Background Information and the Belmont Report
Perhaps more than any other issue in health ethics, the development and refinement of ethical principles for research with human subjects demonstrates a conscious effort to learn from society’s past mistakes. We know about some of the unconscionable violations of human rights that have been perpetrated in the name of research, and it is reasonable to assume that many more violations remain unknown. In the infamous Tuskegee experiment, the U.S. Public Health Service conducted research for many years on the effects of not treating syphilis in African American men. The participants in that study were led to believe that they were receiving treatment, and the researchers even tried to prevent the participants from receiving treatment for syphilis from any other health care provider (Brandt, 1978). In the aftermath of World War II, the public became aware of horrendous medical experiments performed by Nazi doctors, including testing drugs for immunization against smallpox, cholera, and malaria. The postwar military tribunal found that performing medical experiments without consent of the subjects constituted war crimes and crimes against humanity. The tribunal sentenced eight doctors to prison and seven doctors to death. In addition, the tribunal issued the Nuremberg Code, which states the basic requirement of voluntary consent by human subjects of research.
More recently, the increase in the volume of research performed in developing countries and the persistence or worsening of health disparities have led to an increased concern with issues of social justice in research with human subjects. For example, Solomon Benatar (2001), a professor of medicine in South Africa, has written, “It is suggested that privileged people need to hold up a mirror to their lives, and try to see themselves from the perspective of the marginalized and weak in the world today and as historians in the future may see them in retrospect—as decadent and selfish” (pp. 338–339).
In 1979, the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. This influential report identifies three basic ethical principles for research with human subjects: respect for persons, beneficence, and justice. In recent years the Belmont Report has been critiqued on a variety of grounds (see, for example, Childress and others, 2005), but it remains an extremely important resource in the field of research ethics. As Charles Weijer and Guy LeBlanc (2006) put it, “We have not, nor would we, suggest that the Belmont Report is the last word in research ethics. However, it surely is the first word” (pp. 794–795 and n. 8). In addition, the three principles of the Belmont Report provide a convenient way to categorize and analyze the wide range of issues that arise in research on human subjects.
Thus, this chapter begins with an excerpt from the Belmont Report itself, and then separately analyzes the issues arising under each of the report’s ethical principles. The principle of respect for persons encompasses informed consent to participation in research. The principle of beneficence includes balancing the benefits and risks of research. The principle of justice prohibits exploitation of subjects and communities and requires fairness in selecting or excluding potential subjects of research. After analyzing each of these three basic principles, this chapter will evaluate different approaches to two specific issues. The first issue is whether new drugs for serious diseases, such as HIV/AIDS, should be tested against the best existing therapy or against a placebo. The second issue is clarifying the ethical duty that researchers have to their human subjects after completion of the research, particularly when research is performed in developing countries by researchers from developed countries.
The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research
By the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
Part B: Basic Ethical Principles
The expression “basic ethical principles” refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethics of research involving human subjects: the principles of respect of persons, beneficence and justice.
1. Respect for Persons. Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy
In most cases of research involving human subjects, respect for persons demands that subjects enter into the research voluntarily and with adequate information. In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to “volunteer” or to “protect” them presents a dilemma. Respecting persons, in most hard cases, is often a matter of balancing competing claims urged by the principle of respect itself.
2. Beneficence. Persons are 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. Such treatment falls under the principle of beneficence. The term “beneficence” is often understood to cover acts of kindness or charity that go beyond strict obligation. In this document, beneficence is understood in a stronger sense, as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms.
The Hippocratic maxim “do no harm” has long been a fundamental principle of medical ethics. Claude Bernard extended it to the realm of research, saying that one should not injure one person regardless of the benefits that might come to others. However, even avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk of harm. Further, the Hippocratic Oath requires physicians to benefit their patients “according to their best judgment.” Learning what will in fact benefit may require exposing persons to risk. The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks
The principle of beneficence often occupies a well-defined justifying role in many areas of research involving human subjects. An example is found in research involving children. Effective ways of treating childhood diseases and fostering healthy development are benefits that serve to justify research involving children—even when individual research subjects are not direct beneficiaries. Research also makes it possible to avoid the harm that may result from the application of previously accepted routine practices that on closer investigation turn out to be dangerous. But the role of the principle of beneficence is not always so unambiguous. A difficult ethical problem remains, for example, about research that presents more than minimal risk without immediate prospect of direct benefit to the children involved. Some have argued that such research is inadmissible, while others have pointed out that this limit would rule out much research promising great benefit to children in the future. Here again, as with all hard cases, the different claims covered by the principle of beneficence may come into conflict and force difficult choices.
3. Justice. Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of “fairness in distribution” or “what is deserved.” An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally. However, this statement requires explication. Who is equal and who is unequal? What considerations justify departure from equal distribution? Almost all commentators allow that distinctions based on experience, age, deprivation, competence, merit and position do sometimes constitute criteria justifying differential treatment for certain purposes. It is necessary, then, to explain in what respects people should be treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits. Each formulation mentions some relevant property on the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.
Questions of justice have long been associated with social practices such as punishment, taxation and political representation. Until recently these questions have not generally been associated with scientific research. However, they are foreshadowed even in the earliest reflections on the ethics of research involving human subjects. For example, during the 19th and early 20th centuries the burdens of serving as research subjects fell largely upon poor ward patients, while the benefits of improved medical care flowed primarily to private patients. Subsequently, the exploitation of unwilling prisoners as research subjects in Nazi concentration camps was condemned as a particularly flagrant injustice. In this country, in the 1940s, the Tuskegee syphilis study used disadvantaged, rural black men to study the untreated course of a disease that is by no means confined to that population. These subjects were deprived of demonstrably effective treatment in order not to interrupt the project, long after such treatment became generally available.
Against this historical background, it can be seen how conceptions of justice are relevant to research involving human subjects. For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Finally, whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.
Part C: Applications
Applications of the general principles to the conduct of research leads to consideration of the following requirements: informed consent, risk/benefit assessment, and the selection of subjects of research.
1. Informed Consent. Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied.
While the importance of informed consent is unquestioned, controversy prevails over the nature and possibility of an informed consent. Nonetheless, there is widespread agreement that the consent process can be analyzed as containing three elements: information, comprehension and voluntariness.
Information. Most codes of research establish specific items for disclosure intended to assure that subjects are given sufficient information. These items generally include: the research procedure, their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Additional items have been proposed, including how subjects are selected, the person responsible for the research, etc
Comprehension. The manner and context in which information is conveyed is as important as the information itself. For example, presenting information in a disorganized and rapid fashion, allowing too little time for consideration or curtailing opportunities for questioning, all may adversely affect a subject’s ability to make an informed choice.
Because the subject’s ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject’s capacities. Investigators are responsible for ascertaining that the subject has comprehended the information. While there is always an obligation to ascertain that the information about risk to subjects is complete and adequately comprehended, when the risks are more serious, that obligation increases. On occasion, it may be suitable to give some oral or written tests of comprehension.
Special provision may need to be made when comprehension is severely limited—for example, by conditions of immaturity or mental disability
Voluntariness. An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence. Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance. Undue influence, by contrast, occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.
Unjustifiable pressures usually occur when persons in positions of authority or commanding influence—especially where possible sanctions are involved—urge a course of action for a subject. A continuum of such influencing factors exists, however, and it is impossible to state precisely where justifiable persuasion ends and undue influence begins. But undue influence would include actions such as manipulating a person’s choice through the controlling influence of a close relative and threatening to withdraw health services to which an individual would otherwise be entitled.
2. Assessment of Risks and Benefits. The assessment of risks and benefits requires a careful arrayal of relevant data, including, in some cases, alternative ways of obtaining the benefits sought in the research. Thus, the assessment presents both an opportunity and a responsibility to gather systematic and comprehensive information about proposed research. For the investigator, it is a means to examine whether the proposed research is properly designed. For a review committee, it is a method for determining whether the risks that will be presented to subjects are justified. For prospective subjects, the assessment will assist the determination whether or not to participate.
The Nature and Scope of Risks and Benefits. The requirement that research be justified on the basis of a favorable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons
…Accordingly, so-called risk/benefit assessments are concerned with the probabilities and magnitudes of possible harm and anticipated benefits. Many kinds of possible harms and benefits need to be taken into account. There are, for example, risks of psychological harm, physical harm, legal harm, social harm and economic harm and the corresponding benefits. While the most likely types of harms to research subjects are those of psychological or physical pain or injury, other possible kinds should not be overlooked
The Systematic Assessment of Risks and Benefits. It is commonly said that 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
3. Selection of Subjects. Just as the principle of respect for persons finds expression in the requirements for consent, and the principle of beneficence in risk/benefit assessment, the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selection of research subjects.
Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only “undesirable” persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions.
Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators and treated fairly in the course of research. Thus, injustice arises from social, racial, sexual and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, and even if IRBs [institutional review boards] are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects
One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.
Source: U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979
In evaluating the Belmont Report from a global perspective, it is important to consider whether its ethical concepts are universal principles of human life or merely the values of a particular culture or group of cultures. The Belmont Report, as shown in the previous excerpt, specifically refers to “[t]hree basic principles, among those generally accepted in our cultural tradition.” The report authors did not reach the issue of whether principles such as individual autonomy are generally accepted in other cultural traditions, or how those principles might be understood differently in other cultures. The discussion on autonomy and informed consent later in this chapter will evaluate the cultural as well as the practical implications of making a decision to participate as a human subject of research.
In addition, the Belmont Report does not explain in detail why it is ethical to conduct experiments on human beings or why it is ethical to ask human beings to subject themselves to the risks of research. The Hippocratic Oath requires that physicians “do no harm,” but the Belmont Report justifies causing some harm to human subjects on the ground that “avoiding harm requires learning what is harmful.” But why is it ethical to conduct experiments on human beings in order to learn what is harmful? It is not sufficient to merely say that we always do it that way or that we need to do it that way.
From the perspective of Kantian ethics, each individual must be viewed as an end in himself or herself, and not only as a means to an end, such as advancement of scientific knowledge. On utilitarian grounds we could justify using people for the good of society, but we routinely impose limits on the extent to which society may use people, and most people reject a pure utilitarian approach. From the perspective of principlism, we could rely on the prima facie moral duty of autonomy to permit individuals to give their voluntary consent to the risks and harms of research. Nevertheless, we cannot rely solely on the fact that human subjects of research are willing to let researchers expose them to risks and harm, because society routinely imposes limits on the risks and harms to which even competent adults are permitted to subject themselves.
A principlist approach would require balancing the moral duty of autonomy with the potentially conflicting moral duties of beneficence, nonmaleficence, and justice. Under this approach some types of research with human subjects are ethically justifiable and others are not. Each proposal to conduct research with human subjects must be evaluated on its own merits. That is the approach taken by the authors of the Belmont Report, albeit without much analysis of why it is ethical for society to use individuals in this manner. The Belmont Report accepts the common assumption that the basic concept of using humans as subjects of research is ethical so long as certain conditions are met, such as voluntary informed consent and review of the study by an ethics committee.
This approach has contributed to the development of a comprehensive system of institutional review boards (IRBs) to review specific proposals for research with human subjects. Technically, the requirement in the United States for IRB review applies only to research that is funded by the U.S. government. As a practical matter, however, IRB review procedures—or similar procedures—are applied to a large share of global health care research, for several reasons. First, many universities in the United States use the IRB system or a similar system to review research that is funded by sources other than the U.S. government. Second, many of the largest pharmaceutical manufacturers in the world are U.S. companies. Third, countries other than the United States have adopted similar requirements for review of research with human subjects. Finally, the U.S. Food and Drug Administration (FDA) will not approve a drug for sale in the lucrative U.S. market unless the sponsor of the clinical trial meets certain requirements, even if the trial is conducted in another country or sponsored by a non-U.S. organization (U.S. Food and Drug Administration, 2009).
Under these circumstances, procedures for IRB review or similar procedures have become routine in the world of health care research, including clinical trials conducted in developing countries. These procedures include a review of the risks and benefits of the research, the fairness in selection of subjects, and the process for obtaining informed consent.
Many people consider IRB-type procedures to be a crucial safeguard for the protection of human subjects, especially for patients who are members of vulnerable groups. Others criticize IRBs as being bureaucratic organizations that elevate procedure and form over substance. In a 2009 report, the U.S. Government Accountability Office informed Congress “that the IRB system is vulnerable to unethical manipulation, particularly by companies or individuals who intend to abuse the system or to commit fraud, or who lack the aptitude or qualifications to conduct and oversee clinical trials” (p. 4). In addition, critics argue that IRBs protect themselves, their staff, and their institutions by stopping any research that might result in death or injury to identifiable subjects, while ignoring the possibly greater number of deaths or injuries to unidentifiable individuals that could have been prevented by proceeding with the research (Zywicki, 2007). In 2007, David Hyman wrote that there is “no empirical evidence that IRBs have any benefit whatsoever” (p. 756). Hyman even offered to give “$25 to the first person who finds anything in print (as of December 14, 2006) providing empirical evidence that IRBs have any benefit whatsoever” (p. 756, n. 31).
Notwithstanding the lack of empirical evidence, most people continue to accept the value of IRB review for protection of human subjects, essentially as an article of faith. That faith in the IRB may reflect an implicit value judgment by society to err on the side of preventing research that could cause harm to identifiable subjects, regardless of the harm that might be caused to other people by preventing potentially beneficial research. As a decision-making process, the IRB review might be compared to the criminal trial, a process designed for making a decision on behalf of a society about the guilt or innocence of a defendant. It is often said that it would be better for ten guilty persons to go free than for one innocent person to be falsely imprisoned or executed. In the context of health care research, it appears that society has adopted a rule that it would be better to let ten unidentifiable people die or suffer from a disease that might possibly be prevented through research than to allow one identifiable research subject to be killed or injured in the process of research.
Autonomy and Voluntary Informed Consent
The Belmont Report explains that the basic principle of respect for persons includes the two concepts of individual autonomy and protection for individuals with “diminished autonomy.” Autonomy requires that individuals have the opportunity to make their own decisions about whether to participate in research, after they receive appropriate disclosure of the risks through the process of informed consent. Chapter TWOTwo of this book analyzes the ethical issues of informed consent in the context of clinical practice, where health care professionals and their patients might disagree about the adequacy of disclosing the risks. In contrast, this chapter analyzes the ethical issues of informed consent in the context of research with human subjects. In this context as well, researchers and their subjects might disagree about whether the disclosure of risks was sufficient, and whether the consent to participate was truly informed.
One important example of a dispute about informed consent involves a 1996 study by Pfizer, Inc., of the use of the antibiotic trovafloxacin mesylate (trade name Trovan) in children in Kano, Nigeria, during an epidemic of bacterial meningitis (Stephens, 2006). Some children and some guardians of children who participated in the study alleged that Pfizer had failed to obtain informed consent for the children’s participation. This dispute was the subject of complex legal proceedings in Nigeria and the United States. The plaintiffs in the U.S. litigation made the following allegations:
[They] claim that Pfizer, working in partnership with the Nigerian government, failed to secure the informed consent of either the children or their guardians and specifically failed to disclose or explain the experimental nature of the study or the serious risks involved. Although the treatment protocol required the researchers to offer or read the subjects documents requesting and facilitating their informed consent, this was allegedly not done in either English or the subjects’ native language of Hausa. [They] also contend that Pfizer deviated from its treatment protocol by not alerting the children or their guardians to the side effects of Trovan or other risks of the experiment, not providing them with the option of choosing alternative treatment, and not informing them that the nongovernmental organization Médecins Sans Frontières (Doctors Without Borders) was providing a conventional and effective treatment for bacterial meningitis, free of charge, at the same site [Abdullahi v. Pfizer, Inc., pp. 169–170, footnote omitted].
In response, Pfizer, Inc. (2009), insisted that the “1996 Trovan clinical study in Kano was conducted with the approval of the Nigerian government, and consent of the participants’ parents or guardians, and was consistent with both international and Nigerian laws.” During the process of the litigation, a U.S. appellate court recognized the extreme importance of informed consent to international peace, security, and public health, as follows:
Over the last two decades, pharmaceutical companies in industrialized countries have looked to poorer, developing countries as sites for the medical research essential to the development of new drugs Life-saving drugs can potentially be developed more quickly and cheaply, and developing countries may be given access to cutting edge medicines and treatments to assist underresourced and understaffed public health systems, which grapple with life-threatening diseases afflicting their populations.
The success of these efforts promises to play a major role in reducing the cross-border spread of contagious diseases, which is a significant threat to international peace and stability. The administration of drug trials without informed consent on the scale alleged in the complaints directly threatens these efforts because such conduct fosters distrust and resistance to international drug trials, cutting edge medical innovation, and critical international public health initiatives in which pharmaceutical companies play a key role. This case itself supplies an exceptionally good illustration of why this is so. The Associated Press reported that the Trovan trials in Kano apparently engendered such distrust in the local population that it was a factor contributing to an eleven-month-long, local boycott of a polio vaccination campaign in 2004, which impeded international and national efforts to vaccinate the population against a polio outbreak, with catastrophic results. According to the World Health Organization, polio originating in Nigeria triggered a major international outbreak of the disease between 2003 and 2006, causing it to spread across west, central, and the Horn of Africa and the Middle East, and to re-infect twenty previously polio-free countries.
The administration of drug trials without informed consent poses threats to national security by impairing our relations with other countries [Abdullahi v. Pfizer, Inc., pp. 185–187, footnotes and citations omitted].
In addition, the Belmont Report explains that consent must be voluntary in order to be valid. For it to be voluntary, researchers must avoid coercion, which refers to an intentional threat to secure the individual’s agreement to participate, and undue influence, which refers to an inappropriate or excessive reward or payment to secure the individual’s agreement.
The traditional view has been that researchers should not ordinarily pay individuals to participate in research, but may provide reimbursement to compensate individuals for their costs of participating in the study. “Inducement payments for research subjects are thought to be ‘undue’ when they distort the judgment of potential research subjects and undermine the voluntariness of the subject’s consent” (Ballantyne, 2008, p. 184, footnote omitted). But if offering money can be an undue influence that interferes with voluntary consent, what about offering potentially life-saving medical care to individuals, on condition that they agree to participate in the research? Why is that not undue influence and a lack of truly voluntary consent? The majority of research subjects participate as a way to receive medical care (Ballantyne, p. 190). Especially in developing countries, where most people lack access to medical care, individuals often agree to enroll in a clinical trial as the only way to obtain services that they desperately need (Schüklenk, 2004, p. 197). Under those circumstances, researchers offer potentially life-saving care to those patients, and only those patients, who voluntarily agree to participate in their clinical trial.
The Belmont Report recognizes that undue influence would include “threatening to withdraw health services to which an individual would otherwise be entitled.” If the individuals were not otherwise entitled to the services, however, the conventional wisdom seems to be that offering to provide life-saving treatment is not an undue inducement for participation in research. In other words, most people take the position that the desperate situation of the patient is not the researchers’ fault, and it is not the researchers’ problem. As Angela Ballantyne (2008) wrote:
Potential research participants in developing countries are often particularly vulnerable to the anticipated therapeutic benefit of research because of the limited availability of affordable therapies or accessible healthcare Presumably the primary source of potential undue influence resides in the hope of therapeutic benefit from the trial. If this motivation is “undue”, it is a function of the background conditions of poverty against which the trials take place, rather than a function of any additional benefits offered during the trial. The chance that the trial will result in therapeutic benefit for trial participants is an irreducible part of clinical medical research [p. 187, footnote omitted].
One could argue to the contrary, of course, that the conventional view is both too limited and too convenient. As Benatar (2001) wrote, “Medical research, health care, conditions of life around the world and how humans flourish may seem separate, but they are all interdependent” (p. 337). It may be a radical proposition to suggest that there is a potential ethical concern in offering life-saving medical care to poor people in developing countries on condition of participating in a clinical trial. However, it is difficult to see how offering money is undue inducement but offering a chance for survival is not. At the very least, more consideration and analysis of this important issue is needed.
Meanwhile, questions arise about obtaining informed consent from subjects whose cultures and worldviews are very different from those of the industrialized West (Hyder and Wali, 2006, p. 34; Frimpong-Mansoh, 2008). As discussed in Chapter TWO of this book, about informed consent for treatment, individuals in some cultures see themselves as integral parts of their families and communities, rather than as the autonomous decision makers on whom the Western concept of informed consent is based. As Nicholas Christakis (1988) explained, “signing or even thumbprinting a consent form may be deemed highly suspect in certain societies, as may a physician’s ‘excessive’ explanation of the purpose of the research (which may be taken as indicative of some hidden, detrimental purpose)” (p. 35). Others believe that informed consent from the human subjects of research is a universal principle (Hyder and Wali, 2006, p. 34). Harold Shapiro and Eric Meslin (2001) have taken the position that informed consent is applicable to research conducted anywhere in the world, although they acknowledge that procedures to obtain consent might need to be adjusted to the cultures of developing countries (p.140). In an empirical study on the views of developing country health researchers, Adnan Hyder and Salman Wali (2006) concluded that those researchers strongly support the concept of informed consent but favor a flexible approach to the procedures for consent (p. 40).
In evaluating consent procedures, some experts have suggested that consent should be sought from leaders of the subject’s community. According to Christakis (1988), “It may be necessary to secure the consent of a subject’s family or social group instead of or in addition to the consent of the subject himself.” That is, Christakis took the position that in some cases of essential research, consent by a leader of the community might be an alternative to consent by the individual subject (pp. 34–35). However, what the guidelines of the Council for International Organizations of Medical Sciences (2002) state is this: “In no case…may the permission of a community leader or other authority substitute for individual informed consent.” In the United States, individual consent to research may be waived in unusual circumstances, such as a research study on emergency treatment in which individual or family consent is impractical. In those situations, community consultation and education have been used, but some of those studies have been questioned on ethical grounds (Dalton, 2006). With regard to research conducted in Africa, Augustine Frimpong-Mansoh explained in 2008 that consent by community leaders is a “customary African communitarian practice,” and is merely a first step before obtaining informed consent from the individual subject of research (pp. 111, 113).
Even if the consent of community leaders is seen as an additional requirement rather than as an alternative to individual consent, several ethical and practical questions remain. It may be unrealistic to think that an individual could refuse to participate in a study that had been approved already by the leader of his or her community, especially where individuals see themselves as part of a group rather than as autonomous decision makers. In addition, there may be social pressure for individuals to go along with a study that provides some benefits to the community. Moreover, is it ethical to deprive individuals of the right to say yes because the leader of their community has said no? Individuals should not only have the right to refuse to participate in research but should also have the right to participate if they choose to do so.
Frimpong-Mansoh (2008) has argued that prior approval by African community leaders is analogous to the requirement in Western countries to seek approval from administrators of nursing homes or principals of schools before seeking individual consent from residents or students (pp. 110–111). However, there are two problems with that analogy. First, nursing home residents and students might have ways outside the institutional context to participate in clinical trials, but members of an African community might not have such opportunities. Second, it seems inappropriate to treat every member of a community in a developing country as having inherently diminished capacity to make his or her own decisions, as though he or she were comparable to a child or an elderly resident of an institution.
Of course, even in Western countries, individuals do not have the option to give their consent unless and until the applicable IRB has agreed to allow the research to proceed. Perhaps the African communitarian practice of consent by community leaders should be viewed as analogous to approval of proposed research by an IRB. In the next section of this chapter, on beneficence and cost-benefit analysis, we will evaluate the criticism that the system of IRB review may be unduly paternalistic, in that it deprives individuals of the opportunity to make their own choices after full disclosure of the risks.
At the end of this chapter, an activity provides an opportunity to analyze the ethical issues in using prisoners as subjects of research.
Beneficence and Cost-Benefit Analysis
As set forth in the Belmont Report, the basic ethical principle of beneficence is not limited to the traditional concept of helping other people. It also includes the related concept of nonmaleficence, which refers to not causing harm to other people. Thus, the traditional precept in medical ethics to “do no harm” is included within the basic principle of beneficence. In addition, the concept of beneficence, as used in the Belmont Report (as shown in the previous excerpt), includes an obligation to “maximize possible benefits and minimize possible harms.”
Reasonable people may differ in their evaluation of the possible benefits and harms of a particular proposal. In fact, some people have argued that the acceptability of a specific risk will depend on the health conditions and resources of a particular society. More than twenty years ago Christakis (1988) wrote that “AIDS may be so widespread and deadly a disease in Africa that a higher degree of research risk must perforce be tolerated to deal with the problem, and this may well be socially sanctioned” (p. 36). Of course, others may disagree with the proposition that greater risks should be tolerated in that type of situation.
From a libertarian perspective, Richard Epstein (2008) has criticized the Belmont Report’s inclusion of risk-benefit analysis within the concept of beneficence, because it effectively undercuts the principle of individual autonomy: “This report…starts off with a paean to individual autonomy. Yet by the time it is finished, it ends up with paving the way for the creation of centralized planning boards with complete authority to make decisions on what studies may be conducted and how The Report invokes an off-kilter account of individual beneficence…in the Report beneficence includes the ability to make decisions for others by means of a cost/benefit analysis and deprive individuals of the right to make it for themselves” (pp. 580–581). Should individuals have the opportunity to make their own decisions to participate in clinical trials, after full disclosure of the risks, even without approval by an IRB? Epstein argues that the IRB system is too paternalistic, and believes that we should focus instead on providing information to potential subjects. As he put it, we should “use the IRB process as a bulletin board, not a barricade” (p. 582). A contrary argument, of course, is that many potential subjects of research do not have the scientific knowledge, language skills, or education to evaluate the serious risks involved in many research projects. Even if potential subjects had those abilities, their medical conditions might impair their ability to make objective and carefully reasoned decisions about undergoing particular risks.
Issues of Justice and Fairness for Human Subjects
The Belmont Report explains the basic ethical principle of justice as a matter of fairness in distributing the burdens and benefits of research, including fairness in selecting participants. In particular the Belmont Report cautions against using members of vulnerable groups, such as institutionalized persons, poor persons, and minorities, merely because they are convenient or more easily manipulated. When the Belmont Report was issued in 1979, the primary concern in selection of subjects was unfairly imposing the burdens of research on vulnerable persons or groups by improperly selecting them to serve as research subjects. The authors of the report gave little attention to the potential unfairness of excluding people from participation in research, except for the brief admonition that researchers “should not offer potentially beneficial research only to some patients who are in their favor.”
In recent years more attention has been paid to the need to provide fair access to participation in research for members of traditionally underserved groups. Rather than viewing medical research as an evil to be avoided whenever possible, many people now view participation in a clinical trial as a way—and perhaps the only way—to obtain a beneficial or life-saving drug, especially in the case of “last-chance” therapies for cancer. In addition there is now greater recognition of the disparities in health status and in utilization of specific treatments on the basis of race, gender, national origin, age, and other characteristics. In addition to recognizing the unfairness of excluding particular individuals and groups from participation in clinical trials, experts now also understand that they do not have sufficient data on the ways in which particular treatments may have differential effects on women, children, and other categories of patients. This information gap may have resulted from discrimination in the system of recruiting subjects for clinical trials and, to some extent, from additional regulatory requirements for conducting research on children and women of childbearing age. Although such requirements are intended to protect women and children from the harms of research, they may also be having the unintended effects of discouraging their inclusion in clinical trials and thus limiting the usefulness of results. Recently, regulatory authorities have made efforts to encourage or require the sponsors of research to include women, children, and other groups as appropriate when selecting the subjects of research.
When research is conducted in developing countries, the selection of subjects raises even more ethical issues. As explained by Shapiro and Meslin (2001), “If the intervention being tested is not likely to be affordable in the host country or if the health care infrastructure cannot support its proper distribution and use, it is unethical to ask persons in that country to participate in the research, since they will not enjoy any of its potential benefits” (p. 139). That concern, among others, caused commentators to criticize a proposal by a U.S. company to study a new surfactant drug to treat premature infants with respiratory distress syndrome in Latin America, because poor patients in Latin America were very unlikely to have access to expensive surfactant drugs for the foreseeable future (Shapiro and Meslin, 2001, pp. 140–141; Hawkins, 2006, p. 471). This does not mean that all poor residents of developing countries should be categorically excluded from participation in research. As a group of researchers in Ghana has written, “the objective[s] to generate generalizable results and to fairly distribute risks and benefits of research, oblige researchers not to bar underprivileged persons as participants without cause” (Oduro and others, 2008). The principle of justice requires not only that individual subjects of research should have access to drugs tested in the study but also that the drugs selected for study should be relevant to the medical problems in the community in which the subjects reside. In other words, there are ethical implications for researchers and funding organizations in what they choose to study and support.
Another ethical issue of justice is presented by the use of placebo controls in research with human subjects. In essence the issue is whether a potential treatment should be tested against a placebo or against the best existing method of treatment, if any. Sometimes, this issue is referred to as the standard of care debate, with the existing, proven treatment being the applicable standard of care. By failing to use the appropriate standard of care, the use of placebos may unfairly raise the burden on research subjects and thereby violate the ethical principle of justice.
In an influential 1997 article, Peter Lurie and Sidney Wolfe criticized some clinical trials in developing countries for a treatment to limit perinatal (mother-to-child) transmission of HIV. Researchers had already found an effective treatment to reduce perinatal transmission of HIV, but it was very expensive and was difficult to administer in developing countries. Therefore, it was important to determine if a less expensive and more practical treatment regimen would be effective in preventing transmission of HIV. Lurie and Wolfe criticized the clinical trials that tested the proposed new treatment by comparing it to a control group that received only a placebo and therefore was at risk of transmitting HIV. They argued that the trials were unethical and that the proposed treatment should have been tested against the existing treatment, which was already known to be effective.
The issue of placebo controls has generated substantial debate among experts in ethics and research. On this issue the World Medical Association (WMA) has made a series of changes to its Declaration of Helsinki, but those changes have resulted in even more confusion and disagreement. Initially, the Declaration of Helsinki essentially stated that it is ethical to test a proposed treatment against a placebo only if no proven method of treatment exists (World Medical Association, 2000, para. 29). Some people objected strongly to this formulation. In addition to being based on ethics, the dispute may also have been driven by apparently conflicting requirements from, on the one hand, scholarly journals that might refuse to publish papers from researchers who violated the Declaration of Helsinki and, on the other hand, government regulatory authorities that would not approve certain new drugs unless they were tested in a placebo-controlled trial.
The WMA essentially backed down and adopted what it described as a “note of clarification.” This note said that it might be ethical to use a placebo in a clinical trial when a proven method of treatment already existed, if “for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method” (World Medical Association, 2001, para 29, note). Although characterized as a clarification, the note really changed the result by declaring, in effect, that a placebo-controlled trial is ethical whenever the researchers really need to do it. Commentators strongly criticized the WMA (Lie and others, 2004, p. 190), and some argued that the WMA had “lost any moral authority in the hotly contested standards of care debate” (Schüklenk, 2004, pp. 194–195). In particular, commentators objected to the WMA’s position that a scientific necessity should override all ethical considerations (Schüklenk, p. 194; Lie and others, p. 190.) Moreover, Schüklenk (2004) has argued persuasively that what are often described as matters of scientific necessity are really matters of economic concern (pp. 196–197). Meanwhile, Hawkins (2006) has taken a creative and potentially useful approach by distinguishing the obligations that researchers owe their subjects from the obligations that treating physicians owe their patients, and concluding that some placebo-controlled trials are ethical and others are not.
In the 2008 version of the Declaration of Helsinki, the note of clarification is gone and the statement has been revised as follows:
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances:
- The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or
- Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option [World Medical Association, 2008, para. 32].
This 2008 version of the Declaration of Helsinki is not likely to contain the last word on the ethics of placebo-controlled clinical trials.
Finally, a separate issue of justice involves the duty of researchers to provide care to subjects and their communities after completion of the research. As discussed previously, the principle of justice includes fairness in distributing the burdens and benefits of research. Ballantyne (2008) has explained that the research population must receive a larger share of the benefits than it has traditionally received, in order to avoid exploitation (p. 179).
The Belmont Report states that it would be an injustice to deny someone a benefit without good cause if it is a benefit to which the person is entitled. Thus, the question is whether subjects of research and their communities are entitled to posttrial treatment as a matter of reciprocity, by virtue of having subjected themselves to the risks of research and having made a contribution to scientific progress. The principle of beneficence is also applicable to this issue in the sense of minimizing harm, because a failure to continue treatment could lead to drug resistance for both the individual subjects and their communities.
Here again, the WMA’s Declaration of Helsinki has been less than helpful. As originally phrased, the statement on this issue provided that at “the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study” (World Medical Association, 2000, para. 30). Apparently, some people objected to that obligation for practical or financial reasons. The WMA again backed down considerably by adding a “note of clarification” that required researchers merely to identify posttrial access to some appropriate care and allow the applicable ethics committee to consider the arrangements for posttrial care. Interestingly, the WMA did not admit that it was changing its position, but rather described its clarification as a reaffirmation of its previous position (World Medical Association, 2004, para. 30, note).
In the 2008 version of the Declaration of Helsinki, the statement on this issue provides that at “the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits” (World Medical Association, 2008, para. 33).
One example of a dispute over responsibility for posttrial care arose from a proposal to test Tenofovir on female sex workers in Cambodia. The purpose of the proposed trial was to determine if Tenofovir would be effective in preventing HIV infection. However, some of the sex workers in Cambodia protested against the trial. In addition to requesting additional information and better compensation, they requested long-term health insurance for participants in the study (Cha, 2006). In the following excerpt from an article by Kao Tha and colleagues, this controversy is described from the perspective of the potential subjects of research.
Excerpt from “The Tenofovir Trial Controversy in Cambodia: Can a Trial Be Considered Ethical If There Is No Long-Term Post-Trial Care?”
By Kao Tha and Others
The Women’s Network for Unity (WNU) was established in June 2000 by a group of sex workers for sex workers. It provides a foundation for support and builds solidarity and self-empowerment among sex workers….
The first ever Cambodian sex worker–planned and run press conference was held in Phnom Penh on March 29, 2004. The network expressed its opposition to an experiment which is recruiting healthy female sex workers to test an anti-HIV drug, Tenofovir DF, and find out if it is safe to use on HIV-negative women and whether it would reduce the risk of HIV infection. Similar drug trials are starting soon in Ghana, Cameroon, Nigeria and Malawi The researchers are looking for 960 Cambodian sex workers who are HIV-negative to take a pill once a day for one year in exchange for free medical services, counseling and $3 per month. Testing is due to start in the summer of 2004.
The WNU is against the use of sex workers for experimentation in a poor country like Cambodia, especially when the drug has only been tested on healthy monkeys—never on healthy humans. Side-effects of the drug when given as AIDS treatment are diarrhoea, nausea, tendency to major liver and kidney failure and “brittle bone” disease (osteoporosis). According to WNU President Kao Tha, many sex workers worry about being the first healthy humans to test the drug and are worried about the side-effects of taking a drug for prevention purposes: “They said they don’t want to try the drug because they are poor and they are sex workers If they fall ill, who will look after their mothers, children, sisters or brothers? If the researchers are so sure that this drug is safe for HIV-negative women to take, in the short and long term, why won’t they commit to insurance for us and our families? If we get sick or can’t work it can be the difference between life and death for our families”.
What WNU wants
The network wants insurance against possible side-effects of Tenofovir for 30 or more years and not just health care for the duration of the trial. When the researchers are finished and leave Cambodia who will take responsibility for sex workers and their families who may be suffering longer-term side-effects?
WNU believes that all sex workers who participate in the trial have the right to ask questions and be fully informed about the risks and to demand better medical and financial protection. Must poor sex workers in Cambodia take the risk of taking Tenofovir, withstand the side-effects, sacrifice health and income for $3 month and no longer-term guarantees?
If our members agree to take the risk, which may one day benefit people in richer countries and the drug company, then we deserve adequate protection for our future lives and our families. The high cost of this drug means that, even if it is successful in preventing HIV, Cambodian sex workers will never be able to afford it….
Source: Excerpted from “The Tenofovir Trial Controversy in Cambodia: Can a Trial Be Considered Ethical If There Is No Long-Term Post-Trial Care?” by Kao Tha and others, 2004. Research for Sex Work, 7, 10–11. Copyright 2004 by Vrije University Medical Centre in the Netherlands. Reprinted by permission
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