Historical Events behind Current Regulations

Ethical violations and inhumane conducts in clinical research were the reason that led to development of regulatory bodies and regulations / guidelines that govern current practice in clinical research today. Below are some of the major unethical events in clinical research history.

Major Unethical Events in Clinical Research History

The Nazi Experiments (During World War II)

During World War II, some German physicians conducted unethical experiments on concentration camp prisoners without their consent. Prisoners were subjected to inhumane treatments such as exposure to mustard gas in order to test possible antidotes. Many more examples of unethical treatments of prisoners were performed.

Willowbrook Hepatitis Studies (1955-1970)

Starting in 1955, hepatitis studies were conducted at Willowbrook State School in Staten Island, N.Y., where mentally disabled children attended. Hepatitis was a major problem at the school for children and staff. Gamma globulin antibodies (taken from the blood of hepatitis patients) were given to some of the 700 children involved in the studies. Some children were deliberately infected with hepatitis virus. Although consents from parents were obtained, parents were not fully informed of the full risks. In addition, parents who needed care for their children were led to believe that they had little choice over whether or not to participate in the research.

Jewish Chronic Disease Hospital Study (1963)

In 1963, twenty two elderly patients at the Jewish Chronic Disease Hospital in Brooklyn, N.Y. were injected live cancer cells without their knowledge or informed consent. Review proceedings were conducted by the Board of Regents of the State University of New York. It was found that the study had not been presented to the hospital’s research committee. Also, the physicians responsible for the patients’ care had not been consulted. The researchers were found guilty of fraud, deceit, and unprofessional conduct.

The Tuskegee Syphilis Study (1932-1972)

From 1932-1972, a long-term study was conducted at the Tuskegee Institute by the United States Public Health Service (later known as the Center for Disease Control). The project aimed to examine the natural history of untreated syphilis in African American males. More than 400 African American men with syphilis participated, and about 200 men without syphilis served as controls. The men were recruited without informed consent. Misinformation was given where the research procedures done were described as “special free treatment.” Treatments were withheld for those with syphilis, even when penicillin was found to be safe and effective against syphilis. As a result, the death rate among those with syphilis was about twice as high as those in the control group. The study continued until 1972 and only stopped as a result of public outrage after the investigative report from a journalist, Jean Heller from the Associated Press. The public outcry from this study let to U.S. Congress passing the National Research Act in 1974. The Act required regulations that included informed consent and IRB oversight requirement. The Act also created the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research, who in 1979 wrote the “Belmont Report.”

Development of Clinical Research Regulations

Nuremberg Code (1947)

At the end of World War II, the Nuremberg trials were conducted and the Nuremberg Code was established in 1947. Ten elements of human research conduct were given. Below are summaries of the 10 points:

1. Voluntary informed consent is absolutely essential.
2. Research should yield benefit to society.
3. Research should be based on prior animal work.
4. Avoid all unnecessary physical and mental suffering and injury.
5. Research in which death or disabling injury is expected should not be conducted.
6. The risks should be justified by the anticipated benefits.
7. Proper preparations and adequate facilities should be provided to prevent injury, disability, or death.
8. Conducted only by scientifically qualified persons.
9. Subject can withdraw from the research at any time.
10. Researchers must be able to end the study if there is a probable cause to believe that continuation of the experiment will cause injury, disability, or death.

The Nuremberg Code was the first set of principles outlining professional ethics for clinical research. The Code has been the model for many professional and governmental codes since the 1950s, including the Declaration of Helsinki in 1964.

Declaration of Helsinki (1964)

The Declaration of Helsinki was developed by the World Medical Association (WMA) in 1964 with basis from the principles of the Nuremberg Code. The Declaration is the first significant effort of the medical community to regulate itself.

Since its release in 1964, revisions were made to improve the Declaration. Its current form can be found through this link: http://www.wma.net/en/30publications/10policies/b3/index.html. The Declaration set the stage for further creation and implementation of regulatory bodies and regulations.

Belmont Report (1979)

In 1974, U.S. Congress passed the National Research Act which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The National Commission was tasked to compose a set of standard principles for all human subject research. This led to the Belmont Report, which was published in 1979 by the National Commission. The three core principles of the Belmont Report are:

• Respect for Persons – This principle states that individuals are autonomous human beings and must be allowed to choose for themselves. Individuals with diminished autonomy must be afforded special protections. Informed consent and protection of vulnerable subjects are the results of this principle.
• Beneficence – This principle states the philosophy of “Do no harm.” The goal of research should be to maximizing benefits from the research while minimizing risks to the subjects.
• Justice – This principle requires equality in research conduct. Research design must ensure that burdens and benefits are shared fairly. One group should not assume greater research risks for the benefit of another group. Fair procedures and outcomes in the selection of subjects must be in place.

The Institutional Review Board (IRB) (1966)

In 1966, the US Surgeon General Stewart issued a policy requiring institutions to provide review of research activities for the protection of human subjects, for any institution receiving funding from the NIH. The policy was based on existing intramural policies of the NIH. This policy led to the establishment of Institutional Review Boards (IRBs).

Federal Policy for the Protection of Human Subjects – “Common Rule” (1991)

In 1981, U.S. Department of Health & Human Services (HHS) and the Food and Drug Administration (FDA) revised their existing human subjects regulations based on the principles from the Belmont Report. In 1991, the Federal Policy for the Protection of Human Subjects or the “Common Rule” was published. This regulation was codified in separate regulations by 15 Federal departments and agencies. It is also listed as 45 CFR Part 46. For all participating departments and agencies the Common Rule outlines the basic provisions for IRBs, informed consent, and Assurances of Compliance. The Common Rule is used for research funded by the HHS and all participating government departments and agencies.

The Food and Drug Administration (FDA)

The Food and Drug Administration (FDA) is an HHS agency that regulates clinical investigations of products under its jurisdiction, such as drugs, biological products, and medical devices. FDA regulations are published as part of chapter 21 of the CFR, and FDA’s human subject protection regulations are in parts 50, 56, 312 and 812. FDA regulations, while not identical, are harmonized as much as possible with 45 CFR Part 46.

Related pages

1. Country Specific Regulations – Global / International Trial
2. European Medicines Agency (EMA)
3. Food and Drug Administration (FDA)
4. ICH’s GCP Guideline