Introduction
Clinical research has been pivotal in improving human health over the last century. Understanding of human biology and therapeutic innovation are direct results of sound clinical research involving human volunteers. Responsible and careful planning and implementation of research protocols, guided by ethical values and principles, safeguard the very people that the research is intended to benefit. In this chapter, we provide a brief overview of the ethical principles underlying clinical research and the historical context that shapes current standards. We then address practical applications of these principles and explore emerging issues.
Human subjects protection is the centerpiece of clinical research ethics. In most countries, it is regulated by sets of laws and regulations that are shaped by ethical principles, but these form the bare minimal requirements of clinical research ethics. To understand the application of ethical values to clinical research, it is useful to consider the definition and scope of clinical research.
Research is a “systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge” (1). Clinical research is research that directly involves a person or group of people or material of human origin (such as tissues, specimens, or cognition) for which a researcher either interacts directly with human subjects or collects identifiable private information. Under US regulations, in vitro studies using human tissue not linked to a living person are excluded from the definition (2).
Clinical research can be further subdivided into patient-oriented research, epidemiological and behavioral studies, and outcomes and health services research. Patient-oriented research includes research on disease, therapeutic interventions, clinical trials, and development of biotechnologies. From a bioethics perspective, patient-oriented clinical research is the most vulnerable form of clinical research, because the use of human subjects is the basis of the experimental exercise. Participants in clinical research accept risks and inconvenience, often without obtaining direct benefit from their participation, mainly to advance science and benefit others. Therefore, for persons to be willing to participate and for funding to be provided for such research, the design, implementation, and dissemination of findings must be conducted according to the highest ethical standards.
Current understanding of clinical research ethics is guided by several codes of conduct, often the legacies of tragedies in unethical human subjects research (see Chapter 1). These codes of conduct include the Nuremberg Code (3), the Declaration of Helsinki (4), the Belmont Report (5), and the International Conference on Harmonisation Guidances on Good Clinical Practices (ICH-GCP) (6). In the United States, titles 21 and 45 of the Code of Federal Regulations (CFR) (1) provide guidance for human subjects research. To gain a better understanding of these principles, it is important to consider their historical context.
As discussed in Chapter 1, one of the earliest clinical research projects was the study of scurvy attributed to James Lind, a British Royal Navy surgeon in the mid-1700s (7). In addition to Lind’s contribution to medical science of controlled experimentation methods, his practice of experimental observation was novel at the time. The notion of performing experiments directly on human subjects to determine the cause of diseases and superiority of treatment options was certainly not the norm and, to most people at the time, simply immoral.
This attitude persisted for more than a century and led to scrutiny of early human experiments in microbiology and immunology by Edward Jenner, Louis Pasteur, and Walter Reed. In Reed’s classic experiments on yellow fever transmission, he and his colleague, Jesse William Lazear, intentionally inoculated healthy subjects who had volunteered. All of the subjects were willful participants who were informed of the risks and purpose of the experiments, set out in written documents signed by each volunteer. This early example of written informed consent was viewed by some of his contemporaries as adequate to justify its morality (8,9). However, the modern concept of informed consent in clinical research would be cemented only after tragedies occurred decades later. The key incidents shaping our modern conception of research bioethics include the Tuskegee syphilis study, the Nuremberg trials, and the Willowbrook hepatitis study.
The Tuskegee syphilis study, conducted by the US Public Health Service in Macon County, Alabama, has become a classic case study for bioethics in clinical research. The study started in 1932 with a goal of studying the natural history of untreated syphilis. African American men were the research subjects. This observational study continued until 1972 without offering widely available penicillin as treatment to the participants. The study ended only after a news report in the Washington Star drew public attention. Although public debate about the study included allegations of racism as a motivation, several bioethical violations were highlighted in this case. First, the men in the study were recruited from a socially disadvantaged rural community. They were misled or coerced into the study under the impression that the study visits and procedures were part of free treatments and health checks that would otherwise not be available to them. Furthermore, subjects were not given adequate information about the potential hazards and long-term consequences of untreated syphilis to provide informed consent for participation. Most important, the researchers insisted on continuing the trial and withholding effective treatment for syphilis, even after the efficacy of treatment and long-term complications of the condition were known (10,11).
At the conclusion of World War II, the atrocities committed against concentration camp inmates by Nazi doctors in the form of inhumane experiments were brought to light during the 1947 Nuremberg Military Tribunal. Twenty-three doctors and scientists were brought to trial, and 15 were convicted (12,13). The tribunal’s final judgment included a 10-point statement, later known as the Nuremberg Code, that delineated permissible medical experimentation on human subjects. The code can be summarized as follows, with voluntary consent at its core (14):
Voluntary consent of the research participant is essential.
The experiment should yield important results that are good for society and are not otherwise producible.
The experiment should be based on prior animal experiments and knowledge that the results will justify the experiment.
The experiment must minimize harm to participants and have a favorable risk–benefit ratio.
Adoption of the Nuremberg Code was limited among medical researchers at the time, and there was no mechanism for enforcement.
In 1956, Krugman and colleagues led a study of infectious hepatitis at the Willowbrook State School, a New York institution for children with mental retardation. The goal of the study was to investigate the natural history of infectious hepatitis, which the researchers claimed was highly prevalent at Willowbrook. The researchers deliberately infected the children with viral hepatitis and observed the natural history and response to immunoglobulin. The researchers claimed that they obtained informed consent from the children’s parents and that they did not enroll children without parents or those who were wards of the state. Parents were also allowed to withdraw consent at any time. However, evidence suggests that parents were coerced into providing consent in exchange for admission of their children into the institution. Records also suggest that the managers of the institution manipulated the situation by creating a shortage of available residential space. Finally, the researchers attempted to justify inoculation of the participants by claiming that the prevalence of hepatitis was so high in the cohort that they were creating a controlled scenario, which they deemed inevitable given existing conditions at the institution (15–20). This case highlighted the risk of vulnerable populations being exploited for human subject research, and the concerns raised about the validity of an informed consent provided under undue pressure.
In 1964, in response to the increasing prevalence of human subjects research, the World Medical Association published recommendations on ethical principles for physician–researchers, known as the Declaration of Helsinki (21). The guidelines highlighted fundamental differences between the therapeutic role played by treating physicians and the investigational role played by physician–researchers. The declaration has been amended several times, most recently in 2008 (22). In addition to the concepts of voluntary consent, favorable risk–benefit ratio, and sound study design, the statement emphasizes the need for independent ethical review of proposed research protocols.
In the wake of ethical controversies in biomedical research in the 1960s and 1970s (23), authorities in the United States took several steps to improve the standards of human subjects research. One major advancement was the National Research Act of 1974 and resulting formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This commission issued the Belmont Report, a guidance document for human subjects research that distinguishes therapeutic medicine from research, identifies fundamental ethical principles for protecting research participants—respect for persons, beneficence, and justice—and describes how those principles should be applied (5).
Ethical Principles
The ethical principle of respect for persons rests on both the concept of autonomy and the importance of protecting vulnerable persons. Autonomy is a person’s ability to make decisions without inappropriate interference or obstruction. Autonomy also requires ensuring that the person’s choices are respected unless they are harmful to others. The principle of respect for persons also acknowledges that not all persons are capable of self-determination, whether because of age, illness, intellectual or mental disability, or socioeconomic circumstances that limit one’s liberty. For members of such vulnerable populations, appropriate respect and protection is required, and protections for these populations vary based on circumstance.
In the context of clinical research, respect for persons is the foundation of voluntary participation. Potential research participants must be allowed to provide voluntary informed consent before participating in a research study (5).
Beneficence is the obligation to maximize potential benefits and minimize potential harms. In clinical research, investigators must ensure that the study design is scientifically sound and minimizes risks for participants. In studies in which the aims of the research are to determine safety or efficacy of an intervention, an independent ethical review must determine whether the study can be implemented despite the potential risks. Moreover, investigators must establish adequate monitoring processes during the study to minimize risks and must exclude potential participants who are at inappropriately greater risk of harm (23).
This principle refers to the need to ensure that the costs and benefits of the research are distributed fairly. Vulnerable populations have at times borne the burden of participation in risky research—as summarized in the historical examples above—but often are the least likely to benefit from new therapeutic discoveries. More recent concerns about justice extend to our understanding of the benefits of clinical research in providing better data for medical decision making. For example, the US National Institutes of Health (NIH) requires the research funds to have adequate representation of traditionally underrepresented groups, such as women, children, and racial/ethnic minorities, when possible to help develop data about the external validity of clinical trial results for these populations.
Practical Applications
To ensure that a clinical research study is ethical, investigators and regulatory authorities must consider every aspect of the study in light of the principles of autonomy, beneficence, and justice, in addition to any societal or cultural values and governmental regulations that may apply. Such assessment should be undertaken throughout hypothesis generation, study design, site selection, participant recruitment, and data analysis.
Research participants should be enrolled in a study only voluntarily and after making an informed decision. Now a universally accepted standard of practice in clinical research, the informed consent process highlights the principle of respect of persons. In United States, this process is mandated by regulations for federally funded research (24). It includes disclosure of information to the potential participant, comprehension of that information by the participant, and voluntariness of the person’s decision to participate (25). Informed consent is an ongoing process of communication and consent; the informed consent document is a record of this process.
Researchers must disclose details about the research study to potential participants, including:
The objective and rationale of the study.
The duration of follow-up, the commitment required of the participant, and the procedures involved, with special attention to experimental procedures.
Clear descriptions of the risks of participation, potential benefits (including clear explanation of the role of placebos), and available therapeutic alternatives.
Full disclosure of the investigator’s role in the study, especially if the investigator also provides clinical care for the potential participant.
A crucial component of the informed consent process is an adequate understanding by the potential participant of the information provided about the research. The information should be provided in clear, understandable language (including translation for non–English-speaking participants). Potential participants should have adequate time to consider the information and opportunities to ask questions of study personnel. Researchers should recognize that potential participants might have therapeutic misconceptions about the study; examples of especially vulnerable scenarios are when placebos are used, early-phase clinical research in oncology (26), and psychiatric research (27,28). Efforts to improve potential participants’ understanding with the use of multimedia technology have yielded mixed results, but they may be particularly helpful in certain population, such as those with mental illness (29).
Informed consent should be obtained only after the potential participant is well informed and can make a voluntary judgment about participating. Potential participants should be under no undue influence or coercion. Financial incentives, limited access to healthcare for underprivileged populations, and fear of damaging the physician–patient relationship when the researcher is the usual care provider are some of the factors that can contribute to inappropriate influence on persons considering participation in research.
Some prospective participants might not be able to provide informed consent; examples include children, adults with diminished mental capacity, and patients in intensive care settings. If the research poses minimal harm (such as an observational study) or involves only noninvasive sample collection, informed consent by a legally authorized proxy can be straightforward. However, when experimental interventions are involved and they pose more than minimal harm, greater diligence is required. Respect must be shown for potential participant’s prior interests and values when possible. Study design and scientific importance should be reviewed with extra scrutiny by the ethical review committee to ensure that the study cannot instead be performed in a population for whom direct informed consent is feasible. Research involving children should have the potential for direct benefit to the child. However, if such benefit does not exist, the study should not pose more than minimal harm and must be likely to generate results that will benefit others with a similar condition.
In rare situations or when obtaining informed consent is not feasible (such as due to time constraints), the requirement of informed consent might be waived. These situations usually arise in research concerning emergency or life-threatening situations, and when no proven or effective treatment option exists. Consent must be infeasible because of the timing of the intervention. In acute-care interventions, the short time window may preclude identification of a proxy. In such scenarios, a physician not involved in the research must agree that no other reasonable alternative exists.
Research that requires no intervention or interaction with the participant or use of the participant’s identifiable private information also might be exempted from requirements for informed consent (24).
One important method for ensuring that research is ethically sound is to require review of the study by independent parties not directly involved in the research (25). This review includes assessments of the scientific validity of the study design and of the human subjects protections in the protocol, especially the consent process. Most research guidelines and regulations on ethics mandate that an institutional review board (IRB) or local ethics committee conduct an independent review. In the United States, establishment of IRBs is required by the National Research Act of 1974 and by Food and Drug Administration (FDA) regulations issued in 1981 (32).
IRBs have traditionally been decentralized, with local review committees most commonly associated with hospitals and academic centers involved in human subjects research. The usual composition of committees has included members from various backgrounds, including researchers, members of the general public, and members with legal and ethics expertise. The IRB reviews studies before their implementation, assessing the research protocol, informed consent forms, and any participant recruitment materials. The review is intended to ensure that the protocol will select appropriate participants and have a favorable risk–benefit ratio, and that the consent form presents the nature of the study and the commitment required of the participants clearly and accurately. The IRB reviews recruitment materials to prevent the use of misleading content. After an initial review, IRBs provide ongoing periodic oversight to assess protocol amendments, review changes to informed consent documents, and monitor unexpected events (32).
The traditional approach to human subjects protection has recently drawn criticism, as research seems to have outstripped the original design of the review system and as the definition and types of research have expanded. IRBs were originally configured locally because clinical research typically involved single study sites. Today, although large clinical research programs can involve thousands of patients at hundreds of sites around the world, protocol review still is typically required at the local level, even when local scientific expertise may be lacking. In addition to duplication of review efforts, the system lacks dedicated resources for ongoing assessment of safety, given the tremendous workload such duplication generates at the sites. Reforms to address these concerns include the development of central IRB mechanisms for multicenter clinical trials and the development of data safety and monitoring boards to monitor trials on an ongoing basis.
Many people are interested in the results of clinical research, including investigators who are concerned about career advancement, sponsors interested in drug approval and reimbursement, patients interested in access to new treatments, governments charged with holding down the costs of new technology, and the financial community interested in returns on investments in new medical technology. Those interested in the outcome of the study create the potential for conflicts of interest between actors in the system and the public interest in unbiased patient recruitment to clinical trials and unbiased reporting of research results (33).
In addition to financial conflicts of interest, physician–investigators must recognize the potential for conflicts in being both the physician responsible for providing clinical care and the research investigator focused on generating scientific knowledge. The two roles are different, a conflict that has the potential to jeopardize trust in a physician–patient relationship. The blurring of the two roles also can accentuate the “therapeutic misconception” by participants, as discussed earlier (34).
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