Multiple examples of past unethical research studies conducted in the past throughout the world have cast a significant historical shadow on research involving human subjects. Examples include the Tuskegee Syphilis Study from 1932 to 1972, Nazi medical experimentation in the 1930s and 1940s, and research conducted at the Willowbrook State School in the 1950s and 1960s. As the aftermath of these practices, wherein uninformed and unaware patients were exposed to disease or subject to other unproven treatments, became known, the need for rules governing the design and implementation of human-subject research protocols became very evident.

The first such ethical code for research was the Nuremberg Code, arising in the aftermath of Nazi research atrocities brought to light in the post-World War II Nuremberg Trials. This set of international research standards sought to prevent gross research misconduct and abuse of vulnerable and unwitting research subjects by establishing specific human subject protective factors. A direct descendant of this code was drafted in 1978 in the United States, known as the Belmont Report, and this legislation forms the backbone of regulation of clinical research in the USA since its adoption. The Belmont Report contains three basic ethical principles: (1) respect for persons, (2) beneficence, and (3) justice. Additionally, the Belmont Report details research-based protective applications for informed consent, risk/benefit assessment, and participant selection.