The current requirements for investigators and considerations in conducting ethical research should be understood within the context of past abuses, some horrific.
The 1946-1947 Nuremberg trials brought notoriety to the numerous atrocities in WWII concentration camps committed by Nazi physicians under the guise of “experimentation.” Of the 23 individuals tried for such crimes at Nuremberg, 20 were physicians. Sixteen of the 23 were convicted and given sentences ranging from imprisonment to death. (Annas and Grodin, 1992)
At the time of the Nuremberg trial, there were no international standards for ethical conduct in human experimentation. This resulted in the Nuremberg Code, or directives for human experimentation, adopted in 1947:
- Voluntary consent of the human subject is essential.
- There must be no reasonable alternative to conducting the experiment.
- The anticipated results must have a basis in biological knowledge and animal experimentation such that the experiment has potential for yielding fruitful results for the good of society.
- The procedures should avoid unnecessary physical and mental suffering and injury.
- There is no expectation for death or disability as a result of the trial
- The degree of risk for the patient should not exceed the humanitarian importance of the problem to be solved.
- The subjects should be protected against even a remote possibility of death or injury.
- The study must be conducted by qualified scientists, with a high degree of skill and care throughout the experiment.
- The subject can stop participation at will.
- The investigator has an obligation to terminate the experiment if injury, disability or death of the subject seems likely.
The World Medical Association (WMA) held a meeting in 1964 in Helsinki, Finland, and adopted a formal code of ethics for physicians engaged in clinical research. The Declaration of Helsinki reiterates the principles of Nuremberg Code, with particular attention to the duty of the physician to protect the life, health and dignity of the human subject. The Declaration states that research involving human subjects must be formulated in a written protocol which has been reviewed by an ethical review committee distinct from the investigator, must conform to generally accepted scientific principles and should include written informed consent from the participants. Negative as well as positive results should be disseminated and funding sources disclosed.
The Declaration has been revised regularly by the WMA. Considerable discussion has ensued regarding the statements on the ethics of placebo control and the duty of the study planners to provide post-study access for all study participants to what is regarded as a beneficial treatment. The 2008 revision affirms the WMA position on the primacy of the patient and outlines required consents for research on human material, such as blood, tissues, and DNA, and human data as well as requiring clinical trials to be registered in a publicly accessible database.
One well-known example of abuse of ethical research in the USA occurred in 1936 when the US Public Health Service began a study of untreated syphilis in Tuskegee, Alabama (399 men with advanced disease and 201 controls). The study continued long after the availability of penicillin, a proven cure, in the 1950s. The study was stopped in the early 1970s after it was publicized and became an embarrassment to the country. In response to the Tuskegee Syphilis Study, the US Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research through the 1974 National Research Act. This Commission produced the Belmont Report in 1979 which distilled basic ethical guidelines in research with human subjects to three principles: respect for persons or individual autonomy, beneficence, and justice.
Respect for persons (individual autonomy) means that patients have the right to decide what should be done for them with respect to their illness unless the result would be clearly detrimental to others. Respect for persons means that potential subjects for clinical trials are informed of alternative therapies and risks and benefits of participation in a particular trial before they volunteer to participate in that study. Since clinical trials often require participants to surrender some measure of autonomy in order to be randomized to treatment and follow the established protocol, these aspects will be described to the potential subject, along with their freedom to choose to discontinue the study at any time.
Beneficence reflects the patient’s right to receive advantageous or favorable treatment. Investigators are obliged to make practical and useful assessments of the risks and benefits involved in research, which necessitates resolving the potential conflict between risk to participants and benefit to future patients. The beneficence obligation extends to both the particular subjects in a study and to the research endeavor.
Justice addresses the question of fairly distributing the benefits and burdens of research. Compensation for injury due to research is an application of justice. Injustice occurs when benefits are denied without good reason or when burdens are unduly imposed on particular individuals, such as the poor or uninsured.
These principles are applied in the requirements for informed consent of subjects, in the assessment of risks and benefits and fair procedures and outcomes, and in the selection of subjects.
Other international guidelines have been proposed.
- The World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) issued a document entitled International Ethical Guidelines for Biomedical Research Involving Human Subjects, with its latest revision published in 2002.
- UNESCO set forth a Universal Declaration on Bioethics and Human Rights in 2005.
- Timeline of Laws Related to the Protection of Human Subjects