Populations in Research Requiring Additional Considerations and or Protections

Populations in Research Requiring Additional Considerations and/or Protections Introduction The National Bioethics Advisory Committee (NBAC 2001) defines vulnerable subjects as persons who "have difficulty providing voluntary, informed consent arising from limitations in decision-making capacity…or situational circumstances…or because they are especially at risk for exploitation." Many of the regulations and discussions in bioethics that surround protecting human subjects in research are reactions to cases now classified as unethical research practices. Many of these cases involved mistreatment of individuals or groups of individuals now referred to as vulnerable populations, or populations requiring additional considerations and/or protections. Some case examples include: Jewish Chronic Disease Hospital Study U.S. Public Health Service (PHS) Syphilis Study at Tuskegee Nazi Medical Experiments Tearoom Trade Study Willowbrook Hepatitis Study In these cases, the research subjects were, for one reason or another, incapable of protecting their own interests. A lack of an ongoing informed consent process contributed to their vulnerability and allowed these events to occur. The events represent a checkered history and might lead one to ask why vulnerable populations are included in research at all. However, including vulnerable populations is important because in many cases, it is the source of their vulnerability which researchers are attempting to better understand, or to devise ways to mitigate, reduce, accommodate, focus efforts on, or prevent. The question of whether to include a vulnerable population in research leads to a more nuanced question. Once it has been answered affirmatively that it is permissible to conduct research with the identified group, the next step is to ask whether the research could include a less vulnerable population instead, and still answer the research question. One example is research on children. As noted by the National Commission (1977), “The argument in favor of conducting research involving children rests on…the consequences of not conducting research involving children in those instances. Such consequences might include the perpetuation of harmful practices, the introduction of untested practices, and the failure to develop new treatments for diseases that affect children.” Once the question of whether to include a potentially vulnerable population or those requiring additional protections and/or considerations is resolved, the challenge becomes understanding the details of these groups and their potential vulnerabilities. Learning Objectives By the end of this module, you should be able to: Describe the different sources of vulnerability. Distinguish between vulnerable populations in research who are specifically protected in the federal regulations and those who are not. Identify additional protections for vulnerable populations who are not specifically protected in the federal regulations. Explain the effect on autonomy, beneficence, and justice that may arise due to research on vulnerable individuals or groups. Who is vulnerable? Individuals may be considered vulnerable because they do not have the decision-making capacity to provide voluntary informed consent, as in the case of children or the cognitively impaired, or because of the situation they are in (such as, being incarcerated or institutionalized). The following are examples of groups that are often considered vulnerable populations or in need of additional protections or considerations in research: Pregnant women Human fetuses Neonates Prisoners Children Individuals with physical disabilities Individuals with mental disabilities or cognitive impairments Economically disadvantaged Socially disadvantaged Terminally ill or very sick Racial or ethnic minorities Institutionalized persons (for example, persons in correctional facilities, nursing homes, or mental health facilities) These groups require additional consideration and/or protections. They can also be considered potentially vulnerable because they may not be able to make informed decisions for themselves, they may be in situations in which they can easily be manipulated, or they may be a convenient and readily available study population. Vulnerable to what? Before examining the details of certain groups, it is important to understand what one means by the term "vulnerability" as it relates to research. Historically, those who are vulnerable have been subjected to one or more of these four common types of abuses in human research. Common Types of Abuses in Human Research Type of Abuse Explanation Physical Control Subjects who are physically forced to participate in research. This represents a complete lack of voluntariness. When subjects have no choice about whether or not to participate in research and are under the complete physical control of the researchers. Coercion The use of a credible threat of harm or force to control another person. This also represents a lack of voluntariness. Undue Influence The misuse of a position of confidence or power to lead or influence others to make a decision they would not otherwise make. Manipulation The deliberate design and management of conditions or information intended to lead subjects to make a decision they would not otherwise make. Examples include lying about information, withholding information, or exaggerating information. These abuses exist along a continuum of severity with physical control being the most severe and undue influence and manipulation being the least severe (Nelson and Merz 2002, V6980). However, none of these types of abuses are appropriate in the context of research on human subjects. These four abuses can give rise to exploitation, or the action of treating someone unfairly in order to benefit from them in some way. In the context of research, manipulation might be treating subjects in an unfair way in order to benefit from their participation in the research and using the individual subject merely as a means to conduct the research. Sources of Vulnerability: Intrinsic Factors and Attributes Historically, sources of vulnerability are based on an intrinsic factor of an individual or group. This way of understanding sources of vulnerability has affected how the different guidance documents and regulations are written. Read more about how different guidance documents discuss and define vulnerability in research… A common theme in the guidance documents is that vulnerability is primarily described as arising from intrinsic factors, characteristics, or attributes of the individual that, when present, confer the label "vulnerable" to the individual or group. Sources of Vulnerability: Situational Considerations Federal regulations have defined vulnerable populations using a group-based approach and specifically require additional protections for children, pregnant women (and fetuses and neonates), and prisoners (Protection of Human Subjects 2018). This method of classifying vulnerability does not account for situations in which an individual might be vulnerable (such as, someone who is acutely ill). Additionally, the group-based classification of vulnerability does not adequately address when an individual has multiple sources of vulnerability (such as, pregnant minors, individuals with mental illness who are also homeless, and other multiple-category individuals). The NBAC (2001) provided an alternative way of thinking about and analyzing vulnerability. The Commission (NBAC 2001) proposed a more nuanced definition of vulnerability in the context of research: In general, persons are vulnerable in research either because they have difficulty providing voluntary, informed consent arising from limitations in decision-making capacity…or situational circumstances…or because they are especially at risk for exploitation. The NBAC looked at characteristics individuals might have that would prevent them from being able to provide voluntary informed consent. The traits may be thought of as falling into six broad areas: cognitive or communicative, institutional, deferential, medical, economic, and social. Cognitive or Communicative Vulnerability Prospective research subjects who are not able to comprehend information, deliberate, and make decisions about participation in a proposed research study have a cognitive or communicative vulnerability. This vulnerability may be thought of in three broad categories. In any of these situations, subjects may not be able to provide fully informed consent to participate in the research. 1. Capacity-related cognitive vulnerability - subjects to some extent lack capacity to make informed choices. Examples might include young children or adults with cognitive impairments that affect decision-making. 2. Situational cognitive vulnerability - subjects do not lack capacity but are in situations that do not allow them to exercise their capacities effectively. Examples might include when a subject is distracted or during an emergency situation, such as an acute illness or injury. 3. Communicative vulnerability - subjects do not lack capacity, but due to limited ability to communicate with the researchers are not able to exercise their capacities effectively. Examples might include subjects who speak or read different languages than researchers do, or subjects who have speech impairments or difficulty reading. Institutional Vulnerability Prospective subjects in research who are subject to the formal authority of others may have an institutional vulnerability. These individuals have the cognitive capacity to consent but may not be able to make a truly voluntary choice, and may be unduly influenced (or coerced) to participate when they otherwise might not have done so. Institutional vulnerability may arise when subjects are prisoners, enlistees in the military, employees, or college students. For example, college students may be required to be research subjects for course credit or participate to earn a higher grade. In these situations, informed consent may be compromised because it is not truly voluntary. Further, these individuals may be subject to exploitation because of their subordinate status. Deferential Vulnerability Deferential vulnerability is similar to institutional vulnerability, but the authority over the prospective subject is due to informal power relationships rather than formal hierarchies. The power relationship may be based on gender, race, or class inequalities, or they can be inequalities in knowledge (such as in the doctor-patient relationship). Like institutional vulnerability, deferential vulnerability increases the risk of harm because informed consent would be compromised and not fully voluntary. Medical Vulnerability Medical vulnerability arises when prospective subjects have serious health conditions for which there are no satisfactory standard treatments. Such subjects may not be able to adequately weigh the research’s risks and potential benefits, and informed consent would therefore be compromised by inadequate comprehension. Further, these subjects are at risk of exploitation because they may overestimate potential benefit. When subjects blur the roles played by physician-researchers or fail to appreciate the differences between research and treatment, therapeutic misconception may augment medical vulnerability. Economic Vulnerability Economic vulnerability arises when prospective subjects are disadvantaged in the distribution of social goods and services (income, housing, or healthcare). Participation in research offers the possibility of payment or attainment of healthcare or other services that are otherwise not available and induces persons to enroll in a research study when it might be against their better judgment and when otherwise they would not do so. These inducements to enroll threaten the voluntary nature of consent and raise the danger of exploitation. Social Vulnerability Prospective subjects who belong to undervalued social groups may be subject to social vulnerability. The perception of these groups as less valuable to society could lead to reduced concern (by researchers) for risks and burdens on those groups, and increase the risk of exploitation. How the Regulations Define and Address Vulnerability In the U.S. Department of Health and Human Services (HHS) regulations at 45 CFR 46 (Protection of Human Subjects 2018), there are multiple places where vulnerable populations involved in research are either directly referenced or the reference is implied, including in: Institutional Review Board (IRB) Membership (45 CFR 46.107) Criteria for Approval (45 CFR 46.111) Types of Vulnerability Defined in the Federal Regulations HHS at 45 CFR 46.111(b) (Protection of Human Subjects 2018) provides the following list of examples of vulnerable subjects: Children Prisoners Individuals with impaired decision-making capacity Economically or educationally disadvantaged persons The HHS regulations have three subparts that discuss specific additional protections for identified vulnerable populations of individuals when they are going to participate in research. These subparts have been adopted, to varying extents, by some other federal agencies who have adopted the Common Rule (45 CFR 46, Subpart A). Although not a Common Rule agency, the U.S. Food and Drug Administration (FDA), at 21 CFR 56.111(b) (Institutional Review Boards 2015), provides a similar list of vulnerable subject examples. Read more about additional protections for pregnant women, human fetuses, and neonates involved in research under Subpart B… Read more about additional protections pertaining to research involving prisoners as subjects under Subpart C… Read more about additional protections for children involved as subjects in research under Subpart D… Legally Authorized Representative (LAR) When a subject cannot consent, researchers may obtain consent from a LAR when appropriate. The HHS regulations (Protection of Human Subjects 2018) define LAR as, “an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research.” The HHS regulations allow for institutional policy that recognizes an appropriate LAR in the nonresearch context to also apply in the research context if there is no applicable law addressing this issue (that is, if there is no applicable law that defines a LAR for the research context) (Protection of Human Subjects 2018). An Expanded View of Vulnerability: Examples of Additional Vulnerabilities Not Explicitly Covered by the Federal Regulations Despite not being specifically identified in the regulations, various individuals, groups, or situations that may render individuals vulnerable in the context of research, may require specific additional protections. The following are some examples that are important to understand and consider when thinking about research involving vulnerable populations or those requiring additional protections and/or considerations. Vulnerability Due to Critical Illness Vulnerability for the group of critically ill individuals and in the situation of emergency research may be due to intrinsic factors (like altered decision-making capacity, and reduced capacity to consent) and situational factors (like coercive settings, or undue influence and inducements). Read more about critically ill vulnerability… Vulnerability Due to Terminal Illness (Research at the End-of-Life) Persons at the end-of-life may be vulnerable for numerous reasons, including cognitive and physical impairments, which may progress when nearing death. Read more about end-of-life vulnerability… Vulnerability Due to Decisional Impairment It is important to recognize that decisional impairment can result from a variety of intrinsic factors and situational conditions and is not limited to individuals with a psychiatric diagnosis. Decisional impairment exists along a spectrum and therefore must be assessed in the context of the information that must be understood and the nature of the decisions to be made. Read more about decisional impairment… Vulnerability Due to Physical Disabilities or Impairments Physical disabilities and impairments can result in diminished participation in society because the disability limits a major life activity (Equal Opportunity for Individuals with Disabilities 2009). The diminished participation in society can lead to vulnerability both because of an intrinsic factor (such as, a physical limitation the individual experiences) or a situational factor (such as, a lack of an adequate accommodation for the disability allowing for full participation). Intrinsic factors such as a limitation in one of the senses (like sight) can lead to a very strong desire to participate in research that may have the prospect of direct benefit to the subject. This may potentially lead to undue influence. Additionally, situational factors in the study design can lead to vulnerability. For example, not providing a large-print or Braille consent form to an individual who has a visual impairment or blind can interfere with the voluntariness of consent. Vulnerability Due to Economic Disadvantage or Social Marginalization Economically disadvantaged individuals are those who are under-resourced to provide for themselves or their families, and experience particular hardships due to disparities and inequalities in the society in which they live. These situational factors can affect or limit the subject’s voluntariness to participate in research. Socially marginalized individuals are those who lack influence in society or standing for a socially constructed reason (such as, race, religion, or disease state). Individuals who are socially marginalized often lack adequate access to social organizations such as the legal system. The potential for undue influence or manipulation is higher for these subjects. For example, the prospect of getting monetary compensation for participation in research could significantly affect the willingness to participate, influencing the subject to accept greater risks of harm than they would otherwise accept. Economically disadvantaged individuals may also enroll in health research because it could mean access to healthcare where they may not otherwise have access. Vulnerability Due to Social Hierarchy Hierarchical social structures are found in situations throughout society. Examples include hospitalized individuals, nursing home residents, students, employees, prisoners, soldiers, other military personnel, or in some cases ethnic groups (such as, indigenous populations). Hierarchical structures have the potential to create issues centered around power/control, coercion, undue influence, and manipulation. The "higher" hierarchical individual has the ability to exercise power or control over others (subordinates) in some way that is either real or perceived. Examples include: Program directors seeking enrollment in research from residents they directly supervise Faculty members recruiting students they currently teach Commanding officers seeking enrollment in research from soldiers or military personnel that report to them through the chain of command Sexual and Gender Minority (SGM) Status “Sexual and gender minority” is an umbrella phrase that encompasses lesbian, gay, bisexual, and transgender populations as well as those whose sexual orientation, gender identity and expressions, or reproductive development varies from traditional, societal, cultural, or physiological norms (NIH 2017). Members of SGM communities may be vulnerable to discrimination, bullying, violence, and prejudice. Gender differences in societal structures, usually directed towards women, may render one gender vulnerable to these forces as well. Read more about SGM status vulnerability… Vulnerability Due to Uncertain Immigration Status and Individuals Involved in Illegal Activities Individuals or groups of people who are regarded as being involved in illegal activities or are undocumented immigrants may be vulnerable because of the potential consequences that exposure may have to them. This can include risks of retaliation against them by others and legal consequences. The risks of harm are higher with these individuals and can often include group-based risks of harm, such as violating the trust of a portion of society that can have negative public health consequences. For example, if undocumented individuals or those involved in illegal activities fear that they will be exposed when seeking medical care, they may not seek medical care when they need it. This can result in heightening public health consequences for that group of individuals. Research Ethics Implications The three pillars often described in research ethics (respect for persons, beneficence, and justice) are important to examine in the context of vulnerable individuals or groups participating in research. A combination of intrinsic factors and situational conditions that lead to vulnerability also open up the individual or group to potential problems that interfere with one of the pillars, requiring attention by an IRB and potentially additional safeguards being put in place in the research. Autonomous Decision Making (Respect for Persons) There is the possibility that due to intrinsic factors or situational conditions individuals or groups can be open to coercion or undue influence. The National Commission (1977) asserts that coercion occurs when one person intentionally presents an overt threat of harm in order to obtain compliance. An example is a professor telling students, "participate in my research or you will fail the class." Similarly, a physician threatening to abandon a patient who refuses to participate in a study represents coercion. However, the National Commission's definition may be too narrow, as coercion need not be overt. For example, a patient who participates in a study run by her primary care physician, because the patient fears her care is contingent on participation, is reacting to fear of retribution (coercion) (whether the physician intends this or not). Inducements, in contrast, are offers that influence people to make decisions, or do things they would not otherwise do. Inducements and the influence they cause may be acceptable or they may be "undue." The distinction is not always clear or universally agreed upon. Offering $10 USD may be acceptable for an hour-long research study; offering $1,000 USD, or a better grade in a class, is probably not appropriate. In general, inducements constitute an undue influence if they alter a potential subjects decision-making processes such that they do not appropriately consider the research’s risk-benefit relationship. Misunderstanding of the research is also a problem that can interfere with autonomous decision-making. For individuals or groups who are vulnerable, the prospect of direct benefit, whether real or perceived, can dramatically affect the individual’s voluntariness. This can lead to a person accepting a much higher level of risk of harm than they otherwise would accept or subscribing to the false belief that the research may hold out the prospect for direct benefit to them. Beneficence The concept of beneficence in research includes weighing the research’s risks of harm against the benefits. When conducting research involving vulnerable individuals or groups, two issues arise related to risks of harm. 1. There may be changes in the magnitude of an already identified risk of harm due to the vulnerability experienced by the individual or group. 2. There may be previously unrecognized risks of harm that arise because of the vulnerability experienced by the individual or group. Justice There are three considerations that may arise when assessing justice in research involving vulnerable individuals or groups. 1. In some types of research, a vulnerable group may be the primary group on which the research is conducted because the investigation is focused on the source of vulnerability. This means that the research burden is heaviest on the group based solely on the presence of their vulnerability. This also could mean that those who experience this vulnerability may be the primary beneficiaries of the research results. According to the concept of justice in the , research with a vulnerable group may be acceptable. 2. Some individuals or groups who are vulnerable may become the study focus merely for ease or convenience of access, or because risks of harm or burdens to them are trivialized, as the group is undervalued. This is a significant issue and should be monitored carefully. There are historical cases of prisoners or wards of the state being studied because of convenience when there were more appropriate study groups to enroll. This was the case for both the Jewish Chronic Disease case and the Willowbrook case. In these instances, researchers enrolled populations that were both undervalued by society and convenient for them to study. 3. Designing studies to exclude individuals or vulnerable groups from the research because of the complications and additional requirements for studying them is problematic (either real or perceived). In this case, the lack of inclusion hurts the ability to advance understanding and the underlying science and denies the group the potential benefit of research. Guidance for IRBs and Reviewers The breadth of the expanded view of vulnerability described here and the complications involved with adhering to the regulations, combined with a common sense approach to try to protect subjects, result in increased difficulty in the IRBs review of research. Therefore, a stepwise approach to consideration of the research proposal may be helpful. Are subjects vulnerable? It is important to ask researchers to fully describe the population to be studied and the situations in which the potential research subjects find themselves. This should answer both the question about the intrinsic factors or attributes, as well as the situational forces that may give rise to different types of vulnerability. It will also help the IRB and researchers quickly identify if there are any regulations that must be applied. Researchers generally have a much clearer understanding of the circumstances and potential challenges their research subjects face. They are in a unique position to share their insight. When IRBs request this information, it facilitates the review of research and in the best circumstances leads to better designed research studies, improved review of research, and better protection of human subjects. Researchers and IRBs should consider: Is there a power differential between researchers and subjects? Are there potential excessive motivating factors for subjects? Are there potential communication issues for subjects? Are there potential decisional issues for subjects? Is the recruitment process acceptable? Are advertisements acceptable? Are there economic issues that might affect the acceptability of payment arrangements? Is inclusion of vulnerable subjects appropriate? As discussed above, if some potential subjects are vulnerable, the IRB must then decide if inclusion of this population is indeed appropriate. The IRB must consider the competing ethical imperatives of respect for persons (especially protection of persons who lack selfdetermination and require protection), beneficence, and justice (offering a fair opportunity to benefit from participation). Are vulnerable subjects adequately protected? If the inclusion of vulnerable subjects is appropriate, does the research plan (including subject identification, recruitment, and consent) minimize the possibility of coercion, undue influence, manipulation, and exploitation? Meanwhile, does the research plan maximize the likelihood of valid informed consent? At a very minimum, is the process of informed consent valid? That is, is information presented in an understandable manner, do subjects comprehend the details of the research and their rights as research subjects, and is the process of consent conducive to true voluntariness? Many of the previously noted questions are still relevant. In addition, researchers and IRBs should consider: Are there reasonable accommodations provided for subjects who may be disabled? Is information presented to subjects in an understandable and accessible manner? Do subjects comprehend the research details and their rights as research subjects? Is the consent process conducive to true voluntariness? Who is involved in the consent process? Can the subjects consent for themselves? Do the vulnerabilities of the subjects require the additional protections of a research subject advocate? It is important to remember that the review process described here is an iterative process. Adequate protections may now allow inclusion of a population previously considered too vulnerable, or indeed may make a population not vulnerable at all. Summary Vulnerability may be considered in terms of categories (children, fetuses, persons who are cognitively impaired, persons who are economically disadvantaged, and so on) based on intrinsic characteristics of group members. The NBAC (2001) proposed a more nuanced description as persons "who have difficulty providing voluntary, informed consent arising from limitations in decision-making capacity…or situational circumstances…or because they are especially at risk for exploitation," and classified vulnerabilities more broadly as cognitive or communicative, institutional, deferential, medical, economic, or social. Considering this broader NBAC view, many more types of vulnerability can be recognized as having difficulty providing informed consent or being at risk for exploitation. These groups are described above. These vulnerabilities ultimately relate to challenges to the ethical principles underlying human subjects research: Respect for persons Beneficence Justice Researchers and IRBs must carefully consider characteristics of the subject populations and situational factors to determine if there are potential vulnerabilities, and if so, whether there is adequate justification to include these persons in the research and what additional protections may be required. Regarding this last consideration, researchers and IRBs must consider the risk of harm to individual subjects and populations if they are excluded from participation. It is important for researchers and IRBs to evaluate the selection of subjects, taking into consideration the purpose of the research and the setting in which it will take place. They must examine the risks of harm and benefits to vulnerable populations included in research and ensure that provisions to protect them are in place.