Research With Protected Populations-Vulnerable Subjects: A Definition

 

Content Author

 

David Forster, J.D., M.A.

Western Institutional Review Board

 

Introduction

The concept of subject vulnerability is important to research ethics and to regulatory compliance. DHHS regulation 45 CFR 46.111(b) and FDA regulation 21 CFR 56.111(b) require that "when some or all of the subjects are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these subjects." The DHHS and FDA regulations, and International Conference of Harmonization (ICH) guidelines provide partial lists of subjects who should be considered vulnerable, but they do not provide a definition of vulnerable subjects or an explanation of the causes of vulnerability. The goal of this module is to provide an understanding of the concept of vulnerability and to discuss some of the characteristics of vulnerability.

 

Examples from DHHS and FDA Regulations

DHHS regulation 45 CFR 46.111(b) and FDA regulation 21 CFR 56.111(b) provides the following list of examples of vulnerable subjects: "children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons."

 

ICH Guideline 1.61

ICH guideline 1.61 provides the following list of vulnerable subjects:

 

•Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

•Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention.

•Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

 

The Concept of Vulnerability

The Belmont Report identifies three basic ethical principles essential to the review of research:

 

Respect for Persons, Beneficence, and Justice.

 

According to the Belmont Report,

 

"Respect for Persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection."

 

Vulnerable subjects are those subjects with diminished autonomy. It is useful to further analyze the components of autonomy in order to understand which subjects have diminished autonomy.

 

Elements of Autonomy

Autonomy is generally broken down into two general elements in the bioethics literature. The first element is mental capacity, the ability to understand and process information. The second element is voluntariness, freedom from the control or influence of others. Therefore, subjects have full autonomy when they have the capacity to understand and process information, and the freedom to volunteer for research without coercion or undue influence from others.

 

Who Are The Vulnerable Subjects?

When a subject has limitations on either capacity or voluntariness, then the subject is vulnerable. Examples of subjects with a lack of capacity are children and the mentally disabled. Examples of subjects with a potential lack of voluntariness are subjects in emergency situations, subjects in hierarchical social structures, subjects who are economically or educationally disadvantaged, subjects who are marginalized in society, or subjects with fatal or incurable diseases.

 

 

Considerations about Vulnerability

Vulnerability often does not apply uniformly to a given research population. Some of the variables in vulnerability are provided below:

 

•Within any population of vulnerable subjects, individuals will have different levels of vulnerability.

•The level of vulnerability of an individual may change due to changes in capacity or in conditions affecting voluntariness. For instance, a subject with diminished capacity due to pain control medication may have lucid periods. It is the researcher's responsibility to systematically assess capacity to consent prior to and during the research activity.

•The IRB considers a hypothetical group of subjects, whereas the investigator interacts with actual subjects. Therefore, the investigator must take into account the actual vulnerability of a given subject and act accordingly in the consent process and in the conduct of the research.

 

To What Are Vulnerable Subjects Vulnerable?

Subjects who are vulnerable are more likely to have their rights abused in the following ways:

 

•Physical Control - Vulnerable subjects have been physically forced to participate in research at times. This represents a complete lack of voluntariness. A classic example is the use of prisoners of the Nazi Holocaust camps in research with an endpoint of subject death, such as the hypothermia studies. The subjects had no choice about whether or not to participate, and were under the complete physical control of the investigators. A recent example is a surgeon in California who kept a subject under anesthesia to perform research after clinically-required surgery, despite the subject's prior refusal to participate in the research.

•Coercion - The use of a credible threat of harm or force to control another person. An example of coercion is a nursing home resident who was forced to choose between participating in a research study or leaving the nursing home, as reported in the June, 2000, Office of the Inspector General Report OEI-01-97-00195, "Recruiting Human Subjects."

•Undue Influence - The misuse of a position of confidence or power to lead another to make a decision he would not otherwise have made. An example would be a physician's affirmative response to a patient's inquiry of whether the patient should enter a research study, when in fact the physician knows that participation in the study is not in the patient's best interest.

•Manipulation - Deliberate management of conditions or information in such a way as to lead another to make a decision he would not otherwise have made. Examples of information manipulation include lying, withholding information, and exaggeration.

 

Specific Classes of Vulnerable Subjects

There are several classes of vulnerable subjects, with varying degrees of potential vulnerability. These classes are discussed below, including the potential for control, coercion, undue influence, or manipulation.

 

•Children have a wide range of capacity depending on age, maturity and psychological state. There is potential for control, coercion, undue influence, or manipulation by parents, guardians, or investigators, particularly of young children.

•Embryos and Fetuses have absolutely no capacity and are under the direct control of the mother.

•Mentally Disabled Individuals have problems with capacity, which may be continuous or fluctuating, depending on the disability. In addition, they may have limitations on voluntariness because often they are institutionalized or hospitalized, are economically and educationally disadvantaged, and suffer from chronic diseases. As a result, they are potentially subject to control, coercion, undue influence, or manipulation.

•Emergency Situations create a situation where capacity and voluntariness is compromised. There are often limitations to capacity due to the emergency condition. There are often limitations on voluntariness due to time constraints or hospitalization. An example is research on heart attack medications, in which the subjects are asked to consent in the ambulance on the way to the hospital. There is potential for control, coercion, undue influence, or manipulation.

•Hierarchical Social Structures that confront hospitalized patients, nursing home residents, students, prisoners, military personnel, and some ethnic groups create situations where voluntariness can be compromised. There is potential for control, coercion, undue influence, or manipulation.

•Educationally Disadvantaged Subjects may have limitations on understanding of the study they will participate in, and may even be illiterate. The possibility exists for undue influence and/or manipulation.

•Economically Disadvantaged Subjects may be vulnerable due to a limitation on voluntariness. They may enroll in research only to receive monetary compensation (such as in Phase I drug studies), or they may enroll in research to obtain medical care they cannot otherwise afford. There is potential for undue influence or manipulation.

•Marginalized Social Groups may lack influence in society as a result of race, age, disease, or caste systems. These groups often do not have full access to social institutions such as the legal system. There is potential for control, coercion, undue influence, or manipulation.

•Individuals with Incurable or Fatal Diseases often have limitations on voluntariness, and in addition may have problems with capacity caused by disease or medications. These individuals may accept very high risks in desperation for a cure, even when there is little or no prospect of direct benefit.

 

Conclusion

DHHS and FDA regulations provide lists of potentially vulnerable subjects, and require the consideration of additional safeguards for vulnerable subjects, but do not provide a definition of vulnerability or an explanation of the causes of vulnerability. The goal of this module is to show that vulnerability arises from limitations on subjects' capacity or voluntariness, two essential elements of subject autonomy.