When new drugs and medical devices are developed, they need to be tested on humans to ensure their safety and effectiveness. Clinical trials—the tightly regulated and carefully controlled tests of pharmaceuticals in large groups of people—raise many ethical challenges. Some of these challenges revolve around the individuals participating in research: Are people being coerced? Are the clinical trials designed appropriately? Are researchers meeting their obligations and behaving ethically?
Other challenges are more difficult to address because they are embedded in existing institutional practices and policies: Is it ethical to include or exclude certain groups as human subjects in clinical trials based on their nationality, income, or health insurance status? What are the responsibilities of researchers to human subjects and to communities after the clinical trials have concluded? Still further challenges arise as the locations of clinical trials shift from university medical centers to profit-based research centers and as more studies are outsourced to developing countries. The history of abuses to human subjects in the United States has profoundly shaped the range of debates regarding ethical research practices and federal regulation of the research enterprise.
I. Deception and Coercion
II. Informed Consent
III. Ethics of Study Design
IV. Ethical Considerations of Globalization
Deception and Coercion
Until the 1970s, deception and coercion of human subjects were common strategies used to enroll and retain individuals in medical research. A landmark case was the U.S. Public Health Service’s four decades of research on syphilis in rural African American men in Tuskegee, Alabama. In the Tuskegee study, the subjects were told that they were being treated for “bad blood”—the local term for syphilis—even though they were actually not receiving any treatment at all. Instead, the U.S. Public Health Service was interested in watching syphilis develop in these men until their deaths so as to gain an understanding oft the natural course of the disease when left untreated. At the start of the study in the 1930s, there were no cures for syphilis. During the course of the research, however, penicillin was identified as an effective treatment. Still, the men did not receive treatment, nor were they told that they could be cured.
In response to the public outcry following an expose on Tuskegee as well as other unethical uses of human subjects, the U.S. Congress passed the National Research Act of 1974. It established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, a group charged with outlining ethical principles to guide research and recommending ways to regulate it.
By the beginning of the 1980s, the U.S. government had enacted regulations to protect human subjects from potential research abuses. These regulations requires that all participants provide their informed consent before participating in any study, that the risks and benefits of each study be analyzed, and that all research protocols be reviewed and overseen by external reviewers. Today’s institutional review boards (IRBs) are mandated by this regulation. IRBs are research review bodies at universities and hospitals and in the private sector; they exist to ensure that researchers are following regulations, obtaining informed consent, and conducting ethical and scientifically rigorous research.
The requirement of informed consent is the primary means of protecting against the deception and coercion of human subjects. Researchers are required to provide detailed information about their studies, particularly about any potential risks and benefits, to all participants in the study. The participants or their guardians are required to sign the consent document confirming that they have read and understand the risks and benefits of the trial. Informed consent is meant to ensure that human subjects’ participation in clinical research is voluntary. Unfortunately, informed consent has become largely procedural in many research contexts. Although the research trials are often long and complex, human subjects are often informed about the study and prompted for their consent only once, prior to the start of the trial. In response, many bioethicists are calling for a new configuration of informing participants and attaining their consent, a configuration that would treat informed consent as a process that is ongoing throughout the length of a clinical trial.
Although a revision of informed consent may certainly be necessary, it cannot address larger structural issues that must also be examined. Human subjects participate in research for many reasons. Some participate in the belief that research can provide a cure for illness. Others participate because they have limited or no health insurance and can gain access to medical care while participating in the trial. Still others participate for the sake of income in the form of study stipends. These reasons often take precedence over the specific details contained within an informed consent form. In fact, there is currently much debate about the extent to which human subjects should be remunerated for their participation in clinical trials. Because cash incentives may be coercive, many bioethicists argue that the amount of money human subjects receive should cover only those costs—such as transportation and parking, babysitters, time off from work— that are incurred from participation. In any case, the current regulatory environment is not structured to respond to the complex reasons that human subjects might have for enrolling in clinical trials.
Ethics of Study Design
The ethics of clinical trials extend beyond the voluntariness of human subjects’ participation. The designs of the clinical trials themselves is also subject to scrutiny for ethical concerns. Nowhere is this more obvious than in discussions about the use of the placebo—or an inert sugar pill with no inherent therapeutic properties—in clinical research. Placebos are valuable tools in clinical research because they provide a controlled comparison to the treatment or therapy being studied. In other words, clinical trials can compare how human subjects’ conditions change based on whether they received the treatment under investigation or a placebo. This protocol design becomes problematic because there are instances when it might be considered unethical to give human subjects placebos. Some illnesses should not be left untreated regardless of the scientific merit of the study design. In the case of other illnesses, there are many safe and effective products for treatment already on the market, and some argue that clinical trials should measure investigational products against these other treatments in order to provide the best possible care to human subjects.
In order to determine what is ethical, the medical establishment uses the principle of “clinical equipoise” to guide decisions about clinical trials. Within this framework, the design of clinical trials is considered ethical when the various arms of the study—investigational product, old treatment, placebo, and so on—are considered clinically equivalent. In other words, if researchers have no evidence that the new product is better than a placebo or an older treatment, then it is ethical to compare those groups. If, however, there is evidence that one product might be superior or inferior to another, then it is no longer considered ethical to give human subjects a product known to be inferior.
Like many ethical principles, equipoise can be mobilized to guide the design of clinical trials. There are limitations, however, in its application. Importantly, the definition of what evidence counts to achieve equipoise is fairly loose, and the majority of clinical trials that are conducted are done using a placebo. Part of what shapes decisions regarding equipoise and even informed consent is the broader context of clinical trials, especially their funding sources. Since 1990 the pharmaceutical industry has shifted the location of clinical trials from university medical centers to private-sector settings, such as private practices and for-profit clinical research centers. Although the bulk of most clinical research continues to take place in the United States, the pharmaceutical industry is outsourcing more and more studies to the developing world, including countries in Africa, Asia, Eastern Europe, and Latin America.
Ethical Considerations of Globalization
Globalization over the past half century became an important development of economic growth. Proponents stress its benefits in terms of prosperity, while critics highlight the resulting economic disparities and worker exploitation, particularly in low- and middle-income countries. In the realm of clinical trials, pharmaceutical companies and device manufacturers made globalization a core component of their business models. This move raises important questions about the economics and ethics of clinical research. Further questions surface concerning the translation of trial results to clinical practice. At the cutting edge of this quagmire are three main concerns: Who benefits from the globalization of clinical trials? What is the potential for research subject exploitation? Are trial results accurate and valid and can they be extrapolated to other settings?
Some contend the future of the pharmaceutical and device industries is predicated on coming to terms with these questions. Does it sit squarely on the shoulders of the medical research community to voluntarily ensure the ethical and scientific integrity of clinical research globally, or is a law or international policy required? Medical ethicists have suggested that a comprehensive review, perhaps commissioned by the Institute of Medicine or the World Health Organization, is necessary to reach international consensus on these matters.
Both within the United States and abroad, the pharmaceutical industry relies on disenfranchised groups to become human subjects because of their limited access to medical care, their poverty, or their desperation for a cure for illnesses such as HIV/AIDS and other infectious diseases requiring treatment. As a result, the pharmaceutical industry’s practices regarding human subjects can sometimes be highly exploitative. The ethical dilemma that is created concerns the distribution of risks and benefits. Those who are most likely to enroll in clinical trials as human subjects are the least likely to benefit from the results of that research. Debates are currently ongoing about the need for researchers to provide care after the close of a clinical trial in order to make those relationships more reciprocal. Clinical trials create many ethical challenges, ranging from the ethical treatment of individual human subjects to the design and implementation of clinical studies and the distribution of risks and benefits of research within society. The design and conduct of clinical trials has been tightly regulated for several decades, but the changing profile of health care and developments in medical research give rise to new questions. Furthermore, as clinical research continues to grow as a profit-driven industry, ethical questions become increasingly challenging. Although there may not be straightforward or standardized answers to these questions, addressing them should be as important as the medical research that generates the need for clinical trials.
Jill A. Fisher
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