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The Limitations of “Vulnerability” as a Protection forHuman Research ParticipantsCarol Levine a , Ruth Faden b , Christine Grady c , Dale Hammerschmidt d , Lisa Eckenwiler e

& Jeremy Sugarman fa United Hospital Fundb The Johns Hopkins Universityc National Institutes of Healthd University of Minnesotae Old Dominion Universityf The Johns Hopkins University for The Consortium to Examine Clinical Research EthicsPublished online: 17 Aug 2010.

To cite this article: Carol Levine , Ruth Faden , Christine Grady , Dale Hammerschmidt , Lisa Eckenwiler & Jeremy Sugarman(2004) The Limitations of “Vulnerability” as a Protection for Human Research Participants, The American Journal of Bioethics,4:3, 44-49, DOI: 10.1080/15265160490497083

To link to this article: http://dx.doi.org/10.1080/15265160490497083

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Target Article

The Limitations of “Vulnerability”

as a Protection for Human

Research ParticipantsCarol Levine, United Hospital Fund

Ruth Faden, The Johns Hopkins University

Christine Grady, National Institutes of Health

Dale Hammerschmidt, University of Minnesota

Lisa Eckenwiler, Old Dominion University

Jeremy Sugarman, The Johns Hopkins University

for The Consortium to Examine Clinical Research Ethics

Vulnerability is one of the least examined concepts in research ethics. Vulnerability was linkedin the Belmont Report to questions of justice in the selection of subjects. Regulations and policydocuments regarding the ethical conduct of research have focused on vulnerability in terms oflimitations of the capacity to provide informed consent. Other interpretations of vulnerabilityhave emphasized unequal power relationships between politically and economically disad-vantaged groups and investigators or sponsors. So many groups are now considered to bevulnerable in the context of research, particularly international research, that the concept haslost force. In addition, classifying groups as vulnerable not only stereotypes them, but also maynot reliably protect many individuals from harm. Certain individuals require ongoing protec-tions of the kind already established in law and regulation, but attention must also be focusedon characteristics of the research protocol and environment that present ethical challenges.

Keywords

vulnerability

research ethics

decisional capacity

research involving children

research involving prisoners

international research

Open Peer

Commentaries

Gail E. Henderson,Arlene M. Davis, andNancy M.P. King, p. 50

Jonathan D. Moreno, p. 52

Mary Faith Marshall, p. 54

Anita Silvers, p. 56

Amy T. Campbell, p. 58

Nancy S. Jecker, p. 60

Alan B. Jotkowitz, p. 62

David B. Resnik, p. 63

Ari M. VanderWalde, p. 65

Luis Justo, p. 67

Stuart G. Finder, p. 68

Kenneth Kipnis, p. 70

Frederick Grinnell, p. 72

Dorothy E. Vawter,Karen G. Gervais, andThomas B. Freeman, p. 74

Debra A. DeBruin, p. 76

Chalmers C. Clark, p. 78

Sandra Anderson Garcia, p. 81

Joseph P. DeMarco, p. 82

Tricha Shivas, p. 84

Author’s Response

Carol Levine, Ruth Faden,Christine Grady, DaleHammerschmidt,Lisa Eckenwiler, and JeremySugarman, p. W32

A fundamental assumption underlies modern clin-ical research ethics: certain categories of people arepresumed to be more likely than others to be mis-led, mistreated, or otherwise taken advantage ofas participants in research. These populations aredeemed “vulnerable,” a status that generates a dutyfor researchers, review committees, and regulatorsto provide special protections for them. While otherbasic tenets of research ethics—informed consent,for example—have been the topic of extensive dis-cussion and debate, until recently the concept ofvulnerability has been relatively unexamined. Themost prevalent questions raised about vulnerabilityhave been whether to add a particular group to thevulnerable category, with the answer usually being“yes” (Stone 2003; Hawana 2003), and to a lesser de-gree, what form the special protections should take.

After examining the concept of vulnerabilityin the context of current clinical research, we findit wanting. We recognize that certain individuals,who lack decisional capacity or who are in a depen-dent status, or both, require ongoing protections of

the kind already established in law and regulation.The concept of vulnerability, however, fails to ad-dress less settled situations arising from the contextin which contemporary research is conducted.

The research enterprise has changed dramati-cally since the 1970s when the current approach tounderstanding the ethical issues was largely formu-lated. Unlike the research that set the context forthe existing ethical framework, research today hasmany complicating features, including increasingprivatization and globalization of research; a grow-ing number of complex, multisite trials and office-based trials, with treating physicians as researchers;rapid development in the pipelines for novel agents,many based on genomic and proteomic discoveries;and, most recently, an elevated concern with pub-lic health threats such as bioterrorism and new orresurgent infectious diseases.

What Is Vulnerability?

Although concern about research in orphanages,mental institutions, and hospitals dates to at least

The American Journal of Bioethics, 4(3): 44–49, 2004 ajob 44Copyright c© Taylor & Francis, Inc.ISSN: 1526-5161 print / 1536-0075 onlineDOI: 10.1080/15265160490497083

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The Limitations of “Vulnerability” as a Protection for Human Research Participants

the beginning of the twentieth century in theUnited States (Lederer 1995), the prominence ofthe concept of vulnerability and its staying powerin research ethics undoubtedly derives from thespecific political context in which Congress cre-ated the National Commission for the Protection ofHuman Subjects of Biomedical and Behavioral Re-search (the National Commission) in 1974. Revul-sion against the abuses of research on captive pop-ulations in World War II by the Nazis profoundlyaffected the development of international codes ofresearch ethics (Katz 1972), but the National Com-mission was formed as a response to domestic re-search scandals. The revelations began in the UnitedStates in the 1960s, with Henry Beecher’s famousarticle detailing what he considered to be ethi-cally problematic research (Beecher 1966), includ-ing injecting cancer cells into unsuspecting elderlypatients and deliberately exposing institutionalizedretarded children to hepatitis. In the early 1970sthe most influential revelations concerned the mis-leading and harmful use of poor African-Americanmen in a “natural history” study of syphilis (Jones1981).

These scandals created a regulatory climatein which the need for protection was paramount(Rothman 1991), and the National Commissionwas specifically charged with studying particularproblems such as research with the human fetus,children, prisoners, and the “mentally infirm.” Itwas also asked to explicate general ethical principlesrelevant to research with human subjects, which re-sulted in the Belmont Report (U.S. National Com-mission 1979). This report set out the moral foun-dations for the current federal regulations regardingthe conduct of research with human subjects.

Although the Belmont Report linked the re-quirement to protect the autonomy of persons withdiminished capacity to the ethical principle of re-spect for persons, it addressed vulnerability in theframework of the principle of justice, which calls fordistributing the benefits and burdens of research.Vulnerable populations such as “racial minorities,the economically disadvantaged, the very sick, andthe institutionalized” may continually be soughtas research subjects because of their “ready avail-ability in settings where research is conducted,” theReport asserted. Yet they should not bear dispropor-tionate burdens in research. If they do participate,they require special protections because of their “de-pendent status and frequently compromised capac-ity for free consent” (U.S. National Commission1979, 8).

The U.S.-Code of Federal Regulations doesnot define vulnerability but provides special pro-tections for “particularly vulnerable populations,”specifically pregnant women, human fetuses, andneonates; prisoners; and children (45CFR46Subparts B–D). Although used freely in the Insti-tutional Review Board (IRB) Guidebook offered bythe Office of Human Research Protections (OHRP2001), the term vulnerability is not defined in itsextensive glossary.

While the drafters of these guidelines and reg-ulations were reacting to a series of specific his-torical events and groups of research subjects, therecent history of the use of vulnerability is moreexpansive, particularly in the international context.While in the U.S. regulatory system, vulnerabilityhas been ascribed primarily to the absence of, orpresumed diminished, capacity to consent or to de-pendence based on incarceration, in research in de-veloping countries the principal focus has been onbroader concerns about inequalities of power andresources. This opens the category of vulnerabil-ity to many more groups. The Council for Interna-tional Organizations of Medical Sciences’ (CIOMS)guidelines for biomedical research do define, ifnot vulnerability, then at least vulnerable persons:“those who are relatively or (absolutely) incapableof protecting their own interests because they mayhave insufficient power, intelligence, education, re-sources, strength, or other needed attributes to pro-tect their own interests” (CIOMS 2002). Similarly,Zion, Gillan, and Loff define vulnerable people inpolitical terms: “those who lack basic rights andliberties that make them particularly open to ex-ploitation” (Zion 2002).

Beyond individuals or groups, Macklin suggeststhat whole communities or countries may be vulner-able to exploitation, particularly if “investigators orsponsors are from a powerful industrialized countryor a giant pharmaceutical company and the researchis conducted in a developing country” (Macklin2003, 472). In arguing against “double standards”in research in multinational studies—permittingresearch in destitute countries that would not beapproved in wealthy ones—Kottow (2003) distin-guishes between vulnerability and susceptibility.Vulnerability, he says, applies to everyone; whatreally matters in research ethics is susceptibility,which means being poor, undernourished, and lack-ing in medical care and therefore predisposed toadditional harm (Kottow 2003, 460).

In a paper commissioned by the NationalBioethics Advisory Commission, Kipnis (2001)

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analyzed the category of vulnerability not bysubpopulations, but by types of vulnerability. Heoutlined a taxonomy of six types of vulnerabil-ity, which he defined as a limit on the ability toprovide informed consent (Kipnis 2001). Theseare: (1) cognitive: the ability to understand in-formation and make decisions; (2) juridic: beingunder the legal authority of someone such as aprison warden: (3) deferential: customary obedi-ence to medical or other authority; (4) medical:having an illness for which there is no treatment;(5) allocational: poverty, educational deprivation;and (6) infrastructure: limits of the research set-ting to carry out the protocol. In a revised versionof his forthcoming paper, Kipnis added a seventhtype: social vulnerability, that is, belonging to asocially undervalued group. While this taxonomyoffers useful distinctions, it leads to two inferences:that everyone who fits into any of these categories isvulnerable, and that everyone capable of unfetteredconsent is not.

Vulnerability: Too Broad and Too Narrow

As conventionally understood, even if not formallydefined, the concept of vulnerability has three ba-sic, related problems. First, so many categories ofpeople are now considered vulnerable that virtuallyall potential human subjects are included. Considerhow the labeling of groups as vulnerable has bur-geoned. In U.S. regulations, for example, beyondthe protected populations covered by special regu-lations, other “special classes of subjects” are high-lighted in OHRP’s guidebook for special consider-ation. These include cognitively impaired persons;traumatized and comatose patients; terminally illpatients; elderly/aged persons; minorities; students,employees, and normal volunteers; and participantsin international research (U.S. Dept. of Health andHuman Services 2001).

The most recent revision of the World Med-ical Association’s Declaration of Helsinki, whilenot defining vulnerability, simply states: “Some re-search populations are vulnerable and need spe-cial protection” (World Medical Association 2002).The Declaration advises: “The particular needsof the economically and medically disadvantagedmust be recognized. Special attention is also re-quired for those who cannot give or refuse con-sent for themselves, for those who may be sub-ject to giving consent under duress, for those whowill not benefit personally from the research andfor those for whom the research is combined withcare.”

With an even more specific list, the 2002CIOMS guidelines include as vulnerable “junioror subordinate members of a hierarchical group,”such as “medical and nursing students, subordi-nate hospital and laboratory personnel, employeesof pharmaceutical companies, and members of thearmed forces or police.” Furthermore, the guide-lines describe elderly people as “likely to acquireattributes that define them as vulnerable.” Othercategories include residents of nursing homes; peo-ple receiving welfare benefits or social assistance andother poor people and the unemployed; people inemergency rooms; some ethnic and racial minoritygroups; homeless persons, nomads, refugees, or dis-placed persons; prisoners; patients with incurabledisease; individuals who are politically powerless;and members of communities unfamiliar with mod-ern medical concepts.

Under one or another of these rubrics, nearlyeveryone is vulnerable, especially since the bene-fits of research can never be guaranteed in advanceand since much clinical research, by definition, iscombined with care. If everyone is vulnerable, thenthe concept becomes too nebulous to be meaning-ful. Presumably, the purpose of designating a groupas vulnerable is to provide additional protectionsabove those required for all human participants. Forcertain classes, these special protections are codifiedin regulations. For most vulnerable groups, how-ever, the only additional protection is an exhorta-tion to investigators and IRBs to pay “special atten-tion” or to give “special consideration” to research inwhich these groups may be included. As more andmore groups come to be so labeled, the result is thatevery research protocol requires some type of specialattention and IRBs have no guidance on where toconcentrate their limited attention and resources.

Second, if the concept of vulnerability is over-broad, it is also too narrow. An almost exclusiveemphasis on group characteristics that ostensiblyundermine or eliminate the capacity to give consentcan divert attention from features of the research it-self, the institutional environment, or the social andeconomic context that can put participants in harm’sway. Much recent concern, for example, stems fromthe deaths of four research participants. Two of thethree women who died were healthy volunteers affil-iated with medical centers as student or employee;the third was a nurse. The problems that led to theirdeaths were not related to vulnerability as a status,but to serious flaws in protocol design and imple-mentation and in inadequate oversight (Steinbrook2002a; Steinbrook 2002b).

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The other research fatality was a participant ina Phase I gene transfer experiment, who fell intothe broad vulnerability category of a person withan incurable illness. But his genetic disease wasnot seriously debilitating, he was 18 years old andhad the capacity to give consent, and his father wasclosely involved in his decision to participate. Ques-tions about risk also played a central role in discus-sions of the aftermath of this case, as well as con-cerns that the investigators’ financial interests mayhave affected decisions about enrollment and med-ical management. In these four deaths it appearsthat the participants’ capacity to consent was not inquestion.

While consent is surely a serious concern, theroot of the concept of vulnerability lies in the pos-sibility of physical harm. The term derives fromthe Latin vulnus (wound). In ordinary language vul-nerable means “capable of being attacked, harmed,or injured in some way” or, in psychological par-lance, “susceptible of being emotionally damagedor offended.” Goodin (1985) emphasizes that somevulnerabilities are “inherent and immutable”; vul-nerability is inevitable in society because people aredependent on one another. However, he says, “In nocase should [vulnerabilities] be so severe and asym-metrical that one party has exclusive, discretionarycontrol over resources that the other needs to protecthis vital interests” (Goodin 1985, 206). In contem-porary bioethical discourse, one can be vulnerableto being harmed or being wronged. There is muchthat puts research participants at risk beyond theirmembership in a “vulnerable” group.

Third, the concept of vulnerability stereotypeswhole categories of individuals, without distin-guishing between individuals in the group who in-deed might have special characteristics that need tobe taken into account and those who do not. Par-ticular concerns have been raised about consideringall poor people, all pregnant women, all membersof ethnic or racial minorities, and all people withterminal illness as inherently vulnerable (DeBruin2001).

Inclusion in the category of vulnerable has beenchallenged in the past on similar grounds, that is,out of concern that not all members of a group arenecessarily vulnerable. The National Commissionconsidered at great length the use of prisoners as re-search subjects. Prisoners at Jackson State Prison inMichigan asserted that they wanted to have the op-portunity to participate for benefits such as money,better living conditions, and relief from boredom(R. Levine 1986). Nevertheless, current federal

regulations concerning prisoners set very high bar-riers for research.

A more successful challenge came in the 1990s,as women’s health advocates marshaled support formore representation of pregnant women and womenof childbearing age among study populations. Thesegroups had been excluded based on fears of harmto a real or potential fetus and liability to spon-sors. In 1994 the Institute of Medicine (IOM) con-cluded, “volunteers for clinical studies should beoffered the opportunity to participate without re-gard to gender, race, ethnicity, or age” (Mastroianni,Faden, and Federman 1994). The National Insti-tutes of Health policy guidelines that followed theIOM report stated that women should not be ex-cluded from research on the grounds that theywere or might become pregnant (National Insti-tutes of Health 2001). However, inclusion of preg-nant women is governed by regulations in whichthe notion of vulnerability is embedded (45CFR46Subpart B).

Furthermore, some people may be vulnerable incertain circumstances and not in others because ofthe timing of the research (e.g., pregnant women inlabor, the first few hours after a natural or man-made disaster), the emotional impact of the re-search (e.g., a disease from which a loved one hasrecently died), prior experiences, or other personalfactors. Thus, an individual’s needs for special pro-tections in the research context depend not solelyon that person’s inclusion in a group, but impor-tantly on the particular features of the researchproject and the environment in which it is takingplace.

Public policy is a blunt instrument and some-times it is necessary to set cut-offs or designatewhole groups for special treatment because individ-ualized decision making is not feasible. For exam-ple, most jurisdictions in the U.S. designate nearlyeveryone under the age of 18 as a “child.” But itis critical that designated groups be drawn as nar-rowly as possible and for only so long as specialconsideration is otherwise justifiable.

While we have argued that the strategy of rely-ing on categorical vulnerability to guide investiga-tors and IRBs is flawed, we believe that the existingregulations to protect children have been useful andshould be preserved, although modifications mightbe made. In part because there are special regula-tions for research involving children, not all researchprotocols in this category present difficult decisions.Many, perhaps most, follow well-accepted and ethi-cally acceptable patterns. Kipnis (2003) also created

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a taxonomy of seven vulnerabilities for research withpediatric patients.

Furthermore, people with permanent cognitiveimpairments, such as severe mental retardation oradvanced Alzheimer disease, will not attain or re-gain a state of cognitive capacity. While proposedregulations regarding this category have been miredin dissension for years, special protections for re-search involving such persons should be considered.

Nevertheless, merely identifying a research pro-tocol as involving participants who come from par-ticular groups or who might be vulnerable in par-ticular ways is not the only way to determine whichresearch protocols warrant more intensive review,in what particular areas, and then to determine howto strengthen protections. We suggest a broad dis-cussion among researchers, sponsors, study coordi-nators, ethicists, IRB members, policy makers, andresearch participants to determine ways in whichthe concept of vulnerability is useful, but also howto provide more targeted forms of protection for par-ticipants in protocols where vulnerability misses themark.

We offer one such scheme under the rubric “spe-cial scrutiny.” Three criteria for special scrutiny—more focused review of certain kinds of proto-cols that present special ethical challenges—are:(1) the research involves initial experiences of trans-lating new scientific advances into humans, espe-cially when the intervention is novel and/or irre-versible; (2) there is a known or credible risk ofsignificant harm (death or serious disability beingthe clearest examples) and there is no potential ofan offsetting direct medical benefit; or (3) the pro-tocol raises ethical questions about research designor implementation for which there is no consen-sus. Special scrutiny is a mechanism that aims toprovide appropriate protection of all research par-ticipants, not just those officially deemed vulnerable(C. Levine et al. 2004). �

Received 5 November 2003; accepted3 December 2003; posted for commentary5 February 2004.

Acknowledgments

This paper is a project of the Consortium toExamine Clinical Research Ethics (CECRE),which is funded by the Doris Duke CharitableFoundation. Other members of CECRE whoprovided valuable contributions to this manuscriptwere Angela Bowen, M.D., Western IRB; EzekielEmanuel, M.D., Ph.D., National Institutes of

Health; Alan Fleischman, M.D., New YorkAcademy of Medicine; and Kenneth Getz, Cen-terWatch. Kenneth Kipnis, Ph.D., provided usefulunpublished materials and suggested importantreferences.

Competing Interests Statement

The authors declare that they have no competingfinancial interests.

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