Nuremberg Code

A well-known chapter in the history of research with human subjects opened on Dec. 9, 1946, when an American military tribunal opened criminal proceedings against 23 leading German physicians and administrators for their willing participation in war crimes and crimes against humanity. Among the charges were that German physicians conducted medical experiments on thousands of concentration camp prisoners without their consent. Most of the subjects of these experiments died or were permanently crippled as a result.

As a direct result of the trial, the Nuremberg Code was established in 1948, stating that “The voluntary consent of the human subject is absolutely essential,” making it clear that subjects should give consent and that the benefits of research must outweigh the risks.
Although it did not carry the force of law, the Nuremberg Code was the first international document which advocated voluntary participation and informed consent.


In the late 1950s, thalidomide was approved as a sedative in Europe; it was not approved in the United States by the FDA. The drug was prescribed to control sleep and nausea throughout pregnancy, but it was soon found that taking this drug during pregnancy caused severe deformities in the fetus. Many patients did not know they were taking a drug that was not approved for use by the FDA, nor did they give informed consent. Some 12,000 babies were born with severe deformities due to thalidomide.

U.S. Senate hearings followed and in 1962 the so-called “Kefauver Amendments” to the Food, Drug, and Cosmetic Act were passed into law to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers were required to prove to the FDA the effectiveness of their products before marketing them.

Tuskegee Syphilis Study (1932-1972)

An equally well-known chapter in history occurred during a research project conducted by the U.S. Public Health Service. Six hundred low-income African-American males, 400 of whom were infected with syphilis, were monitored for 40 years. Free medical examinations were given; however, subjects were not told about their disease. Even though a proven cure (penicillin) became available in the 1950s, the study continued until 1972 with participants being denied treatment. In some cases, when subjects were diagnosed as having syphilis by other physicians, researchers intervened to prevent treatment. Many subjects died of syphilis during the study. The study was stopped in 1973 by the U.S. Department of Health, Education, and Welfare only after its existence was publicized and it became a political embarrassment. In 1997, under mounting pressure, President Clinton apologized to the study subjects and their families.

Declaration of Helsinki

In 1964, the World Medical Association established the “Declaration of Helsinki,” which provides recommendations guiding medical doctors in biomedical research involving human subjects. The declaration governs international research ethics and defines rules for “research combined with clinical care” and “non-therapeutic research.” The Declaration of Helsinki was revised in 1975, 1983, 1989, and 1996 and is the basis for effective clinical practices used today.

  • Research with humans should be based on the results from laboratory and animal experimentation
  • Research protocols should be reviewed by an independent committee prior to initiation
  • Informed consent from research participants is necessary
  • Research should be conducted by medically/scientifically qualified individuals
  • Risks should not exceed benefits

National Research Act (1974)

Because of the publicity from the Tuskegee Syphilis Study, the National Research Act of 1974 was passed. The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This commission was tasked with identifying the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects. It was also tasked with developing guidelines that should be followed to assure that such research is conducted in accordance with these ethical principles.

The commission drafted the Belmont Report, a foundational document in for the ethics of human subjects research in the United States.

The Belmont Report
Principle Application

Respect for persons

  • Individuals should be treated as autonomous agents.
  • Persons with diminished autonomy are entitled to protection.

Informed consent

  • Subjects, to the degree that they are capable, must be given the opportunity to choose what shall or shall not happen to them.
  • The consent process must include three elements:
    • information,
    • comprehension, and
    • voluntariness.


  • Human subjects should not be harmed.
  • Research should maximize possible benefits and minimize possible harms.

Assessment of risks and benefits

  • The nature and scope of risks and benefits must be assessed in a systematic manner.


  • The benefits and risks of research must be distributed fairly.

Selection of subjects

  • There must be fair procedures and outcomes in the selection of research subjects.

Current Regulations

In 1981, the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) issued regulations based on the Belmont Report. The DHHS issued the Code of Federal Regulations (CFR) Title 45 (public welfare), Part 46 (protection of human subjects). The FDA issued CFR Title 21 (food and drugs), Parts 50 (protection of human subjects), and 56 (Institutional Review Boards).
In 1991, the core DHHS regulations (45 CFR Part 46, Subpart A) were formally adopted by more than a dozen other departments and agencies that conduct or fund research involving human subjects as the Federal Policy for the Protection of Human Subjects, or the “Common Rule.” In 1991, the Department of Veterans Affairs promulgated this same rule at 38 CFR Part 16. Today, the 1991 version of the “Federal Policy,” as it is known, is widely shared by federal departments and agencies.
The main elements of the Common Rule include the following:

  • requirements for assuring compliance by research institutions;
  • requirements for researchers obtaining and documenting informed consent;
  • requirements for Institutional Review Board (IRB) membership, function, operations, review of research, and record keeping; and
  • additional protections for certain vulnerable research subjects (pregnant women, prisoners, and children)

In addition, certain federally sponsored and much privately sponsored research is subject to the regulations of the Food and Drug Administration (FDA) at 21 CFR Parts 50 and 56. FDA regulations confer protections on human subjects in research when a drug, device, biologic, food additive, color additive, electronic product, or other test article subject to FDA regulation is involved. FDA regulations and the provisions of the Common Rule are largely congruent, although some significant differences exist.
Both the Common Rule and the FDA regulations provide protections for human subjects in research.