Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability (Research Involving Human Participants V1)
Introduction
This chapter addresses two issues central to the ethical analysis conducted by Institutional Review Boards (IRBs), analysis of risks and potential benefits and the protection of vulnerable individuals, and recommends policy in the form of regulation and guidance to govern the review of research.
The current regulatory requirements relating to these ethical issues reflect the principles underlying the recommendations of the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (Belmont Report) (National Commission 1979). For example, the application of the ethical principle of respect for persons gives rise to the concern for vulnerability; the application of the principle of beneficence leads to the necessity of assessing risks and potential benefits; and the principle of justice requires investigators to attend to the process of recruiting research participants, particularly as it relates to the inclusion of individuals categorized as vulnerable.
In protecting the rights and welfare of participants in research, it is especially important to protect them from avoidable harm. An IRB's assessment of risks and potential benefits is central to determining that a research study is ethically acceptable and would protect participants, which is not an easy task, because there are no clear criteria for IRBs to use in judging whether the risks of research are reasonable in relation to what might be gained by the research participant or society.
When an IRB determines that risks are reasonable, it must also ensure that all segments of society have the opportunity to participate, as appropriate. But some individuals might be considered vulnerable because of either intrinsic characteristics (e.g., mentally or terminally ill) or situational factors (e.g., living in poverty, employees of the institution conducting the research) that render their fully informed and voluntary participation more susceptible to coercion or exploitation. Recognizing the various types of vulnerability and providing adequate safeguards can also prove challenging for IRBs.
IRB Approval of Research
Current regulations instruct IRBs in approving research studies to determine that that all of the following requirements are met:
- Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
- Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.
- Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.
- Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by 46.116.
- Informed consent will be appropriately documented, in accordance with, and to the extent required by 46.117.
- When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
- When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
- When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects (45 CFR 46.111; 21 CFR 56.111 [FDA regulations differ only in regulation citations]).
Scrutinizing research studies according to these criteria is not always a straightforward process, because it is difficult for any set of regulations to fully anticipate the variety of research situations that might arise and because the federal regulations often lack specificity with respect to a particular requirement (e.g., protecting privacy or confidentiality). Moreover, little guidance is available to assist IRBs in their reviews. For example, the, IRB Guidebook, published by the former Office for Protection from Research Risks (OPRR), has not been updated since 1993 (OPRR 1993). Consequently, IRBs often tend to focus more on matters where clearer regulatory direction is available, for example, reviewing the language used for consent forms, rather than on areas that require more judgment. Furthermore, investigators have a tendency to mimic their IRBs in this respect and focus on the more straightforward ethical issues (e.g., avoiding easily recognizable physical harms) and easily defined bureaucratic requirements (e.g., a signed consent form).
This pragmatic focus is understandable, given the limited guidance provided for interpreting many aspects of the regulations. For example, with the exception of those populations that are protected by additional regulatory requirements (i.e., fetuses and pregnant women, prisoners, and children), the federal oversight system offers no direction regarding the types of additional protections that are needed for other vulnerable individuals, even for those identified in the regulations, such as mentally disabled persons and economically or educationally disadvantaged persons. In addition, investigators and IRBs often struggle with the meaning of crucial terms such as minimal risk, minor change, and minor increase over minimal risk, on which key ethical and regulatory decisions rest.1 Applying these regulatory requirements to nonclinical research is even more difficult and cumbersome, because the limited regulatory detail provided is written in the context of clinical research (i.e., that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context (45 CFR 117(c)(2)).
Aside from the challenges involved in understanding and applying the federal regulations, changes in the research environment have influenced how investigators conduct research and, to some degree, how regulatory requirements are applied. For example, growth of Internet-accessible health information databases has raised novel concerns about protecting privacy and confidentiality;2 increased interest in the study of social problems that may uncover illicit behavior has heightened awareness regarding the importance of confidentiality protections (Fitzgerald and Hamilton 1996; Fitzgerald and Hamilton 1997); and increases in overall educational attainment for Americans (Census Bureau 2000) have raised questions concerning which groups should be labeled educationally disadvantaged. In addition to the effects that these types of social and technological changes can have in the research environment, 10 years of experience with the Common Rule and 20 years of experience with the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) regulations suggest that it is time to re-examine the criteria for research approval as described in the regulations (45 CFR 46.111; 21 CFR 56.111). Clarity in both the regulations and guidance would help investigators and IRBs more effectively and efficiently carry out their responsibilities, thereby improving protections, increasing public trust in the enterprise, and promoting research involving human participants.
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Risks of Harms and Potential Benefits to Participants and to Society
The principle of beneficence states that persons should be 'treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being' (National Commission 1979, 6). Therefore, the principle requires that investigators attempt to maximize possible benefits and minimize possible harms. In research, however, the process of gathering data to gain knowledge of benefit to society may expose some individuals to harm, and IRBs must determine, therefore, 'when it is [ethically] justifiable to seek certain benefits despite the risks involved, and when the [potential] benefits should be foregone because of the risks' (National Commission 1979, 7). In the simplest terms, IRBs assess risks and benefits. However, risk refers both to the probability that harm may occur and its magnitude. Thus, the term small risk is ambiguous, for it could mean that the probability of the harm is small, or that the magnitude (i.e., seriousness) of the possible harm is insignificant, or both. On the other hand, benefit refers only to the magnitude of the positive outcome, not to its probability. Thus, harms are properly contrasted with benefits, and risks (i.e., possible harms) with potential benefits.
Federal regulations incorporate the obligation of beneficence by requiring IRBs to ensure that risks are minimized to the extent possible, given the research question, and are reasonable in relation to potential benefits (45 CFR 46.111(a)(1)-(2); 21 CFR 56.111(a)(1)-(2)). Such an analysis of risks and potential benefits often will be complex, because IRBs are called on to assess the balance between any number and type of risks and potential benefits. The current regulations do not further elaborate how risks and potential benefits are to be assessed, and little additional guidance is available to IRBs. The National Bioethics Advisory Commission (NBAC) discussed these issues at some length in two previous reports (NBAC 1998; NBAC 1999b) and has made specific recommendations in this area. Among the important considerations NBAC has raised is how IRBs and prospective participants might not evaluate risks and potential benefits in the same way. To account for this factor, in making assessments of risks and potential benefits, IRBs must find ways to be sensitive to the perspectives of prospective participants (NBAC 1998).
Types of Harms
Harms can be categorized broadly as physical, psychological, social, economic, legal, or dignitary; these categories are not mutually exclusive, however, and more than one type of harm might be present in a given research study. The terms 'harm' and 'injury' have distinct meanings in law, but as in the work of the Health Education and Welfare Task Force (DHEW 1977) and the President's Commission (1982), the terms are used interchangeably in this report.
Physical harms include injury, illness, pain, suffering, or discomfort. This category encompasses such diverse harms as death in a cancer study, myocardial infarction related to a maximal exercise treadmill test, and discomfort related to the requirement to lie still in an MRI machine for an extended period during an imaging study.3 Psychological harms include the research participant's negative perception of self, emotional suffering (e.g., anxiety or shame), or aberrations in thought or behavior. Examples of such harms were found in Milgram's 'Obedience to Authority' experiments (Milgram 1974). Psychological harms also include distress, anger, or guilt related to the disclosure of sensitive or embarrassing information (NBAC 1999a) and distress and fear upon learning of one's likelihood of developing a disease for which there is no treatment or cure (Glass et al. 1997; Marteau and Croyle 1998; Meiser and Dunn 2000). Psychological harms also could be associated with refusal to participate in a research study, such as the guilt that arises when a prospective participant does not wish to donate allogeneic bone marrow to be used in an experimental manner to treat a patient with AIDS.4 Social harms involve the negative effects on one's interactions or relationships with others.5 For example, research findings or even study participation itself may expose participants to insurance or employment discrimination or other forms of social stigmatization (NBAC 1999b). Research findings may also damage a participant's relationship with others, for example, when paternity status is disclosed in genetic or child development studies.6 Economic harms involve the imposition, direct or indirect, of financial costs on participants.7 For example, participants in clinical research may incur financial obligations for treatments that are higher than those associated with standard therapies. In some studies, participants may need to take time off from work or pay for transportation or childcare to enable them to take part in the research. They also may be faced with loss of health insurance, or even loss of employment.8 Legal harms are legal actions that could be taken against the participant, such as arrest, conviction, incarceration, or lawsuits. Such harms could occur, for example, in studies of possession or use of illicit drugs, sexual abuse, or workplace theft.9 Dignitary harms are those incurred when individuals are not treated as persons with their own values, preferences, and commitments,10 but rather as mere means, not deserving of respect.11 Such harms occur in failures to respect personhood or in violations of justice. These types of harms might be present, for example, in research studies in which informed consent is not obtained or in genetic research that results in the discrimination against the individual participant (NBAC 1999b, 45 - 46). Determinations concerning the probability of physical harms are often easier to make than those involving the probability of nonphysical harms. For example, the magnitude and probability of harms associated with a blood draw are well known and can be objectively quantified. This is generally not the case for psychological, social, economic, and legal harms. Although IRBs are able to identify such nonphysical potential harms, it is often difficult to determine the probabilities of their occurrence. IRBs, therefore, can err in either direction, by assuming a higher probability and recommending unnecessary protections or preventing research from being conducted or by assuming a lower probability and allowing research to occur without all the appropriate protections. Although a good deal of information has been gathered about some nonphysical harms, for example, the risks from disclosures associated with transmitting or storing certain types of information, the possibility of such harms is not widely appreciated. Efforts should be made to ensure that IRBs are sensitive to the possibility that nonphysical harms might occur and that they better understand how to consider such risks in their assessments.
Risks to Those Other Than Participants
Risks may accrue not only to research participants, but also to persons not directly involved in research, such as to the participants' family, loved ones, other contacts, social groups, and to society in general (National Commission 1979; NBAC 1999b). For example, in a previous report, NBAC recommended that to the extent that risks of harm to groups can be anticipated, investigators should design their research studies to minimize these risks and should consult with representatives of relevant groups regarding study design (NBAC 1999b). This recommendation was directed to investigators as one important measure that could be taken without revising the federal regulations. However, encouraging investigators may not be sufficient. Both individuals and other groups experience research risks, so it is appropriate for IRBs to be given explicit authority and guidance in how to consider them.
All of the types of risks described above could accrue to others affected by the research. For example, in a study of a new live virus vaccine, there may be risks to participants' family members or other contacts who could contract the attenuated disease. In some states, there may be legal risk to parents whose minor children participate in a study of illegal activity.12 Genetic research may result in certain groups being associated with certain diseases, thus exposing members of those groups to the possibility of stigmatization or discrimination in insurance or employment.13 Society in general may incur harm related to research involving procedures, such as xenotransplan-tation or studies of viruses in which there may be some potential of releasing pathogenic organisms.14
Current regulations focus only on individual participants. However, other individuals and communities not directly involved in research can also bear risks that are associated with a research study, but that are not acknowledged or mentioned in the regulations. If IRBs focus only on risks to individual research participants, they fail to apply fully the principle of beneficence, because the scope of this principle can extend beyond the individual participants in the research.15
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Minimizing Risks
Once risks have been identified, IRBs and investigators must ensure that they are minimized to the extent possible within the limitations imposed by the nature of the research study. Risks may be reduced in a variety of ways, for example, by assuring that the study design is valid; the investigator and research study personnel are qualified; the necessary infrastructure is in place to conduct the research and deal with any harmful sequelae; participant privacy and confidentiality are adequately protected; participants are properly monitored; criteria for participant enrollment and withdrawal are appropriate; a timely treatment plan is in place; and prospective participants at undue risk of harm are excluded.16
Types of Potential Benefits
IRBs should identify potential benefits associated with a research study. Generally, IRBs consider potential benefits as accruing either to society or to participants. Just as research studies might involve risks to individuals other than the participants, they might also provide potential benefits to others, especially the participants' community.
Potential Benefits to Society
The goal of research is to develop knowledge that is beneficial to society. In considering whether to approve a proposed research study, IRBs must make judgments about the importance of the knowledge that is likely to result from research studies. The importance of the knowledge to be gained may increase when significant new findings are expected; when it may result in new products, treatments, or cures; or when it is applicable to many different social groups.
The assessment of whether risks are reasonable in relation to the potential gain in knowledge is difficult to make, because those who participate in research and who will be exposed to the risks are often not the same individuals who stand to benefit from the research. Thus, the IRB must be able to clearly identify what might be learned from the research and decide whether the gain in knowledge justifies the exposure of participants to harm. For studies involving little risk, this assessment is not so difficult. However, when the research involves significant risks to human participants, for example, death or disability, the IRB must carefully weigh the risks and the potential gain in knowledge.
Potential Benefits to Participants
Individuals may directly benefit from participation in certain types of research, such as studies designed to offer interventions or procedures that offer a prospect of benefit. For example, potential benefits include receiving clinically significant information that could be used to influence the care provided, receiving standard treatments or interventions as part of the research, such as counseling and testing, or gaining access to experimental therapies that may improve the participant's health status. These types of benefits are to be contrasted with unplanned or unanticipated benefits that are secondary to the objectives of the study. Sometimes, unanticipated direct benefits can result that are relevant to the research objectives. For example, in a research study on treatment for injection drug users, participants were asked to keep daily diaries as a data collection strategy, which served to raise self-awareness about the effect of daily habits on drug use. As a result, some users sought treatment (Singer 2000; Singer et al. 2000). When identifying potential direct benefits to participants, however, IRBs should consider only those that might result strictly from study participation.
Individuals might also benefit indirectly from participation in certain types of research, from experiencing increased social contact, sharing information with another person, or gaining personal satisfaction from participating in the research (NBAC 1998). Indirect benefits typically are not planned by investigators in their research design and do not relate to the objectives of the research study. In addition, they are likely to vary among research participants. Although these benefits should be acknowledged, they should not weigh in the judgment of IRBs regarding the balance of risks and potential benefits to the participant. To the extent that indirect benefits can be anticipated, however, investigators should design research to increase them.
For purposes of IRB review, incentives for and payments associated with participation in research (e.g., remuneration for transportation, childcare, or lost work time) should not be considered potential benefits to research participants (OPRR 1993). Such potential benefits to research participants make it feasible to participate, but they do not result directly from study procedures in which the individuals participate. Including such incentives as potential benefits in the IRB assessment would inappropriately skew judgments concerning risks and potential benefits, because nearly any level of research risk could be offset by such gains if they were significant enough, for example, if participants were promised large sums of money for participating in research. Although IRBs should not consider such incentives or payments as benefits, they should recognize that prospective participants might consider them as such. Thus, IRBs should determine whether incentives or payments are set so high that they induce prospective participants to enroll without carefully considering the risks involved in participation.
Potential Benefits to Others
Research institutions, social groups, or communities also can benefit from research. Institutions benefit, for example, from enhanced capacity to conduct research or by receiving resources to improve a program as a result of a research study. Communities can benefit through improved access to programs or through the emergence of programs targeted to specific groups within the community. Research can result in the preservation of local history, customs, or practices that might otherwise be lost. IRBs should acknowledge that these potential benefits might be present and should consider ways to increase their likelihood as part of the research design. However, they should not weigh them in assessing risks and potential direct benefits to the participants.
Relation of Risks to Potential Benefits
Once risks and potential societal and direct benefits have been identified and ways to minimize risks have been considered, IRBs must judge whether the risks are reasonable in relation to potential benefits. These can be difficult judgments to make, because IRBs might have to compare the significance of different types of risks and potential benefits, which are often difficult to quantify (Martin et al. 1995). Further, IRBs have little guidance on how to classify and compare risks and potential benefits. It would be impossible to provide IRBs with a single algorithm for making such decisions that would do justice to the large variety of cases that might come before them. However, the counsel provided in the Belmont Report should guide IRB deliberations:
It is commonly said that potential benefits and risks must be 'balanced' and shown to be 'in a favorable ratio.' The metaphorical character of these terms draws attention to the difficulty of making precise judgments. Only on rare occasions will quantitative techniques be available for the scrutiny of research protocols. However, the idea of systematic, nonarbi-trary analysis of risks and benefits should be emulated insofar as possible. This ideal requires those making decisions about the justifiability of research to be thorough in the accumulation and assessment of information about all aspects of the research, and to consider alternatives systematically. This procedure renders the assessment of research more rigorous and precise, while making communication between review board members and investigators less subject to misinterpretation, misinformation and conflicting judgments (National Commission 1979, 16 - 17).
An IRB may approve a research proposal only if it judges that the risks are 'reasonable' in relation to potential benefits (National Commission 1979). This judgment may be an IRB's single most important and difficult determination, because it ensures that when research participants voluntarily consent to participate in a research study, they are offered a 'reasonable choice.' 17 Research with significant risks could be approved after such an analysis if the potential benefit is significant. However, this does not imply that there is no upper limit to the determination of acceptable risk. For any research study involving significant risk, not only should the local IRB find the risks reasonable in relation to the potential benefits, but also so should a larger community of investigators, IRBs, and the public.
Historical Perspective: The Foundation Provided by the National Commission
A coherent conceptual framework is needed for the analysis of risks and potential benefits, and yet there is evidence that this is not provided by current regulations. For example, it has been suggested that the National Commission espoused three distinct views on the analysis of risk: risk assessment based on an analysis of the whole protocol, analysis of risks for whole protocols based on the combined analysis of each of the particular components within a protocol; and distinct analyses of risks for individual components of research protocols without judging the whole protocol as a single unit.18 Each of these views is reflected in the current federal regulations.
In its first report, Research on the Fetus, the National Commission presented a framework for risk analysis that relies on categorizing research studies into two types, therapeutic and nontherapeutic (National Commission 1975) and made separate recommendations concerning the evaluation of risks for each type of research. Current DHHS regulations concerning fetal research (45 CFR 46 Subpart B) incorporate this framework.19 According to some commentators, this 'whole protocol' approach, which requires that entire research studies be classified as either therapeutic or nontherapeutic, is flawed (Levine 1986).20 The National Commission characterized therapeutic research as 'designed to improve the health condition of the research subject by prophy-lactic, diagnostic, or treatment methods that depart from standard medical practice but hold out a reasonable expectation of success' (National Commission 1975, 6). Levine has argued that the concept of therapeutic research is a contradiction in terms:
There is, of course, no such thing as a 'systematic collection of data or observations' designed to improve the health condition of a research subject 'that departs from standard medical practice.' Thus, the [National] Commission developed recommendations for the conduct of a nonexistent set of activities (Levine 1986, 298).
Because the purpose of research is to acquire knowledge, no research study as a whole can be accurately classified as therapeutic research. Indeed, for this reason the National Commission later rejected this whole protocol framework. NBAC has also recognized the difficulty of such a framework (NBAC 1998, 46). As a result of this conceptual flaw, the whole protocol framework allows any research study to be classified as therapeutic as long as it contains at least one component that offers the potential of direct benefit to the participant. However, such research might include nontherapeutic components involving significant risk. For example, a pharmacokinetic study might involve the administration of a standard therapy followed by extensive nontherapeutic testing. In the whole protocol approach, the entire protocol would be classified as therapeutic and there would be no limit to the number of nontherapeutic procedures that could be administered to participants with the protocol still classified as therapeutic. Indeed, IRBs might fail to consider the risk associated with the nontherapeutic procedures, because the conceptual framework encourages them to think about the entire protocol as offering the prospect of some direct benefit. Thus, it is difficult to envision research participants being adequately protected under such a framework.21
In its reports Research Involving Prisoners (1976) and Research Involving Children (1977), the National Commission rejected the distinction between therapeutic and nontherapeutic research, recognizing that an entire research study could not be considered fully therapeutic, but that, instead, protocols might contain therapeutic or nontherapeutic components. Thus, the National Commission eliminated the conceptual problem that stems from the category of therapeutic research. However, the National Commission did not avoid the ethical problems described above. It adopted the language of components, but retained an analytical model based on assessing the protocol as a whole. For example, in its report on research on children, the National Commission endorsed one set of recommendations for research involving no more than minimal risk, another for research involving therapeutic components that exceed the minimal risk threshold, and yet another for research involving nontherapeutic components that exceed this threshold. It has been argued that this framework also suffers from several weaknesses.22 All research studies containing components that offer the prospect of direct benefit to research participants also contain components that do not offer the prospect of benefit and only answer the research question(s). Thus, two different sets of recommendations for assessing risks would apply in a research study involving children that contains both therapeutic and nontherapeutic components in which both components involve more than minimal risk. Because the recommendations that comprise this framework refer to a research study as a whole involving a particular type of component, it is unclear how multiple recommendations could be applied simultaneously to an entire study. Although the model avoids the linguistic confusion associated with a whole protocol approach, it still fails to analyze risk and potential benefits separately for therapeutic and nontherapeutic components.23 Nevertheless, current DHHS regulations concerning research involving prisoners (45 CFR 46 Subpart C) and children (45 CFR 46 Subpart D) incorporate this framework.24 Finally, in its report Institutional Review Boards (1978) the National Commission began to move toward a framework that involved the analysis of components of a research study rather than the study as a whole; however, it did not adopt specific recommendations for performing such an analysis of risk. Requirements relating to analysis of risks and potential benefits in the Common Rule (45 CFR 46 Subpart A) seem to be based on this framework.25 The lack of a single coherent, fully developed conceptual framework hinders the efforts of IRBs to assess and evaluate risks and potential benefits of research studies. At best, the terms 'therapeutic' and 'non-therapeutic' are confusing. By labeling research or procedures as therapeutic, it implies that these activities are beneficial when, in fact, the very purpose of research is to make that determination. NBAC has not used these terms in its previous reports, and it does not do so here. Rather, components should be assessed on the basis of whether they offer the prospect of direct benefits to the individuals being studied or general, more indirect benefits to society.
A Framework for the Analysis of Risks of Harms and Potential Benefits
Charles Weijer has proposed a framework based on a 'component analysis' that he believes provides a better ethical analysis of research that contains a mixture of components, some that offer the prospect of direct benefit to research participants and others with the sole intent of answering the research question(s).26 In the context of a research study, all components are designed to answer the research question(s). Components may include one or more procedures. However, some components also offer the prospect of direct benefit to research participants, while others do not; the latter solely offer the potential societal benefit of knowledge. For example, a research study designed to test whether aspirin or aceta-minophen reduces fever more effectively uses a number of procedures, including the administration of aspirin to one group; the administration of acetaminophen to another group; the randomization of participants to these two groups; and the measurement of fever. All of these procedures are included in the study design because they are needed to answer the research question(s). However, some of these procedures are also designed to offer the prospect of direct benefit to participants, for example, the administration of aspirin or of acetaminophen. Others, such as randomization, temperature taking, and chart comparisons, do not offer the prospect of such direct benefits; their sole intent is to answer the research question(s). Although a research study must be examined in its entirety, the two types of components should be judged differently.
The component-based approach to the analysis of risks and potential benefits requires IRBs to sort research study procedures into these two types of components to determine their ethical acceptability. The first type consists of those components containing particular procedures that may offer the prospect of direct benefit to participants. The second type includes procedures that do not. Most procedures in a research study are easily classified into one of these two types of components. However, in some studies, it might not be clear into which component the procedures best fit, for example, a survey involving a questionnaire and measurements of health in which clinically meaningful results (e.g., blood pressure) are reported back to participants, but no treatment is offered. Further, in any research study using diagnostic procedures that might provide useful health information to the participant in addition to the information provided for the study, such as the use of CAT scans to study brain activity that could also identify tumors, the classification of such procedures may be ambiguous and therefore requires careful consideration by the IRB.
IRBs should be able to identify whether a clear and direct benefit to society or the research participants might result from participating in the study. However, IRBs should be cautious in classifying procedures as offering the prospect of direct benefit. In fact, if it is not clear that a procedure also offers the prospect of direct benefit, IRBs should treat the procedure as one solely designed to answer the research question(s). A major advantage of this approach is that it avoids justifying the risks of procedures that are designed solely to answer the research questions based on the likelihood that another procedure in the protocol is likely to provide a benefit.
To the extent possible, IRBs should independently weigh the risks and potential benefits of each type of procedure. The risks associated with individual procedures offering the prospect of direct benefits are justified in relation to their potential to benefit the participant in addition to their potential to generate knowledge, and those procedures designed solely to answer the research question(s) are justified in relation to their potential to generate knowledge.
Recommendation 4.1:
An analysis of the risks and potential benefits of study components should be applied to all types of covered research (see Recommendation 2.4). In general, each component of a study should be evaluated separately, and its risks should be both reasonable in themselves as well as justified by the potential benefits to society or the participants. Potential benefits from one component of a study should not be used to justify risks posed by a separate component of a study.
Components Designed Solely to Answer the Research Question(s)
All research involves the administration of procedures and use of methods solely for the purpose of answering the research question(s). These procedures or methods can be questionnaires, interviews, chart reviews and use of existing data, observations, randomization, and clinical procedures such as blood draws. Many health services studies and most epidemiological, behavioral, and social science studies as well as historical research involve only such components.
By definition, risks associated with components containing procedures designed solely to answer the research question(s) can be justified only by the potential benefit associated with the knowledge gained, not by the potential direct benefits to individual participants. Freedman argued that this judgment requires the opinion of both scientific experts and community representatives (Freedman 1987b). Community representatives might come from geographic areas or from affected participant communities (e.g., persons with a particular disorder). Involving community representatives can be challenging, as it is sometimes difficult to define relevant groups or individuals who can represent the community (Davis 2000). As risks increase, scrutiny from the communities that may be affected by the research findings will help to ensure public confidence and trust that participants are offered 'reasonable choices.'
Components That Also Offer the Prospect of Direct Benefits
Clinical and other types of research studies might include procedures that, in addition to answering the research question(s), also offer the prospect of direct benefit to participants, such as drug interventions, surgical and medical procedures, or educational, psychological, and behavioral interventions. They might also include diagnostic and other procedures that guide the administration of treatment, even if these procedures are not routinely administered.27 Studies with components containing procedures of this kind pose their own distinctive challenge in the ethical analysis of risks and potential benefits.
Here too, IRBs must determine whether the relation between risks and potential benefits is reasonable. To do so, IRBs should determine whether the procedures meet the criteria of research equipoise (see Exhibit 4.1) in addition to being justified in terms of the potential knowledge gain for society. Investigators and IRBs should understand that the term research equipoise applies to any type of research involving interventions or procedures that offer the prospect of direct benefit to participants, which a test would also need to be applied to research studies involving the evaluation of any intervention that is designed to benefit those who would receive it. For example, educational interventions, such as teaching reading skills or providing public health interventions, such as smoking cessation and psychological interventions should also be subject to the test of research equiposel
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Exhibit 4.1: Research Equipoise
'Research equipoise', a new term introduced in this report, describes the state in which genuine uncertainty exists regarding which intervention, experimental or control (including placebos), is better (Freedman 1987a, 144). Normally, this concept is referred to as clinical equipoise, because it is used in medicine. However, because the concept can be applied to other areas of practice, such as public health or psychology, the term should be broadened.
Accepted practice is defined as practice that falls within the bounds of what is considered standard, that is, what the community of expert practitioners accepts. The standard of research equipoise recognizes explicitly that it is the community of experts that establishes standards of practice (Freedman 1987a). Thus, the judgment that a state of research equipoise exists is an acknowledgement that study interventions are thought to be fully consistent with accepted practice.28
A judgment of research equipoise relies on a comparison of the risks and potential benefits of the proposed study interventions with those of accepted practice. Research equipoise does not require numeric equality of intervention risks or potential benefits. Rather, research equipoise requires approximate equality in the relation between the risks and potential benefits of the study and control interventions. A variety of intervention-related factors are likely to contribute to the determination of this assessment, including, among others, the relative efficacy of the intervention, the probability and magnitude of side effects, ease of administration, and participant compliance.29 An experimental intervention may pose greater risk to participants than accepted practice, as long as it also offers the prospect of greater direct benefit to the participant and the relation between the risks and potential benefits falls within a range of equivalency to accepted practice.30
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would include, for example, health education interventions, clinical psychology interventions, and public health interventions.
Clinical trials involving the use of drugs, vaccines, or other biologic products are other examples of research studies in which IRBs would subject the experimental procedures to a test of research equipoise. However, such a test would also need to be applied to research studies involving the evaluation of any intervention that is designed to benefit those who would receive it. For example, educational interventions, such as teaching reading skills or providing public health interventions, such as smoking cessation and psychological interventions, should also be subject to the test of research equipoise.
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Procedure for Assessing the Balance Between Risks and Potential Benefits
Figure 4.1 outlines the framework for risk and potential benefit analysis that IRBs should undertake in reviewing research. The proposed component analysis offers several advantages:
First, the model can be applied to all types of research.
Second, it focuses the attention of the IRB appropriately on distinct procedures for which the ethical analysis is different. Components designed solely to answer the research question(s) are judged based on an analysis of whether the risks are reasonable in relation to the potential gain in knowledge, while components that also offer the prospect of direct benefit must meet an additional standard of research equipoise. That is, the balance of risks and potential benefits associated with the study interventions are equivalent to those associated with accepted practice and, therefore, there is genuine uncertainty (among experts) about whether the study intervention or accepted practice is preferred.
Third, under this model, components that are designed only to answer the research question(s) cannot be justified based on the inclusion of other procedures that offer the prospect of direct benefit. This aspect of the model prevents investigators conducting clinical trials, for example, from including additional procedures, such as biopsies, blood tests, or scans, that are unlikely to yield any information of benefit to society by justifying them on the basis of including an intervention that holds the prospect of direct benefit, such as an experimental oncology treatment.
The proposed ethical analysis should be performed after risks have been identified and, to the extent possible, minimized by investigators. Only that part of the framework that is relevant to a particular research study should be used. In the case in which a research study involves only the use of components designed solely to answer the research question(s), the IRB and investigators would follow only the left side of Figure 4.1. For example, in a study involving the economic analysis of identifiable data, only the part of the framework relating to components designed solely to answer the research question(s) is used. Likewise, for any research study that does not involve components that hold the prospect of direct benefit to participants, the relevant ethical analysis is only that part of the model relating to components designed solely to answer the research question(s). Examples of such procedures are surveys, records review, blood draws, and other procedures used solely to identify health conditions. Procedures administered in experiments as part of data collection, such as using varying stimuli in a psychological perception experiment or using drugs to alter cognitive states, are evaluated only by the components outlined on the left side of Figure 4.1.
For research involving both types of components (those that solely answer the research question[s] and that also offer the prospect of direct benefit to participants), IRBs should follow both sides of Figure 4.1. Whether one side or both sides of the suggested framework are used, each component of the protocol is considered in turn. IRBs should conclude that risks are reasonable in relation to the potential benefits only when all of the individual procedures have met their respective ethical criteria (see examples in Exhibit 4.1). In the end, an IRB must determine that the research study in its entirely is ethically acceptable.
Standard procedures may be used in a research study in at least four ways, and in each case, they are evaluated differently. First, standard procedures might be used as a control. When standard procedures are used as a control to evaluate the experimental intervention, IRBs must assess them as they do experimental procedures by following the right side of Figure 4.1. (See Exhibit 4.2 for an example.) Second, standard procedures might be used solely to answer the research question(s), such as blood draws or CAT scans. IRBs should follow the left side of Figure 4.1 to assess such procedures. Third, standard procedures might be offered in conjunction with a research study, but not as part of the research study. For example, in a study involving known cases of HIV, participants might be offered counseling and testing for other sexually transmitted diseases (STDs). However, because the STD counseling and testing procedures do not relate to the research question(s) and are instead offered as part of standard practice in a STD clinic, the use of standard procedures in this case should not be factored into the ethical analysis by the IRB. Fourth, some research studies might involve the evaluation of an ongoing standard procedure. That is, the standard procedure would occur or be offered regardless of the existence of a research study. For example, a research study might be designed to evaluate the sensitivity and specificity of a surveillance system to detect cases of disease, with the surveillance system a standard, ongoing procedure, and additional data collection techniques added in order to evaluate the surveillance system. In this scenario, the surveillance system is not part of the research study and should not be part of the ethical analysis of the research study. But the additional data collection is research and should be part of the ethical analysis.
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Minimal Risk
Current federal regulations for the protection of research participants call for the classification of research as involving either minimal risk or greater than minimal risk.31 As defined in the federal regulations:
Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (45 CFR 46.102(i); 21 CFR 56.102(i)).
This classification is ethically relevant, because it is intended to provide protection to human participants by focusing IRBs' attention on riskier research. When used as a sorting mechanism, this classification determines the level of review required of an IRB.32 For example, under the current regulations, if a research study is determined to pose only minimal risk and involves a procedure contained on the expedited review list, it may be evaluated using the expedited review process in which the IRB chair or a designee may review the research study in accordance with all the required regulations (45 CFR 46.110(b); 21 CFR 56.110(b)). Research involving more than minimal risk requires full IRB review. As the risk of research increases above the minimal risk threshold, protections for participants become more stringent. For example, with greater than minimal risk research the process of informed consent cannot be waived or altered (45 CFR 46.116(d)).
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Definition of Minimal Risk
The definition of minimal risk in federal regulations (45 CFR 46.102(i); 21 CFR 56.102(i)) does not specify an unambiguous standard. That is, risks involved in the research study are compared to those encountered in daily life, but it is unclear whether daily life applies to healthy individuals or the target group of the research. Existing sources of guidance offer conflicting interpretations of the standard to be used in determining level of risk.33 In the context of its discussion of research involving children, the National Commission defined a so-called absolute standard when it defined minimal risk as 'the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical or psychological examination, of healthy children' (National Commission 1977). This standard was not adopted in the regulations pertaining to research involving children (45 CFR 46 Subpart D). However, DHHS regulations concerning research involving prisoners limit minimal risk to the experience of healthy individuals. In 1993, OPRR endorsed such an absolute standard interpretation for Subpart A (Ellis 1995). OPRR's interpretation is inconsistent with DHHS' intention as expressed in the preamble of the 1981 version of 45 CFR 46 which stated that 'the risks of harm ordinarily encountered in daily life means those risk encountered in the daily lives of the subjects of the research.' 34 If minimal risk is not characterized in terms of the daily life and experiences of healthy individuals, then it might be taken to refer to the daily life and experiences of research participants. If this is the case, then the same intervention could be classified as minimal risk or greater than minimal risk, depending on the health status of the research participants and their particular experiences. For example, a bone marrow aspiration would not be considered minimal risk in relation to the daily life of a healthy individual, but it might well be determined to fall within this category in relation to the experience of a person with acute leukemia. Such an understanding entails a relative standard for minimal risk.
A relative standard for minimal risk would allow ill participants to be exposed to greater risks than healthy participants. Such a standard would impose disproportionate burdens of research on the ill and provide weaker protections for them than for healthy individuals. This would violate the ethical principle of justice.
IRBs should use a standard related to the risks of daily life that are familiar to the general population for determining whether the level of risk is minimal or more than minimal. The standard should not refer to the particular risks encountered by particular persons or groups. It should refer, therefore, to common risks, for example, driving to work, crossing the street, getting a blood test, or answering questions over the telephone.35 Research, then, involves no more than minimal risk when it is judged that the level of risk is no greater than that encountered in the daily lives of those in the general population. The general population standard is less restrictive than the healthy individuals standard; however, the general population standard more accurately captures the risks that are familiar to most persons.
When a research study is determined to involve no more than minimal risk, the IRB should also consider whether the procedures in question pose additional risks to some of the potential research participants. In such cases, additional protections might be required to reduce the level of risk among that subgroup. For example, drawing a small quantity of blood would normally be considered a minimal risk procedure; its risks do not exceed those normally encountered by the general population. However, if a particular research study involved participants with immunosuppressive disorders, a blood draw may present a higher level of risk, and additional procedures to reduce exposure to infections may be required.
It must be stressed that, in making the determination that a research study involves no more than minimal risk, the IRB must take into consideration all types of risk posed. For example, a research study involving a blood draw to study HIV might involve not only the relatively inconsequential physical risks associated with a blood draw, but also all the nonphysical risks mentioned earlier that might be associated with, for example, learning ones HIV status or having that information released to people other than the investigators.
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Use of the Concept of Minimal Risk as a Sorting Mechanism
The concept of minimal risk serves to focus the IRBs attention on riskier research. Minimal risk is used in determining which research studies can be reviewed using procedures other than the full IRB (see Chapter 2). Currently, research studies that are judged to be minimal risk and fall into one of nine categories of study types may be reviewed using the expedited process. For purposes of determining level of review, there are no relevant ethical differences between studies involving minimal risk that do not fall into one of these categories and those that do. Therefore, all studies judged to involve no more than minimal risk should be eligible for review using procedures other than full IRB review.
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Limited Utility of the Category of Minimal Risk
The current regulatory system and IRBs place too much attention on determining whether research fits into the minimal risk category. As suggested in the framework proposed above for the analysis of risks and potential benefits, risks fall into a two-dimensional continuum of the likelihood of the harm (probability) and the severity of the harm if it were to occur (magnitude). Likelihood of harm runs from very low to high, and the severity of the harm runs from trivial to fatal. IRBs must judge the combination of these two dimensions. A low likelihood of a trivial harm would engender little concern, a high likelihood of a trivial harm or a low likelihood of a severe harm tends to raise more concern, and a high likelihood of a severe harm is of the greatest concern. Investigators and IRBs can seek to minimize risks by designing the study in such a way that there is a reduced likelihood of possible harms, that the magnitude of possible harms is reduced, or both. To establish norms for separating risks into two categories without acknowledging the degree of variation in those risks might foster a misrepresentation of the nature of risk, which might result in an inadequate appreciation of the IRBs responsibility to insist on appropriate protections and to evaluate and minimize all the risks involved in a research study.
Indeed, as discussed in Chapter 2, for research studies involving novel or controversial ethical issues, no single local IRB should assume sole responsibility for conducting the analysis of risks and potential benefits. The proposed National Office for Human Research Oversight should work with the research community to define such research. This pool of research is not likely to be large and might include, for example, certain gene therapy studies that present novel issues or significant unknown risk, xenotransplantation studies, studies involving genetically altered vectors to control certain infectious diseases, or some studies involving low doses of toxic substances in humans to test antidotes that present novel issues or significant and perhaps unknown risks. Some of these kinds of studies are ethically acceptable and should be conducted. However, this type of research would benefit from additional scrutiny, such as a national review panel, with public input into the review process. In fact, investigators should engage the target community of participants in discussion regarding this research, because having only one or two members who represent the pool of prospective participants on the IRB might not provide a sufficient perspective. The purpose of additional review would be to provide the expertise and experience for these types of studies and to offer guidance so that they could be reviewed ultimately by local IRBs.
In two previous reports, NBAC has recommended the use of national panels for such review, in some areas of research involving persons with mental disorders that may affect decisionmaking capacity and for research using human embryonic stem cells, and the need to involve the public (NBAC 1998; NBAC 1999b). In both reports, NBAC asserted that oversight at the national level could provide the public and policymakers with additional assurance that research involving high risks is being carefully reviewed. Some public commentators expressed strong concerns that such national review could be burdensome and unnecessarily delay research.36,37,38 These are legitimate concerns. However, with careful planning, national oversight mechanisms could be implemented in ways that are constructive and that ensure efficiency and timeliness.
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Recommendation 4.2:
Federal policy should distinguish between research studies that pose minimal risk and those that pose more than minimal risk (see Recommendation 2.5). Minimal risk should be defined as the probability and magnitude of harms that are normally encountered in the daily lives of the general population. If a study that would normally be considered minimal risk for the general population nonetheless poses higher risk for any prospective participants, then the Institutional Review Board should approve the study only if it has determined that appropriate protections are in place for all prospective participants.
Protocol submitted to IRB for review.
- IRB staff review to ensure all requirements addressed, protocol ready for IRB review.
- Return for revision and resubmission as necessary.
IRB reviews to
- Identify risks and potential benefits to participants and others.
- Minimize risks.
IRBs ethical analysis of risks and potential benefits after risks identified and minimized, possible benefits identified.
Components Designed Soley to Answer the Research Question(s) 'Are the Risks Reasonable in Relation to Potential Benefits of Knowledge?'
- Requires assessment of the studys objective.
- May require input from experts and community representatives.
Components that Also Offer the Prospect of Direct Benefits to Participants - Are the Risks Reasonable in Relation to Potential Benefits to Participants?
- Assessment of risks and potential benefits made separately for experimental and control procedures.
- Does study pass test of research equipoise?
Insufficient data exist to validate whether control or experimental procedure more likely to provide more favorable risk/benefit combination. May require input from experts and community representatives.
Study Acceptable Only if All Components Pass Ethical Tests
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Exhibit 4.2: Using the Framework to Assess Risks and Potential Benefits
The following examples are taken from recently published research to show how research procedures can be separated into those solely designed to answer the research question(s) and those that also offer the prospect of direct benefit to participants. The risk/potential benefit analysis can be used with studies involving no more than minimal risk as well as studies involving more than minimal risk.
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Example 1: Analysis of Existing Data
Investigators studied gender differences in industry wages by analyzing data from the 1988 Current Population Survey. Variables in the analysis include hourly wage, level of education, years of work experience, size of the metropolitan area in which workplace is located, whether the workplace is in an urban or rural area, geographical region of the United States, marital status, race, type of occupation, and type of industry.
If the data are unidentifiable, the research should not be covered under the oversight system, because no human participants are involved. If the data are identifiable (i.e., coded), then an IRB should review the research. In this case, risks are associated with breaches in confidentiality, and the IRB should determine whether confidentiality protections are appropriate. Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society.
Based on this analysis, this study should be eligible for review using procedures other than the full board because it involves no more than minimal risk.
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Example 2: Face-to-Face Interviews Involving Sensitive Issues and a Small Sample
Investigators studied the effect of traumatic experiences on memory. Five individuals who were incarcerated between 1942 and 1945 in Auschwitz were the participants. A detailed questionnaire was given concerning personal characteristics (e.g., age, education, and place of work), concentration camp characteristics, daily routine at the camp, and events that occurred while there. They were also shown ten photos of famous Nazis who were either known nationally or active at Auschwitz. Interviewers administered the questionnaires in the participants homes and conducted interviews in Hebrew or German. Investigators analyzed responses for accuracy based on historical accounts.
Concerns of the IRB should be threats to privacy, breaches in confidentiality, and psychological risks, such as distress. The sample size may result in individuals being identified even if no direct identifiers are maintained. Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society. Investigators might argue that participants might feel better after the interview and derive some satisfaction from talking about their experiences. However, these types of indirect benefits should not be taken into consideration in the risk/potential benefit analysis.
Based on the analysis of the components of this study, it should receive full IRB review because some components pose more than minimal risk.
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Example 3: Observational Study Using Mail Questionnaires to Evaluate the Effects of State Law on Behavior
Investigators studied the effects of two divorce laws on the functioning of parents and children immediately after separation and two years later. In this state, until 1987 the divorce law was no-fault and permissive of joint custody. In 1988, a new law went into effect that focused on parental functions and responsibilities rather than custody. Investigators identified divorcing couples through their divorce petitions. One hundred couples were identified in 1987 and 100 in 1988 and were sent a questionnaire at the time of separation. If they responded to the questionnaire, they were sent another questionnaire two years later. Individuals were asked to respond to questions about themselves regarding depression, social withdrawal, irritability, work problems, and childrearing problems. They were asked to answer questions about their children regarding depression, anxiety, eating behavior, sleeping patterns, nighttime fears, and withdrawal. They also responded to questions regarding the circumstances of the separation, including parental substance abuse and child abuse.
Primary concerns of the IRB should be threats to privacy and breaches in confidentiality. Privacy and confidentiality risks related to psychological, social, and legal harms are heightened, because divorcing spouses might attempt to obtain through legal mechanisms information about the other or physically harm the other based on information disclosed in the survey. Other issues would include whether cases of child abuse must be reported. Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society. Thus, the study should receive full IRB review.
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Example 4: Psychological Experiment to Study Human Cognition and Behavior
Investigators studied the relationship between task difficulty and performance, because performance sometimes improves when tasks become more difficult. In this experiment, motor difficulty and cognitive difficulty were manipulated in a recognition task. Sitting in front of a computer, student participants were instructed to move the cursor using a standard analog joystick as quickly and accurately as possible into contact with an image that they thought matched the sample image. Within the different experimental groups, exposure time of the sample stimulus was altered (fast versus slow), and ease of moving the joystick was altered (easy versus hard). Students were offered course credit for participating in the study.
Primary concerns of the IRB should be whether offering course credit for participation is an undue inducement; whether there are any physical risks associated with operating a hard-to-move joystick; and whether there are any psychological risks associated with task difficulty, such as frustration or loss of self-confidence. Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society. This study should be eligible for review using procedures other than full board review because it involves no more than minimal risk.
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Example 5: Clinical Trial to Determine Safety and Immunogenicity of a Vaccine
Investigators conducted a Phase I, dose-escalating trial of a prophylactic recombinant human papillomavirus vaccine candidate in healthy participants. The study was designed to evaluate the safety and immunogenicity of two dose levels of the vaccine in a double-blind, randomized, placebo-controlled trial. To determine whether the dose of the vaccine or the addition of alum or MF59 adjuvant would influence the reactogenicity or immune response, a dose-escalation design was used, starting with the lower dose of the vaccine alone, then with alum added to the vaccine, then with MF59 added to the vaccine, and the design repeated with the higher dose of the vaccine. Assessments included a physical examination and laboratory tests prior to enrollment and clinical evaluations and clinical and immunologic tests before each injection at 0, 1, and 4 months and 1 month after each injection.
The trial was not designed to offer a potential direct benefit (protection from human papillomavirus) to participants. The vaccine, the design of the trial, and all of the assessments were administered solely to answer the research question(s) related to safety and immunogenicity. Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefits analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society. Thus, the study should receive full IRB review.
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Example 6: Clinical Trial to Test Efficacy of a Drug
Investigators conducted a trial to determine whether paroxetine, an antidepressant, would reduce depressive symptoms in patients with malignant melanoma who were treated with a high dose of interferon therapy. The investigators used a double-blind, placebo-controlled trial design. Participants were randomly assigned to either the experimental arm or the control arm of the trial. Paroxetine or placebo was administered for two weeks before initiation of the inter-feron therapy as well as during the treatment period. Participants were evaluated at regularly scheduled intervals for depressive symptoms. Assessments included depression and anxiety rating scales, a neurotoxicity rating scale used in the measurement of psychiatric and physical symptoms related to cytokine therapy, and a psychiatric evaluation.
This trial was designed to offer the prospect of direct benefit to participants in addition to answering the research question(s). In this study, the research (whether paroxetine reduces depression-like symptoms) takes place in the context of providing standard medical care (interferon therapy). The use of standard medical care should not be factored into the risk/potential benefit analysis of the IRB. The research study procedures are of two types. The first type, designed solely to answer the research question, includes the trial design (randomization and double-blindness) and the assessment measures. The risk/potential benefit analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society. The other types of procedures are those that offer the prospect of direct benefits. These procedures are the experimental and control conditions. In addition to determining that these procedures will yield potentially useful societal knowledge, they are evaluated in terms of whether they meet the test of research equipoise, that is, whether there is disagreement among experts as to whether either should be preferred as accepted practice.
This study should receive full IRB review
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Vulnerability
Because most research involves uncertainty, all research participants are vulnerable in some sense. However, it has been suggested that vulnerability, in the context of research, should be understood to be a condition, either intrinsic or situational, of some individuals that puts them at greater risk of being used in ethically inappropriate ways in research.39 Individuals can be used in ethically inappropriate ways even if they have given their informed consent to participate in a research study. For example, poor individuals are enrolled in research even though the benefits of the research will be used primarily by more economically privileged individuals (Cohen 1996; Kolata and Eichenwald 1999). In addition, numerous studies have revealed specific disease associations in certain groups (e.g., sickle cell disease in African Americans, Tay Sachs disease and breast cancer in Ashkenazi Jews), which has led to discrimination and stigmatization when research results are inappropriately reported (King 1998; Weijer 1999a; Weijer 1999b; Wilkinson 1974). More recently, in a study testing whether an experimental measles vaccine could be used in infants too young to receive the standard vaccine, African American and Latino families were not told that the vaccine was experimental or that it had been associated with increased death rates in Africa (Cimons 1996; Gamble 1997; Glenn 1996).
In general, persons are vulnerable in research either because they have difficulty providing voluntary, informed consent arising from limitations in decision-making capacity (as in the case of children) or situational circumstances (as in the case of prisoners), or because they are especially at risk for exploitation (as in the case of persons who belong to undervalued groups in our society). An adequate characterization of vulnerability must attend to both types of concern.
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Current Protections
Subpart A of the federal regulations describes two requirements related to the enrollment of vulnerable persons in research. First, IRBs must determine that the selection of subjects is equitable, and, in so doing, should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons (45 CFR 46.111(a)(3); 21 CFR 56.111(a)(3)). Second, IRBs must ensure that when some or all of the subjects are likely to be vulnerable�dditional safeguards have been included in the study to protect the rights and welfare of these subjects (45 CFR 46.111(b)); 21 CFR 56.111(b) [FDA regulations differ only in sentence structure]).
Some federal departments have additional regulations that provide protection for specific groups. The Department of Education has additional regulations protecting children, the Department of Justice has regulations protecting prisoners, and DHHS has additional protections for selected vulnerable populations: Subpart B pertains to pregnant women and fetuses, Subpart C to prisoners, and Subpart D to children. The Central Intelligence Agency (CIA) and the Social Security Administration follow the DHHS subparts. From this summary, it is clear that coverage of vulnerable individuals is uneven across the federal government. This lack of additional protection is particularly worrisome because every department (except CIA and the Department of Transportation) responding to a survey conducted by NBAC indicated that it sponsored or conducted research involving individuals who are vulnerable in some way.40 The subparts in the DHHS regulations provide two general types of substantive protections.
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Table 4.1: Agency Sponsorship or Conduct of Research That Targets Participants with Vulnerabilities *
| Agency |
Children |
Prisioners |
Pregnant Women |
Fetuses |
Mentally Disabled Persons |
Economically Disadvantaged Persons |
Educationally Disadvantaged Persons |
Other |
| TOTALS |
13/16 |
6/16 |
8/16 |
4/16 |
9/16 |
10/16 |
10/16 |
|
| CIA |
|
|
|
|
|
|
|
|
| DOC |
|
|
|
|
|
|
|
|
| NTIA |
X |
X |
X |
X |
X |
X |
X |
|
| NIST |
X |
X |
|
|
|
|
|
X |
| Census |
|
|
|
|
|
X |
|
|
| DOD |
X |
X |
X |
|
X |
|
X |
Military Students |
| ED |
X |
X |
X |
|
X |
X |
X |
|
| DHHS |
|
|
|
|
|
|
|
|
| ACF |
X |
|
X |
|
|
X |
X |
|
| AHRQ |
X |
|
X |
|
X |
X |
X |
|
| CDC |
X |
X |
X |
X |
X |
X |
X |
|
| FDA |
X |
|
X |
|
X |
|
|
|
| HCFA |
X |
|
X |
|
X |
|
|
Elderly |
| HRSA |
X |
|
X |
|
|
X |
|
|
| IHS |
X |
X |
X |
X |
X |
X |
X |
X |
| NIH |
X |
X |
X |
X |
X |
X |
X |
X |
| OPRR |
|
|
|
|
|
|
|
|
| SAMHSA |
X |
X |
X |
|
X |
X |
X |
|
| HUD |
X |
|
|
|
|
X |
|
|
| DOE |
X |
|
|
|
X |
|
|
Workers |
| DOJ |
|
|
|
|
|
|
|
|
| OJP |
X |
X |
X |
|
X |
X |
X |
|
| COPS |
|
X |
|
|
X |
X |
X |
|
| BOP |
|
X |
|
|
X |
X |
X |
|
| FBI |
|
X |
|
|
|
|
|
|
| DOT |
|
|
|
|
|
|
|
|
| FAA |
|
|
|
|
|
|
|
|
| USCG |
|
|
|
|
|
|
|
|
| FHA |
|
|
|
|
|
|
|
|
| NHTSA |
|
|
|
|
|
|
|
|
| VA |
X |
|
X |
X |
X |
X |
X |
Veterans |
| NASA |
X |
|
|
|
|
|
|
Workers |
| NSF |
X |
X |
X |
X |
X |
X |
X |
|
| SSA |
X |
|
|
|
X |
X |
X |
|
| CPSC |
X |
|
|
|
|
|
|
|
| EPA |
X |
|
|
|
|
X |
X |
|
| USAID |
X |
|
X |
|
|
X |
X |
|
First, in some instances, the regulations limit the level of risk to which participants with vulnerabilities may be exposed. For example, two of the four categories of research involving prisoners are permitted only if the research is no more than minimal risk and are described as follows:
- study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
- (B) study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects (45 CFR)
Second, in some cases, the subparts impose stricter informed consent requirements for vulnerable individuals as compared to the requirements for competent adult participants. For example, in the regulations governing research involving children, permission of the childs parent or guardian (in some cases, permission of both parents) and assent of the child (if the child is capable of giving assent) are required before enrollment of the child can proceed (45 CFR 46.408).
The current DHHS regulations regarding vulnerable individuals are beset with various conceptual and practical difficulties. For example, the subparts offer no definition of vulnerability and no analysis of the types of characteristics that render persons vulnerable.41 The list of vulnerable groups (children, prisoners, pregnant women, fetuses, mentally disabled persons, and economically and educationally disadvantaged persons) provided in Subpart A, 45 CFR 46.111 and 21 CFR 56.111 is incomplete on the one hand and overly broad on the other. For example, injection drug users, the seriously ill, the elderly, and undocumented immigrants could, in particular circumstances, also be considered vulnerable.42 On the other hand, vulnerability is sensitive to context, and individuals may be vulnerable in one situation but not in another. For example, people of low income are rendered vulnerable in studies offering large financial incentives to take on research risk. In addition, the regulations provide inadequate guidance about the types of safeguards that would be appropriate to protect against the risks associated with vulnerability. Subpart A of the regulations requires IRBs to ensure that such individuals are protected, but it does not describe how to achieve such protection.43 In addition to the shortcomings in the regulations, at least two aspects of the current research enterprise suggest a need to evaluate the protections for vulnerable research participants. Increases in research funding are leading to more research involving human participants, and as more people become research participants, more individuals with vulnerabilities are likely to be included. Moreover, because clinical research often holds the prospect of direct benefit and may be perceived as a means of access to health care, serious illness or lack of health insurance may significantly intensify a persons desire to be involved in research.
Although the use of subparts in the DHHS regulations makes it clear which groups should be considered vulnerable, this advantage is outweighed by several disadvantages. Given the limited required safeguards, the current regulations provide insufficient respect for persons and are not sufficiently responsive to the full array of vulnerability experienced by prospective participants. The use of regulatory subparts is not the optimal means by which to protect vulnerable individuals for the following reasons:
- Providing protections for all potentially vulnerable groups would require developing an unwieldy list of additional subparts
- To the extent that different groups may require the same types of protection, the addition of a long list of subparts may introduce unnecessary duplication in the regulations
- A group-based approach to vulnerability leaves unanswered questions about how to safeguard persons with multiple vulnerabilities
- The status of particular groups may change. For example, as members of a particular group become increasingly less subjected to stereotypes, they become increasingly less prone to social vulnerability. Although IRBs and investigators should remain concerned about this general category of vulnerability, their treatment of this particular group should reflect its changing social status. Accommodating such a changing social reality would require regulatory change to a group-based subpart approach to vulnerability, but not to an analytical approach. In order to improve the protections found in the current subparts, each subpart would have to be revised based on an analytical understanding of vulnerability in order to fully reflect its nature and variability and to contain appropriate safeguards.
Group-based subparts classify certain persons as vulnerable, rather than classifying situations in which individuals might be considered vulnerable. For example, persons with severe illnesses for which there are no acceptable treatments may be medically vulnerable in certain kinds of clinical trials, but not vulnerable at all in many other types of research (e.g., survey research).
An analytic approach provides a context-sensitive understanding of vulnerability that avoids the implementation of unnecessary protections, which not only impede the progress of research, but also fail to respect the per-sonhood of the potential participants. Thus, an analytical approach not only provides for greater regulatory efficiency than group-based categorization, but it provides more appropriate safeguards. Further discussion is needed regarding the issue of whether a subpart approach to regulation provides appropriate safeguards.
Nonetheless, the current system of protections should be revised to accommodate different types of vulnerability. An analysis of these characteristics or circumstances provides a list of at least six types of vulnerability.44 Each type of vulnerability is discussed below, and suggestions are made about the types of safeguards that should be required to prevent harming participants who are vulnerable in these ways. Historically, such safeguards have been designed to be protectionistic, focusing exclusively on the risks involved in research. Thus, vulnerable persons have too often simply been excluded from research that might have yielded benefits to them or the groups to which they belong. In developing appropriate safeguards, a balance should be reached between protecting vulnerable persons from harm in research and allowing them to share in its potential benefits (Backlar 2000; Kahn et al. 1998; NBAC 1998).45
Cognitive or Communicative Vulnerability
Prospective research participants who are insufficiently able to comprehend information, deliberate, and make decisions about participation in a proposed research study have a cognitive or communicative vulnerability. Prospective participants might be vulnerable in this way for one of three reasons. First, those with capacity-related cognitive vulnerability, such as young children, or adults with cognitive impairments that affect decision-making, to some extent lack capacities to make informed choices. Second, those with situational cognitive vulnerability do not lack capacity, but are in situations that do not allow them to exercise their capacities effectively, such as stressful emergencies.46 Third, those with a communicative vulnerability, such as participants who speak or read different languages than do investigators, do not lack capacity, but are in situations that do not allow them to exercise their capacities effectively. This type of vulnerability heightens the risk that investigators will not fully respect the prospective participants because standard informed consent procedures will not suffice. Because this report focuses on competent adults, only situational cognitive and communicative vulnerability will be discussed.
Every effort must be made to enable prospective research participants to exercise autonomous choice (NBAC 1998, 9, 57), and investigators should make every effort to reduce situational barriers that impinge on the ability of prospective participants to exercise their authority. Sometimes, when a situational barrier is temporary, it might be possible to delay enrollment of prospective participants until the situation has passed. In other cases, it might be best to obtain informed consent from participants before exposure to the situation that limits autonomy, for example, obtaining consent from pregnant women who will be studied during labor and delivery. Sometimes such situations are structural. For example, sometimes investigators and prospective participants speak different languages. Language barriers can be reduced by using translators or translating consent forms.
Institutional Vulnerability
Prospective participants may have an institutional vulnerability when they have the cognitive capacity to consent but are subject to the formal authority of others who may have independent interests in whether the prospective participant agrees to enroll in the research study. The most commonly cited examples of individuals facing such institutional influences are prisoners and enlistees in the military, but the category also includes college students when they are required to be research participants for course credit or when such participation could affect their grades. This type of vulnerability increases the risk that ones decision concerning participation will not be truly voluntary, consequently increasing the risk that ones personhood will not be fully respected.47 In addition, it presents the risk that the subordinated status of these individuals will be exploited.
To safeguard against the ethically inappropriate enrollment of institutionally vulnerable persons, special attention should be paid to both participant selection and the voluntariness of the choice of prospective participants. Ways to reduce vulnerability might include working with institutional officials before initiating the research study to ensure that there are no inappropriate incentives or pressures to enroll, and when possible, not informing institutional staff about which individuals are participating. For example, if study participation takes one hour, those who refuse could be offered the option of staying in the study area for an hour. In this way, institutional staff would not know who participated and who did not.
Selection of participants from within the institutional setting should be fair and immune from the influence of institutional authorities. For example, in the informed consent process, investigators should emphasize that participation is voluntary, and protections should be in place to protect prospective participants from possible retaliation for their decisions (e.g., no effect on parole status or grades). In addition, during the informed consent process, no institutional authority should be present, except for possibly an ombudsperson.
Deferential Vulnerability
Prospective participants might have a deferential vulnerability when they have the cognitive capacity to consent but are subject to the authority of others who might have independent interests in whether prospective participants agree to enroll in the research study. This category raises the concern that the interests of the prospective participants could be subordinated to those of others. However, with deferential vulnerability, the subordination is affected not by formal hierarchies (as it is with institutional vulnerability), but instead by informal ones.48 Such informal power relationships can be socially constructed (e.g., based on gender, race, or class inequalities, or they can be inequalities of power and knowledge of the kind that occur in doctor-patient relationships), or they can be more subjective in nature (e.g., parents who regularly defer to the wishes of their adult children regardless of their own concerns).49 In any case, deferential vulnerability may be subtle. Like institutional vulnerability, deferential vulnerability heightens the risk that the prospective participants decisions will not be truly voluntary. In addition, it presents the special risk that the subordinated status of these individuals will be used to someone elses advantage, resulting in their exploitation.
It should be noted that not all deferential behavior is subordinating. For example, some individuals might so trust their physicians expertise that they defer to them about enrolling in a research study. Physician-investigators should be especially aware of this vulnerability, because when they approach their patients about enrolling in a research study, they could be concerned that refusing will negatively affect attitudes toward them or the quality of care they will receive. Here, as with institutional vulnerability, care must be taken to design the research study to ensure that the informed consent process is truly voluntary and that investigators do not take advantage of the subordinated status of prospective participants. Safeguards might include employing research staff who are sensitive to such deference and who can assess whether the participant is truly exercising autonomy and who can adjust the informed consent process to the prospective participant. Investigators should consider whether to have discussions with the prospective participant with or without the presence of the party to whom he or she ordinarily defers.
Medical Vulnerability
This category concerns potential participants who have serious health conditions for which there are no satisfactory standard treatments (e.g., metastatic cancer or rare disorders).50 Seriously ill individuals are often drawn to research because they or their physicians believe it is the best alternative to standard treatment. In these dire circumstances it can be difficult for prospective participants to weigh the risks and potential benefits associated with the research. This type of vulnerability increases the risk that informed consent might be based on misunderstanding potential benefits or might be motivated by a desire to find a treatment. It also increases the risk that these participants will be exploited, because either they have unreasonable expectations about the potential benefits or investigators mislead them about risks and potential benefits, and the risks are not reasonable in relation to the potential benefits (Brody 1998).51 In research involving the medically vulnerable, every effort must be made to ensure that prospective participants are presented with accurate information (to avoid exploitation) and that they comprehend that information. Assuring appropriate comprehension might require more than attending to the clarity of information provided. Because physician-investigators might harbor unrealistic expectations for their patients-participants, and because patients-participants too easily blur the roles played by physician-investigators, these situations can lead to what has been called the therapeutic misconception (Appelbaum et al. 1987; Fost 1998; Levine 1992). In these cases, medical vulnerability could be reduced by having an impartial third party approach prospective participants about enrollment and conduct the informed consent process or by having investigators make third parties available to discuss the research. Prospective participants could also be given time to consider the risks and potential benefits of the study and make a decision about participation. As much as possible, individuals should not learn of a diagnosis or that a standard treatment has failed at the same time that they are being asked to participate in a research study.
Some safeguards relating to physician-investigators can be used. Separating the multiple roles of physicians can help to reduce the therapeutic misconception. For example, when possible, the treating physician should not be the investigator. In addition, regular and ongoing education of physicians regarding the informed consent process will reduce the likelihood of overemphasizing potential benefits and underemphasizing risks.
To avoid the exploitation of prospective participants, every effort should be made to optimize the balance between risks and potential benefits in such research without compromising its scientific integrity (Brody 1998).52 IRBs can play a significant role in reducing medical vulnerability by carefully weighing the risks and potential benefits to be certain that procedures that offer the prospect of direct benefit are not used to justify procedures that involve considerable risk and no prospect of direct benefit. Further, in doing so, IRBs would ensure that prospective participants are offered a reasonable choice.
Economic Vulnerability
Prospective participants might have an economic vulnerability when they have the cognitive capacity to consent but are disadvantaged in the distribution of social goods and services such as income, housing, or health care. This type of vulnerability heightens the risk that the potential benefits from participation in the research study might constitute undue inducements to enroll, threatening the voluntary nature of the choice and raising the danger that the potential participants distributional disadvantage could be exploited. For example, offers of large sums of money as payment for participation or access to free health care services (for conditions not related to the research) could lead some prospective participants to enroll in a research study when it might be against their better judgment and when otherwise they would not do so. To safeguard against this vulnerability, IRBs should make certain that research offers a reasonable choice to prospective participants. This might be an easy assessment for the IRB reviewing a research study in which payment is involved, and the amount of payment could be reduced. However, it can be more difficult for the IRB when the potential benefits include access to free medical care or social or other services.
Social Vulnerability
Prospective participants might have a social vulnerability when they have the cognitive capacity to consent but belong to undervalued social groups. The treatment of members of such groups is not simply attributable to their economic vulnerability, although it is true that members of undervalued groups often lack financial resources. Social vulnerability is a function of the social perception of certain groups, which includes stereotyping and can lead to discrimination. In any case, the perceptions devalue members of such groups, their interests, their welfare, or their contributions to society.
These social perceptions are pervasive and often insidious and can affect persons conceptions of certain groups. Thus, investigators, IRB members, and research sponsors should be sensitive to such social perceptions and their effects, and efforts should be made to allow members of such groups to participate in decisionmaking and oversight processes (CDC et al. 1998; Eckenwiler 1999; Eckenwiler 2000). Involving the community in the various stages of the research process, especially in study planning, can be helpful in reducing stereotyping and stigmatization. Also, investigators and IRBs should consider whether studies can be designed to include participants from all segments of society, rather than only or primarily from socially undervalued segments.
Aligning Protections with Vulnerabilities
Although there may be some overlap among the six distinct, ethically relevant types of vulnerability described above, each depicts a particular susceptibility to be used in ethically inappropriate ways in research. Moreover, many individuals might experience more than one of these vulnerabilities. For example, prospective participants might be poor, seriously ill, and not conversant in English. When multiple vulnerabilities exist, appropriate safeguards to address each vulnerability should be in place.
This model improves on the current DHHS regulations, which focus on groups of vulnerable people rather than on types of vulnerability, in three ways. First, it recognizes a fuller array of vulnerabilities that might be experienced by members of a particular group, while current regulations often fail to recognize that members of a vulnerable group might be vulnerable in more than one way. For example, current regulations recognize the institutional vulnerability of prisoners, but not their economic or social vulnerability. Second, the model portrays certain individuals as vulnerable in certain circumstances, while the current regulations classify entire groups as vulnerable. For example, current regulations classify all pregnant women as vulnerable, even though women are seldom vulnerable because of the pregnancy itself. Rather, pregnant women might at certain times be medically vulnerable (e.g., during labor). In addition, the current regulations classify economically disadvantaged persons as vulnerable, but, in certain situations, they would not be (e.g., certain types of survey research involving no remuneration).
The proposed model better expresses respect for persons by allowing people to be treated as individuals rather than as members of a group. Such an analytical model both challenges investigators and enables them and IRBs to extend their consideration of vulnerability beyond the incomplete list of vulnerable groups provided in the current regulations and to account for variations among prospective participants.
Third, the model also suggests appropriate safeguards for each type of vulnerability. The current system proposes two general sorts of safeguards: limiting the risk to which participants may be exposed and implementing stricter consent requirements. Given the limited variety of substantive safeguards required, current regulations are not sufficiently responsive to the full array of vulnerabilities. Safeguards must be tailored to respond to particular types and should avoid the exclusively protectionistic attitude toward vulnerability inherent in the current regulations. In general, the suggested safeguards have been designed to strike a balance between protecting vulnerable persons from harm and allowing them to reap the potential benefits of participation in research.
For all types of vulnerability, IRBs should ensure that the risks to which vulnerable persons are exposed would be acceptable to all prospective participants, i.e., those who are vulnerable as well as those who are not. Because the perspectives and experiences of vulnerable persons can differ considerably from those who are not vulnerable, vulnerable persons should be encouraged to participate in the study design and oversight processes (CDC et al. 1998; Eckenwiler 1999; Eckenwiler 2000).53 Such participatory processes serve as important safeguards in research involving vulnerable persons and can help to build trust in the research enterprise.
In designing a research study, investigators should consider how they would handle prospective participants who are vulnerable. To the extent possible, investigators and IRBs should try to identify, at the time of the IRBs initial review of a research study, the types of vulnerabilities of individuals who might be enrolled. In many studies, enrolling prospective participants who might be vulnerable can be anticipated by its stated purpose and design or by the inclusion criteria. When such individuals can be identified up front, IRBs can require that appropriate safeguards be in place before the initiation of the study. However, in some studies, it might not be possible to anticipate the inclusion of prospective participants with vulnerabilities until enrollment. In general, such prospective participants should not be enrolled until the protocol has been discussed with the IRB and then potentially revised and approved. IRBs should not halt the study, but should consider delaying enrollment of these individuals. In addition, IRBs should develop mechanisms for reviewing such protocols.
Finally, unless the particular research study requires such an approach (e.g., a research study of the efficacy of a particular drug when used in children), as a matter of justice, it is never appropriate to target persons with vulnerabilities for disproportionate inclusion or exclusion in research. This position is endorsed in a previous NBAC report (NBAC 1998).
Use of Minimal Risk as It Relates to Vulnerability
It has been suggested that research involving no more than minimal risk should receive full IRB board review if it involves vulnerable persons.54 However, this is not necessarily true. If all types of risk are identified and considered and research components are appropriately determined to involve no more than minimal risk, then such research should be eligible for review using procedures other than full IRB review, because such research, by definition, involves no more risk than is normally encountered in the daily life of the general population. To require full board review for research involving such little potential for harm is to adopt an unsupportable protectionist stance that imposes unnecessary bureaucratic procedures. The protection of vulnerable research participants must be balanced with the pursuit of benefits both to those participants and to society. At the same time, any review of research involving vulnerable individuals is responsible for ensuring that the protections include appropriate safeguards to protect against the particular vulnerabilities involved. However, as the level of risk increases above minimal risk, the level of scrutiny should also increase, as should the protections required by an IRB.
Appropriate type-specific safeguards should be put in place to protect persons with such vulnerabilities. For example, for research involving socially vulnerable persons, it is appropriate to educate investigators, IRBs, and sponsors about stigmatizing and discriminatory social conceptions of these persons and to design studies to avoid the reflection or perpetuation of such problematic social conceptions. Given the existence of such safeguards, investigators should not exclude such persons from research involving greater than minimal risk in any of the components, for to exclude them would be to deprive them of whatever potential direct benefits they might receive from the research and to deprive their communities and society in general from the benefit of knowledge the research might generate. Moreover, to exclude these persons would be to treat them as though they are not autonomous agents, which would be a violation of the principle of respect for personhood. Once safeguards are in place that are tailored to address their particular variety (or varieties) of vulnerability, vulnerable persons who have the cognitive capacity to provide informed consent should be allowed to exercise autonomous choice about their participation in research. IRBs should exclude such persons from research studies only if they determine that appropriate safeguards cannot satisfactorily be put in place. However, efforts must be made to institute these safeguards and to allow for the inclusion of such persons in the research study.
Recommendation 4.3:
Federal policy should promote the inclusion of all segments of society in research. Guidance should be developed on how to identify and avoid situations that render some participants or groups vulnerable to harm or coercion. Sponsors and investigators should design research that incorporates appropriate safeguards to protect all prospective participants.
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Summary
No person should be enrolled in research until an IRB concludes that the risks are reasonable in relation to the potential benefits. Research studies often involve multiple components or procedures. With some components, the procedures that participants will endure will involve some risk with no direct potential benefit accruing to them. In these situations, some limitation should be placed on the amount of risk that can be imposed, regardless of the participants willingness to participate. Other components of a study might involve procedures that also offer the prospect of direct benefit, for example, when standard medical interventions are being compared in a patient population. In such cases, it is essential that participants and investigators do not fall into the therapeutic misconception, in which they come to believe that participating in research is tantamount to being in a more traditional therapeutic relationship. Thus, for research that has both types of components, it is important that risks and potential benefits be appropriately evaluated by the IRB. In other words, the possibility that one component of a study will provide benefits should not be used to justify otherwise unacceptable elements of the research, the potential benefits of which (if any) accrue solely to society.
Even when risks are reasonable and informed consent is obtained, it may nonetheless be wrong to enroll certain individuals as participants. Although individuals should not be arbitrarily excluded from research because they are viewed as vulnerable, often it is not any personal characteristic that causes this vulnerability, but certain situations that make individuals prone to exploitation. Often, safeguards can be provided in the research so that it does not create situations in which people are unnecessarily harmed and so that it protects their rights and welfare. Research participants should be treated equally and with respect, and whenever possible, research should be designed to encourage the participation of all groups, while protecting their rights and welfare.
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Footnotes