Learning objectives

• to identify different grounds of vulnerability in biomedical research
• to analyze ethical implications of research on vulnerable populations
• to assess normative framework for research on vulnerable populations
• to apply this framework to analyze the cases
• to appraise conceptual difficulties in defining vulnerability

Introduction

Definition of vulnerability

According to the Declaration of Helsinki, vulnerable groups and individuals “may have an increased likelihood of being wronged or of incurring additional harm.” Generally speaking, vulnerable individuals or populations are those whose decision making capacity and ability to exercise and protect their rights is restricted due to their mental, social, economic or ethnical status, age or health condition or, in other words, those who in one or more ways are at risk of harm through research.

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[1].

It should, however, be noted that although all research ethics guidelines refer to vulnerability and/or vulnerable subjects, only few explicitly define the term. The concept is still surrounded by debates because of the insufficiently defined scope and, consequently, its practical application[2] [3] - “In particular, vulnerability has been charged with being both too broad and too narrow. An overly broad concept captures all research participants, creating conceptual confusion over the meaning of ‘special protections’, while an overly narrow concept may leave some vulnerable participants at risk and without the needed protection”[4].

Vulnerable groups deserve special attention as their ability to give informed consent as well as to make sound decisions regarding their participation in the course of research projects can be affected by their limited capacity to make informed decisions (participants with mental diseases or minors), or low health literacy (economically deprived persons), or because their dependency on investigators or authorities of research facilities (e.g. nursing homes, places of detention).

Thus, all the guidelines encourage RECs and researchers to take those groups into special consideration and to apply additional safeguards for their participation.

Group vs individual vulnerability

It should be noted that traditionally, vulnerability in research has been to label entire classes of individuals as vulnerable. However, vulnerability is highly dependent on the context and different specific characteristics may constitute vulnerability. According to the CIOMS guidelines, in some contexts vulnerability might even be related to gender, sexuality and age[5].

One of the groups traditionally considered as vulnerable are individuals lacking competence which is associated to certain diagnosis (e.g. mental illness). However, the issue of competence is complex. Diagnosis as such cannot be an indication of incompetence of a particular individual, thus “both researchers and REC members should be careful in order not to be too ready to make uninformed assumptions and employ inaccurate stereotypes”[6]. On the other hand, it must be noted that such a “individualized” approach to vulnerability might look problematic in RECs’ practice as RECs do not deal with individual research participants directly but evaluate research proposals (documentation).

Special safeguards

The most stringent condition for the inclusion of vulnerable populations into medical research has been introduced by the recent version of the Declaration of Helsinki – it says that in any case, vulnerable groups can be included only if research [of comparable effectiveness] cannot be carried out on those who are not vulnerable: “Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group”[7].  

On the one hand, it can be assumed to be an additional safeguard for the disadvantaged groups of society, on the other hand, the provision has received substantive critiques as limiting access to research which can be directly beneficial for the vulnerable populations (e.g. free medications, interventions or care, which would otherwise be inaccessible).[8]

Other international guidelines do not provide with such a condition for all vulnerable groups, but rather indicate special categories of vulnerable population which deserve special protection. Although different guidelines vary in this respect, it can be noted that there is an international consensus that minors and persons which are not able to give informed consent on their behalf should deserve special protection (BMR protocol, CT Regulation, CIOMS, DoH). Some of the guidelines also define the conditions for inclusion of pregnant and breastfeeding women (BMR protocol and CT Regulation) and persons in places of detention (BMR protocol) into research in which the results do not have the potential to produce direct benefit to their health.

General conditions set by most of the international documents for inclusion of minors and persons not able to consent are the following:

• the results of the research have the potential to produce real and direct benefit to his/ her health;
• research of comparable effectiveness cannot be carried out on the individuals capable of giving consent;
• the person undergoing research has been informed of his/ her rights described by the law defending his/ her protection, unless this person is not in a state to receive the information;
• the necessary authorization has been given specifically and in writing by the legal representative or an authority, person or body provided for by law (Art. 15);
• the person concerned does not object.

If research has no potential to produce the results of direct benefit to the health of a participant, the above-mentioned conditions are applied together with the following additional ones:

• the research aims to contribute to the improvement in the scientific understanding of the individual’s condition, disease or disorder to the ultimate attainment of the results capable of conferring benefit to the person concerned or to other people in the same age category, or afflicted with the same disease or disorder, or being in the same condition;
• the research entails only minimal risk and minimal burden for the individual concerned, and any consideration of the additional potential benefits of the research shall not be used to justify an increased level of risk or burden.

You can find more detailed information about the provisions of the international guidelines on inclusion of vulnerable groups into biomedical research in the Appendix to this Module.

It must be noted that local regulations on the proxy decision-making and other protecting measures for vulnerable groups might vary from country to country due to the cultural and legal differences.

The concept of minimal risk and specific requirements for inclusion of minors into biomedical research and persons in emergency situations are discussed in Module “Research Involving Children” and Module “Research in Emergency situations” in more detail.

Consequences of over-protection

A need for special safeguards on vulnerable individuals has its historical roots and reflects an ethical obligation to protect those who can be exposed to increased risks and harms. However, paradoxically, these safeguards have ended up with the situation where some of the vulnerable populations, e.g. children, were denied efficient and safe drugs as many marketed drugs that are commonly used, or could potentially be used in children, have not been studied in the relevant age groups and so are not approved by regulatory authorities for use in children [9] [10]. Thus in order to not leave specific groups of patients without necessary new treatments (“therapeutic orphans”) and to avoid an over-protection, currently most of international guidelines (e.g. CIOMS, DoH) encourage the inclusion of underrepresented groups in medical research[11].