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Case example
Mr. Simpson, a high school biology teacher, is a community member of the Institutional Review Board (IRB) at University Medical Center (UMC), the nearby academic medical center. (US federal regulations require that health care institutions establish IRBs to review and approve all publicly funded biomedical research on human subjects conducted at the institution.) At today’s meeting of the UMC IRB, members are considering a research proposal entitled “Angina Pain Relief and Outcome Network Study,” or APRONS. Dr. Russell, Professor of Cardiology, explains that APRONS is a proposed multi-institution clinical trial of treatments for patients with stable coronary artery disease (narrowing of the arteries of the heart), and that he will be the lead investigator of this study at UMC. The study intends to enroll as research subjects more than 2000 patients with this condition over a period of three years. Patient-subjects will be randomly assigned to receive one of the following three interventions:
1. Optimal medical (drug) therapy to relieve angina (severe chest pain caused by inadequate blood supply to the heart) and to control progression of the disease.
2. Percutaneous coronary intervention (PCI), also called coronary angioplasty – a procedure in which a clinician feeds a catheter (a flexible tubular instrument) from an artery in the patient’s leg through the blood vessels into an artery of the heart, then inflates a balloon to dilate that artery. When the balloon inflates, it implants an expandable wire mesh tubular device, called a stent, inside the artery. The expanded stent remains in the artery to keep it open. Subjects in this group will receive optimal drug therapy after PCI.
3. Sham PCI – a similar procedure in which a clinician feeds a catheter from an artery in the patient’s leg through the blood vessels into an artery of the heart, but then removes the catheter without any additional intervention. Subjects in this group will receive optimal drug therapy after the sham procedure.
Patient-subjects in groups two and three will not be told which of the two procedures they have received until the study is completed. All study subjects will receive identical counseling and support for lifestyle changes to prevent disease progression, including smoking cessation, exercise, and diet. The investigators will follow these patient-subjects over the next four years and will compare the effect of the three interventions on three outcomes: chest pain, myocardial infarction (heart attack), and patient death from cardiac or vascular causes.
Mr. Simpson has several reservations about this proposed research. He knows that the first two treatments are already in wide use for patients with heart disease, and so he wonders why they need further investigation. He is especially concerned about the third intervention. How, he wonders, can the investigators justify an invasive procedure that has clear risks, but does nothing to treat a patient’s partially obstructed coronary artery? Given these concerns, Mr. Simpson is unsure whether he should vote to approve or reject the APRONS study proposal.
An obvious and fundamental goal of health care professionals is the provision of beneficial treatment to patients suffering from illness, injury, or disability. This is not their only goal, however. Consider, for example, this statement from the fifth principle of the “Principles of Medical Ethics” of the AMA: “A physician shall continue to study, apply, and advance scientific knowledge …”1 This principle asserts a duty to advance scientific knowledge, and it makes no mention of patients. Contemporary physicians, and most other health care professionals, receive extensive training in the biomedical and behavioral sciences. Acting as scientists, they contribute to knowledge by engaging in research, defined as “a systematic investigation including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.”2
Why does the AMA assert a fundamental responsibility of physicians to advance scientific knowledge, presumably through biomedical research? One rationale might be the intrinsic value of knowledge, based on our innate curiosity about ourselves and the world around us. This rationale supports basic research in all of the sciences – physical, biological, behavioral, and social. A second, and perhaps more compelling, rationale for research by physicians and biomedical scientists links research to the fundamental medical goal of providing beneficial treatment for patients. Research in the biomedical sciences is essential to understanding the structure and function of our bodies and the causes and effects of disease and injury. That understanding, in turn, can enable the development and evaluation of new and more effective treatments to cure or ameliorate disease and injury. Because research plays an essential role in achieving the goals of health care, the AMA recognizes participation in advancing scientific knowledge through research as a fundamental professional responsibility of physicians.
Investigators engage in biomedical research in several different settings. Laboratory, or “bench,” research examines biochemical and physiological processes in living cells and tissues “in vitro,” that is, “in glass,” in a controlled laboratory environment outside of the organism. Animal research examines biological processes and the effects of drugs and other interventions on animal subjects, usually housed in a protected environment. Finally, human subjects research examines biological processes and therapeutic interventions in human beings, including both healthy research subjects and patients with illness or injury. Each of these types of research makes essential contributions to scientific knowledge, and each raises significant ethical questions. Bench and animal research serve the therapeutic goals of health care by increasing our understanding of basic biological processes and by identifying promising candidates for effective treatment of disease and injury. Tissues in vitro and animal subjects are significantly different in their structure and function from living human beings, however, and therefore promising experimental treatments must also be tested on human subjects.
Bench scientists, animal researchers, and investigators performing studies on human subjects have multiple moral responsibilities in common. These responsibilities include honesty in the collection and reporting of research results and in the disclosure of errors, appropriate management of potential conflicts between scientific integrity and financial self-interest, and fairness in the allocation of credit for research contributions.3 Because health care professionals practicing in clinical settings most often engage in research on human subjects, and because this research poses especially serious ethical issues, the rest of this chapter will focus on human subjects research.
Two historical examples
As noted above, without biomedical research, including research on human subjects, to determine what treatments are effective, health care professionals cannot achieve their central goal of providing beneficial therapy for their patients. It seems obvious, therefore, that human subjects research is a morally permissible and indeed a morally praiseworthy activity. What, then, are the morally serious or controversial issues posed by this research? Two notorious twentieth-century examples, research on concentration camp inmates in Nazi Germany during World War II, and US Public Health Service research on black patients with syphilis in Alabama, provide compelling evidence of unethical practice in research on human subjects. A brief review of these examples shows how research on human subjects can violate fundamental moral norms.
Nazi medical research
During World War II, Nazi military physicians stationed at concentration camps in Germany and its occupied territories carried out a wide variety of research studies on inmates of those camps.4 Medical research was one function of the camps, along with forced labor and their primary function of extermination of so-called “inferior races” under the Nazi racist ideology, a morally repugnant event now identified as the Holocaust. Many of these research studies had overtly eugenic or military purposes that were highly morally suspect – they included studies of new methods for sterilization and execution, studies of conditions affecting military personnel, such as rapid decompression from high altitude, immersion in cold water, and exposure to infectious diseases, and studies of the relative role of genetics and environment in identical twins. The physician-investigators conducted this research on prisoners without their consent. Most of the studies inflicted severe injury and great suffering, and many included the intentional killing of the subjects.
The Nuremberg “Doctors’ Trial,” conducted by a US Military Tribunal in 1946–1947, prosecuted twenty physicians and three other defendants for murder and other war crimes, based on their roles in medical research conducted at Nazi concentration camps.5 At this trial, US prosecutors presented detailed evidence about these experiments, emphasizing the grave injuries, severe suffering, and death intentionally inflicted on thousands of the research subjects. Sixteen of the defendants were convicted, and seven were sentenced to death. In their published judgment, the Doctors’ Trial judges articulated a set of ten principles for the protection of human research subjects.6 That declaration, called the Nuremberg Code, asserts the rights of subjects to consent to and to withdraw from research studies, and the duties of investigators to insure that their research has appropriate goals and a scientifically valid design and that it protects subjects from grave or unnecessary harms.
Tuskegee syphilis study
In 1932, the US Public Health Service initiated a long-term study of the natural history of untreated syphilis, a common and serious sexually transmitted infection.7 The study subjects were poor black sharecroppers and laborers with latent syphilis in Macon County, Alabama. Subjects were deceived about the purpose of the study. Told that they were being treated for “bad blood,” the subjects were in fact deliberately denied treatment for syphilis, and were prevented from receiving treatment elsewhere, even after a highly effective treatment, the antibiotic penicillin, became widely available in the early 1950s. Subjects agreed to participate in the study in exchange for free meals, free medical examinations and treatment for minor conditions at the Tuskegee Veterans Hospital, and burial insurance. Investigators examined the subjects annually to observe the progression of the disease and conducted autopsies to determine the cause of their deaths.
The study continued until 1972, when The New York Times published a front-page article, “Syphilis Victims in U.S. Study Went Untreated for 40 Years,” by investigative reporter Jean Heller.8 Public revelation of the Tuskegee Study evoked a storm of criticism and condemnation, a formal investigation by the US Department of Health, Education, and Welfare, and congressional hearings conducted by Senator Edward Kennedy. In 1974, the federal government awarded more than nine million dollars to the surviving study subjects in an out-of-court settlement.9 Also in 1974, Congress created a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to recommend moral and legal guidelines for research on human subjects.10 In the four years of its existence, the National Commission published ten reports with recommendations on the protection of research subjects. In 1997, twenty-five years after the Tuskegee Study was halted, President Bill Clinton issued a formal apology to the study subjects and their families on behalf of the US government.11
Although the Nazi concentration camp research and the Tuskegee syphilis study are perhaps the most infamous cases of abuse of human research subjects, they are only two of multiple examples in the medical and bioethics literature.12 How, then, can the substantial benefits of research on human subjects be achieved while also respecting the interests and rights of the subjects? The next sections will examine criteria and procedures for the protection of human research subjects.
Criteria for human subjects research
The years since the publication of the Nuremberg Code in 1947 have seen the adoption of multiple codes of human subjects research ethics, including the Declaration of Helsinki of the World Medical Association (adopted 1964, last revised 2013) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects of the Council for International Organizations of Medical Sciences (adopted 1982, last revised 2002).13 The United States and many other nations have enacted multiple regulations for the protection of human subjects; the set of basic US regulations has the informal title “The Common Rule.”14 These codes and regulations identify a number of basic criteria for morally permissible research on human subjects, including informed consent, risk-benefit assessment, confidentiality, and equitable selection of subjects. Let’s examine each of these criteria in turn.
Informed consent
As described above, Nazi researchers forced concentration camp prisoners to participate in harmful and often lethal experiments. The first principle of the Nuremberg Code asserts a clear response; it states that “the voluntary consent of the human subject is absolutely essential.” As in the case of clinical care (see Chapter 8, “Informed consent to treatment”), informed consent has become a moral and legal cornerstone of research on human subjects. Because the major goal of research, namely, acquiring new knowledge, is significantly different from the primary goal of treatment, namely, benefiting the patient, requirements for informed consent in the two contexts are also different. The US Common Rule, for example, requires that investigators provide the following eight specific types of information to potential research subjects as part of the informed consent process:
1. a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
2. a description of any reasonably foreseeable risks or discomforts to the subject;
3. a description of any benefits to the subject or to others which may reasonably be expected from the research;
4. a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;
5. a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained;
6. for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatment are available if injury occurs and, if so, what they consist of, or where further information may be obtained;
7. an explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject; and
8. a statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.15
With this information, potential subjects can make their own voluntary and informed decisions about whether to participate in research, based on their evaluation of the purposes of the research, the expected risks and benefits of the research to them, and alternative treatment options. Just as there are generally recognized exceptions to the duty to obtain patient informed consent to treatment, however, there are also exceptions to the duty to obtain subject informed consent to participation in research. Some potential subjects, including fetuses, children, and adults who lack decision-making capacity, cannot give informed consent. Prohibiting all research on these subjects would protect them from research-related harms, but it would also make them “therapeutic orphans,” that is, it would deny them the benefits of research to develop and provide new treatments designed specifically for them. Research codes and regulations, therefore, generally permit informed consent by authorized surrogate decision-makers for patient-subjects who lack decision-making capacity, often with additional restrictions to protect these more vulnerable subjects from exploitation or harm.
The Common Rule also recognizes that some types of morally justifiable research could not be conducted without alteration or waiver of some of the elements of informed consent. One prominent example is research on new techniques in the emergency treatment of sudden illness or injury. In this circumstance, the eligible patient-subjects have usually lost decision-making capacity, surrogates are generally not available, and interventions must be initiated very quickly. New regulations were adopted in 1996 to permit waiver of informed consent in emergency medicine research, provided that investigators satisfy multiple other conditions designed to protect the interests of the subjects of this research.16
An ongoing problem in obtaining informed consent to participation in research is a phenomenon called ‘the therapeutic misconception.’ This term was coined to describe the persistent belief of patient-subjects that the primary purpose of the treatment they will receive in a research study is to benefit them individually, as would ordinarily be the case in clinical care outside a research study.17 This belief often persists despite investigators’ efforts to explain that one major purpose of research is to generate new knowledge and that research methods, including randomized assignment to different treatment groups, the use of control groups that will receive a placebo or a sham therapy, and double-blind procedures in which neither the investigator nor the patient-subject knows which treatment the subject is receiving, are not designed to benefit subjects and may not in fact serve their best interests. Appelbaum and colleagues suggest that one explanation for the strength of the therapeutic misconception is the implicit expectation of patients that their physicians will always act in their best interests.18 To overcome this expectation, investigators must convince their patient-subjects that the goals and procedures used in a proposed research study are significantly different from those of clinical care. Study information should clearly identify the risks of participation, in addition to any potential benefits. To distinguish the research endeavor from clinical care, this information could be provided by a person other than the patient’s physician, and the patient-subject’s understanding of the information could be assessed by posing questions about research goals and methodology. Insofar as the therapeutic misconception may increase the number of patients willing to enroll in a research study, however, physician-investigators may be reluctant to make great efforts to overcome it and thereby undermine their own interest in recruiting research subjects.
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