Module 1

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Module 1: History of Research Abuse of Human Subjects

Institutional Review Board (IRB) Training for Research Involving Human Subjects

Learning Objective: This lesson covers several well-known instances of unethical research involving human subjects, and provides a historical context for why ethical and regulatory requirements for the conduct of research have been developed over the last 50 years in the United States. Upon completion of this lesson, you should be able to recognize some of the historical ethical violations in research that influenced the development of ethical principles and legal requirements currently governing human subjects research.

History

Until the middle of this century, concerns about the ethics of the practice of medicine centered around therapeutic medicine, not research medicine. National and international efforts to protect the rights and welfare of human subjects of research have occurred often in response to ethical violations -- situations in which researchers were found to have ignored the fundamental rights of human subjects. The Nazi Party in Germany committed egregious acts in the name of science that shocked the world community

Infamous Cases - Nazi War Crimes

In order to ensure the supremacy of the Aryan Race, the Nazi party in Germany desired to find a secret way of sterilizing large populations. Three experiments involving sterilization were in progress when WWII ended in 1945.

1. Dried plant juice was put into flour that was fed to the general population. This was supposed to sterilize women predominately.

2. Intrauterine injections of a silver nitrate solution were given to women, without their consent during routine physical examinations.

3. Men stood at a counter to complete forms while being exposed without their knowledge to sterilizing doses of X-radiation.

In addition to sterilization experiments, Nazi physicians and researchers were under great pressure to develop an effective vaccine for typhus fever to administer to German troops. At Buchenwald concentration camp, experiments were conducted in which prisoners were administered vaccine (or placebo) and then injected with blood from patients infected with typhus fever. Between 1942 and 1943 about 729 people were subjected to such experiments, and 154 died. In addition, other prisoners served as a “passage group.” In order to keep the virus virulent and alive, the researchers would inject the virus into prisoners, when these people developed the acute illness, their blood was removed and injected into other prisoners.

The horrors of the preceding and many other “experiments,” were exposed during and after WWII. The people who conducted these experiments were tried separately from other Nazi war criminals because of their professional status as physicians and researchers, and because of the atrocious nature of their crimes.

During the trial at Nuremberg, fundamental ethical principles for the conduct of research involving humans were codified into the Nuremberg Code, which sets forth ten conditions that must be met before research involving humans is ethically permissible (e.g., the need for voluntary consent of subjects, a scientifically valid design that could produce fruitful results for the good of society).

The Nuremberg Code became the first international standard for the conduct of research. You can access it through the NIH web site at http://helix.nih.gov:8001/ohsr/

To date, little has been made of the data generated from the Nazi experiments. There is ongoing discussion in scientific and ethical communities concerning whether it is ethically permissible to use or publish the data.

Infamous Cases - The Willowbrook Study

From 1963 through 1966, studies were carried out at the Willowbrook State School for “mentally defective persons.” These studies were designed to gain an understanding of the natural history of infectious hepatitis and subsequently to test the effects of gamma globulin in preventing or ameliorating the disease. The subjects, all children, were deliberately infected with hepatitis virus; early subjects were fed extracts of stools from infected individuals and later subjects received injections of more purified virus injections. Investigators defended the deliberate injection of these children by pointing out that the vast majority of them acquired the infection anyway while at Willowbrook, and perhaps it would be better for them to be infected under carefully controlled research conditions.

During the course of these studies, Willowbrook closed its doors to new inmates, claiming overcrowded conditions. However, the hepatitis program, because it occupied its own space at the institution, was able to continue to admit new patients. Thus, in some cases, parents found that they were unable to admit their child to Willowbrook unless they agreed to his or her participation in the studies. This case caused a public outcry because of the perception that the parents and their children were given little choice about whether or not to participate in research.

Infamous Cases - The Jewish Chronic Disease Hospital Study

In 1963, studies were undertaken at New York City’s Jewish Chronic Disease Hospital to develop information on the human transplant rejection process. These studies involved the injection of live cancer cells into patients who were hospitalized with various chronic debilitating diseases.

Previous studies had indicated that healthy persons reject cancer cell implants promptly. Patients with widespread cancer also reject homografts, however, rejection is delayed substantially when compared with healthy subjects.

Researchers said that consent had been given orally, but was not documented. They felt that documentation was unnecessary since it was customary to undertake much more dangerous medical procedures without the use of consent forms.

Further, patients were not told that they would receive cancer cells because, in the view of the investigators, this would frighten the patients unnecessarily. Investigators defended this view on the basis that they had good cause to predict that the cancer cells were going to be rejected.

Infamous Cases - Radiation Tests on Mentally Impaired Boys

From 1946 to 1965, 19 boys who thought that they were participating in a science club were fed radioactive milk by researchers who wanted to learn about the digestive system. The experiments were performed at the Fernald State School in Massachusetts. Researchers from Harvard University and the Massachusetts Institute of Technology fed radioactive form of iron and calcium to the boys, sometimes in their breakfast milk, to study the body’s ability to digest minerals.

Infamous Cases - The Tuskegee Syphilis Study

This study was conducted in the U.S. and was designed to determine the natural history of untreated latent syphilis. Over 400 black men with syphilis and about 200 men without syphilis, who served as the controls, were the subjects. During the study, the men were told they were being treated for “Bad Blood.”

The men were recruited without informed consent. In fact, they were misinformed and told that some of the procedures done in the interests of research (e.g., spinal taps) were actually “free special treatment.” By 1936, it became apparent that many more infected men than controls had developed complications. Ten years later a report of the study indicated that the death rate among those with syphilis was about twice as high as it was among the controls. In the 1940’s, when penicillin, known to be effective in the treatment of syphilis became available, the men were neither informed of this, nor treated with the antibiotic.

The study continued until the first accounts of it appeared in the national press in 1972, at which time an ad hoc advisory panel was formed by the government to give advice on how to assure that such experiments would never be conducted again. The government continues to pay millions of dollars yearly to surviving subjects and the families of the deceased subjects. “Our challenge in the public health service is to create that system that people can trust, and to continue to strengthen that system,” said CDC Director Dr. David Satcher. In May of 1997, President Clinton issued a formal apology to the last eight survivors of the study.

Summary of Important Points in this Lesson

The three ethical principles of The Belmont Report are: Respect for Persons, Beneficence, Justice (The Belmont Report is the in-depth subject of another training module). In general, the cases that have evoked the greatest public outcry (such as those reviewed here) have violated or seemed to violate the requirements of all three of the fundamental ethical principles in the Belmont Report.

The research activities reviewed in this lesson imperiled the life or health of vulnerable or disadvantaged persons without their informed consent. It was infamous cases such as these and others that focused national attention on the need to protect human research subjects.