Before discussing the current system for the protection of human subjects in research, it is important to review some of the significant historical events that have influenced current ethical guidelines and US Department of Health and Human Services (HHS) regulations. This history has been abbreviated to two major research violations   that influenced subsequent human subjects protections, but there have been many more instances than the two discussed here:

• Nazi Medical Crimes
• Syphilis Study at Tuskegee

As a result of research violations over time, ethical principles and policies were developed and strengthened by governments and research organizations. These include:

• The Nuremburg Code
• APA ethical standards
• The Belmont Report
• Office of Human Research Protection at National Institutes of Health

Institutional Review Boards (IRB) for research involving humans were established to ensure that the benefits of proposed research outweighed the risks, and that human research subjects are treated with honesty, respect, and trust. IRB committees consist of five or more qualified members assigned to review research done by an organization such as a college, medical facility, or government agency.

Clinicaltrials.gov lists over 2,000 research studies being conducted just in New Hampshire.

2.1. Nazi Medical War Crimes (1939-1945)

Although not the first example of harmful research on unwilling human subjects, the experiments conducted by Nazi physicians during World War II were unprecedented in their scope and the degree of harm and suffering to which human beings were subjected.

“Medical experiments” were performed on thousands of concentration camp prisoners and included deadly studies and tortures such as injecting people with gasoline and live viruses, immersing people in ice water, and forcing people to ingest poisons.

In December 1946, the War Crimes Tribunal at Nuremberg indicted 20 physicians and 3 administrators for their willing participation in the systematic torture, mutilation, and killing of prisoners in experiments. The Nuremberg Military Tribunals found that the defendants had:

• Corrupted the ethics of the medical and scientific professions
• Repeatedly and deliberately violated the rights of the subjects

The actions of these defendants were condemned as crimes against humanity. Sixteen of the twenty-three physicians/administrators were found guilty and imprisoned, and seven were sentenced to death.

More information may be found in: Annas, GJ, and Grodin, MA. 1992. The Nazi Doctors and the Nuremburg Code, Human Rights in Human Experimentation. New York: Oxford University Press.

2.2. Outcomes of the Nazi War Crimes (1947)

The  Nuremberg  Code  

In the August 1947 verdict, the judges included a section called Permissible Medical Experiments. This section became known as the Nuremberg Code, and was the first international code of research ethics.

This set of directives established the basic principles that must be observed in order to satisfy moral, ethical, and legal concepts in the conduct of human subject research. The Code has been the model for many professional and governmental codes since the 1950s and has, in effect, served as the first international standard for the conduct of research.

The Code Provides Ten Directives for Human Experimentation:

1. Voluntary consent of the human subject is absolutely essential
2. The experiment must yield generalizable knowledge that could not be obtained in any other way and is not random and unnecessary in nature
3. Animal experimentation should precede human experimentation
4. All unnecessary physical and mental suffering and injury should be avoided
5. No experiment should be conducted if there is reason to believe that death or disabling injury will occur
6. The degree of risk to subjects should never exceed the humanitarian importance of the problem
7. Risks to the subjects should be minimized through proper preparations
8. Experiments should only be conducted by scientifically qualified investigators
9. Subjects should always be at liberty to withdraw from experiments
10. Investigators must be ready to end the experiment at any stage if there is cause to believe that continuing the experiment is likely to result in injury, disability or death to the subject

American Psychological Association 

The American Psychological Association began to develop a Code of Ethical Standards that addressed issues in human subjects research, particularly in behavioral research.

2.3. Syphilis Study at Tuskegee  (1932-1972)

Arguably the most notorious example in the United States of the violation of the rights and welfare of human subjects was the long-term study of black males conducted by the United States Public Health Service in Tuskegee, Alabama. This study of the natural history of untreated syphilis was initiated in the 1930s and continued until 1972.

The Syphilis Study at Tuskegee involved approximately 600 African-American men: about 400 with syphilis (cases) and about 200 without syphilis (controls). These men were recruited without informed consent and, in fact, were led to believe that some of the procedures done in the interest of research (e.g., spinal taps) were actually “special free treatment.”

By 1936, it was apparent that many more infected men than controls had developed complications, and 10 years later, reports indicated that the death rate among those with syphilis was about twice as high as it was among the controls. In the 1940s, penicillin was found to be effective in the treatment of syphilis. The Syphilis Study at Tuskegee continued, however, and the men were neither informed about nor treated with the antibiotic.

2.4 Outcomes of the Syphilis Study at Tuskegee

The first accounts of this study appeared in the national press in 1972. The resulting public outrage led to the appointment of an ad hoc advisory panel by the Department of Health, Education and Welfare (which later was split into the Department of Education and the Department of Health and Human Services [HHS]) to review the study and develop recommendations to ensure that such experiments would never again be conducted.

Outcomes included:

1. National Research Act of 1974
2. Basic HHS Policy for Protection of Human Research Subjects
3. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

More information may be found in:

• Brandt, AM. 1978. Racism and Research: The Case of the Tuskegee Syphilis Study. Hastings Center Report 8(6): 21-29, and in
• Jones, JH. 1993. Bad Blood: Tuskegee Syphilis Experiment. Rev. ed. New York: Free Press
  

2.5  Impact on the Current Human Research Studies

The U.S. Department of Health and Human Services (HHS) issued regulation 45 CFR 46 which has five subparts. Subpart A is known as the Common Rule and provides a set of protections for research subjects. Subparts B, C, and D provide additional protections for specific vulnerable populations (B: pregnant women and fetuses; C: prisoners; D: children; E: IRB registration).

The Office for Human Research Protections (OHRP) within HHS provides guidance, educational programs, regulatory management, and advice on ethical and regulatory issues in biomedical and behavioral research. The OHRP reviews allegations of noncompliance with the Common Rule in projects conducted or supported by HHS. The determinations from its investigations and any corrective actions are posted on its website.

The International Compilation of Human Research Standards includes over 1,000 laws, regulations, and guidelines from 133 countries that protect human subjects. It also includes practices followed by international committees and organizations like the World Health Organization (WHO) or the United Nations Educational, Scientific, and Cultural Organization (UNESCO).

2.6 Additional Historical Information

For more about the evolution of human research subjects protection, if you like history . . .

Use the drop-down arrows below to view details of the major bioethics violations and the corresponding development of human research protections in the U.S.