A Belmont Report for Animals?

Abstract: Human and animal research both operate within established standards. In the United States, criticism of the human research environment and recorded abuses of human research subjects served as the impetus for the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the resulting Belmont Report. The Belmont Report established key ethical principles to which human research should adhere: respect for autonomy, obligations to beneficence and justice, and special protections for vulnerable individuals and populations. While current guidelines appropriately aim to protect the individual interests of human participants in research, no similar, comprehensive, and principled effort has addressed the use of (nonhuman) animals in research. Although published policies regarding animal research provide relevant regulatory guidance, the lack of a fundamental effort to explore the ethical issues and principles that should guide decisions about the potential use of animals in research has led to unclear and disparate policies. Here, we explore how the ethical principles outlined in the Belmont Report could be applied consistently to animals. We describe how concepts such as respect for autonomy and obligations to beneficence and justice could be applied to animals, as well as how animals are entitled to special protections as a result of their vulnerability.

The year 2019 commemorates the fortieth anniversary of the Belmont Report. As a foundational document in research ethics, it establishes the principles to which human research should adhere: respect for persons (generally articulated as respect for autonomy), obligations to beneficence and justice, and special protections for vulnerable individuals and populations. These principles then provide a base from which actionable and robust operational requirements-namely, informed consent, assessment of risks and benefits, and selection of subjects rationally flow. In the United States, the Belmont Report is an essential reference for institutional review boards that evaluate human research proposals. The principles outlined in the report serve to protect potential human research subjects, including those with compromised capacity to provide informed consent. Drawing on the work of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, which authored the Belmont Report, many federal agencies and private and public institutions have adopted a uniform set of regulations known as the "Common Rule," which offers specific protections for children, incarcerated individuals, and pregnant women and their fetuses. 1 The development and publication of the Belmont Report followed concerns about human research, including examples detailed in Henry Beecher's 1966 paper "Ethics and Clinical Research," which revealed that human research was frequently conducted with insufficient attention to informed consent, risks to participants, or sound ethical justification. 2 By 1972, news reports exposed concerns about the fortyyear-long U.S. Public Health Service Syphilis Study at Tuskegee. Researchers did not obtain informed consent from the African American men targeted for inclusion in 21 replacement (e.g., the replacement of all animals), 11 reduction (e.g., a reduction of the number of animals used in a study to what is considered minimally necessary for adequate statistical power), 12 and refinement (e.g., attention to general wellbeing rather than just reduction in procedure-generated stress or distress). 13 However, these changes have not occurred universally, and the 3Rs framework still does not reflect a set of principles by which to judge the ethical permissibility of proposed research conduct. 14 The 3Rs framework assumes the necessity of animal research, reflecting the prevailing "science first" attitude outlined by Russell and Burch, as well as a general presumption that, when in conflict, human interests outweigh animal interests.
Recently, there have been limited changes in animal research policy, reflecting shifts in attitudes, and notably, a critical reexamination of the presumption that all research with animals is justified by benefits for humans. For example, following substantial public controversy and a 2010 Congressional request, the NIH commissioned the formation of an Institute of Medicine (IOM) Committee on the Use of Chimpanzees in Biomedical and Behavioral Research. Although the IOM Committee was asked to offer guidance only on the scientific necessity of chimpanzees in biomedical and behavioral research, it determined that assessment of the necessity of chimpanzee research could not fully avoid ethical considerations. Though its report left numerous moral questions about animal research unanswered, 15 the Committee concluded that chimpanzees are largely unnecessary to ongoing and future research endeavors. 16 By 2013, NIH phased out all chimpanzee research protocols that did not satisfy the Committee's principles and corresponding criteria. In November 2015, in part because of changes in the conservation status assigned captive chimpanzees by the U.S. Fish and Wildlife Service, NIH announced it would no longer support biomedical research on chimpanzees. 17 Public concerns and attention to animal research policy have also extended to other species. In 2018, Senator Cory Booker introduced legislation in the U.S. Senate that would seek to prevent all nonhuman primate research independently considered to be unnecessary or unethical. 18 Numerous scientists, legal scholars, and other professionals endorsed the legislation. Similarly, as a result of public opposition and Congressional action, maternal deprivation and addiction experiments involving monkeys, fatal experiments on dogs and cats, and some other animal experiments have come under increased scrutiny and, in some cases, these experiments have been halted. 19 Such changes in policy and practice reflect growing public sentiment. Roughly half of Americans think that medical testing on animals is morally unacceptable, and public opposition to animal research has steadily increased over the past decade. 20 According to a Gallup Poll, approximately one-third of Americans believe that animals should have the same rights as people to be free from harm and exploitation. 21 Outside the U.S., there has been similar attention to animal research policy. In 2010, the EU Parliament called for immediate restriction on the use of great apes in research, and for phasing out the use of all nonhuman primates. Numerous countries in Europe and around the world have enacted total or partial bans on the use of some animals in research. 22 A number of high profile reports on research with nonhuman primates have been issued internationally in the last decade, including the 2006 UK Weatherall Report 23 and the European Commission's SCHER report. 24 However, both of these reports simply presumed the "necessity" of research with nonhuman primates and failed to provide a meaningful and impactful analysis based on established ethical principles. These reports, like others, have neglected the fact that research deemed as necessary raises the need for but does not replace 22 ethical considerations or imply that such research is ethical. Furthermore, although some attention in the U.S., Europe, and elsewhere has focused on nonhuman primate and nonprimate species such as dogs and cats, decisions involving other animals also deserve broader and more consistent ethical guidance, given similarities in capacities, vulnerabilities, and corresponding moral questions across species.

Grounds for Extending Human Research Principles to Animals
To date, no expansive, sustained, and organized effort like that of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research has addressed the use of animals in research. No document regarding animal research has approximated the scope and influence of the Belmont Report despite advancements in our understanding of animals' emotional and intellectual capacities. 25 As described elsewhere, animal experimentation is arguably plagued by many moral problems analogous to those Henry Beecher described: that is, issues related to consent, harm, and lack of benefit to the experimental subject. 26 Within human populations, there are significant differences in mental capacity, moral aptitude, and other qualities that have been used historically to justify differences in the presumed moral status and treatment of humans and other animals. As other authors have argued, no compelling argument for this view has been identified. 27 Nonetheless, there is a universal expectation that humans with unequal gradations of these qualities will be treated in accordance with the same basic underlying principles that are broadly recognized within biomedical ethics, as well as in other areas of society. 28 Using widely recognized and accepted principles to guide research decisions offers a distinct advantage over other approaches. Understood as fundamental moral commitments, principles serve as a foundation for reasonable and internally consistent analysis and action, although their specification may differ from one context or situation to another.
The importance of similarly principled changes in animal research ethics is highlighted by reflection on the current state of the foundations of research ethics (writ large to include the scientific use of both humans and other animals). Current standards in research ethics for humans and for animals are significantly different, and this differential treatment exists despite some of the clear and relevant similarities between potential human and animal research subjects. Appeals to anthropocentric speciesism are the most common justification for treating animal subjects differently, but they have consistently failed to stand up to philosophical scrutiny. 29 Many have scientifically justified the use of animals in research by citing their similarities to humans, while neglecting how the common potential for vulnerability and mental and physical suffering influences ethical justifications. Humans and other animals have interests in self-preservation, living free of unnecessary constraints, and meeting their basic and complex needs. Like humans, other animals are susceptible to having their basic interests discounted. Additionally, characteristics determining quality of life are relevant to the consideration of an individual's interests, regardless of species classification, and qualification for special protections. 30 Nothing other than ideological bias and serious human fears of death and disease can motivate the consistent prioritizing of human interests over the relevantly similar interests of other animals. These fears and biases do not make for sound ethical judgment. A very basic insight from moral philosophy is that an objective ethic is not compatible with arbitrary distinctions, values, or standards. This, indeed, lies at the foundation of philosophical critiques of moral theories like ethical egoism, and such prejudices as ableism, classism, ethnocentrism, heterosexism, racism, and sexism. Similarly, the differential treatment of human and animal research subjects is grounded in arbitrary distinctions, values, and standards. Such differential treatment does not just adversely affect the objectivity of animal research ethics. The edifice of human research ethics is also built on these arbitrary distinctions, values, and standards. Until this situation is appropriately rectified, the objectivity of human and animal research ethics will remain in question.
In light of these issues, here, we assume that justifications for significant differences between human and animal research regulations based on a claim that humans have a higher moral status are mistaken. Accordingly, we assume that animal interests should be given approximately equal moral weight as human interests and therein consider the implications of extending human research principles to animals. We describe how widely recognized concepts within biomedical ethics, such as respect for autonomy and obligations to beneficence and justice (as reflected in the Belmont Report), could be applied to animals, as well as how animals could be entitled to special protections as a result of their vulnerability. 31

Respect for Persons (Autonomy) and Informed Consent
Within the Belmont Report, "respect for persons" incorporates two separate but related moral requirements: to acknowledge autonomy and to protect those with diminished autonomy. Though it is possible that the Commission had other intentions in selecting the principle of "respect for persons," 32 its documented intent "requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them." 33 Autonomy commonly refers to the capacity for self-determination. It is both a capacity for self-rule, and an ability to protect or further one's own interests. As a result, it is intimately related to vulnerability. Subjects who lack autonomy lack the ability to adequately represent their own interests, which makes them vulnerable to exploitation and harm.
There are many open questions about the degree to which humans and other animals display autonomy or autonomous action. 34 It is now generally accepted that animals-including chimpanzees, crows, elephants, macaques, orcas, and wolves, among others-form daily goals and order their behavior accordingly. 35 Alliances or coalitions, displayed by animals such as chimpanzees, dolphins, and others, reflect goals and planned behaviors that extend beyond momentary concerns. Older members of these animal communities behave in ways that satisfy their preferences, which effectively track what they value and their basic interests. 36 Many animals also provide for their young, indicating that they also track the preferences or interests of animals in their care. 37 These behaviors and attendant capacities evidence a capacity for self-determination. In humans and animals, the capacity for self-determination can change acutely or chronically over the course of a lifetime as a result of neurological, psychological, and emotional maturation or degeneration, or other changes in aptitude. Nonetheless, selfdetermination, of varying degrees, is essential to wellbeing in humans and many animals, and interference with self-determination can lead to physical and mental 24 distress, as well as disorders such as learned helplessness, posttraumatic stress disorder, and depression. 38 As the Belmont Report indicates, autonomy is also characterized by an ability to make informed decisions free of undue influence. External "circumstances that severely restrict liberty," as in the case of prisoners, can adversely impact one's ability to exercise autonomy. 39 Sources of fear and other forms of intimidation, such as captivity, can limit the expression of self-determination.
Though it is important to acknowledge capacities like autonomy and their implications, as the Belmont Report points out, it is as important to protect those with diminished autonomy, whether such diminishment is due to factors that are intrinsic or extrinsic to the individual. In such cases, two general rules apply. To the degree they are able, even individuals with compromised autonomy should be provided opportunities to choose what will or will not happen to them-a standard of welfare that is also increasingly recognized as applicable to animals. 40 However, to the degree that individuals are incapable of making informed decisions, they should be protected from harm.
The application of respect for persons in human research typically takes the form of seeking and securing informed consent before inclusion in a research study. Informed consent requirements generally include three elements: the delivery of sufficient information, comprehension, and voluntariness. 41 Guidelines provide opportunities for those with diminished capacities to represent their own interests in the decisionmaking process by respecting "the objections of…subjects," 42 allowing individuals to dissent even if they are not deemed to have the capacity to provide informed consent. In some cases, surrogate decisionmakers charged with choosing what is in the potential research subject's best interests may offer permission on the individual's behalf. Regardless of the circumstance, coercion, in which an individual is threatened with harm, and undue influence are prohibited: "Inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable." 43 There remain unanswered empirical and conceptual questions about autonomous capacities in animals. Human-animal interactions, and the crudeness of our understanding of animals, are unlikely to permit meaningful informed consent. Therefore, it is important to consider whether concepts used in human research such as dissent, assent, and surrogate decisionmakers are sufficient for formulating decisions about the use of animals in research.
Within pediatric research ethics, researchers and regulators increasingly recognize that the sustained dissent of even very young children should be respected, unless perhaps the study promises direct benefits that are otherwise unavailable. This requirement is motivated by obligations to avoid harm associated with disrespecting the corresponding level of self-determination of the child. 44 Elsewhere, requisite capacities needed to express sustained dissent have been described. 45 Briefly, young children who express sustained dissent (1) have the capacities to experience pain or distress; (2) can anticipate its occurrence; and (3) can express a preference that the pain or distress stop (or not occur). Many animals also possess these capacities, as evidenced by relevantly similar neurological structures, escape or avoidance behaviors, and the expression of behavioral preferences. However, an absence of escape or avoidance behaviors does not necessarily indicate an absence of dissent. 46 Like children, animals are more likely to adapt or suppress certain behaviors in an attempt to protect themselves from individuals in a position of power or influence-further underscoring their vulnerability. Captive conditions and other practices used during the course of laboratory research interfere with animals' capacities to express dissent, deepening their vulnerability to manipulation and coercion. Therefore, in the current context, absence of sustained and recognizable indicators of dissent alone is generally not a sufficient criterion for permitting research with animals to proceed.
There are unresolved questions about whether animals can express assent in ways humans reliably understand. 47 Assent, compared with dissent, may be considered a more morally rigorous requirement for participation in research or other activities. As an affirmative expression of agreement, assent implies active participation, whereas an absence of dissent can suggest passive or confused participation and therefore less certainty about a willingness to participate. However, in most cases involving animals, it is unlikely that, even in the best of circumstances, they could make an informed decision about the potential risks or benefits of research generated by perceived human needs.
The potential use of surrogate decisionmakers in animal research also presents special difficulties. First and foremost, consent from human surrogate decisionmakers is always suboptimal compared with consent from a capable research subject. However, current regulatory guidelines involving individuals who cannot provide consent (e.g., young children) allow for the input of a surrogate decisionmaker (e.g., at least one parent) who can provide or refuse permission on the child's behalf. In these cases, respect for sustained dissent and assent of the child (if they are capable of providing it) are also required. However, as outlined above, the case of animals raises particular challenges related to dissent and assent. Since convincing arguments for why nonbeneficial research is acceptable in those who cannot provide consent are lacking, a conservative standard is required.
In practice, respect for the autonomy and vulnerability of animals would require respecting their freedom and choices to the extent that they are capable of asserting their decisions, and to the extent we are capable of understanding their choices. At the very least, the following criteria would be required: an absence of punishment, coercion, restraint, or confinement; real options and alternatives appropriate to the individual and their normal circumstances; and surrogates who are not unduly compromised in their capacity to represent the animal's interests by their own personal or professional conflicts of interest. Surrogate decisionmakers should also be capable of making an independent, informed decision free of coercion or undue inducement. If a surrogate cannot reliably understand the cognitive, ethological, and ecological factors required for the health and wellbeing of the individual animal, and impartially represent their individual interests, a cautionary approach would require avoiding enrollment in research.

Beneficence and Assessment of Risks and Benefits
According to the Belmont Report, the principle of beneficence is interpreted as an obligation. Beneficence is often taken to mean "doing good," but in the Belmont report, the principle is based on two general rules: (1) do no harm (nonmaleficence; a principle believed by many scholars as also embodied in the Hippocratic Oath); and (2) maximize possible benefits while minimizing possible harms. 48 These rules, interpreted literally, would clearly be in tension, as there is a difference between not harming and merely minimizing harm (or risk of harm). However, in human research, the principle of beneficence is operationalized through a 26 requirement that possible risks to participants are minimized and that there is a favorable benefit/risk ratio for participants.
The dual requirement that harms are minimized and that there is a favorable benefit/risk ratio is noteworthy, since either rule by itself would be insufficient. For example, if the only requirement for the principle of beneficence were that the risk of harms be minimized relative to proposed research, some human research could be deemed permissible even when potential harms significantly outweigh potential benefits. Conversely, having only a requirement for a favorable benefit/ risk ratio without an obligation to minimize harms would allow research that included preventable or unjustifiable harms to proceed. Thus, it is only in tandem that these two rules (when properly executed) ensure that undue and preventable harms are avoided.
The existing regulatory situation is quite different for animals. For example, the 3Rs framework utilized by most institutional review committees often leads to claims that animal research does require benefit/risk analysis, since funding sources are expected to assess benefits in their funding decisions and institutional review committees attempt to reduce harms associated with specific protocols. 49 However, in the absence of a direct comparison of potential harms and benefits, problematic research resulting in significant harms to animals can readily proceed. This problem is particularly exacerbated in exploratory research involving animals, in which purported benefits may only amount to faint promises of discoveries. In practice, harms to animals are afforded comparably little weight. 50 The situation reflects a problem that the Belmont Report (and subsequent regulatory policies) avoided by including a dual criteria notion of beneficence.
The IOM Committee's finding regarding chimpanzees provides a clear example of the failings of the current approach used in animal research. The Institutional Animal Care and Use Committees (IACUCs) at institutions performing research with chimpanzees completed their official duties in reviewing research protocols, minimizing harms relative to proposed protocols. Nevertheless, most or all of federally funded chimpanzee research was ultimately deemed unnecessary, and presumably scientifically and ethically unjustified, by the IOM Committee. In this case and others, the absence of a direct comparison of potential harms and benefits, or a pro forma exercise to meet review committee expectations, would continue to permit ethically problematic research.
Though duties of nonmaleficence and beneficence are alluded to in some animal research guidelines, current provisions do not afford sufficient attention to these principles. For example, the most recent edition of the Guide for the Care and Use of Laboratory Animals requires that, for certain research, "the IACUC is obliged to weigh the objectives of the study against potential animal welfare concerns." 51 Recently, American and European organizations overseeing the use of animals in research released a two-part set of recommendations for benefit/risk analysis in animal research. 52 However, as noted by Anna Olsson and colleagues, the report "has no legal status and is less than clear on a number of points." 53 Individuals responsible for reviewing protocols involving animals still have no clear framework by which to prohibit research with an unfavorable benefit/risk profile. As a consequence, full rejection of a protocol is rare; instead, protocol review commonly focuses on modifications along the lines of the 3Rs that may still fail to create a favorable benefit/risk profile. Sincere attention to the principle of beneficence in animal research would, in contrast, necessarily include: (1) a full assessment to the extent possible of actual and potential harms; (2) a full assessment of potential benefits; and (3) an approach that allows for a transparent and rigorous direct comparison of the risk of harms and potential benefits, along with conditions on what benefit/risk profiles are acceptable.
Within human research, the principle of beneficence requires that the nature and scope of physical, psychological, social, and other harms be considered. However, consideration of a full scope of harms is far less common or perhaps even possible in the general practice of animal research. If considered, risks associated with animal research would include, but not be limited to: harms associated with breeding and transport; separation from parents, siblings, and other conspecifics; an inability to control access to that which meets one's own basic needs; a lack of safety and security; thwarting of an animal's preferences; an inability to fulfill one's full developmental potential; deprivation of a normal, species-appropriate, natural environment; and being killed. 54 In particular, confinement and captivity in themselves introduce significant risk. 55 Certain forms of captivity are inherently harmful to animals because these conditions deprive them of ethologically appropriate environments and activities, of liberty and movement, and of basic psychological and social needs, including stimulation, play, and family. Some forms of captivity also impose experiential harms, including stress, boredom, pain, fear, and loss. Currently, within the practice of animal research, the risk-that is, the magnitude and probability-of all of the aforementioned harms is often severe and certain. 56 Within human research, measured risks and benefits may also include those that affect "the families of the individual subjects, and society at large (or special groups of subjects in society)." 57 Similarly, for animals, in addition to the harms to prospective subjects, other potential harms should be considered. For instance, in the case of free-ranging animals or descendants of 'wild-caught' animals, the direct environmental costs as well as the indirect environmental costs of supporting these practices should be included in any risk assessment.
In contrast to much research on humans, it is rare for justifications offered for animal research to be focused on benefits to individual animals included in experiments. 58 No clear moral justification for this position is offered in existing laws, policies, or guidelines, though nonspecific, perceived future benefits to humans are often cited as a rationale for the use of animals in research. As in the case of human research, it is important for institutional review committees to ensure research proposals do not exaggerate potential benefits of research. Though it is impossible to predict the potential value of various scientific discoveries, the possibility of unexpected future benefits also exists for research involving humans. Nonetheless, such uncertainty has not prevented ethics committees from requiring a realistic assessment of potential benefits as part of the approval process for human research proposals. Similarly, uncertainty should not be an impediment to conducting a realistic assessment of potential benefits (or risks) for research involving animals.
The Belmont Report also goes farther, suggesting "the assessment of risks and benefits requires a careful arrayal of relevant data, including, in some cases, alternative ways of obtaining the benefits sought in the research." 59 Even if research has in the past resulted in a particular benefit such as an advancement of knowledge, it is in many cases possible that the benefit could have been achieved through some other less harmful means. It is similarly important for an assessment of benefits 28 of research on animals to accurately reflect whether such benefits could only be procured through the proposed research, or whether anticipated benefits could be achieved via alternative methods now or in the future. 60 Identifying an appropriate approach for a rigorous comparison of potential harms and benefits is arguably the most conceptually challenging aspect of benefit/ risk analyses. Even in the case of inter-human comparisons, there is rarely agreement about how to weigh particular risks against particular potential benefits. For individuals who can provide consent, individual differences influence a willingness, or lack thereof, to undergo specific risks in anticipation of potential benefits. The case is made more difficult when an individual is unable to provide consent. Nonetheless, even when conflicts occur between commitments to the production of societal benefits and risks of harms to individuals, human subjects are commonly protected from serious harms including severe pain, psychological distress, permanent disability, suffering, death, and prolonged captivity-factors which are commonly experienced by many animals used in research. A commitment to nonmaleficence would require that animals be similarly protected from serious harm. However, in current practice, potential benefits to humans, and even the scientific question itself, are given much more weight than known or potential harms to animals. As other authors have argued, a principle of equal consideration of interests would require that harms to animals should be weighed equivalently to relevantly similar harms in humans. 61 Likewise, potential harms to humans from ungeneralizable or misleading findings should also be included in a full benefit/risk assessment. 62

Justice and the Selection of Subjects
"Who ought to receive the benefits of research and bear its burdens?" This is the question of justice posed by the Belmont Report. 63 Attention to justice emerged as a result of perceived injustices associated with the systematic selection of individuals for research because of their easy availability, socioeconomic status, compromised position, or manipulability. For example, in the nineteenth and twentieth century, economically disadvantaged patients seeking healthcare within public institutions bore the burdens of research, whereas wealthier private patients reaped its benefits. Later in the twentieth century, researchers systematically targeted prisoners in Nazi concentration camps, African American men living in Tuskegee, Alabama, the Havasupai of the Grand Canyon, hospitalized children with cognitive disabilities, and other vulnerable or exploited populations. 64 Though the harms imposed on these disparate populations ranged from deceit to torture, each abuse has contributed to an historical background for how "conceptions of justice are relevant to research involving human subjects." 65 Consideration of the principle of justice within the Belmont Report has given rise to moral requirements for fair procedures and outcomes in the selection of subjects, including attention to social justice: "It can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions." 66 Generally, individuals, especially those with impaired autonomy, should not be subjected to risks disproportionate to the benefits of the research, and if individuals are members of groups unlikely to benefit from the research, such individuals may need to be excluded from research altogether. 67 Currently, animals are deliberately and commonly chosen for research as a result of their easy availability and manipulability, as well as institutional and cultural biases in society. Like human populations who were historically and systematically targeted, animals also have a "frequently compromised capacity for free consent." 68 Animals overwhelmingly bear the burdens of research without accessing the benefits. Though vulnerable human populations, including children and prisoners, are protected as a result of their compromised abilities to provide informed consent, animals are currently excluded from similar protections despite possessing similar vulnerabilities.
The concept of vulnerability is widely used but not well-defined in ethical guidelines. The Belmont Report, like many other statements, guidelines, and codes for research ethics, does not define vulnerability. It lists some of the groups or individuals who can be considered vulnerable subjects, including "racial minorities, the economically disadvantaged, the very sick, and the institutionalized," 69 all of whom, historically, were frequently exploited because they were oppressed, easy to access, powerless, or had no one to advocate for their rights and protection. The Common Rule also lists prisoners, children, and pregnant women and their fetuses as groups requiring special protections.
The Council for International Organizations of Medical Sciences (CIOMS) provides perhaps the most comprehensive definition of vulnerability to be found in research codes. 70 Vulnerability is defined as either (1) lacking the traits of an autonomous person (the incapacity to protect one's own interests, i.e., vulnerability is defined as intrinsic to an individual), or (2) being unable to act autonomously due to constraints on one's freedom to act (the inability to protect one's own interests, i.e., vulnerability is defined as the result of extrinsic conditions). A previous iteration of the CIOMS guidelines stated that "vulnerable persons are those who are relatively (or absolutely) incapable of protecting their own interests. More formally, they may have insufficient power, intelligence, education, resources, strength, or other needed attributes to protect their own interests." 71 Under this substantive understanding of vulnerability, it is clear how both children and prisoners are vulnerable. The former group is primarily vulnerable because they fundamentally lack the ability to comprehend and consent to research, or to advocate for their own interests, and the latter is primarily vulnerable because the very conditions of captivity and institutionalization produce external constraints on their autonomy and ability to make free, uncoerced choices and protect their own interests.
Recent work attempting to better understand the concept of vulnerability, as it applies to humans in research and beyond, can be used to further demonstrate how animals are vulnerable subjects in the context of research. 72 Catriona Mackenzie, Wendy Rogers, and Susan Dodds have developed a taxonomy that captures the variety of ways in which the concept of vulnerability is deployed. 73 They identify three types of vulnerability: inherent, situational, and pathogenic. Inherent vulnerabilities are intrinsic features of existence to which humans and animals are susceptible as biological creatures (e.g., illness, disease, accidental injury, pain, suffering, and death), while situational vulnerabilities are extrinsic and arise 30 from the context or situation in which individuals or groups find themselves. Pathogenic vulnerabilities form a subset of situational vulnerability and can be brought about either through morally dysfunctional relationships, or when attempts to remedy existing vulnerabilities instead worsen them.
Animals in research are vulnerable in all of these ways. As biological creatures they are inherently or intrinsically vulnerable; their embodiment, basic survival needs, and more complex needs endow a susceptibility to harm that can be realized during the course of research. As in the case of humans, animals' experiences matter to their wellbeing. Since many animals have complex needs and are susceptible to suffering if their needs aren't met, a just approach necessitates that their fundamental needs are treated as similar to those of humans-with full and equal consideration. Treating these animals otherwise, simply because of their easy availability and convenience, undermines obligations to justice. 74 The treatment of animals in society, including in the current research environment, also exposes animals to situational vulnerability. Even animals with the potential to develop the cognitive capacities necessary to make autonomous decisions and protect their own interests are typically deprived of these capacities in captivity, for the same reasons that involuntarily captive and institutionalized humans lack them: the conditions of captivity act as an external constraint on their abilities to act to protect their own interests. Such constraints include their complete dependence on their captors, as well as the use of coercion and inducements to attain compliance or cooperation.
Animals are also pathogenically vulnerable. Motivations for including them in research reveal at least one source of their pathogenic vulnerability. Animals are often selected as research subjects because of asymmetrical power relations, dependency, and species-based discrimination. Human institutions systematically embed a failure to recognize many animals as entities with intrinsic value, instead treating them as expendable instruments for human convenience. The increasing use of genetically modified animals in research is a particularly profound example of pathogenic vulnerability. Humans develop and breed these genetically modified individuals in an attempt to replicate or simulate a human medical condition, with the intention of subjecting them to the harms of research.
In light of the dependent position of many animals in society, their intrinsic and extrinsic vulnerabilities, and an inability to provide informed consent, such animals should be treated as vulnerable subjects. Within human research, vulnerable subjects typically cannot be exposed to risks exceeding those encountered in normal daily life in safe environments (i.e., minimal risk) or a minor increase over minimal risk, particularly when there is no direct benefit to the individual. The Belmont Report does not provide direct ethical guidance for nontherapeutic research with vulnerable subjects, such as children, that exceeds a minimal risk standard. 75 The Common Rule restricts such research, but does not prohibit it so long as it is likely to result in generalizable knowledge about a "serious problem affecting the health or welfare" of the individual's "group" (in the case of a child, the group would be children with the condition targeted by the research). 76 Studies that involve more than a minor increase over minimal risk, with no prospect of direct benefit for the individual who cannot provide consent, must be referred to the federal government, which can convene an expert panel to review the research proposal. If approved, such studies typically require multiple permissions, including the permission of 31 each parent and the assent of the child in the case of research involving children. Some have proposed that a similar system could be invoked for animals. 77 However, such approaches may not be morally sufficient to guide decisions about the use of animals in research.
Animals are in some ways more vulnerable, as individuals and as a class, than human populations who cannot provide informed consent. For example, whereas a parent or guardian who represents a child's best interests can provide permission on their behalf (sometimes with a child's assent), it is much more difficult for a human to represent the interests of an animal, since many humans seem not to understand the needs, desires, or interests of other animals as well as they can (presumably) understand other humans. 78 There are possible exceptions to this, such as companion animals, whom conscientious guardians may know well. 79 However, generally, these differences suggest that the risk threshold for research involving animals should be as low as, or lower than, the risk threshold mandated for vulnerable human populations, including children. 80 It would also suggest a need for greater certainty that the risk threshold is not exceeded. A cautious view would require that if animals cannot consent or assent, almost no form of known harm-particularly serious harm-is acceptable. Permissible research might include that which might provide a direct benefit to the individual (with a favorable benefit/risk profile), in the absence of dissent, as well as permission from an appropriate surrogate decisionmaker. As with surrogate decisionmakers for humans, knowing and understanding an individual's interests, needs, and preferences is necessary but not sufficient to represent that individual's best interests.

A Way Forward
The principles outlined in the Belmont Report do not operate in isolation but in concert. Each represents a crucial dimension of the moral landscape of human research. Here, we have suggested how these enduring principles together could be applied to decisions about the use of animals in research, which-like human research-has historically been plagued by inconsistencies and moral controversy.
Extending and adapting the principles outlined in the Belmont Report to animals would take into account animals' preferences, interests, and vulnerabilities, and therefore have a significant impact on the use of many animals in research, just as a similar approach has influenced human research. Acknowledging the vulnerability of some human research subjects, and protecting them from exploitation, has had a significant impact on the permissibility of research with some human populations. It is difficult to predict what the full effects of acknowledging and acting in accordance with the vulnerability of animals might be, but as is true in the case of vulnerable humans, the possibility of producing undesirable consequences for the conduct of research does not by itself end the moral debate. Indeed, restrictions on research with vulnerable humans has forced researchers to find other ways of doing research with consenting subjects, and further restrictions on animal research can be expected to force change as well. However, it is a logical fallacy to argue that a claim is false or implausible because of its undesirable consequences. As we have indicated, there is ample evidence that many animals are vulnerable in the same ways that some humans are vulnerable. If we are to be 32 morally consistent, those similarities will matter, and figure into any calculations about the moral permissibility of using animals in research. As in the case of humans, it is also important to address the very factors that lead to situational and pathogenic vulnerability in the first place.
One way forward might involve reconceptualizing and restructuring animal research to be more akin to human clinical research. Such an approach involves 'animal patients,' who may be considered 'natural' models for human disease since they spontaneously develop a condition or disease analogous to that found in humans. 81 Rather than being genetically modified or bred for the sole purpose of experimentation, and housed in laboratory conditions, animal patients live in homes with noninstitutional human caregivers and guardians. They can be enrolled into a clinical trial in a way that is analogous to the way human patients are enrolled into multicenter clinical trials. That is, when animal patients present to a veterinarian and are diagnosed with a condition or disease of interest for which experimental subjects are being sought, they could be offered participation in the research. If the animal's guardian consents to their becoming a research participant, they could remain in the guardian's care, and depending on the nature of the research, they could continue to reside in their own home environment while participating in the research. 82 The requirements for surrogate consent in this type of research would be similar to those designed to protect children and other vulnerable persons, the most important being that the consent of a guardian alone would not be enough to justify the subject's inclusion in research. The research would also need to satisfy other ethical conditions, including the minimization of risk and ensuring a favorable benefit/risk ratio for the patient-that is, the actual animal patient, and not hypothetical humans, would have to enjoy some benefits (or minimally, likely benefits) in exchange for bearing the risks and burdens of the research. A surrogate should also be able to withdraw consent at any time during the relevant study.
The ethical benefits of such an approach include a substantial shift in the balance of burdens to benefits for animals involved in research. Individual animals could benefit by receiving a potentially effective experimental treatment (if potential harms are minimized); animals involved in research would no longer be routinely killed; otherwise healthy animals would not be exposed to alien diseases; and nonhuman species could also benefit from enhanced veterinary knowledge about treating naturally occurring diseases. Additionally, the many burdens, vulnerabilities, and sources of experimental confounding imposed by captivity and confinement would be significantly mitigated.
Other approaches could also align with the principles outlined in the Belmont Report. These could include noninvasive, observational research on animals in their natural environments and data collection by noninvasive means in natural environments, the use of tissue stored in tissue banks, and other data and materials collected for therapeutic purposes. Additionally, efforts could be made to increase participation in research by humans with the capacity to provide informed consent. Such efforts would better align with the concept of social justice outlined in the Belmont Report; specifically, that there should be an order of preference in the selection of classes of subjects that is protective of the most vulnerable members of society. Finally, research priorities and funding should favor innovation that does not include animals or other individuals who cannot consent to research.

Conclusion
Scientific knowledge about the capacities of animals increasingly demonstrates that they possess ethically significant capacities like autonomy/self-determination, and capacities to experience pain and psychological distress that are relevantly similar to human capacities. We have also argued that the vulnerability of animals in research is similar to the vulnerability of some humans in the context of their use as potential research subjects. Together, the ethically significant capacities of animals and their vulnerability as research subjects warrant more protections from the harms of research than current regulatory schemes and guidelines provide. Nothing less than ethically-grounded, principled guidelines, similar to those found in the Belmont Report, can adequately address the ethical inconsistencies and inadequacies of research with animals.