As the Nuremberg trials progressed, it became clear that no accepted guidelines for human experimentation existed to define what was or was not legal or ethical. The resulting Nuremberg Code (U.S. Government Printing Office, 1949) described 10 directives for human experimentation. Voluntary consent by the subject of the experimentation was considered essential. Voluntary consent means the subject (or legal representative) not only has the legal capacity to consent, but also has sufficient information upon which to make an informed choice. The design of the study should provide results for the good of society that cannot be obtained by other means. The study design should incorporate the previous knowledge of the disease or research question at hand, such that the clinical study is justified by the state of the knowledge. The experiments should be designed and conducted to avoid unnecessary suffering or injury to the subject. Death or disabling injury as an expected outcome should not be allowed. The degree of risk should be balanced by the benefit to society from the information gained. Subjects should be protected from anticipatable injury, disability, or death. The experiments should only be conducted by qualified individuals. The subject must have the option of voluntary withdrawal from the study at any time or for any or no reason. Finally, researchers must be prepared to terminate the study if they have cause to believe that continuation of the study is likely to result in injury, disability, or death to the subjects.

The Declaration of Helsinki was issued in 1964 by the World Medical Association and has undergone seven revisions (World Medical Association, 2000). It expanded on the Nuremberg Code, particularly in regard to vulnerable populations (children, mentally disabled, temporarily incapacitated). It included two additional concepts as well.

The first concept was that the interests and protection of the individual subject was to always take precedence over the interest of society. The World Medical Association has focused heavily on the role of the physician to safeguard the health of the subject in any medical research. The second concept was that every subject was to receive the best known therapy during the course of the study. This concept is a restatement of the concept of equipoise. Equipoise requires that the investigator honestly not know if the experimental therapy or intervention is better than the control therapy or intervention. Once a therapy or intervention has been demonstrated to be effective for a given disease condition, the use of an inactive or nontherapeutic control or placebo is no longer ethical. Because of the comparison with an active control rather than a placebo, the resulting effect sizes, or difference in outcome measure between the experimental and control groups, may be much smaller.

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was formed as a result of the National Research Act in 1974. This commission put forth the Belmont Report in 1979 (National Commission for the Protection of Human Subjects, 1983). The Belmont Report outlined three guiding ethical principles: the respect for persons, beneficence, and justice.

The respect for a person’s ethics incorporates several aspects we see in current regulations. This principle requires not only the recognition of individuals as autonomous, but also that those with diminished autonomy are entitled to protection. Respect for the individual’s autonomy is reflected in informed consent requirements. An individual cannot make an autonomous decision in the absence of information regarding the risks and benefits of that decision. Critical illness, mental disability, or circumstances that severely restrict liberty may limit an individual’s autonomy and thus entitles the individual to specific protections. Applied to prisoners, this principle would require that prisoners be given the opportunity to volunteer to participate in research, while being protected from coercion or undue influence to participate in research in which they would not otherwise volunteer to participate.

The second principle is beneficence. This is expressed both as do no harm and maximize possible benefits and minimize possible harms. This principle can be viewed both in terms of the individual and society. Research into treatment methods for childhood diseases, for example, may provide societal benefits that justify the research, even though the individual subjects may not benefit directly. With vulnerable subjects, research that presents greater than minimal risk but does not present immediate and direct benefit to the subject involved requires continuous oversight.

The third principle is justice. This principle applies to who assumes the risks and who accrues the benefits. The selection of research subjects needs to be based on the research question rather than the ease of availability, compromised ability, or manipulability of the subject. As an example, the Tuskegee Syphilis Study risks were assumed by a disadvantaged minority, whereas the benefits applied to the much wider society.

These principles require that research that would benefit groups that we have typically considered vulnerable should include those groups as study subjects while ensuring adequate protection for their participation. Before the 1970s, vulnerable groups, if they were protected, were generally protected by exclusion from the study (Schwenzer, 2008). This has led to the situation whereby a large proportion of drugs developed for use in children have not been studied in children (Choonara, 2000, Impicciatore and Choonara, 1999 and Pandolfini and Bonati, 2005). With the recognition that vulnerable groups were underrepresented in clinical research in general, additional protections were instituted along with an effort to include these groups. In the United Sates, clinical trials can be conducted under the auspices of 16 governmental agencies, among them the Department of Agriculture, Department of Defense, and the Department of Health and Human Services, each of which had its own set of rules protecting human subjects. The core requirements from these various agencies were consolidated into the Common Rule (45 CFR Part 46) in 1991. The Department of Health and Human Services added guidelines to deal with vulnerable subjects (pregnant women, fetuses, children, and prisoners), which were not in the Common Rule. These additional guidelines deal primarily with the selection, informed consent, and special considerations for these populations. The concept of who represents a vulnerable subject continues to evolve and now generally includes the groups described in Box 48-1.