (8) Was a search date provided? (9) Was a search string provided? (10) Was a critical appraisal conducted? (11) Did the study mention alignment with relevant guidelines, e.g., SYRCLE, CAMARADES, or PRISMA? We resolved discrepancies by discussion. This appraisal method was initially tested in a separate umbrella review. Detailed application guidelines are available in the S2 Data . The inter-rater agreement was calculated using Cohen’s Kappa. Of note, we included all systematic reviews into our final analysis, regardless of their risk of bias.

Assessment of translational proportions and development times

Definition of translation..

We used the following working definition of translation: the process of turning observations from animal experiments into interventions that improve the health of human individuals and the public [ 18 ].

Study year and outcomes.

For each individual intervention identified in the eligible systematic reviews, 2 independent reviewers extracted: (1) the first published animal study testing the respective intervention; and (2) the first clinical study testing the respective intervention. We included any type of clinical studies including pilot studies or case series, and (3) the first randomized controlled trial (RCT) testing the respective intervention. In addition, for all clinical studies/RCTs, we extracted the main study outcome as defined by the authors of the respective study, grouped into 4 classes, i.e., whether the intervention had a positive, negative, mixed, or neutral effect on the corresponding disease outcome [ 19 ], any outcome was considered, e.g., primary or secondary outcome. We extracted these data in first priority from the respective systematic reviews. If these data were not available in the systematic reviews, we searched Medline (Ovid) and Embase for corresponding clinical studies/RCTs. For this, we used a search string comprising the intervention and disease name, including synonyms. For clinical approval of an intervention, we considered FDA approval (by searching the FDA webpage for respective therapies) as well as UK and Swiss medical guidelines for recommended use of respective interventions. We resolved discrepancies by discussion.

Data synthesis and analysis

Narrative synthesis and descriptive statistics..

We provide a narrative summary of the extent of bench-to-bedside translation, supported by descriptive statistics of extracted parameters.

Meta-analysis on relative risks.

To assess the concordance between animal and human studies, we conducted a meta-analysis on relative risks, i.e., the ratio of the proportion of positive animal studies to the proportion of positive clinical studies. We conducted this only in case of specific interventions for specific diseases entities (e.g., atorvastatin for glioblastoma). To reduce noise of the dataset, we restricted our analysis to therapies that were the subject of 5 or more published animal studies. As primary outcome, we pooled relative risks to obtain an overall relative risk and 95% confidence intervals. We fitted a random-effects model to the data [ 20 ] and estimated the amount of heterogeneity, i.e., τ 2 , using the DerSimonian—Laird estimator. We calculated the Q-test for heterogeneity and the I 2 statistic. We used the R package meta for the meta-analysis [ 21 ] (RRID: SCR_019055).

Kaplan–Meier survival analysis for development times.

To estimate the time-to-event from first animal study to clinical studies/RCTs and eventually official endorsement (i.e., the lag time), we conducted a Kaplan—Meier analysis. We used the packages survminer (RRID: SCR_021094) and survival (RRID: SCR_021137) for this survival analysis.

All statistical analyses were conducted in the R programming environment (version 4.2.2). We considered a two-tailed P value < 0.05 statistically significant.

Eligible publications and general study characteristics

Eligible studies..

In total, 5,227 original publications were retrieved from our database search, and 1 publication from reference lists of reviews on related topics. After abstract and title screening, 656 publications were eligible for full-text search. After screening the full text of these studies, 122 articles (2% of deduplicated references) were included for qualitative synthesis ( Table 1 ) and a subset of 62 for quantitative synthesis ( Fig 1 ).

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https://doi.org/10.1371/journal.pbio.3002667.t001

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Flow chart for inclusion of systematic reviews or scoping reviews with or without meta-analysis which investigate translation of interventions in animal models of human diseases.

https://doi.org/10.1371/journal.pbio.3002667.g001

The eligible systematic reviews comprised a total of 4,443 animal studies and 1,516 clinical studies (median 21 animal and 8 human studies per systematic review).

Most studies have been published in the last 5 years (88 since 2018). Most studies were from the United States of America (27 studies, 22%), Canada (19, 16%), the Netherlands, (16, 13%), Australia (13, 11%), Italy (13, 11%), and the United Kingdom (10, 8%). Thirty-six studies were collaborative efforts between 2 or more countries.

Diseases and therapies.

The studies covered 54 unique different human diseases/conditions ( Table 1 ). The most common ICD-11 disease classes addressed by the systematic reviews were “diseases of the nervous system” (32% of studies), “diseases of the musculoskeletal system and connective tissue” (11%), “mental and behavioral disorders” (9%), “diseases of the circulatory system” (9%), “diseases of the digestive system” (8%), and “neoplasms” (8%).

These reviews included a total of 367 unique therapeutic interventions including drug and non-drug treatments ( Table 1 ). The median interval between the first animal experiment and publication of the respective systematic review was 15 years (range: 3 to 63 years, total observation time 6,736 years). All therapies and diseases are listed in S1 Table .

Risk of bias assessment.

The inter-rater agreement Kappa was 0.76. We considered most of the included reviews to be at low risk of bias for providing a search date, a search string, a study flow chart, and reporting screening and data extraction by 2 reviewers. However, few studies published a study protocol, and a substantial number of systematic reviews did not perform a risk of bias assessment, thus posing high risk of bias in these domains ( Fig 2 ). Given that most included systematic reviews were deemed at low risk of bias, we anticipated no relevant impact on our overall conclusions.

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The data underlying this figure can be found on https://osf.io/frjm4 (Sheet: Mastersheet_including_RoB ). The code underlying this figure can be found S1 Code ( https://osf.io/9fgru ).

https://doi.org/10.1371/journal.pbio.3002667.g002

Qualitative summary of translation in different biomedical fields

Therapies were tested in a variety of diseases, including neurological, musculoskeletal, psychiatric, circulatory system, digestive, skin, lung, and metabolic diseases ( S2 – S8 Tables).

Most studies discussed potential hurdles for translation of findings from animal to human studies. A prevalent observation was the disparity in methodological approaches between animal experiments and human studies. Specifically, several studies highlighted that experimental conditions in animal research often do not mirror clinically relevant scenarios [ 22 – 33 ]. For example, treatments for stroke were frequently tested on young, healthy animals, which contrast the typically multimorbid elderly patient population in clinical settings [ 22 ]. Poor study quality and inadequate reporting, predominantly in animal studies, were also recurrent concerns [ 34 – 36 ]. A noticeable reduction in effect size from animal to human studies was documented by several reviews [ 24 , 37 – 40 ]. This trend was substantiated by a systematic review and meta-analysis which examined the preclinical-to-clinical development trajectory of 37 treatments for acute ischemic stroke, encompassing 50 phase 3 clinical trials, 75 early clinical trials, and 209 animal studies [ 36 ]: It observed a progressive reduction in efficacy from animal research to early clinical trials and then to Phase 3 clinical trials. This decline was attributed to shortcomings in preclinical study rigor (such as the absence of randomization and blinding), differences in study design, including the use of differing outcomes, and insufficient statistical power in both animal studies and preliminary clinical studies.

Another comprehensive systematic review covering therapies for cardiac arrest encompassed 415 animal and 43 clinical studies. This review, which evaluated 190 pharmacological interventions, found a limited number of positive outcomes in clinical studies [ 41 ]. In addition, many animal studies were conducted subsequent to the publication of a corresponding clinical study [ 41 ]. And similar to stroke, there were substantial variation in experimental methodologies between animal and human studies. For example, drugs were typically administered approximately 9.5 min post-cardiac arrest in animal studies, compared to roughly 19.4 min in human studies [ 42 ].

Finally, one study traced the developmental pathway of an oncolytic virus used in cancer therapy [ 43 ]. While animal experiments exhibited 80% to 100% regression rates in tumours, human studies only demonstrated a range of 0% to 24%. Intriguingly, more rigorously conducted studies showed smaller effect sizes. And the authors emphasize that even successful biotherapeutic interventions might not present a straight-forward translational journey.

Quantitative overview of therapy translation overall and by discipline

In these systematic reviews, and only accounting for therapies where more than 10 years has elapsed since the initial animal experiment, 50%, 40%, and 5% of therapies entered any human study, an RCT, or have been (FDA) approved (281 therapies, Fig 3A ). Diseases of the circulatory system (166 therapies, including stroke: 34%, 29%, and 1%, respectively) and mental health disorders (16 therapies: 50%, 31%, and 0%, respectively) showed particularly low translational proportions ( Fig 3B and 3D ). Diseases of the musculoskeletal system (13 therapies, 100%, 62%, and 15%, respectively) and cancer (15 therapies, 73%, 47%, and 20%, respectively) showed relatively high translational proportions ( Fig 3E and 3F ). Translational proportions considering all therapies independent of time gap between animal and clinical studies were slightly lower ( Table 1 and S1 Fig ). Translational proportions per disease are illustrated in Fig 4 with cardiac arrest, multiple sclerosis, and stroke assessing the most therapeutic interventions in animals ( S9 Table ).

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Proportions of translation from animals to any clinical study (green), to an RCT (yellow), or to (FDA) approval (red) overall (A), for circulatory system diseases (B), for neurological diseases (C), for mental health disorders (D), for musculoskeletal diseases (E), and for cancer (F). The data underlying this figure can be found on https://osf.io/frjm4 (Sheet: Translation ). The code underlying this figure can be found in S1 Code ( https://osf.io/9fgru ). RCT, randomized controlled trial.

https://doi.org/10.1371/journal.pbio.3002667.g003

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The quantity of therapies that are initially tested in animal studies (blue), subsequently entering any clinical trial (green), advance to a randomized controlled trial (yellow), and eventually achieve regulatory approval (red). The total number of therapies for each category is annotated at the upper right corner of the respective graph. The data underlying this figure can be found on https://osf.io/frjm4 (Sheet: Diseases ). The code underlying this figure can be found S1 Code ( https://osf.io/9fgru ). ACL, anterior cruciate ligament; ALS, amyotrophic lateral sclerosis; ARDS, acute respiratory distress syndrome; OCD, obsessive compulsive disorder.

https://doi.org/10.1371/journal.pbio.3002667.g004

Chronology of animal-to-human translation

Because less than half of the therapies transitioned from animal experiments to clinical studies, we were not able to estimate the overall median durations ( Fig 5 ). However, if only considering therapeutic interventions entering any clinical study, an RCT, or obtaining (FDA) approval, the median lag times were 5 years [95% CI: 5 to 6], 7 years [95% CI: 6 to 8], and 10 years [95% CI: 4-not estimable], respectively ( S2 Fig ). The maximum time from first animal study to any clinical trial, and RCT, or FDA approval was 44 years, 58 years, and 34 years, respectively. Notably, in several instances, the first animal experiment was documented after the first clinical trial (49 therapies, representing 31%) or RCT (28 therapies, accounting for 22%).

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Lag times for therapies from first animal study to any clinical study (A), to a randomized controlled trial (RCT, B), or to (FDA) approval (C). The data underlying this figure can be found on https://osf.io/frjm4 (Sheet: Translation ). The code underlying this figure can be found S1 Code ( https://osf.io/9fgru ). RCT, randomized controlled trial.

https://doi.org/10.1371/journal.pbio.3002667.g005

Concordance between animal and human studies

In evaluating concordance, we restricted our analysis to therapies that were the subject of 5 or more published animal studies, encompassing 62 therapies. These therapies were examined across 1,496 animal studies, 515 clinical studies, and 220 RCTs. Out of these, positive outcomes were identified in 1,181 (79%) animal studies, 317 (61%) clinical studies, and 111 (50%) RCTs ( Table 2 ). The overall alignment between positive outcomes in animal and clinical studies, represented by the relative risk, was 0.86 [95% CI: 0.80 to 0.92] ( Fig 6 ). This alignment was especially pronounced in therapies for neurological diseases at 0.99 [0.66 to 1.06], involving 23 therapies, and circulatory system diseases (inclusive of stroke) at 0.88 [0.76 to 1.01], involving 12 therapies. Conversely, lower concordance was observed for digestive system diseases (0.86 [0.75 to 0.99], 7 therapies), musculoskeletal diseases (0.67 [0.515 to 0.862], 6 therapies), cancer (0.66 [0.49 to 0.88], 3 therapies), and mental health disorders (0.60 [0.37 to 0.97], 7 therapies) ( S2 – S8 Figs).

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https://doi.org/10.1371/journal.pbio.3002667.t002

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Forest plot of concordance rates (relative risks) between animal and human studies. A random-effects model was fitted to the data. The data underlying this figure can be found on https://osf.io/frjm4 (Sheet: Mastersheet_including_RoB ). The code underlying this figure can be found S1 Code ( https://osf.io/9fgru ). CI, confidence interval; RR, relative risk.

https://doi.org/10.1371/journal.pbio.3002667.g006

Main findings

Our umbrella systematic review evaluated (1) the proportion of therapies which translate from animal studies to human application, including timeframes; and (2) the consistency between animal and human study results. We observe a notable consistency between results from animal and human studies including a relatively large proportion of therapeutic interventions entering early clinical trials. However, only a minority of therapeutic intervention achieved regulatory approval.

Findings in the context of existing evidence

Translation across biomedical fields..

Our review shows a high consistency between findings from animal and human studies, similar to studies outside of therapy translation [ 44 ]. In addition, a surprisingly high proportions of therapies entered early clinical development: half of the therapeutic interventions made the transition from animal studies to early human clinical studies (34% to 100% across different biomedical fields). Furthermore, 40% of these therapies progressed to the more rigorous RCT stage (29% to 62% for different biomedical fields). However, a strikingly low proportion—only 5%—of therapies achieved official approval (0% to 20% across the biomedical spectrum).

How can we make sense of the fact that animal studies and early clinical trials seem to show promise, yet there is very limited official approval for these therapies? There are 2 possible explanations: One scenario is that the strict requirements of RCTs and regulatory approval are causing many potentially valuable treatments to be left behind. The other scenario is that both animal studies and early clinical trials may have limitations in their design, such as a lack of proper randomization and blinding, which affects their internal validity [ 45 ]. This could lead to unreliable findings in both domains, ultimately resulting in the exclusion of these therapies in more rigorous clinical trial settings like RCTs. This line of reasoning also includes the so called efficacy-effectiveness gap, i.e., the differences in outcomes between patients treated in ideal and controlled circumstances of clinical trials versus real-world scenarios [ 46 , 47 ].

We lean towards the second scenario for 2 reasons. First, as therapies progress to more rigorous study designs, their numbers do decrease as shown by our data, which contrasts to the mostly small and uncontrolled early clinical trials where these therapies were initially tested. Second, drawing from the field of clinical neurology, many therapies that have shown promise in animal studies and early trials reported as successful candidates herein, such as melatonin and mesenchymal stem cells for stroke, have not yet become standard clinical practice [ 48 ]. A similar pattern can be seen in other neurological diseases like Alzheimer’s disease and spinal cord injury, where there are several therapies with promising preclinical results but limited practical translation [ 49 , 50 ].

Potential hurdles for successful translation.

Several factors contribute to the challenges in translating therapies from animal models to human application, as discussed by many of the included reviews. First, there is a notable discrepancy in the contexts of animal testing versus human application. For example, treatment strategies tested on young, healthy animals, such as those for stroke, may not directly apply to the more complex scenarios of elderly patients with multiple health conditions. Second, there is an overall poor quality of many animal studies. These studies often have inherent design flaws, lacking critical elements like blinding or randomization. This absence can bias the results and affect their applicability to the human case, i.e., their external validity. Third, there seems to be a disconnect between animal and human research [ 51 ]. This warrants a stronger focus on educating a new generation of translational scientists [ 52 ]. Fourth, when it comes to human studies, they can suffer from being underpowered or relying on outcome measures that do not capture the efficacy of a treatment [ 53 ]. For example, early phase clinical trials testing interventions for neurological diseases are commonly underpowered [ 54 ]. Similarly, clinical trials may use trial outcomes not genuinely reflecting real-world patient settings such as complex composite outcomes, commonly seen in trials of cardiovascular diseases [ 55 ] or assessing cognitive domains in dementia trials not relevant for patients [ 56 ]. Lastly, animal and human studies commonly address different questions: whereas animal studies tend to focus on mechanisms, human studies tend to focus on effectiveness of an intervention.

How can we improve translation?

While finding a straightforward solution is challenging, we emphasize 2 crucial elements to enhance the transition from preclinical studies to clinical applications: the robustness and generalizability of data. ALS research illustrates data robustness issues, with treatments effective in animal models often failing in human studies [ 57 ]. On the other hand, the variability in experimental protocols and tools affects how generalizable the results are [ 58 , 59 ]: drugs effective across diverse laboratory settings tend to promise better outcomes in human studies [ 60 ]. In addition, outcomes from animal and early clinical studies must align with actual clinical needs [ 59 ]. Incorporating these measures could not only streamline drug development but also positively impact animal welfare by reducing research waste [ 61 , 62 ].

Could low translation be an innate characteristic of translational animal research? Instead of disposing animal research due to low translation, a more telling comparison might be drawing parallels between translational rates in animal research and sectors like medical device approvals, where development largely bypasses animal use [ 63 ]. It might emerge that translation proportions could be similarly modest in these animal-free sectors.

We did not systematically assess differences in animal models or therapy parameters such as therapy type (drug versus non-drug) for different disease categories—for example, comparing conditions where animal and human therapy outcomes show high consistency (such as neurological or circulatory system diseases) against those with lower consistency (such as mental health issues or cancer). Future research could explore these factors as potential moderators on the alignment of results between animal studies and human applications. Additionally, future studies should examine how the source of trial sponsorship, comparing investigator-initiated versus industry-sponsored trials, influences translational success, given that industry-sponsored trials appear to exert a greater influence on clinical guidelines [ 64 ].

Limitations

The findings of this study come with notable limitations:

First and most importantly, the therapies herein included were identified through systematic reviews specifically focusing on translation which will likely bias the factual translation. Such reviews may be more commonly conducted in fields where at least some therapies have already achieved clinical translation.

Second, the journey of transitioning a therapy from animal experiments to human application is intricate, bearing a multidimensional nature [ 43 ]. Our methodology, however, simplified this process by categorizing clinical studies as positive, neutral, or negative.

Third, the outcomes of clinical studies were classified based on the authors’ conclusions, which may lead to biased interpretations if the authors frame their findings to support a beneficial therapeutic outcome [ 65 ]. This phenomenon, known as “spin,” could result in an overestimation of clinical trials with beneficial outcomes.

Fourth, it is prudent to recognize that animal studies can have indirect benefits in the translation process. For example, they might enhance our mechanistic comprehension of diseases, even if not directly leading to a successful therapeutic application in humans.

Fifth, this umbrella review is confined to studies published in English, which may lead to the omission of relevant data published in other languages.

Our umbrella review also has strengths:

First, we employed a rigorous systematic review methodology, which aids in mitigating potential biases.

Second, it offers a comprehensive perspective by spanning a variety of biomedical fields, therapeutic modalities, and human diseases, and including a relatively large number of therapies and diseases.

Third, we have undertaken both qualitative and quantitative assessments of translational rates, constituting sensitivity analyses.

Conclusions

Our umbrella review presents translational proportions across various biomedical fields, detailing the progression times from animal studies to clinical development. Although the consistency between animal and early clinical studies was high, only a minority of therapeutic interventions achieved regulatory approval. To enhance development of therapies for clinical application, it is imperative to emphasize the robustness and generalizability of experimental approaches, ensuring rigorous animal and human research.

Supporting information

S1 data. supplementary data..

https://doi.org/10.1371/journal.pbio.3002667.s001

S2 Data. Supplementary data.

https://doi.org/10.1371/journal.pbio.3002667.s002

S1 Fig. Translational proportions for all therapies (neglecting development time).

https://doi.org/10.1371/journal.pbio.3002667.s003

S2 Fig. Lag times for clinical therapy development from first animal study only considering therapies which transitioned to a clinical trial.

https://doi.org/10.1371/journal.pbio.3002667.s004

S3 Fig. Meta-analysis on concordance rate for neurological diseases (relative risk).

https://doi.org/10.1371/journal.pbio.3002667.s005

S4 Fig. Meta-analysis on concordance rate for circulatory system diseases (relative risk).

https://doi.org/10.1371/journal.pbio.3002667.s006

S5 Fig. Meta-analysis on concordance rate for diseases of the digestive system (relative risk).

https://doi.org/10.1371/journal.pbio.3002667.s007

S6 Fig. Meta-analysis on concordance rate for musculoskeletal diseases (relative risk).

https://doi.org/10.1371/journal.pbio.3002667.s008

S7 Fig. Meta-analysis on concordance rate for cancer (relative risk).

https://doi.org/10.1371/journal.pbio.3002667.s009

S8 Fig. Meta-analysis on concordance rate for mental health disorders (relative risk).

https://doi.org/10.1371/journal.pbio.3002667.s010

S1 Table. Studies, interventions, and development status of included systematic reviews/therapeutic interventions.

https://doi.org/10.1371/journal.pbio.3002667.s011

S2 Table. Translational assessment of interventions for neurological diseases.

https://doi.org/10.1371/journal.pbio.3002667.s012

S3 Table. Translational assessment of interventions for diseases of the musculoskeletal system and connective tissue.

https://doi.org/10.1371/journal.pbio.3002667.s013

S4 Table. Translational assessment of interventions for psychiatric disorders.

https://doi.org/10.1371/journal.pbio.3002667.s014

S5 Table. Translational assessment of interventions for diseases of the circulatory system.

https://doi.org/10.1371/journal.pbio.3002667.s015

S6 Table. Translational assessment of interventions for diseases of the digestive system.

https://doi.org/10.1371/journal.pbio.3002667.s016

S7 Table. Translational assessment of interventions for cancer.

https://doi.org/10.1371/journal.pbio.3002667.s017

S8 Table. Translational assessment of interventions for other disorders/conditions.

https://doi.org/10.1371/journal.pbio.3002667.s018

S9 Table. Number of therapeutic interventions tested in animals, entering any clinical trial, any RCT, and eventually obtaining regulatory approval per disease/condition (n = 54).

https://doi.org/10.1371/journal.pbio.3002667.s019

S1 Code. Analysis code.

https://doi.org/10.1371/journal.pbio.3002667.s020

Acknowledgments

We thank Emma-Lotta Säätelä and Nik Bärtsch for help with data curation.

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Animal Testing Research Paper

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Research Paper on Animal Testing: An Ethical Examination

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Animal testing, a cornerstone of scientific research for centuries, has consistently ignited ethical debates regarding its implications for animal welfare and its necessity in advancing human knowledge. This research paper delves into the historical evolution, methods, and ethical considerations surrounding animal experimentation. By juxtaposing the ethical arguments in favor of and against animal testing, this paper seeks to explore the intrinsic rights of animals, the translatability of experimental results from animals to humans, and the potential harm inflicted upon test subjects. Additionally, the paper highlights emerging alternative testing methods, changing legal landscapes, and evolving societal perceptions, concluding with reflections on future trends and the balance between scientific progress and ethical responsibility.

Introduction

The practice of animal testing has deep historical roots and has been an integral aspect of scientific inquiry for centuries. As early as the Hellenistic period, animals were dissected to understand the intricacies of their physiological processes, paving the way for foundational knowledge in biology and medicine (LaFollette and Shanks, 1996). Fast forward to the 21st century, animal experimentation remains an indispensable component of research, notably in areas like pharmaceuticals, cosmetics, and behavioral studies. Its contributions to the development of life-saving medications and treatments are undeniable, highlighting its enduring significance.

However, the use of animals in research is not without its ethical challenges. As our understanding of animal cognition and sentience has expanded, so too have concerns about the morality of subjecting them to potentially harmful experiments. Proponents of animal testing argue that it remains the most viable method for certain types of research, emphasizing its critical role in scientific advancements (Rollin, 1981). Critics, on the other hand, question the humane treatment of animals and contend that the results obtained from animal studies often don’t translate reliably to human scenarios, making the practice both cruel and scientifically questionable (Singer, 1975).

This research paper endeavors to delve deeply into the multifaceted issue of animal testing. It seeks to explore the historical context, the current debates surrounding its ethics, the scientific validity of the results obtained, potential alternatives, and the evolving societal perceptions. By providing a comprehensive examination of animal testing, we aim to equip readers with a nuanced understanding, shedding light on both the undeniable contributions and the moral quandaries of this contentious practice.

Historical Background of Animal Testing

The history of using animals for experimentation can be traced back to ancient times. Ancient Greeks, including prominent figures like Aristotle and Erasistratus, utilized animals for anatomical studies, dissecting them to comprehend the mysteries of life and physiology (French, 1975). This foundational work paved the way for future scientists, such as Galen in the 2nd century AD, who relied heavily on animal dissections to develop an understanding of anatomy and medicine that would dominate European medicine for the next millennium.

With the advent of the Renaissance and the subsequent scientific revolution, the scope and methodology of animal testing underwent profound transformations. The 19th century, in particular, witnessed a surge in vivisection, the practice of operating on living animals for experimental purposes. This era gave rise to controversies over animal welfare, leading to the first laws aiming to regulate animal experimentation. Claude Bernard, a renowned physiologist of this period, both advanced the use of animals in experimental medicine and grappled with the ethical complexities it presented (Bernard, 1957). As the 20th century progressed, regulated animal testing became an industry standard in various fields, especially in pharmaceuticals, ensuring drug safety and efficacy before human trials.

The contributions of animal testing to medical and scientific advancements are vast. From the development of essential vaccines to life-saving surgical procedures, animal experiments have played a pivotal role. For instance, the discovery of insulin in the 1920s, which transformed the treatment of diabetes, was a direct result of experiments on dogs (Bliss, 1982). Similarly, the development of the polio vaccine in the 1950s relied on studies conducted on monkeys. These discoveries, among countless others, underscore the profound impact of animal testing on medical science, leading to therapies and treatments that have saved countless human lives.

Methods of Animal Testing

Animal testing encompasses a diverse array of procedures, ranging from observation to invasive surgeries. Fundamental practices include injecting animals with potential new medications to check for side effects, exposing them to radiation, or inducing traumatic injuries to study healing processes (Rowan, 1984). In toxicity testing, substances like cosmetics or household products are administered orally, through inhalation, or applied to the skin to determine safety levels. Another prevalent technique is the Draize eye test, in which a substance is placed in one eye of an animal, typically rabbits, to test for irritation or corrosion, with the untreated eye acting as a control (Balls et al., 1995). Behavioral studies might involve placing animals in stressful or anxiety-inducing situations to analyze psychological responses.

The selection of animals for testing often hinges on the research question and the biological similarities between the animal and humans. Mice and rats, being mammals, share genetic, biological, and behavioral characteristics with humans, making them primary choices for studies related to diseases, genetics, and pharmacological effects (Tannenbaum & Bennett, 2015). Rabbits are frequently used in toxicity and irritation tests due to their sensitive skin and eyes. Larger mammals, such as dogs and primates, are used in advanced phases of research, especially when human-like physiology or complex behaviors need to be observed. Birds, fish, and amphibians also find places in specific studies, such as developmental or environmental research.

As public awareness and concern about animal welfare grew, especially in the 20th century, numerous countries established regulations to oversee animal testing. The U.S. Animal Welfare Act of 1966, with its subsequent amendments, is a central piece of legislation setting standards for the treatment of animals in research (Carbone, 2004). Similarly, the European Union introduced the Directive 2010/63/EU, emphasizing the principles of the “Three Rs”: Replacement (using alternative methods), Reduction (minimizing animal use), and Refinement (enhancing animal welfare in experiments). Such regulations mandate appropriate housing, pain management, and the establishment of ethical review committees to assess the validity and necessity of proposed animal tests.

Ethical Arguments in Favor of Animal Testing

One of the primary ethical justifications for animal testing is the potential benefits it offers to humanity. Throughout history, animal experimentation has been instrumental in significant medical and scientific advancements. Insulin, for instance, was first discovered through experiments on dogs, transforming diabetes from a fatal disease to a manageable condition (Bliss, 1982). The development of vaccines, from polio to rabies, also relied heavily on animal testing. Such advancements have saved or improved millions of lives, and proponents argue that the ethical weight of these benefits often outweighs the moral cost of animal suffering.

Another central argument is the notion that animals, especially those lower down the evolutionary ladder, have a different moral status than humans. This perspective doesn’t necessarily deny animals’ capacity for suffering but suggests that their suffering might be outweighed by the higher moral worth or rights of humans. Some philosophers, like Cohen (1986), contend that while animals might have interests, they do not possess rights in the same way humans do. In this view, humans have obligations toward animals, like treating them humanely, but these obligations do not equate to granting animals rights that would prohibit their use in potentially beneficial research.

The ongoing use of animal testing is also defended on the grounds that, in many cases, there are no viable alternatives that can replicate the complex biological systems of living organisms. While in vitro methods or computer models can offer valuable insights, they often cannot fully mimic the intricate interplay of cells, tissues, and organs within a living body (Russell and Burch, 1959). Until more comprehensive alternatives are developed, proponents argue, animal testing remains a necessary tool in understanding diseases, testing potential treatments, and ensuring the safety of new products.

Ethical Arguments Against Animal Testing

Central to the ethical arguments against animal testing is the belief in the intrinsic rights of animals. Regan (1983) is one of the prominent figures in this argument, positing that animals are “subjects-of-a-life,” meaning they have inherent value separate from their usefulness to humans. This perspective suggests that animals, much like humans, have rights that protect them from harm, exploitation, or being treated as mere means to an end. Regan’s assertion challenges the traditional hierarchical placement of humans above animals in moral consideration, emphasizing that animals too deserve a life free from suffering, pain, and premature death.

A significant criticism of animal testing centers on its scientific validity, especially the transferability of its results to human contexts. Greek and Greek (2010) argue that, due to fundamental biological differences between species, results from animal tests can be misleading and may not always predict human outcomes accurately. Such arguments emphasize that the anatomical, metabolic, and cellular differences between animals and humans can lead to flawed conclusions. Cases where drugs showed promise in animal trials but later caused unforeseen side effects in humans further bolster this contention.

Ethical objections often highlight the potential for undue suffering and harm to animals subjected to testing. Singer (1975) argues from a utilitarian perspective, asserting that the suffering endured by animals often outweighs the potential benefits to humans. This standpoint revolves around the belief that causing pain, distress, or death to animals for experimental purposes is unjustifiable, especially when the benefits are uncertain or when alternative methods exist. It’s worth noting that the ethical acceptability becomes even more questionable in tests for non-essential products like cosmetics.

The rapid progression of alternative testing methods further strengthens the arguments against animal experimentation. As Garland and Bailey (2015) have highlighted, advances in in vitro testing, tissue engineering, and computer modeling now offer scientifically sound and ethically preferable alternatives to traditional animal tests. The emergence of these techniques underscores the possibility of conducting research without compromising animal welfare. Their progression also underlines the contention that continued reliance on animal testing may be more about tradition and convenience than necessity.

Alternative Approaches to Animal Testing

In Vitro Testing and Tissue Engineering

In recent years, in vitro testing has emerged as a formidable alternative to animal experimentation. As opposed to in vivo tests, which are conducted on live organisms, in vitro methods study biological properties in test tubes or petri dishes. A substantial benefit of these tests is that they employ human cells, thereby directly mimicking human physiology and often producing more relevant results. Pioneering work by Mertz (2012) demonstrates that in vitro methodologies can precisely simulate the human body’s response to various drugs or chemicals, making them invaluable in toxicology and pharmacology studies.

Tissue engineering, a subset of in vitro testing, involves cultivating three-dimensional tissues that can emulate entire organ functions. Atala et al. (2010) have showcased the potential of tissue-engineered human organs, such as kidneys and livers, to replace animal models in drug metabolism and disease research. Their groundbreaking work not only promotes humane research practices but also promises more accurate predictions of human responses.

Computational Methods and Computer Modeling

Computational methods, particularly computer modeling, have garnered attention as another alternative to animal tests. These models, grounded in mathematical algorithms, can predict biological responses to various compounds. Russel and Burch (1959), pioneers in the field, argue that these predictive models, by integrating existing biological and chemical data, can often replicate or even surpass the accuracy of animal-based tests. With advances in technology and machine learning, computer-based simulations have become even more sophisticated, increasingly reducing the need for live animal experimentation.

Human-Based Testing: Micro-dosing

A more direct approach to gauge human responses without resorting to extensive animal testing is through micro-dosing. In this technique, volunteers are administered extremely low, non-therapeutic doses of a test substance, enabling researchers to study its effects and metabolic pathways in the human body without risking the individual’s health. Garnering support from experts like Lappin and Garner (2003), micro-dosing provides real-time insights into how drugs behave in the human system, mitigating the interspecies variability that often complicates interpretations in animal studies.

Collectively, these innovative approaches not only reduce our dependence on animal models but also usher in a new era of research marked by heightened accuracy and ethical consideration.

Legal and Institutional Frameworks

Animal testing, due to its ethical implications, is one of the most stringently regulated practices in scientific research. In many nations, the use of animals in experimentation is governed by detailed statutes and guidelines. A cornerstone among these regulations is the 3Rs principle—Replacement, Reduction, and Refinement—introduced by Russel and Burch (1959). This principle mandates that animals should only be used if no other non-animal alternative exists (Replacement), the number of animals used should be minimized (Reduction), and their suffering should be alleviated as much as possible (Refinement). The directive 2010/63/EU of the European Union, for instance, sets comprehensive standards for the protection of animals used for scientific purposes, emphasizing the 3Rs principle.

Globally, the regulatory landscape for animal testing shows considerable variation. In the European Union, as noted, Directive 2010/63/EU ensures that animals are only used when absolutely necessary, and researchers are required to demonstrate the lack of alternative methods before proceeding with animal tests. The United States, on the other hand, primarily regulates animal testing through the Animal Welfare Act (AWA) of 1966. Though the AWA sets standards for care and treatment, it does not categorically prohibit any specific type of animal use in research. In contrast, India, following the footsteps of the EU, implemented a series of bans starting in 2013 on the testing of cosmetics on animals, becoming the first country in South Asia to do so (Rowan, 2018).

Central to the regulatory landscape of animal testing are ethics committees, also referred to as Institutional Animal Care and Use Committees (IACUCs) in the U.S. These committees play a pivotal role in scrutinizing and approving animal research proposals. As highlighted by Festing and Wilkinson (2007), every research project that intends to use animals must be critically evaluated by these committees for its scientific merit, ethical justification, and adherence to the 3Rs principle. Beyond approval, these committees also oversee the proper care, housing, and treatment of animals in research institutions, ensuring that standards are consistently met. Their existence underscores the collective responsibility of the scientific community and society to ensure the humane treatment of animals.

In summary, while animal testing remains a contentious issue, legal and institutional frameworks act as critical safeguards. By establishing strict regulations, promoting transparency, and ensuring consistent oversight, these frameworks aim to strike a balance between scientific advancement and ethical responsibility.

Societal and Cultural Perceptions of Animal Testing

Public perception of animal testing has witnessed a significant transformation over the past several decades. Historically, during the early periods of biomedical research, animal experimentation was largely accepted by society as a necessary means to achieve scientific and medical advancements (Rupke, 1987). It was seen as a critical step in understanding human physiology and developing treatments for diseases. However, as the 20th century progressed, especially from the 1960s onwards, there was a growing awareness and concern about animal rights and welfare. The publication of books like Peter Singer’s “Animal Liberation” in 1975 ignited public debate and spurred reconsideration of the ethics surrounding the use of animals in research. By the late 20th and early 21st centuries, with increased access to information and more visible advocacy, the issue of animal testing became a prominent societal concern, with many questioning its moral and scientific validity.

Advocacy groups and activists have played an indispensable role in shaping societal views on animal testing. Organizations like People for the Ethical Treatment of Animals (PETA) and the Humane Society have not only campaigned against the cruel treatment of animals in labs but have also funded research into alternative testing methods (Monamy, 2009). Through protests, media campaigns, and educational programs, these groups have drawn attention to the suffering experienced by lab animals and have propelled animal testing to the forefront of public discourse. Additionally, the undercover exposures of certain malpractices in research facilities by activists have occasionally sparked public outrage and have led to increased calls for regulatory reform.

Attitudes toward animal testing are also deeply embedded in cultural contexts. In Western societies, particularly in Europe, there has been a noticeable shift towards greater animal rights recognition and opposition to animal testing, especially for cosmetics and non-essential products (Franklin, 1999). This can be attributed, in part, to the Judeo-Christian belief in stewardship, where humans have a responsibility to care for all living creatures. In contrast, many Asian cultures, influenced by socio-religious norms, might view the human-animal relationship differently. For instance, in certain Confucian traditions, the hierarchical ordering of society extends to animals, leading to a more utilitarian view of animal use (Kawamura, 2013). However, it’s essential to note that rapid globalization and exposure to international discourses on animal rights are leading to changing perspectives even in these regions.

In conclusion, societal and cultural perceptions of animal testing are multifaceted and continually evolving. While once seen as a necessary component of scientific progress, the ethics of animal testing are now widely debated, reflecting a broader societal shift towards valuing animal welfare and rights.

The Future of Animal Testing: Trends and Predictions

One of the most promising avenues for the future of animal testing lies in the development and refinement of alternative testing methods. In recent years, there has been significant growth in in vitro testing techniques, where human cells are used to replicate specific bodily reactions (Langley, 2015). Advances in biotechnology have also brought forth organ-on-a-chip technology, where human organs are replicated on microchips to study drug effects and disease processes. Furthermore, computational biology and computer modeling are rapidly becoming sophisticated tools to predict how substances can affect humans, reducing the need for animal models (Combes & Balls, 2014).

Given the progression of alternative methods, many predict a sizable reduction or even a cessation of animal testing in specific research fields. The cosmetic industry, for instance, has seen a significant decline in animal testing due to both ethical concerns and the development of alternative methods. Certain regions, like the European Union, have already imposed bans on animal-tested cosmetics, setting a precedent for other industries and regions to follow (van der Valk et al., 2018). Moreover, with the continued advancement and validation of alternatives, regulatory bodies worldwide might update their requirements, further reducing the dependency on animal models.

As society progresses, ethical considerations regarding animal welfare are anticipated to become even more central to research practices. With increasing public awareness and advocacy, research institutions may adopt more transparent practices, ensuring that any remaining animal testing adheres strictly to the 3Rs principle: Reduction, Replacement, and Refinement (Tannenbaum & Bennett, 2015). Additionally, ethicists predict a future where the moral weight given to animals’ interests, especially higher mammals with complex cognitive capacities, may equate more closely to that of humans, further intensifying the ethical scrutiny surrounding animal testing.

In summation, the future of animal testing appears poised for change. The convergence of ethical concerns, technological advancements, and regulatory shifts suggests a future where animal testing becomes less prevalent, with a more pronounced emphasis on humane and ethical research practices.

Animal testing, since its inception, has undeniably advanced human knowledge and improved countless lives through medical and scientific breakthroughs. Yet, the ethical cost attached to this progress is equally undeniable. The quandary arises from the conflict between the benefits reaped by humanity and the suffering endured by animals, forcing us to grapple with complex moral questions regarding the intrinsic rights of animals and their place in research.

As our understanding of animals’ cognitive and emotional capacities grows, so does our ethical responsibility toward them. The gains made in the name of science and medicine have to be continually weighed against the moral implications of using sentient beings for experimental purposes. It becomes vital, then, to ask not just if we can achieve a specific scientific goal through animal testing, but if we should.

In the contemporary era, the trend leans towards an increasing emphasis on finding ethical alternatives. Not merely because of the moral pressure, but also due to the realization that, in some instances, animal models may not be the most accurate or efficient means of understanding human-centric outcomes. Therefore, the future beckons a synthesis of ethical considerations and scientific pursuits, necessitating robust dialogue among researchers, ethicists, policymakers, and the general public. By fostering open discourse and investing in innovative research methodologies, it is conceivable to envision a future where scientific advancement and ethical responsibility coalesce seamlessly. As society continues its march forward, it bears the collective responsibility to ensure that progress does not come at the expense of our moral compass, advocating for a future where animals no longer bear the brunt of our curiosities and ambitions.

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  • What Animal Studies Are Revealing About Their Minds—and Ours

N ever underestimate the mind of a crow. Members of a family of birds that includes ravens, rooks, magpies, and jays, crows have been known to bend wire into hooks to retrieve food; drop nuts in a road so passing cars will crack them open; and recognize humans who have posed a threat, harassing them on-sight even months after their first encounter. But some of the smartest crows of all may be found in the animal physiology lab at the University of Tübingen in Germany. It’s there that the birds are mastering a skill you couldn’t manage until you were up to 4 years old: counting.

In a new study published in Science , researchers trained three crows to emit one to four caws in response to seeing the numbers 1, 2, 3, or 4 projected on a screen. The birds also learned to count out the proper number of vocalizations when cued by sounds, with a guitar chord eliciting a single caw, a cash register eliciting two, a drum roll signaling three, and a frequency sweep calling for four. In doing so, the birds matched or beat the numeracy skills of human children who often don’t master rudimentary counting until kindergarten.

Says animal physiologist and study co-author Andreas Nieder : “When faced with a set of three objects and asked, ‘How many?’ toddlers recite the speech sounds ‘one, two, three’ or even ‘one, one, one.’ We show that crows have the ability to count vocally [too].”

And crows aren’t the only creatures that understand simple math. Similar skills have been observed in studies of comparatively intelligent animals including gorillas, dolphins, elephants, the rhesus macaque, and the squirrel and capuchin monkeys. Even the less-clever rat can fathom basic arithmetic, with a recent study in Science Advances showing that the animals can be trained to hear two or three tones and then press a button corresponding to one number or the other. The learning didn’t come easy: It took two months for the rats to make that distinction, but it was the fact that they could do it at all—not that they were slow on the uptake—that was the true news.

The last few months alone have been something of a boom time for research into the intelligence and behavior of animals. German researchers discovered a sort of pre-verbal stage in finches —similar to the babbling stage in humans—that leads to their becoming fluent in song. Studies in Sweden and Vienna explored the role of play among barnyard chicks and a species of falcon. French researchers studied advanced use of sticks as tools in chimps , and other work in the U.S. made similar findings among otters . And perhaps most remarkably, researchers in Indonesia published a study about a wild orangutan, nicknamed Rakus by the scientists, that was observed chewing the leaves of a plant with known medicinal and analgesic properties and applying the resulting pulp to a wound on its face.

“It may be that Rakus learned this behavior from other animals in his birth area,” says lead author and animal behaviorist Isabelle Laumer of the Max Planck Institute in Germany. It is also possible that he came upon the discovery on his own, she says, accidentally applying the plant juice to himself by touching his wound while feeding on the leaves. “Rakus may have felt immediate pain release, causing him to repeat the behavior several times and subsequently apply solid plant matter,” adds Laumer.

All of these studies and more have implications not just for our understanding of animals, but for our understanding of ourselves, as creatures with often-similar brain structures. In one European study , researchers pinpointed twin regions in the human brain that allow us to recognize emotions in other people’s faces, and found corresponding regions in the brains of mice, raising the possibility that one of our most sophisticated traits—our ability to read the minds and moods of others—might be distributed throughout the animal kingdom.

“These evolutionarily conserved mechanisms should be common in most mammals,” says Francesco Papaleo, senior researcher at the Instituto Italiano de Tecnologia in Genoa, Italy, and a co-author of the study. “Properly recognizing and appropriately responding to altered emotions in others is essential for survival.”

The play is the thing

Of all of the recent research, it is the studies that explore play that illustrate the most engagingly ingenuous side of animals. Domestic chickens may be nobody’s idea of a personable species, but a May study in Frontiers of Ethology observed extensive play behavior in young hatchlings, especially males. Investigators raised the chicks in relatively spartan cages and then periodically transferred them to playpen areas with other chicks, aged from 6 to 53 days. In the presence of the rest of the flock, the males engaged in a wide range of play behaviors—all in sight of females—including frolicking, wing-flapping, jumping, and sparring. When the researchers introduced a rubber worm into the pens, the nearest male would pick it up and scurry around with it. Known in the wild as worm-running or tidbitting, the behavior, which can involve other forms of food as well, is an apparent display for the benefit of the females—a means of impressing them with the male’s resource-gathering skills. 

“We still don’t know the adaptive function of play for any species,” said Per Jensen, professor of ethology at Linköping University in Sweden and a co-author of the study, in a statement. “However the present study indicates that a possible function is to prepare animals for specific challenges they may encounter later in life. In a species like the chicken, where only males compete for territories, it makes sense that they engage in more social play as young.”

Falcons display similar behavior for equally practical reasons. A February study in the Journal of Raptor Research documented the Falkland Islands species known as Striated Caracaras routinely engaging in play with sheets of plastic, sea cabbage, stones, and even sheep dung. To qualify as play, animal and human behavior has to meet several criteria, including being voluntary and repeatedly performed, appearing intrinsically rewarding, and lacking apparent purpose. But appearances notwithstanding, there may be decidedly practical functions to play.

In the case of the falcons, which live in a place in which food resources are more available in some seasons than in others, playing with objects might reveal an unexpected nutrient source. “The more caracaras interact with the world around them, the more opportunities they have to learn what is food and what isn’t,” said study co-author and behavioral ecologist Katie Harrington, of the University of Veterinary Medicine in Vienna, in a statement. 

Animals, including homo sapiens, also play to practice combat, hunting, mating, and territorial claims, all of which are needed later in life. “That we see play in so many different species—including humans—tells us that it’s a really important component of our behavioral repertoire,” adds Harrington in an email to TIME. “We tend to see age differences, where younger individuals play more than older individuals. Studying the diversity of play can help us learn how and why it developed to be so important.”

The canine mind

Far and away the most studied animal mind in the world may belong to the domestic dog, if only because, with 471 million pet dogs worldwide, every home becomes something of a real-time, real-world behavioral lab. Still, it is the formal, peer-reviewed research that produces the most rigorous findings, and there is no shortage of that work. In one May study published in Animal Behaviour , investigators from the University of Helsinki subjected 987 dogs to various tests of behavior and problem-solving skills, looking for the traits such as impulsiveness, persistence, independence, and willingness to turn to humans for assistance, which help dogs function better either as working animals, domestic animals, or both.

In one test , the dogs were shown a short, clear cylinder containing a treat that was accessible only by an opening at either end of the container rather than through its transparent but impenetrable middle. The fewer times a subject dog mouthed the closed part of the cylinder before turning to the open end, the higher it scored. Another, similar test placed a treat behind a clear, V-shaped wall that required the dog to detour around the barrier, rather than simply bumping up against it in an attempt to get at the reward. A third test placed a treat inside a clear, locked box that was impossible for the dog to open—measuring how persistent the animal would be before giving up and turning to a human for help. A little persistence is considered good. Too much suggests a lack of learning curve.

Rohan looks on as her owner Paula Perez holds a ball during a test at the Eotvos Lorand University in Budapest

On the whole, says Saara Junttila, doctoral researcher with the university’s faculty of veterinary medicine and lead author of the paper, dogs with lower inhibitory control were good problem solvers and excelled in working roles and in canine sports, but were less tractable and trainable in the home.

“As an example, the Belgian shepherd Malinois was one of the fastest breeds at solving the V-detour task, and this breed spent a lot of time trying to solve a problem independently rather than looking at a human. [But it] is considered to be a more challenging breed [to train],” Juntilla says. “Other breeds such as the golden retriever may be more suitable for the role of pet dog, as they turn to humans during a problem-solving situation and have higher inhibitory control.”

The findings have implications not just for canine behavior but for humans, too. Some researchers have found parallels between attention deficit hyperactivity disorder (ADHD) in people and similar distractibility and impulsiveness in dogs. 

“Our results do seem to indicate that ADHD-type traits occur together,” says Junttila. “We found that dogs with low inhibitory control were more impulsive, less trainable, and had higher activity levels. People with ADHD [also] often have lower inhibitory control, impaired academic success, and higher impulsivity and hyperactivity.”

Dogs and people overlap in other ways, too. In one recent study published in Biologia Futura , investigators found that dogs that had been trained to imitate human behavior—such as turning or sitting or nodding their heads—do not need the cues to be delivered only in person, but could also obey them when simply seeing an image of a person on a computer screen. The dogs were better at imitating behavior when they saw the human from a perspective with which they were familiar—from the front or the side, for example, as opposed to from above. But either way, the investigators saw significance in the ability of the animals to make the leap that a two-dimensional image was effectively equivalent to a three-dimensional person.

Says lead author Claudia Fugazza, professor of ethology at Eötvös Loránd University in Budapest: “In general, dogs seem to be able…to extract the relevant information from 2D projections and use it to act appropriately in the 3D, real life context.” The findings have meaning that go beyond canine parlor tricks, opening up the possibility of virtual human-dog communications, serving to entertain the animals and provide emotional support to human companions.

Tooling about

The ability to use even simple tools was once seen as a talent limited to humans. Research has long since upended that belief, with studies showing a range of tool use among animals, including orangutans , which create whistles out of leaves to chase away predators; dolphins , which use marine sponges to scour the seafloor and stir up prey; and even the degus , a chinchilla-like rodent, which can be taught to use small rakes to look for food. New research is now turning up insights into the talents of one of nature’s most prodigious tool-users—the otter—with findings suggesting that the female of the species outperforms the male in this sophisticated skill.

The otters’ most common tool is a rock, which the animals use to crack open abalone shells to get to the tender meat inside. In a new study in Science , researchers from the University of Texas, Austin, and elsewhere observed 196 radio-tagged sea otters off the coast of California and discovered that the animals were using other tools as well—including shells and hard trash—to break open their prey. Females generally employed a wider array of tools than males did, an innovation they arrived at by necessity, as their smaller size and somewhat weaker jaws make cracking or biting open prey harder. Not only does more sophisticated tool use spare them tooth damage that they might otherwise sustain by trying to bite prey, it also provides them greater energy needed to raise and feed pups.

Chimps too are even better at tool use than commonly understood. The animals are most famously known for their ability to use twigs stripped of leaves to fish into small openings in logs and extract termites as food. New research in PLOS Biology found that this is not a static talent, but rather one that the animals improve throughout their lives, learning to fish for the insects by age 2 or so, and steadily improving their grip and eye-hand coordination over the years.

“The most efficient grips and actions to hold and manipulate stick tools continue to develop at least until [age] 15 [and] well into adulthood,” says lead author Mathieu Malherbe, primatologist with the Max Planck Institute in Germany.

This means war

Not every new trait animals exhibit is a noble one—a fact that is borne out by a recent study of bonobos. Colloquially known as the hippie chimp, for their generally peaceable ways and their matriarchal social structure, the great ape species turns out to be a lot more aggressive than thought, at least when it comes to male-on-male violence. Writing in the journal Current Biology , researchers from Harvard University found that male bonobos actually engage in three times the amount of mano-a-mano combat than their more warlike cousin, the chimpanzee. But the reason for the difference is paradoxical.

On the whole, chimps are significantly more violent as a group than bonobos, with bands of males engaging in sometimes mortal combat with other bands over access to food, territory, and females. This makes it essential that bonds within each tribe remain close—ensuring that the group presents the most united front when facing other tribes. Bonobos, which do not engage in organized warfare, can afford more squabbling and friction within the group without making themselves vulnerable to outsiders.

“The most likely causes of male aggression [among bonobos] are over who gets to stay in a feeding tree or at a good feeding spot,” says Martin Surbeck, assistant professor of human evolutionary biology at Harvard and a co-author of the study. “Chimpanzees depend on each other and thus have a lot of incentive not to make a fuss out of each potential conflict, while the individualistic nature of bonobo society makes aggression just way less costly and more frequent.”

The lovable scavenger

If the Striated Caracaras falcon is known for play, its cousin, the Chimango Caracaras, is developing a reputation for domestic bliss. In another study in the Journal of Raptor Research, investigators found elaborate co-parenting behavior between male and female pair-bonded birds. Among most species of raptors, the larger female incubates the eggs and defends the nest while the smaller male hunts for prey. Male and female Chimango Caracaras, however, which are scavengers, show little difference in size, and thus share responsibilities for gathering food as well as caring for the young.

A team led by PhD candidate Diego Gallego-Garcia of the Center for the Study and Conservation of Birds of Prey in Argentina studied 70 of the species’ nests and observed incubation, brooding, and food delivery responsibilities being evenly shared by both parents. The male and female alike also showed an understanding of the chicks’ needs throughout the day—brooding them more in the morning when temperatures were lower, for example. It is the species least lovely trait—its carrion diet—that contributes most to such an egalitarian household.

In raptors that kill live animals, says Gallego-Garcia, smaller males bring prey to the nest, but do not feed the chicks, relying on the larger female to “chunk the food” into bite-sized pieces. This, he says, “ties the female to the nest and prevents it from leaving to hunt. However in scavenger species, since carrion is usually brought as pieces of raw meat, it is more manageable for nestlings. This way the female is free to leave the nest and hunt, allowing for the biparental care that we observe.” 

The balanced home is an animal grace note—one of a great many across both the human and the non-human world. “The case of the Chimango Caracara is rare among raptors, but is a general rule in most other birds, and not uncommon in mammals,” says Gallego-Garcia. “This reinforces the idea that, in these cases, both members of the couple are necessary for the successful rearing of the offspring.” As it goes in animals, so it goes in us.

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Write to Jeffrey Kluger at [email protected]

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PREPARE: guidelines for planning animal research and testing

Adrian j smith.

1 Norecopa, c/o Norwegian Veterinary Institute, P.O. Box 750, Sentrum, Oslo, Norway

R Eddie Clutton

2 Royal (Dick) School of Veterinary Studies, Easter Bush, Midlothian, UK

Elliot Lilley

3 Research Animals Department, Science Group, RSPCA, Southwater, Horsham, West Sussex, UK

Kristine E Aa Hansen

4 Section of Experimental Biomedicine, Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway

Trond Brattelid

5 Division for Research Management and External Funding, Western Norway University of Applied Sciences, Bergen, Norway

There is widespread concern about the quality, reproducibility and translatability of studies involving research animals. Although there are a number of reporting guidelines available, there is very little overarching guidance on how to plan animal experiments, despite the fact that this is the logical place to start ensuring quality. In this paper we present the PREPARE guidelines: Planning Research and Experimental Procedures on Animals: Recommendations for Excellence. PREPARE covers the three broad areas which determine the quality of the preparation for animal studies: formulation, dialogue between scientists and the animal facility, and quality control of the various components in the study. Some topics overlap and the PREPARE checklist should be adapted to suit specific needs, for example in field research. Advice on use of the checklist is available on the Norecopa website, with links to guidelines for animal research and testing, at https://norecopa.no/PREPARE .

Résumé

Il existe de nombreuses inquiétudes au sujet de la qualité, de la reproductibilité et de la traduisibilité des études impliquant des animaux de laboratoire. Bien que de nombreuses orientations en matière de reporting soient disponibles, il existe très peu de principes directeurs sur la manière de planifier les expérimentations animales, malgré le fait qu'il semble logique d'étudier cette question pour pouvoir assurer la qualité des expériences. Dans cet article, nous présentons le document intitulé « PRÉPARATION : Lignes directrices pour la planification de la recherche et des procédures d'expérimentation animale : Recommandations en matière d'excellence ». Le document « PRÉPARATION » couvre les trois principaux domaines qui déterminent la qualité de la préparation des études menées sur les animaux : l'élaboration des études, le dialogue entre les scientifiques et le laboratoire animal, et le contrôle de la qualité des différentes composantes de ces études. Certains sujets peuvent se recouper et la check-list du document « PRÉPARATION » doit donc être adaptée en fonction des besoins spécifiques, par exemple pour les travaux de recherche sur le terrain. Des conseils sur l'utilisation de la check-list sont disponibles sur le site Internet de Norecopa https://norecopa.no/PREPARE , qui inclut notamment des liens vers les lignes directrices relatives à la recherche et à l'expérimentation animales.

Bedenken zu Qualität, Reproduzierbarkeit und Übertragbarkeit von Studien mit Versuchstieren sind weit verbreitet. Es existieren zwar verschiedene Berichtsleitlinien, doch allgemeingültige Richtlinien bezüglich der Planung von Tierexperimenten gibt es kaum – trotz der Tatsache, dass dies der logische Ausgangspunkt für die Gewährleistung von Qualität ist. In diesem Dokument präsentieren wir die PREPARE-Richtlinien: Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (Planung von Forschung und Versuchen mit Tieren: Empfehlungen für Excellence). PREPARE berücksichtigt die drei umfassenden Bereiche, die die Qualität der Vorbereitung von Tierstudien bestimmen: Erarbeitung, Dialog zwischen Wissenschaftlern und Tiereinrichtung sowie Qualitätskontrolle der einzelnen Komponenten der Studie. Dabei überlappen sich einige Themen, und die PREPARE-Checkliste sollte an die konkreten Erfordernisse angepasst werden, zum Beispiel in der Feldforschung. Hinweise zur Nutzung der Checkliste sind auf der Norecopa Website zu finden, darunter Links zu Richtlinien für Tierforschung und Tierversuche: https://norecopa.no/PREPARE .

Existe una preocupación generalizada sobre la calidad, reproducibilidad y aplicación de los estudios con animales de investigación. A pesar de que existe una serie de directrices disponibles, no hay muchas normas globales sobre cómo planificar los experimentos con animales, a pesar del hecho de que ese es el punto más lógico para empezar a garantizar la calidad. En este estudio presentamos las directrices de PREPARACIÓN: Planificación de procedimientos experimentales y de investigación con animales: recomendaciones para conseguir la excelencia. Este estudio cubre las tres áreas generales que determinan la calidad de la preparación de estudios con animales: formulación, diálogo entre científicos y las instalaciones para animales, y el control de calidad de los distintos componentes del estudio. Algunos temas se solapan y la lista de comprobación del estudio de preparación debería adaptarse a las necesidades específicas, por ejemplo en la investigación de campo. Para asesoramiento sobre el uso de la lista de comprobación viste la página web de Norecopa, con enlaces a directrices para la realización de pruebas e investigación con animales, en https://norecopa.no/PREPARE .

Introduction

The quality of animal-based studies is under increasing scrutiny, for good scientific and ethical reasons. Studies of papers reporting animal experiments have revealed alarming deficiencies in the information provided, 1 , 2 even after the production and journal endorsement of reporting guidelines. 3 There is also widespread concern about the lack of reproducibility and translatability of laboratory animal research. 4 – 7 This can, for example, contribute towards the failure of drugs when they enter human trials. 8 These issues come in addition to other concerns, not unique to animal research, about publication bias, which tends to favour the reporting of positive results and can lead to the acceptance of claims as fact. 9 This has understandably sparked a demand for reduced waste when planning experiments involving animals. 10 – 12 Reporting guidelines alone cannot solve the problem of wasteful experimentation, but thorough planning will increase the likelihood of success and is an important step in the implementation of the 3Rs of Russell & Burch (replacement, reduction, refinement). 13 The importance of attention to detail at all stages is, in our experience, often underestimated by scientists. Even small practical details can cause omissions or artefacts that can ruin experiments which in all other respects have been well-designed, and generate health risks for all involved. There is therefore, in our opinion, an urgent need for detailed but overarching guidelines for researchers on how to plan animal experiments which are safe and scientifically sound, address animal welfare and contain links to the best guidance available on more specific topics.

The purpose of this paper is to provide planning guidelines, fulfilling a comparable role to reporting guidelines such as ARRIVE 14 and others. 15 – 19 We have called them PREPARE (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence). They are designed to be applicable to all types of animal research and testing, including field studies, but they also contain topics concerning the management of animal facilities, since in-house experiments are dependent upon their quality. Some elements will be more relevant than others, but experimental bias and inappropriate statistical methodology are frequent causes of poor study design. PREPARE seeks to address the needs of all stakeholders: the animals, their caretakers and animal technologists, technical staff, scientists and designated responsible persons, including named veterinarians, training and competency officers and facility managers. PREPARE should also prove helpful for those evaluating proposals for animal studies, including funding bodies, ethical review boards, national committees and regulatory authorities. A more detailed discussion of these guidelines, with links to global resources is available at https://norecopa.no/PREPARE . A comparison between the ARRIVE and PREPARE checklists may also be found there.

The PREPARE guidelines cover 15 main topics as shown in Table 1 .

The PREPARE guidelines short checklist.

TopicRecommendation
1. Literature searches□ Form a clear hypothesis, with primary and secondary outcomes.
□ Consider the use of systematic reviews.
□ Decide upon databases and information specialists to be consulted, and construct search terms.
□ Assess the relevance of the species to be used, its biology and suitability to answer the experimental questions with the least suffering, and its welfare needs.
□ Assess the reproducibility and translatability of the project.
2. Legal issues□ Consider how the research is affected by relevant legislation for animal research and other areas, e.g. animal transport, occupational health and safety.
□ Locate relevant guidance documents (e.g. EU guidance on project evaluation).
3. Ethical issues, harm–benefit assessment and humane endpoints□ Construct a lay summary.
□ In dialogue with ethics committees, consider whether statements about this type of research have already been produced.
□ Address the 3Rs (replacement, reduction, refinement) and the 3Ss (good science, good sense, good sensibilities ).
□ Consider pre-registration and the publication of negative results.
□ Perform a harm–benefit assessment and justify any likely animal harm.
□ Discuss the learning objectives, if the animal use is for educational or training purposes.
□ Allocate a severity classification to the project.
□ Define objective, easily measurable and unequivocal humane endpoints.
□ Discuss the justification, if any, for death as an endpoint.
4. Experimental design and statistical analysis□ Consider pilot studies, statistical power and significance levels.
□ Define the experimental unit and decide upon animal numbers.
□ Choose methods of randomization, prevent observer bias, and decide upon inclusion and exclusion criteria.
5. Objectives and timescale, funding and division of labour□ Arrange meetings with all relevant staff when early plans for the project exist.
□ Construct an approximate timescale for the project, indicating the need for assistance with preparation, animal care, procedures and waste disposal/decontamination.
□ Discuss and disclose all expected and potential costs.
□ Construct a detailed plan for division of labour and expenses at all stages of the study.
6. Facility evaluation□ Conduct a physical inspection of the facilities, to evaluate building and equipment standards and needs.
□ Discuss staffing levels at times of extra risk.
7. Education and training□ Assess the current competence of staff members and the need for further education or training prior to the study.
8. Health risks, waste disposal and decontamination□ Perform a risk assessment, in collaboration with the animal facility, for all persons and animals affected directly or indirectly by the study.
□ Assess, and if necessary produce, specific guidance for all stages of the project.
□ Discuss means for containment, decontamination, and disposal of all items in the study.
9. Test substances and procedures□ Provide as much information as possible about test substances.
□ Consider the feasibility and validity of test procedures and the skills needed to perform them.
10. Experimental animals□ Decide upon the characteristics of the animals that are essential for the study and for reporting.
□ Avoid generation of surplus animals.
11. Quarantine and health monitoring□ Discuss the animals' likely health status, any needs for transport, quarantine and isolation, health monitoring and consequences for the personnel.
12. Housing and husbandry□ Attend to the animals' specific instincts and needs, in collaboration with expert staff.
□ Discuss acclimatization, optimal housing conditions and procedures, environmental factors and any experimental limitations on these (e.g. food deprivation, solitary housing).
13. Experimental procedures□ Develop refined procedures for capture, immobilization, marking, and release or rehoming.
□ Develop refined procedures for substance administration, sampling, sedation and anaesthesia, surgery and other techniques.
14. Humane killing, release, reuse or rehoming□ Consult relevant legislation and guidelines well in advance of the study.
□ Define primary and emergency methods for humane killing.
□ Assess the competence of those who may have to perform these tasks.
15. Necropsy□ Construct a systematic plan for all stages of necropsy, including location, and identification of all animals and samples.

A more detailed discussion, with references and links, is available at https://norecopa.no/PREPARE , together with a downloadable pdf version of this checklist in several languages.

The guidance in this paper should be adapted to the individual research project, animal species and location. The topics in the checklist in Table 1 will not be relevant to all projects, some topics overlap, and they may have to be addressed in a different order to that in the table.

Division of labour, costs and responsibility

Some elements will be the responsibility of the animal facility itself, rather than the individual research group, since they determine the standard of the facility as a whole. However, a research project often raises questions which are not covered by the facility’s normal work routines. These include activities which have potential health and safety risks. Early and open dialogue between the facility and research group, to create a good atmosphere for collaboration, is therefore essential. For example, if a facility cannot safely conduct an experiment without structural changes or investment in new equipment, this should be discussed with the research group at an early stage, however tempting it may be to start collaboration on a prestigious project. Animal welfare and ethics committees can be a useful forum for some of this dialogue. 21 A set of general planning guidelines such as PREPARE can be used to help formulate a contract between the research group and the facility. This ensures prior agreement on two significant practical issues: the parameters to be recorded during the study, and the division of labour and costs between the facility and the research group. Failure to do this may result in lost data, making it impossible to publish the research findings, adding to the waste of resources and animal lives. An example of a contract based upon the PREPARE guidelines is given on the website.

The relationship between PREPARE and other guidelines

Over recent years, guidelines have been produced on many subjects related to the use of research animals including harm–benefit assessment, study design, capture, transport, breeding, housing, identification and marking, administration of substances, blood sampling, anaesthesia and analgesia, surgery, humane endpoints and humane killing.

The PREPARE guidelines build upon guidance that was developed at the Norwegian School of Veterinary Science over a 20-year period, 22 and they are intended to be an overarching set of recommendations to promote good practice. A comprehensive and curated global list of individual guidelines, databases, information centres and discussion forums can be found on Norecopa’s website in the 3R Guide database ( https://norecopa.no/3r-guide-database ), which is linked to the online version of PREPARE.

The European Union (EU) Directive 2010/63 refers to guidelines for education, training and competence, and for the housing, care and use of research animals. 23 Guidance documents from the European Commission, endorsed by the Member States, are a valuable source of information on these topics, 24 and may also prove to be useful to non-EU countries. For example, Appendix 1 of the Guidance on Project Evaluation and Retrospective Assessment contains preformulated questions for building a project application template, including harm–benefit assessment. 25 These topics have been embedded in PREPARE.

The relationship between PREPARE and ARRIVE

The speaker notes for ARRIVE 26 state that they ‘provide a logical checklist with all the things that need to be considered when designing an experiment’. There are, in our experience when planning animal research, a number of additional points which need to be addressed at the planning stage, but which are easily overlooked or dismissed as unimportant. This was our motivation for the construction of the PREPARE guidelines. Attention to detail not only helps promote excellent study quality and optimal animal welfare, but also the safety of humans and animals affected directly or indirectly by the work. Particular considerations highlighted in the PREPARE guidelines, which are not so prominent in the ARRIVE guidelines, include a harm–benefit assessment; health risks, waste disposal and decontamination; quarantine and health monitoring; the use of humane endpoints; the fate of the animals (humane killing, release, re-use or re-homing); and necropsy.

A Swiss study indicates that journal endorsement alone does not ensure guideline use: half of the researchers who had last published in a journal endorsing ARRIVE had never heard of the guidelines. 27 Emphasis on reporting guidelines in the EU Commission’s Guidance on a common education and training framework 28 and in recommendations produced by other authorities will hopefully improve this situation.

Concluding remarks

It is our hope that the PREPARE guidelines will draw scientists’ attention to the wide range of factors which require consideration at the planning stage. This should lead to an increase in scientific validity, reproducibility and animal welfare. Improving the quality of publications will also facilitate systematic reviews, thereby generating new knowledge through the synthesis of evidence, without the use of animals. 29 , 30

Planning guidelines have greater potential than reporting guidelines for assisting funders, regulators and ethical review committees in the assessment of applications for new projects. We therefore propose that funders make adoption of the principles in PREPARE or similar guidelines a condition of funding.

As with the ARRIVE (reporting) guidelines, the PREPARE (planning) guidelines are neither meant to be mandatory, absolutely prescriptive, nor a standard formula. Biomedical subspecialities may find it useful to produce their own supplementary guidelines, such as Australian scientists have done for osteoarthritis research 31 and the STAIR conferences 32 for stroke models. The Strategic Planning Poster from FRAME (Fund for the Replacement of Animals in Medical Experiments) provides a flowchart with good general advice on planning animal research. 33 PREPARE is designed to provide a detailed, universally relevant checklist which reduces the risk of problems, artefacts or misunderstandings arising once studies have begun. Furthermore, it can serve as the basis for a contract for the distribution of labour between the animal facility and research group. This will also reduce the risk of the researchers being unable to respond to journals’ requests for more observations in an experiment, which can lead to manuscript rejection, wasting both animal lives and human resources.

‘ It is perfectly true, as philosophers say, that life must be understood backwards. But they forget the other proposition, that it must be lived forwards. ’ (Søren Kirkegaard 1813–1855) 34

Acknowledgements

Early versions of these guidelines were inspired by the pioneering work of Öbrink and coworkers. 35 , 36 An earlier version of the contract between researchers and the animal facility was published in compendia in Laboratory Animal Science produced by the Norwegian School of Veterinary Science. 22 We thank Anton Krag, Norwegian Animal Protection Alliance, Oslo; Dr Ute Weyer, Animal and Plant Health Agency, UK; Professor Malcolm Macleod, Centre for Clinical Brain Sciences, University of Edinburgh, and the referees for their valuable advice during the preparation and review of this paper.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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CRediT author statement

CRediT (Contributor Roles Taxonomy) was introduced with the intention of recognizing individual author contributions, reducing authorship disputes and facilitating collaboration. The idea came about following a 2012 collaborative workshop led by Harvard University and the Wellcome Trust, with input from researchers, the International Committee of Medical Journal Editors (ICMJE) and publishers, including Elsevier, represented by Cell Press.

CRediT offers authors the opportunity to share an accurate and detailed description of their diverse contributions to the published work.

The corresponding author is responsible for ensuring that the descriptions are accurate and agreed by all authors

The role(s) of all authors should be listed, using the relevant above categories

Authors may have contributed in multiple roles

CRediT in no way changes the journal’s criteria to qualify for authorship

CRediT statements should be provided during the submission process and will appear above the acknowledgment section of the published paper as shown further below.

Term

Definition

Conceptualization

Ideas; formulation or evolution of overarching research goals and aims

Methodology

Development or design of methodology; creation of models

Software

Programming, software development; designing computer programs; implementation of the computer code and supporting algorithms; testing of existing code components

Validation

Verification, whether as a part of the activity or separate, of the overall replication/ reproducibility of results/experiments and other research outputs

Formal analysis

Application of statistical, mathematical, computational, or other formal techniques to analyze or synthesize study data

Investigation

Conducting a research and investigation process, specifically performing the experiments, or data/evidence collection

Resources

Provision of study materials, reagents, materials, patients, laboratory samples, animals, instrumentation, computing resources, or other analysis tools

Data Curation

Management activities to annotate (produce metadata), scrub data and maintain research data (including software code, where it is necessary for interpreting the data itself) for initial use and later reuse

Writing - Original Draft

Preparation, creation and/or presentation of the published work, specifically writing the initial draft (including substantive translation)

Writing - Review & Editing

Preparation, creation and/or presentation of the published work by those from the original research group, specifically critical review, commentary or revision – including pre-or postpublication stages

Visualization

Preparation, creation and/or presentation of the published work, specifically visualization/ data presentation

Supervision

Oversight and leadership responsibility for the research activity planning and execution, including mentorship external to the core team

Project administration

Management and coordination responsibility for the research activity planning and execution

Funding acquisition

Acquisition of the financial support for the project leading to this publication

*Reproduced from Brand et al. (2015), Learned Publishing 28(2), with permission of the authors.

Sample CRediT author statement

Zhang San:  Conceptualization, Methodology, Software  Priya Singh. : Data curation, Writing- Original draft preparation.  Wang Wu : Visualization, Investigation.  Jan Jansen :  Supervision. : Ajay Kumar : Software, Validation.:  Sun Qi:  Writing- Reviewing and Editing,

Read more about CRediT  here opens in new tab/window  or check out this  article from  Authors' Updat e:  CRediT where credit's due .

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    Programming, software development; designing computer programs; implementation of the computer code and supporting algorithms; testing of existing code components. Validation. Verification, whether as a part of the activity or separate, of the overall replication/ reproducibility of results/experiments and other research outputs. Formal analysis