History of Research Ethics
Prior to 1906, when the Pure Food and Drug Act was passed, there were no regulations regarding the ethical use of human subjects in research. There were no consumer regulations, no Food and Drug Administration (FDA), no Common Rule, and no Institutional Review Board (IRB). What follows is a brief discussion of why federal rules and regulations were established and why the IRB became a necessity.
A well-known chapter in the history of research with human subjects opened on December 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.
Thalidomide. 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 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 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 Good Clinical Practices used today.
Issues addressed in the Declaration of Helsinki include:
- 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 ). Due to 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, which was charged to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles.
The Commission drafted the Belmont Report, a foundational document in for the ethics of human subjects research in the United States.
- Nazi atrocities in World War II drew attention to the lack of international standards on research with human subjects and led to the formulation of the Nuremberg Code.
- The thalidomide disaster led to the adoption of the "Kefauver Amendments" to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the effectiveness of their products before marketing them.
- The Declaration of Helsinki is the basis for Good Clinical Practices used today.
- The Tuskegee Syphilis Study is probably the worst case of unethical human subjects research in the history of the United States.
- The National Research Act codified the requirement that human subjects in research must be protected and set the stage for the issuance of the Belmont Report.
THE BELMONT REPORT
Carrying out its charge, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research prepared the Belmont Report in 1979. The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. The Report is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. The three basic ethical principles and their corresponding applications are:
Respect for persons
- Individuals should be treated as autonomous agents
- Persons with diminished autonomy are entitled to protection.
- 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:
- comprehension, and
- 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
The Belmont Report established three basic ethical principles – respect for persons, beneficence and justice – which are the cornerstone for regulations involving human subjects.
In 1981, the Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) issued regulations based on the Belmont Report. DHHS issued 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 "Common Rule." In 1991, the Department of Veterans Affairs promulgated this same rule at 38 CFR Part 16. Today, the 1991 Federal Policy is shared by 17 Departments and Agencies, representing most, but not all, of the federal Departments and Agencies sponsoring human-subjects research.
The main elements of the Common Rule include :
- 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.
- 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.