Summary: Protecting Research Participants (Research Involving Human Participants V1)
Introduction
Protecting the rights and welfare of those who volunteer to participate in research is a fundamental tenet of ethical research. A great deal of progress has been made in recent decades in changing the culture of research to incorporate more fully this ethical responsibility into protocol design and implementation. In the 1960s and 1970s, a series of scandals concerning social science research and medical research conducted with the sick and the illiterate underlined the need to systematically and rigorously protect individuals in research (Beecher 1966; Faden and Beauchamp 1986; Jones 1981; Katz 1972; Tuskegee Syphilis Study Ad Hoc Advisory Panel 1973). However, the resulting system of protections that evolved out of these rising concerns - although an improvement over past practices - is no longer sufficient. It is a patchwork arrangement associated with the receipt of federal research funding or the regulatory review and approval of new drugs and devices. In addition, it depends on the voluntary cooperation of investigators, research institutions, and professional societies across a wide array of research disciplines. Increasingly, the current system is being viewed as uneven in its ability to simultaneously protect the rights and welfare of research participants and promote ethically responsible research.
Research involving human participants has become a vast academic and commercial activity, but this country's system for the protection of human participants has not kept pace with that growth. On the one hand, the system is too narrow in scope to protect all participants, while on the other hand, it is often so unnecessarily bureaucratic that it stifles responsible research. Although some reforms by particular federal agencies and professional societies are under way,1 it will take the efforts of both the executive and legislative branches of government to put in place a streamlined, effective, responsive, and comprehensive system that achieves the protection of all human participants and encourages ethically responsible research.
Clearly, scientific investigation has extended and enhanced the quality of life and increased our understanding of ourselves, our relationships with others, and the natural world. It is one of the foundations of our society's material, intellectual, and social progress. For many citizens, scientific discoveries have alleviated the suffering caused by disease or disability. Nonetheless, the prospect of gaining such valuable scientific knowledge need not and should not be pursued at the expense of human rights or human dignity. In the words of philosopher Hans Jonas, "progress is an optional goal, not an unconditional commitment, and...its tempo... compulsive as it may become, has nothing sacred about it" (Jonas 1969, 245).
Since the 1974 formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and the activities in the early 1980s of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, American leaders have consistently tried to enhance the protections for human research participants. The research community has, in large part, supported the two essential protections for human participants: independent review of research to assess risks and potential benefits and an opportunity for people to voluntarily and knowledgeably decide whether to participate in a particular research protocol.
The charter of the National Bioethics Advisory Commission (NBAC), a presidential commission created in 1995, makes clear the Commission's focus: "As a first priority, NBAC shall direct its attention to consideration of protection of the rights and welfare of human research subjects." In our first five years, we focused on several issues concerning research involving human participants, issuing five reports and numerous recommendations that, when viewed as a whole, reflect our evolving appreciation of the numerous and complex challenges facing the implementation and oversight of any system of protections.2 The concerns and recommendations addressed in these reports reflect our dual commitment to ensuring the protection of those who volunteer for research while supporting the continued advance of science and understanding of the human condition. This report views the oversight system as a whole, provides a rationale for change, and offers an interrelated set of recommendations to improve the protection of human participants and enable the oversight system to operate more efficiently.
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Respecting Research Participants
Whether testing a new medical treatment, interviewing people about their personal habits, studying how people think and feel, or observing how they live within groups, research seeks to learn something new about the human condition. Unfortunately, history has also demonstrated that researchers sometimes treat participants not as persons but as mere objects of study. As Jonas observed: "Experimentation was originally sanctioned by natural science. There it is performed on inanimate objects, and this raises no moral questions. But as soon as animate, feeling beings become the subject of experiment...this innocence of the search for knowledge is lost and questions of conscience arise" (Jonas 1969, 219).
How, then, should people be studied? For over half a century, since the revelations of medical torture under the guise of medical experimentation were described at the Nuremberg Trials,3 it has been agreed that people should participate in research only when the study addresses important questions, its risks are justifiable, and an individual's participation is voluntary and informed.
The principles underlying the Belmont Report: Ethical Principles and Guidelines for the Protections of Human Subjects of Research (Belmont Report) (National Commission 1979) have served for over 20 years as a leading source of guidance regarding the ethical standards that should govern research with human participants in the United States. The Belmont Report emphasized that research must respect the autonomy of participants, must be fair in both conception and implementation, and must maximize potential benefits while minimizing potential harms. The report's recommendations provided a coherent rationale for the federal policies and rules that created the current U.S. system of decentralized, independent research review coupled with some degree of federal oversight. But although the Belmont Report is rightly hailed as a key source of guidance on informed consent, assessment of risk, and the injustice of placing individuals (and groups) in situations of vulnerability, the principles the report espouses and the regulations adopted as federal policy 20 years ago have often fallen short in achieving their overarching goal of protecting human research participants. Moreover, since the Belmont Report was published, additional concerns have arisen that require much-needed attention today.
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Ensuring Independent Review of Risks and Potential Benefits
A central protection for research participants is the guarantee that someone other than the investigator will assess the risks of the proposed research. No one should participate in research unless independent review concludes that the risks are reasonable in relation to the potential benefits. In the United States, the Institutional Review Board, or IRB, has been the principal structure responsible for conducting such reviews.
Independent review of research is essential because it improves the likelihood that decisions are made free from inappropriate influences that could distort the central task of evaluating risks and potential benefits. Certainly, reviewers should not have a financial interest in the work, but social factors may be just as crucial. Reviewers may feel constrained because they are examining the work of their colleagues or their supervisors, and they should not participate in protocol review unless they are able to separate these concerns from their task. All reviewers who themselves are members of the research community should recognize that their familiarity with research and (perhaps) their predilection to support research are factors that could distort their judgment. Truly independent and sensitive review requires more involvement of individuals drawn from the ranks of potential research participants or those who can adequately represent the interests of potential research participants.
A critical purpose of independent review is to ensure that risks are reasonable in relation to potential personal and societal benefits. This is a precondition to offering people the opportunity to volunteer, since informed consent alone cannot justify enrollment. When reviewed for risks and potential benefits, research studies must be evaluated in their entirety. Studies often include different components, however, and the risks and potential benefits of each should also be examined separately, lest the possibility of great benefit or monetary enticement in one component cause potential participants or IRBs to minimize or overlook risk in another. No matter what potential benefit is offered to individual participants or society at large, the possibility of benefit from one element of a study should not be used to justify otherwise unacceptable elements.
In our view, IRBs should appreciate that for some components of a study, participants might incur risks with no personal potential benefit - for example, when a nondiagnostic survey is included among the components of a psychotherapy protocol or when placebos are given to some participants in a drug trial. For these elements, there should be some limitation on the amount of social and physical risk that can be imposed, regardless of the participants' willingness to participate or the monetary (or other) enticement being offered. Further, the possibility of some benefit from one element of a study should not be used to justify otherwise unacceptable elements of research whose potential benefits, if any, accrue, solely to society at large. If aspects of a study present unacceptable risks, protocols should not be approved until these elements are eliminated. If removing the risky component would impair the study as a whole, then the entire study should be redesigned so that each of its elements presents risks that are reasonable in relation to potential benefits.
Other parts of studies can obscure risks, such as when standard medical interventions are compared in a patient population, leading some participants and researchers to discount the risks because they are associated with known therapies. It is essential that participants and investigators not be led to believe that participating in research is tantamount to being in a traditional therapeutic relationship. Regardless of whether there is the possibility or even the likelihood of direct benefit from participation in research, such participation still alters the relationship between a professional and the participant by introducing another loyalty beyond that to the participant, to wit, loyalty to doing good science. It is too often forgotten that even though the researchers may consider participants' interests to be important, they also have a serious, and perhaps conflicting, obligation to science.
Years of experience with the current system of independent review have demonstrated that there are enduring questions about how to arrive at such impartial judgments and how to go about deciding when potential benefits justify risks that are incurred solely by participants or the community from which they come. In recent years, increasing strains on the system have undermined the practice of independent review. IRBs are overburdened by the volume of research coming before them, a strain that is compounded by concerns about training of IRB members and possible conflicts of interest. In addition, the constantly changing nature of research challenges existing notions about what constitutes risks and potential benefits.
Because IRBs are so central to the current oversight system, they need better guidance on how to review and monitor research, how to assess potential benefits to research participants and their communities, and how to distinguish among levels of risk. This report provides such guidance in the following areas: determining the type of review necessary for minimal risk research; ensuring that research participants are able to make voluntary decisions and are appropriately informed prior to giving consent; providing adequate protections for privacy and confidentiality; identifying appropriate measures needed when participants are susceptible to coercion or are otherwise placed in vulnerable situations; and monitoring ongoing research. In addition, the report recommends that IRB members and staff complete educational and certification programs on research ethics before being permitted to review research studies.
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Obtaining Voluntary Informed Consent
Even when risks are reasonable, however, no one should participate in research without giving voluntary informed consent (except in the case of an appropriate authorized representative or a waiver). Investigators must make appropriate disclosures and ensure that participants have a good understanding of the information and their choices, not only at the time of enrollment, but throughout the research. Engaging in this process is one of the best ways researchers can demonstrate their concern and respect for those they aim to enroll in a study. It also serves as the best means for those who do not wish to participate to protect themselves.4 Recommendations from our previous reports are reinforced in this report, which emphasizes the process of providing information and ensuring comprehension rather than the form of documentation of the decision to give consent. Both the information and the way it is conveyed - while meeting full disclosure requirements - must be tailored to meet the needs of the participants in the particular research context. In addition, documentation requirements must be adapted for varying research settings, and the criteria for deciding when informed consent is not necessary must be clarified so that participants' rights and welfare are not endangered.
The decision to participate in research must not only be informed, it must be voluntary. Even when risks are reasonable and informed consent is obtained, it may nonetheless be wrong to solicit certain people as participants. Those who are not fully capable of resisting the request to become participants - such as prisoners and other institutionalized or otherwise vulnerable persons - should not be enrolled in studies merely because they are easily accessible or convenient. This historic emphasis on protecting people from being exploited as research participants, however, has failed to anticipate a time when, at least for some areas of medical research, people would be demanding to be included in certain studies because they might provide the only opportunity for receiving medical care for life-threatening diseases.
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Making Research Inclusive While Protecting Individuals and Categorized as Vulnerable
Vulnerable individuals need additional protection in research. Although certain individuals and populations are more vulnerable as human participants than others, people whose circumstances render them vulnerable should not be arbitrarily excluded from research for this reason alone. This includes those viewed as more open to harm (e.g., children), more subject to coercion (e.g., institutionalized persons), more "complicated" (e.g., women, who are considered more biologically complicated than men), or more inconvenient (e.g., women with small children, who are viewed as less reliable research participants due to conflicting demands on time). Calling competent people intrinsically "vulnerable" can be both insulting and misleading. It is not their gender or other group designation that exposes them to injury or coercion, but rather their situation that can be exploited by ethically unacceptable research. That is, it is their circumstances, which are situational, that create the vulnerability. At other times it is the intrinsic characteristics of the person - for example, children or those with certain mental or developmental disorders - that make them generally vulnerable in the research setting.
The response, whenever possible, should not be to exclude people from research, but instead to change the research design so that it does not create situations in which people are unnecessarily harmed. To do otherwise is to risk developing knowledge that helps only a subset of the population. To the extent that the results are not generalizable, the potential societal benefits that justify doing the research are attenuated. Research participants must be treated equally and with respect. Whenever possible, research should be designed to encourage the participation of all groups while protecting their rights and welfare.
To accomplish this, we recommend that rather than focusing primarily on categorizing groups as vulnerable, investigators and IRBs should also recognize and avoid situations that create susceptibility to harm or coercion. Such situations may be as varied as patients being recruited by their own physicians; sick and desperate patients seeking enrollment in clinical trials; participants being recruited by those who teach or employ them; or studies involving participants with any characteristic that may make them less likely to receive care and respect from others (e.g., convicted criminals or intravenous drug users). In these circumstances, rather than excluding whole groups of people, researchers should design studies that reduce the risk of exploitation, whether by using a different method of recruitment, by using a recruiter who shares the participants' characteristics, or by some other technique. This is not always easy. It requires researchers to consider carefully their research design and the potential pool of participants. At times, it will mean anticipating that otherwise seemingly benign situations may become more complex because a particular participant or group of participants will be unusually susceptible to harm or manipulation. At other times, the nature of the vulnerability may require using a different research design. Ethical research does not avoid complexity. Rather, it acknowledges the full range and realities of the human condition.
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Compensating for Harms
Despite all these precautions, however, some research participants might be harmed. Participants who are harmed as a direct result of research should be cared for and compensated. This is simple justice. The fact that they offered to participate in no way alters the view that mere decency calls for us to take care of these volunteers. Unfortunately, this is a greater challenge than it might appear. For those who endure harm while participating in research, it is often very difficult to separate injuries traceable to the research from those that stem from the underlying disease or social condition being studied. For others, appropriate care and compensation would be far beyond the means of the researchers, their sponsors, and their institutions. Two decades ago, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research called for pilot studies of compensation programs - a recommendation that was not pursued. It is time to reconsider the need for some type of compensation program and to explore the possible mechanisms that could be used were one to be adopted. Regardless of individual motives, research participants are providing a service for society, and justice requires that they be treated with great respect and receive appropriate care for any related injuries. It should always be remembered that it is a privilege for any researcher to involve human participants in his or her research.
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Establishing a Comprehensive, Effective, and Streamlined System
In the United States, government regulations, professional guidelines, and the general principles highlighted in the Belmont Report (1979) form the basis of the current system of protections. In the earliest stages of adoption, the federal regulations were fragmented and confusing. Even today, they apply to most - but not all - research funded or conducted by the federal government, but have inconsistent and sometimes no direct application to research funded or conducted by state governments, foundations, or industry. They apply to medical drugs and devices and vaccines approved for interstate sale, but not to some medical innovations that would remain wholly within state borders. And they apply to other research only when the investigators and their institutions volunteer to abide by the rules.
A comprehensive and effective oversight system is essential to uniformly protect the rights and welfare of participants while permitting ethically and scientifically responsible research to proceed without undue delay. A fundamental flaw in the current oversight system is the ethically indefensible difference in the protection afforded participants in federally sponsored research and those in privately sponsored research that falls outside the jurisdiction of the Food and Drug Administration. As a result, people have been subjected to experimentation without their knowledge or informed consent in fields as diverse as plastic surgery, psychology, and infertility treatment. This is wrong. Participants should be protected from avoidable harm, whether the research is publicly or privately financed. We have repeated this assertion throughout our deliberations, and recommendations in this regard appear in four previous reports (NBAC 1997; NBAC 1999a; NBAC 1999b; NBAC 2001).
In this report, we recommend that the protections of an oversight system extend to the entire private sector for both domestic and international research. A credible, effective oversight system must apply to all research, and all people are entitled to the dignity that comes with freely and knowingly choosing whether to participate in research, as well as to protection from undue research risks. This is consistent with our 1997 resolution that no one should be enrolled in research absent the twin protections of independent review and voluntary informed consent.
Even when current protections apply, the interpretation of the federal regulations can vary unpredictably, depending on which federal agency oversees the research. Even the most basic, common elements of the federal rules took a decade to develop into regulations, because there was no single authority within the government to facilitate and demand cooperation and consistency. There still is no such single authority.5 This has slowed the diffusion of basic protections and made it almost impossible to develop consistent interpretations of the basic protections or those relevant to especially problematic research, such as studies involving children or the decisionally impaired. Nor has there been a unified response to emerging areas of research, such as large-scale work on medical records and social science databases or on stored human biological materials.
Today's research protection system cannot react quickly to new developments. Efforts to develop rules for special situations, such as research on those who can no longer make decisions for themselves, have languished for decades in the face of bureaucratic hurdles, and there is no reason to believe that efforts to oversee other emerging research areas will be any more efficient. In addition, the current system leaves people vulnerable to new, virtually uncontrolled experimentation in emerging fields, such as some aspects of reproductive medicine and genetic research.
Indeed, some areas of research are not only uncontrolled, they are almost invisible. In an information age, poor management of research using medical records, human tissue, or personal interview data could lead to employment and insurance discrimination, social stigmatization, or even criminal prosecution.6 The privacy and confidentiality concerns raised by this research are real, but the federal response has often been illusory. There is almost no guidance and certainly no coordination on these topics. The time has come to have a single source of guidance for these emerging areas, one that would be better positioned to effect change across all divisions of the government and private sector, as well as to facilitate development of specialized review bodies, as needed.
In this report we propose a new independent oversight office that would have clear authority over all other segments of the federal government and extend protections to the entire private sector for both domestic and international research. A single office would decide how to introduce consistency or reforms, and only that office would develop mechanisms to provide specialized review when needed. We recognize the challenges to such a proposal. For example, an independent office might lack the political support accorded an existing cabinet-level department. Although assigning one department, such as the Department of Health and Human Services, the role of "first among equals" would allow it to advocate forcefully for uniform rules across the government, without special provisions it would not have the authority to require other departments to comply, nor is it certain to escape the temptation to develop rules premised on a traditional, biomedical model rather than the wider range of research to be covered.
Federal research protections should be uniform across all government agencies, academe, and the private sector, but they should be flexible enough to be applied in widely different research settings or to emerging areas of research. Furthermore, any central coordinating body should be open to public input, have significant political or legal authority over research involving human participants - whether in the public or private sector - and have the support of the executive and legislative branches of government.
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Education as the Key to Promoting Local Responsibility
Currently, federal protections depend on a decentralized oversight system involving IRBs, institutions, investigators, sponsors, and participants. We endorse the spirit and intent of this approach, specifically its contention that the ethical obligation to protect participants lies first with researchers, their sponsors, and the IRBs that review their research. Protecting research participants is a duty that researchers, research institutions, and sponsors cannot delegate completely to others or to the government. In addition, merely adhering to a set of rules and regulations does not fulfill this duty. Rather, it is accomplished by acting within a culture of concern and respect for research participants.
It is unrealistic to think that ethical obligations can be fully met without guidance and resources. To help researchers and IRBs fulfill their responsibilities, the federal government should promote the development of education, certification, and accreditation systems that apply to all researchers, all IRB members and staff, and all institutions. These tools should help researchers craft and IRBs review studies that pose few problems and to know when their work requires special oversight. Today, investigators and IRBs are rightly confused over issues as basic as which areas of inquiry should be reviewed and who constitutes a human participant.
Education is the foundation of the oversight system and is essential to protecting research participants. In all of our reports, we have highlighted the need to educate all those involved in research with human participants, including the public, investigators, IRB members, institutions, and federal agencies. In Cloning Human Beings (1997), we recommended federal support of public education in biomedical sciences that increasingly affect our cultural values. In Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity (1998), we called for practice guidelines and ethics education on special concerns regarding this population. In Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries (2001), we recommended measures to help developing countries build their capacity for designing and conducting clinical trials, for reviewing the ethics and science of proposed research, and for using research results after a trial is completed.
In this report, we again acknowledge the inadequacy of educational programs on research ethics in the United States. This deficiency begins at the highest level within the federal oversight system and extends to the local level at individual institutions. We recommend that investigators and IRB members and staff successfully complete educational programs on research ethics and become certified before they perform or review research, that research ethics be taught to the next generation of scientists, and that research ethics be included in continuing education programs.
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Clarifying the Scope of Oversight
Many areas of scientific inquiry are "research," and many of these involve human participants, but only some need federal oversight, while others might be better regulated through professional ethics, social custom, or other state and federal law. For example, certain types of surveys and interviews are considered research, but they can be well managed to avoid harms without federal oversight, as the risks are few and participants are well situated to decide for themselves whether to participate. On the other hand, certain studies of medical records, databases, and discarded surgical tissue are often perceived as something other than human research, even when the information retrieved is traceable to an identifiable person. Such research does need oversight to avoid putting people at risk of identity disclosure or discrimination without their knowledge. Federal policies should clearly identify the kinds of research that are subject to review and the types of research participants to whom protections should apply. When research poses significant risks or when its risks are imposed on participants without their knowledge, it clearly requires oversight. However, meaningless or overly rigid oversight engenders disdain on the part of researchers, creates an impossible and pointless workload for IRBs, and deters ethically sound research from going forward.
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Ensuring That the Level of Review Corresponds to the Level of Risk
Even within areas of research that need oversight, many individual studies will involve little or no risk to participants. Although current federal policies allow for some distinction between research involving minimal risk and research involving more than minimal risk, the distinction operates mostly in terms of how the research will be reviewed - that is, how procedures are to be followed. But the distinction should be based on how the research is pursued, how the participants are treated, and how the work is monitored over time. Overall, the emphasis should be on knowing how to protect participants rather than on knowing how to navigate research regulations. Instead of focusing so much on the period during which a research design is reviewed, oversight should also include an ongoing system of education and certification that helps researchers to anticipate and minimize research risks. Oversight should also make it easier for researchers to collaborate with their colleagues here and abroad without the burden of redundant reviews.
Research review and monitoring should be intensified as the risk and complexity of the research increase and at all times should emphasize protecting participants rather than following rigid rules. In addition, the review process should facilitate rather than hinder collaborative research among institutions and across national boundaries, provided that participants are protected.
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Providing Resources for the Oversight System
Creating a system that protects the rights and welfare of participants and facilitates responsible research demands political and financial support from the federal government as well as the presence of a central coordinating body to provide guidance and oversee education and accreditation efforts. The oversight system should be adequately funded at all levels to ensure that research continues in a manner that demonstrates respect and concern for the interests of research participants.
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Conclusions
The current system for protecting human participants in research is in need of reform. It does not protect all research participants, and where protection is offered, it is often burdened by excessive bureaucracy, confusing or conflicting interpretations of rules, and an inability to respond to emerging areas of research. We recommend that a new oversight system be adopted that is led by a responsive and authoritative federal office, that emphasizes researcher education and research design as the primary means to protect participants, and that encourages responsible research while protecting all research participants.
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Footnotes
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References
- Beecher, H.K. 1966. "Ethics and Clinical Research." New England Journal of Medicine 274(24):1354`1360.
- Faden, R.R., and T.L. Beauchamp. 1986. A History and Theory of Informed Consent. New York: Oxford University Press.
- Institute of Medicine (IOM). 2001. Preserving Public Trust: Accreditation and Human Research Participant Protection Programs. Washington, D.C.: National Academy Press.
- Jonas, H. 1969. "Philosophical Reflections on Experimenting with Human Subjects." Daedalus 98:219`247.
- Jones, J.H. 1981. Bad Blood: The Tuskegee Syphilis Experiment. New York: The Free Press.
- Katz, J. 1972. Experimentation with Human Beings. New York: Russell Sage Foundation.
- National Bioethics Advisory Commission (NBAC). 1997. Cloning Human Beings. 2 vols. Rockville, MD: U.S. Government Printing Office.
National Bioethics Advisory Commission
- 1998. Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity. 2 vols. Rockville, MD: U.S. Government Printing Office.
- 1999a. Ethical Issues in Human Stem Cell Research. 3 vols. Rockville, MD: U.S. Government Printing Office.
- 1999b. Research Involving Human Biological Materials: Ethical Issues and Policy Guidance. 2 vols. Rockville, MD: U.S. Government Printing Office.
- 2001. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. 2 vols. Bethesda, MD: U.S. Government Printing Office.
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission). 1979.
- Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C.: U.S. Government Printing Office.
- Tuskegee Syphilis Study Ad Hoc Advisory Panel. 1973. Final Report. Washington, D.C.: U.S. Department of Health, Education, and Welfare.