Vulnerability in Biomedical Research: A Historical Reflection and Practical Implications for HIV Cure-Related Research

Abstract

The concept of vulnerability in bioethics was first referenced in 1979, when the Belmont Report highlighted the need for special consideration of certain populations in the application of its general principles of respect for persons, beneficence, and justice in research with human participants. Since then, a body of literature has emerged regarding the content, status, and scope, as well as ethical and practical implications of vulnerability in biomedical research. The social history of HIV treatment development has at various points reflected and actively influenced bioethics' debate on vulnerability. In the late 1980s and early 1990s, people with AIDS activist groups drafted landmark patient empowerment manifestos like The Denver Principles, fighting to have greater involvement in the design and oversight of clinical trials related to HIV treatment, and in doing so, pushed against research ethics protocols created with the intention of protecting vulnerable populations. The determination of appropriate benefit/risk profiles in clinical trials was no longer limited to the purview of clinicians and scientists, but began to include the perspectives of people with HIV (PWH) and affected communities. In contemporary HIV cure-related research, where participants often risk health for no personal clinical benefit, the community's voiced motivations and objectives for participation continue to challenge population-based accounts of vulnerability. While the development of a framework for discussion and the establishment of clear regulatory requirements are necessary to support the practical and ethical conduct of research, they risk distraction from the fundamental value of voluntary participation and potentially overlook the unique history and perspectives of PWH in their participation in the quest toward an HIV cure.

Background

Vulnerability—which comes from the late Latin word vulnerabilis—who can be wounded—is at the core of medicine. It is the wound, the disease, the ailment that creates the bond between patient and health care provider, between the one who is exposed and the one who exposes. The idea of the healer presupposes the idea of one in need of healing.

However, despite its centrality to medicine, the concept of vulnerability receives scant attention in medical ethics. The exception is in clinical research ethics, where vulnerability—as a characteristic of research participants—is central. The concept originated formally in the 1979 Belmont Report, which outlined three basic principles for medical ethics: (1) respect for persons (participants should be treated as autonomous individuals, and those with diminished autonomy should be granted additional protections), (2) beneficence (interests of study participants should be maximized), and (3) justice (distribution of burdens and benefits of research should be fair).

Under the framework of justice, the Belmont Report highlighted vulnerable populations such as “racial minorities, the economically disadvantaged, the very sick, and the institutionalized” as requiring special protections because of their “dependent status and frequently compromised capacity for free consent.”¹ Vulnerability, as defined by the Belmont Report, is that which may persist even when appropriate information is provided, and informed consent procedures otherwise sufficient for authorized authorization are in place.² In other words, vulnerability that exists within certain groups is what necessitates additional protection and consideration above what is standard to informed consent.

Since 1979, this group or population-based model of vulnerability has been widely applied to research guidelines and bioethical principles, including the Declaration of Helsinki and the 1991 Council for International Organization of Medical Sciences (CIOMS), which gives examples of vulnerable groups: “people receiving welfare benefits or social assistance and other poor people and the unemployed, people in emergency rooms, some ethnic and racial minority groups, homeless persons, nomads, refugees or displaced persons, prisoners, patients with incurable disease, individuals who are politically powerless, and members of communities unfamiliar with modern medical concepts.”^3,4

Still, there is a growing body of literature debating the taxonomy and usefulness of this view of vulnerability.^5,6 Discussion has been largely centered on the concept as it is applied to populations—while “vulnerable populations” became a Medical Subject Heading term in 2003 and is a keyword in multiple ethics thesauruses, including the Bioethics Thesaurus, “vulnerability” without its “population” appendage has not yet gained such formal recognition.

Much of the debate has been centered on the appropriateness of expanding or narrowing who is included within a “vulnerable population.” The notion has been criticized for its overinclusiveness to the point of losing meaning and for stereotyping or stigmatizing those who are included in “vulnerable categories.”⁵ These concerns have been raised about considering all socioeconomically disadvantaged people, all ethnic or racial minorities, and all people with terminal illness as inherently vulnerable.⁷

In 2001, Kipnis was commissioned by the National Bioethics Advisory Commission (NBAC) to generate a new framework of vulnerability that strayed from this membership-dependent definition. Kipnis' six dimensions of vulnerability—cognitive, juridical, deferential, medical, allocational, and infrastructural—do indeed create a more nuanced, situation-centered taxonomy for the concept, yet they do not entirely escape the focus on individual incapacity or deficiency. In a revision to his article, Kipnis added a seventh dimension—social vulnerability, which he defined simply as belonging to “undervalued social groups.”

His proposed intervention for social vulnerability was allowing for increased participation in “decision making and oversight processes.” He argued that these categories served to provide a “checklist of circumstances that, along with other conditions, can invalidate the permissibility of research, to identify the necessary features of vulnerability and determine the “supplementary measures” required to address these vulnerabilities, and to serve as grounds for determining a researcher's guilt in taking unfair advantage of a specific population.⁸

Other notable attempts at redefinition include proposals to assign layers of vulnerability to individuals rather than to label specific groups as vulnerable, to develop a need-based rather than consent-oriented model of vulnerability, and to embrace the concept of universal human vulnerability with a focus on developing institutions that minimize the inequalities that create additional vulnerability.^9
–11 These proposals offer not only new ideas but also reflect the attitudes and movements within research ethics as a discipline.

Reviewing the trajectory of vulnerability within research ethics, it is evident that writers of each wave of new guidelines and regulations were reacting to specific historical events that shaped attitudes about what are and are not appropriate practices in research involving human research participants. In the wake of the abusive practices and experimentation inflicted by Nazi doctors, the 1947 Nuremberg Code emphasized the need for informed consent.

Research without informed consent, however, continued well beyond, including Robert Heath's work involving patients in an indigent psychiatric hospital in New Orleans in the 1960s and most publicly, the U.S. Public Health Service Study at Tuskegee, the injustices of which broke in a 1972 New York Times story, thus exposing American hypocrisy during the Nuremberg Trials. It was in this climate of intense public and professional pressure that Congress created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974, the group that went on to write the seminal Belmont Report, which asserted “the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.”¹

Discussion

“Off-Limit” populations

Under the framework of the principle of justice, the Belmont Report called for fair distribution of the benefits and burdens of research. It highlighted how vulnerable populations, including “racial minorities, the economically disadvantaged, the very sick, and the institutionalized,” had been disproportionally sought after and utilized due to their “ready availability in settings where research is conducted.” The Belmont Report asserted that these groups ought not to bear disproportionate burdens in research and require special protections if they do participate, due to their “dependent status and frequently compromised capacity for free consent.”¹ Modern interpretations of the Belmont Report have echoed and amplified this idea that researchers have an ethical responsibility to restrict involvement of vulnerable groups and that special justification is required for their involvement.¹² Others have argued that membership in certain groups, like those receiving palliative care, unequivocally disqualifies their participation in research.¹³

This approach has been challenged on the concern that not all members of a named group are equally or necessarily vulnerable. Often, the challenge has been from the very groups and people who have been labeled as vulnerable. For example, the authors of the Belmont Report dwelled particularly on the topic of prisoners as research participants. Yet notably, prisoners at Jackson State Prison in Michigan advocated for their right to participate for benefits such as financial compensation, better living conditions, and personal interest.

Similarly, the unanticipatedly disastrous outcome of in utero exposure to thalidomide in the 1950s prompted the U.S. Food and Drug Administration (FDA) to tighten the requirements for new drugs entering the market and laid the groundwork for universal exclusion of pregnant women from clinical trials.¹⁴ In the 1990s, women's health advocates turned their attention to the lack of research inclusion of female participants, both pregnant and of child-bearing age, who had been overwhelmingly excluded under vulnerability arguments, based on fears of harming either a real or potential fetus. Without research inclusion, they argued, there would remain a dearth of evidence-based knowledge specific to women. Their challenge was ultimately successful—in 1994, the Institute of Medicine asserted that “volunteers for clinical studies should be offered the opportunity to participate without regard to gender, race, ethnicity, or age.”¹⁵

Policy guidelines from the National Institute of Health (NIH) soon followed, explicitly stating that women should not be excluded from research on the grounds that they were or may become pregnant. Still, the legacy of female research participant exclusion remains: a 2011 study on all medications approved by the U.S. FDA from 1980 to 2010 found that 91% of medications approved for use by adults lacked sufficient data on safety, efficacy, and fetal risk of medication taken during pregnancy.¹⁶ Today, the clinical detriments of these evidence gaps are being recognized and steadily addressed: on World AIDS Day 2021, the World Health Organization and The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) announced a call-to-action for the acceleration of new drug studies for pregnant and breastfeeding women with HIV.^17,18

Vulnerability and the history of HIV-related research

In the early days of the HIV/AIDS epidemic, specific groups, namely “homosexual men,” were singled out as especially vulnerable.¹⁹ Rounding out what was often referred to as the “Four-H Club,” a number of groups explicitly identified by the Centers for Disease Control and Prevention (CDC) in 1983 were heroin-users, hemophiliacs, and Haitians.²⁰ The effect of these early categorizations was, as Denis Duclos wrote in 1987, an othering that bred stigmatization: “When one tackles the existence of dangers, accidents, and diseases, one of the most recurrent discursive mechanisms is to designate a particular category of individuals to which one does not belong and who are likely to ‘carry’ the risk.”

In his book AIDS and Accusation: Haiti and The Geography of Blame, Paul Farmer details the ramifications of the Haitian accusation narrative, including evictions and unexplained employment termination of thousands of Haitian-Americans and the ripple effects these had on their dependent rural Haitian families. This very real stigmatization that underlies labels of vulnerability was ironically addressed in the AIDS Research, Guidance for Institutional Review Boards (IRBs), which took a new approach in remedying vulnerability—it emphasized confidentiality as an imperative in protecting the rights and welfare of research participants in 1984.²¹

Yet overwhelmingly, the impact of the HIV/AIDS epidemic was its criticism of the FDA and its protectionist regulations, criticisms that changed the course of research ethics and its position on vulnerability in the 1980s.²⁰ In the context of the HIV/AIDS epidemic and the urgent need for new drugs, these regulations began to look like bureaucratic obstructionism with lethal consequences and comparisons with Nazi medicine reemerged.²² The Silence = Death poster, with its pink triangle, which had been originally associated with the persecution of gay people in Nazi Germany, was a cornerstone of the AIDS Coalition to Unleash Power (ACT UP) movement.

Across the country, grassroot protestors in the ACT UP movement called for deregulation and the right to undertake risky clinical trials for drugs if deemed desirable by autonomous people with HIV (PWH) in hopes of staying alive. Within ACT UP's Treatment and Data Committee, Mark Harrington, who had no formal medical training, but later won the MacArthur “genius” grant for his work on AIDS, formed the Science Club, which compiled and prepared a detailed assessment of NIH-sponsored clinical trials on AIDS.

People facing imminent death, the Science Club argued, should be able to participate in clinical trials with experimental drugs that were reasonably safe, even if they were ineligible or unable to enroll formally in a trial. This approach to clinical research, known as the “parallel track,” was formalized by the FDA in 1990, and continues to be a model for clinical trials for those with life-threatening conditions and no therapeutic alternative.²²

Globalization of randomized controlled trials for HIV treatment not only helped contribute to milestone scientific discoveries but also led to high-profile ethical controversies that continue to inform how all biomedical research is conducted in low- and middle-income countries.^23,24 It is important to consider how the exaggerated power dynamics between investigators and participants in these scenarios might impact participants' autonomy and vulnerability. For example, in the late 1990s and early 2000s, several years after the discovery that zidovudine significantly reduces the rate of maternal-fetal transmission of HIV,²⁵ international collaborative trials conducted in nine African countries sparked debate within the scientific community over the use of placebo controls.²³

The debate led to a reconsideration of when it is appropriate to use placebo in conditions where a known effective treatment is available, but local existing health care infrastructure may be limited.²⁶ The 2000 revision of the Declaration of Helsinki and a 2002 revision of the Council for International Organizations of Medical Sciences (CIOMS) reflected movement away from placebo use in these contexts.^27,28

In addition, the HIV/AIDS epidemic is credited with the beginning of imperative inclusion of pregnant women in clinical research, since the topic of perinatal transmission of HIV was one that urgently demanded evidence-based information.¹⁴ By the mid-1990s, the patients' rights movement grew to include not only the HIV/AIDS community but also patients with cancer and other life-threatening conditions, and converged with the FDA and pharmaceutical industry to work toward the same goal of deregulation of research.¹⁴

With the evolution of new HIV treatments, HIV-related research has now transformed its objective into HIV cure-related studies with the goal of keeping HIV suppressed without ART. In particular, a new area of research, HIV cure-related studies involving terminally ill PWH have both served as an exciting new approach to understanding the behavior of the virus within otherwise difficult-to-access deep tissue reservoirs and as a stimulus for discussion of vulnerability in end of life (EOL) and the appropriateness of clinical research participation within this specific population.^29
–31 Although some have argued that it is unethical to engage people at the EOL in clinical trials, others have asserted that it is equally unethical to withhold such an opportunity to individuals simply due to their membership in a group, that informed consent is not compromised by their membership status, and that such paternalism undermines patient autonomy and ignores the diversity of a population.^13,37

This argument of blanket disqualification by virtue of belonging to a potentially “vulnerable population,” a definition of vulnerability mired in protectionism, particularly falters when one considers the impact and legacy of the HIV community in patients' rights movements and the community's voiced desire to participate in research aimed at advancing therapeutic options.³²

Altruism as a motivator for research participation was key to the early HIV epidemic as it is to the current community of PWH, and could serve as a stronger foundation than self-gain for participants at the EOL.^32,33 As a case in point, the Last Gift study at the University of California San Diego (http://lastgift.ucsd.edu/) involves PWH at the EOL who have elected to donate their tissues at the time of death to advance the search toward an HIV cure.

These individuals represent a unique phenotype within the larger PWH community—having lived with the virus for decades, including the era before ART, they speak poignantly about how their HIV diagnosis forced them to face the prospect of mortality. Their experience, and the layers of vulnerability they face, stands in contrast to those faced by people who are newly diagnosed with HIV or by people who are at higher risk of HIV infection.^34

–39

In conversations with Last Gift study participants and their next-of-kin/loved ones, sociobehavioral researchers found that HIV research participation at the EOL provides a tremendous feeling of control, accomplishment, hope, and peace of mind at a time when people would otherwise be classified as “vulnerable.”^38
–40 Having once faced the prospect of their own mortality when HIV was untreatable in the 1980s, PWH feel empowered to participate in this novel research. HIV-specific altruism was found to be a safeguard against vulnerability, oftentimes nested within the context of community, scientific advancement, and moral obligation. Altruistic motivators included love for humanity and desire to give back to the field of HIV research and future generations of PWH. For some PWH at the EOL, the Last Gift study provides an opportunity for altruism in death, legacy and existentialism, a more complete progression toward activism, and a deep sense of purpose.⁴⁰

One Last Gift study participant—Michael Danielson—who desired to be publicly known, was diagnosed with amyotrophic lateral sclerosis, a progressive nervous system disease affecting the nerve cells of the central and peripheral nervous system with no curative treatment. Yet even at the EOL, when he had lost physical functioning—a form of medical vulnerability as characterized by Kipnis—he became one of the most resilient public advocates for HIV cure-related research at the EOL in the name of science, and medical-aid-in-dying, in the name of dignity and compassion.⁴¹ Danielson's story, and so many more like his, actively challenges the categorizations of vulnerability foisted upon research participants with multiple conditions at the EOL.

While the research participants of studies like Last Gift may formally belong to “vulnerable categories,” they nevertheless display tremendous resilience, strength, awareness, and altruism. Not only do these characteristics help to alleviate concerns around vulnerability but they also demonstrate the need for a participatory research model where members of a participating community are given the opportunity to educate researchers about the terms in which they would like to be involved, the background with which informed consents and informed research designs and conclusions can be made, and the language that ought to be used to respectfully communicate research findings.

Conclusions

In his impassioned 1989 piece for the Journal of Infectious Diseases, “The Case for Patient Access to Experimental Therapy,” activist Martin Delaney wrote, “AIDS is the medical equivalent of war. Just as changing the rules of medicine is necessary on the battlefield, changing the rules of drug licensing is needed to save lives in this epidemic.”⁴² While the habitual use of militaristic language to describe scientific undertakings has since fallen out of favor,⁴³ the changes brought on by the HIV/AIDS epidemic provide a useful prism for a nuanced understanding of vulnerability and the ways in which research ethics has attempted to manage it by ways of dictums, definitions, and rules. As detailed by this analysis, vulnerability and its tumultuous conception within research ethics cannot be sufficiently addressed by a fixed approach.

The way to ensure appropriate protection for research participants is not for researchers and ethicists to expand their definition of vulnerability to include ever more comprehensive lists and guidelines. Participatory research models, such as that of the Last Gift study, offer an alternative to this obliterative and potentially paternalistic impulse to vulnerability, one aligned more closely with that of philosophy. In such an approach, vulnerability is an opportunity for communication, contemplation, reflection, dialog, and mutual education between researchers and research participants. Indeed, researchers interested in studying groups that are potentially vulnerable should view communication with and counsel from leaders in the community as imperative and instrumental to their study design, recruitment, consent, retention, conclusions, and communication.

Footnotes

Authors' Contributions

E.R. was part of the initial conceptualization of the article, wrote the primary version of the article, and did the literature review. J.T. was part of the initial conceptualization of the article and reviewed the article providing crucial community perspective. A.K. was part of the initial conceptualization of the article and reviewed the article providing crucial community perspective. S.C.-G. was part of the initial conceptualization of the article and reviewed the article providing crucial community perspective. P.K.R. was part of the initial conceptualization of the article and reviewed the article. D.M.S. was part of the initial conceptualization of the article and reviewed the article. K.D. was part of the initial conceptualization of the article, wrote the primary version of the article, and did the literature review. S.G. was part of the initial conceptualization of the article and wrote the primary version of the article.

Author Disclosure Statement

D.M.S. consulted for Model Medicines, Bayer, Lucira, Pharma Holdings, Evidera, Vx Biosciences, Fluxergy, Linear Therapies, and Model Medicines. All other authors declare no conflict of interest.

Funding Information

This work was supported by R21MH118120, P01 AI131385, P01 AI169609, AI147821, DA051915, AI164559, and AI158293. The work was also supported by The James B. Pendleton Charitable Trust.

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