Research with human subjects

Among the most sweeping reform in the second half of the twentieth century was in the arena of medical research with human subjects. For much of medicine’s history, the improvement of care for patients has been through the trial-and-error method of experimentation. Few therapies, when initially applied, had any guarantee of success, and some were fraught with the risk of further injury or debilitation to the patient. Early medical researchers were practicing physicians whose small-scale experiments were conducted solely for therapeutic benefit. The goal of experimentation was undertaken not as much to benefit future patients as to heal the very individual under the immediate care of the practicing physician.⁵ Most research was, at least in its intent, benevolent and humanistic with the Hippocratic ideal of “doing no harm” providing the guiding norm of the experimenter’s conduct. Nonetheless, two key events revealed how flagrantly this norm can be ignored when the focus shifts to utilitarian goals other than the safety and welfare of humans.

Nazi Germany will forever be remembered for war crimes committed against the human race. Millions of victims lost their lives not only to the actual military conflict of World War II but also to the mass exterminations of innocent members of “undesirable” ethnic groups and other minorities. The techniques for these exterminations were perfected by Nazi physicians whose gruesome acts were later publicly revealed in the Nuremberg war criminal trials and documented by American observer Dr. Leo Alexander.⁶ The trials revealed how physicians and administrators conspired to engage in medical experiments, such as forced sterilizations, poisonings, the infliction of simulated combat injuries, exposure to infections and extreme weather conditions, and ultimately the refinement of euthanasia techniques on those deemed mentally or physically “defective.” There were approximately 275,000 victims over a 10-year span of time. After these staggering revelations, an international tribunal of judges developed what is known as the Nuremberg Code, a statement of 10 principles that govern the ethical conduct of medical experimentation with human subjects. At the heart of the code is that the “voluntary consent of the human subject is absolutely essential” and that freedom from coercion, force, duress, or deception be a condition of participation in any form of experimentation. Expanding the moral framework for the conduct of medical research in the Nuremberg Code, the World Medical Association adopted the Helsinki Declaration in 1964.

Unfortunately, the efforts of Nuremberg and Helsinki did not end the problems with human research. Even within the United States, these important principles did not filter into the consciousness or conduct of physician experimenters, which became all too apparent in the infamous research project now known as the Tuskegee Syphilis Study. From 1932 to 1972, the U. S. Public Health Service (USPHS), later known as the Centers for Disease Control and Prevention (CDC), engaged in a research study that involved 400 African American men in Macon County, Alabama. During the course of 40 years, what began as a small time-limited project to improve the treatment of syphilis among poor minorities expanded into a full-blown plan marked by deception and discrimination that yielded no new information about the disease and offered no bona fide treatment for subjects.⁷ When the study first began in the early 1930s, the treatment for syphilis consisted of a difficult regimen of arsenic and mercury vaccinations. Although the treatment offered some control, this method proved to be no definitive cure for the illness. The study was initiated with hopes of understanding the disease and finding the definitive cure, but evolved merely into an observation of how the disease progressed through its various stages, culminating in death in many cases.

Participants in the study were led to believe that they were being provided real treatment for what the physician researchers called bad blood, a euphemistic term for any kind of blood-related condition. Treatment amounted essentially to various placebos combined with painful nontherapeutic spinal taps. Subjects were induced to participate in the study through the offer of free treatment, meals, and transportation. Free burial insurance was promised on the condition that the research subjects permit an autopsy on their deaths for documentation of the effects of the end stages of the disease. Even after World War II, when the curative antibiotic of penicillin became widely available, subjects of the study were prohibited from receiving it so that researchers might continue to track the disease’s effects on the unsuspecting subjects’ bodies. The deception and coercion continued until USPHS investigator Peter Buxtun learned of the project from a colleague. Frustrated in his attempts to end the study by working within the USPHS, Buxtun turned to the press, and reporter Jean Heller broke the story in July 1972.⁸

The public and political outcry that followed the revelation of the study culminated in its immediate suspension and Congressional passage of the Federal Research Act of 1974, which created two significant entities.⁹ First, the act established what is now known as the Office for Human Research Protections, which mandates that all institutions that receive federal funding for research with human subjects maintain institutional review boards with oversight for the safety and ethical treatment of research subjects. Second, the act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The commission, composed of physicians, researchers, attorneys, theologians, and philosophers, was assigned to craft guidelines that would serve as a moral foundation for future human research regulation.⁵ By 1979, the commission had arrived at a policy statement known as the Belmont Report.¹⁰ The report highlighted three basic ethical principles that guide all medical research involving humans in the United States. The principle of respect for persons requires that participation in research be based on the voluntary informed consent of the subject of the study. The principle of beneficence calls for a comprehensive risk and benefit assessment that weighs the potential harm against the potential benefit to the current subjects or future patients. The principle of justice requires that research subjects be chosen equitably (unlike Tuskegee) and that a fundamental fairness in both benefits gained and risks incurred be shared by research participants. Justice also requires that the more vulnerable members of society, such as children, prisoners, pregnant women, and the mentally challenged, be given added protection in research.

Reforms and regulations that emerged from Tuskegee and the Belmont Report now ensure that essential elements be present in every medical or behavioral research study that involves persons. These elements are voluntary participation, informed consent, comprehension by the subject of the nature and purpose of the study, full disclosure of risks and benefits, disclosure of alternatives to participation in research (as in the case of treatment associated with clinical trials), and the option to withdraw from the study without penalty.

More recently, President Barack Obama authorized the Presidential Commission for the Study of Bioethical Issues to conduct a thorough review of domestic and international regulations on human subjects research to determine whether current rules still provide adequate protection. This directive occurs following the new revelations of unethical research in Guatemala from 1946 to 1948 in the U.S. Public Health Services Sexually Transmitted Diseases Inoculation Study.¹¹

End-of-life cases

Controversial patient care cases involving end-of-life decision making hold a prominent place in the development of the bioethics movement. Three cases are particularly noteworthy; all involved young women, each of whom was severely incapacitated and unable to participate in decisions regarding life-sustaining therapy. The first landmark case is that of Karen Ann Quinlan.¹² Karen was a 21-year-old woman in New Jersey who, in 1975, suffered a severe anoxic brain injury after an accidental overdose of alcohol and drugs. Karen never regained consciousness and remained dependent on a ventilator for breathing and a feeding tube for nutrition and hydration. Eventually, she was given the diagnosis of a persistent vegetative state (PVS), a neurologic condition characterized by a “complete unawareness of the self and the environment, accompanied by sleep-wake cycles with either complete or partial preservation of the hypothalamic and brainstem autonomic functions.”¹³ Patients with PVS display “eyes open” unconsciousness and may have gross involuntary movements, but do not respond to external stimuli or engage in any purposeful activity. After some months, Karen’s parents came to the realization that their daughter would likely never regain consciousness or the ability to have any meaningful interaction with others. Following what they believed would be her own wishes, they asked physicians to remove the ventilator and allow Karen to die a natural death. Karen’s physicians adamantly opposed this idea, believing this to be an act of euthanasia, or worse, murder. Karen’s parents then petitioned the courts, and her case eventually came before the New Jersey Supreme Court. The Supreme Court ruled in the parents’ favor on the basis that Karen had a fundamental right to privacy and the right not to have treatment continued against her will. The Court wrote that “the State’s interest (to preserve life) weakens and the individual’s right to privacy grows as the degree of bodily invasion increases and the prognosis grows dim. Ultimately there comes a point at which the individual’s rights overcome the State’s interest.”¹² Physicians slowly weaned Karen from the ventilator while continuing her tube feedings and hydration (Karen’s parents never asked for the removal of the tube). Remarkably, Karen lived an additional 10 years before she died in a nursing home in 1986.

A second landmark case is that of Nancy Cruzan, a case sometimes referred to as the first “right to die” case to go before the United States Supreme Court.¹⁴ In 1983, Nancy was a 24-year-old woman who lost control of her vehicle on an icy road late one night in Missouri. She was found lying face down in a ditch after being ejected from her overturned car. Nancy had stopped breathing and had no detectable heartbeat for a brief period of time. Rescue personnel intervened to restore her respiratory and cardiac function. Like Karen Ann Quinlan, Nancy had had an anoxic brain injury that led to the eventual diagnosis of a PVS. Nancy was eventually transferred from an acute care setting to a rehabilitation facility where, despite years of effort, no improvements were seen in her condition. Unlike Karen Ann, Nancy was not dependent on a ventilator but was similarly sustained with a gastrostomy tube for feeding and hydration. Four years after her injury, Nancy’s parents asked physicians to remove the feeding tube with the understanding that Nancy would die. They contended that Nancy had remarked about never wanting to be artificially sustained if she could not be “at least halfway normal.”¹⁴ Physicians resisted, and Nancy’s parents turned to the courts for help. The Supreme Court of Missouri ruled against them with the argument that sufficient evidence of Nancy’s true wishes did not exist to justify the withdrawal of life support, particularly in light of the consequence of death. Denial of the Cruzans’ wishes on Nancy’s behalf led to an appeal to the U.S. Supreme Court and set the stage for one of the most famous medical legal cases in U.S. history.

The U.S. Supreme Court received the case in December 1989 and issued a ruling in June 1990. In somewhat of a split decision, the Court, on Constitutional grounds, affirmed both certain rights and requirements for all parties in determining a course of action in cases like Cruzan’s. The Court acknowledged an individual’s right to refuse treatment, even such treatment as life-sustaining tube feeding and hydration. Yet the Court went on to say that the state of Missouri could require “clear and convincing evidence” that such refusal was made while that person was still competent. On these grounds, the Cruzan case was remanded to Missouri for further adjudication. The emergence of new evidence that indicated that Nancy would not have wanted life-sustaining treatment in her current condition led to a Missouri lower court permitting the withdrawal of the feeding tube. Nancy died in December 1990.

The Cruzan case, and the memory of the Quinlan case before it, propelled the creation of federal legislation designed for individuals to state their desire to refuse life-sustaining treatment under the conditions set forth by the Supreme Court, even if rendered incompetent and unable to communicate. The Patient Self-Determination Act of 1990 established on a national level the legitimacy of previously written advance directives as valid legal expressions of an individual’s desire for no treatment in end-of-life circumstances.¹⁵ These advance directives, often referred to as living wills (and in many states including durable power of attorney for health care decisions), in theory meet the “clear and convincing” evidence standard required by the U.S. Supreme Court. Currently, all 50 states recognize and honor some form of written advance directives. However, problems persist in these difficult cases in both the interpretation of generalized written statements and the infrequency of use among the public.^16,17 As the next case shows, the absence of clear communication and understanding among family members over end-of-life wishes in medical care sometimes yields disastrous consequences.

The case of Terri Schiavo is the most recent of the series of tragic end-of-life cases to be pushed onto the national stage.^18,19 Terri was a 26-year-old woman in 1990 when she had a cardiac arrest most likely as a result of an electrolyte imbalance from an ongoing eating disorder. Like Quinlan and Cruzan before her, she had a severe anoxic injury that rendered her a total care patient in a PVS for 15 years, dependent on a percutaneous endoscopic gastrostomy tube for nutrition and hydration. Early on in her care, Terri’s husband, Michael, and her parents, Bob and Mary Schindler, were united in efforts to keep Terri alive and restore her to some level of conscious functioning. Within a few years, Michael came to the conclusion that Terri would not make any recovery and sought to remove the feeding tube to allow Terri to die. The Schindlers, deeply religious, vehemently opposed this request. They believed that removal of the tube was an act of murder and that continued aggressive effort could restore Terri to wakefulness. The Schindlers also questioned the diagnosis of PVS; they believed that Terri both recognized and communicated with them in her own limited way.

Fundamental disagreement between Michael and the Schindlers over Terri’s fate led to a bitter and international public dispute waged in the courts for more than a decade. The Schindlers petitioned to have Michael removed as Terri’s guardian and garnered the support of the Florida state legislature and Governor Jeb Bush, who signed a one-time stay forbidding the removal of the feeding tube pending further legal appeal. On three separate instances, the U.S. Supreme Court refused to hear the case, each time affirming the appropriateness of lower court findings in favor of Michael Schiavo. In the end, Michael’s position as Terri’s guardian was upheld and the courts allowed the removal of the percutaneous endoscopic gastrostomy tube. Terri died on March 31, 2005, with her husband at her side. After her death, Michael permitted, at the request of the Schindlers, a neuropathologic autopsy that revealed severe atrophy of the brain. The official cause of death by the medical examiner was listed as “complications from anoxic encephalopathy.”²⁰