the concept of ‘vulnerability’ in research ethics: an ... · to the enshrinement and...

RESEARCH Open Access

The concept of ‘vulnerability’ in researchethics: an in-depth analysis of policies andguidelinesDearbhail Bracken-Roche1,2, Emily Bell1, Mary Ellen Macdonald3 and Eric Racine1,2,4,5*

Abstract

Background: The concept of vulnerability has held a central place in research ethics guidance since its introduction inthe United States Belmont Report in 1979. It signals mindfulness for researchers and research ethics boards to thepossibility that some participants may be at higher risk of harm or wrong. Despite its important intended purpose andwidespread use, there is considerable disagreement in the scholarly literature about the meaning and delineation ofvulnerability, stemming from a perceived lack of guidance within research ethics standards. The aim of this study wasto assess the concept of vulnerability as it is employed in major national and international research ethics policies andguidelines.

Methods: We conducted an in-depth analysis of 11 (five national and six international) research ethics policiesand guidelines, exploring their discussions of the definition, application, normative justification and implications ofvulnerability.

Results: Few policies and guidelines explicitly defined vulnerability, instead relying on implicit assumptions and thedelineation of vulnerable groups and sources of vulnerability. On the whole, we found considerable richness in thecontent on vulnerability across policies, but note that this relies heavily on the structure imposed on the data throughour analysis.

Conclusions: Our results underscore a need for policymakers to revisit the guidance on vulnerability in research ethics,and we propose that a process of stakeholder engagement would well-support this effort.

Keywords: Research ethics, Vulnerable populations, Vulnerability, Research policy, Ethics policy, Research oversight

Background: the function of vulnerability inresearch ethics guidance and policyResearch on human subjects is thought to be fundamen-tally ethically challenging, requiring ethics standards toguide researchers as well as approval and oversight of re-search proposals from independent committees. Societyallows researchers to invite individuals to participate in re-search once certain conditions are met, including a re-search ethics board’s (REB, also known as InstitutionalReview Boards, or IRBs, or Research Ethics Committees,or RECs) determination that risks and benefits are

appropriately balanced, that the proposed strategy for sub-ject recruitment is fair, and that voluntary, informed con-sent will be sought from each potential subject [1]. Theconcept of vulnerability, which finds it origins in theUnited States Belmont Report of 1979 [2], plays a centralrole in research ethics thinking, drawing attention to situ-ations where these conditions may not be met [1]. Since1979, the number of legal and non-legal research ethicspolicies and guidelines has increased tremendously and,with them, the use and scope of the concept of vulnerabil-ity or vulnerable populations [2, 3]. However, there ismuch scholarly disagreement over the appropriate mean-ing and application of this concept in research ethics, andpolicymakers are charged with the challenge of navigatingthis contentious landscape in the development and refine-ment of research guidelines and policies [4]. A growing

* Correspondence: [email protected] Research Unit, Institut de recherches cliniques de Montréal, 110Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada2Biomedical Ethics Unit and Division of Experimental Medicine, McGillUniversity, Montréal, QC, CanadaFull list of author information is available at the end of the article

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body of literature critiques and aims to advance the wayvulnerability is conceptualised and employed in researchethics, with major debates regarding foundational ele-ments of this important ethical concept [5–10].

Major debates surrounding the concept of vulnerability inresearch ethicsThere is widespread agreement that some research par-ticipants may be particularly vulnerable and in need ofspecial protections, yet the concept of vulnerability itselfhas been described as ‘vague’ [11], with a lack of consen-sus in the scholarly literature regarding the concept’scentral features. Contrasting accounts have been pro-posed regarding the justification of vulnerability andwhich ethical principles translate into obligations for thespecial protection of vulnerable research participants.Some accounts propose a justice-based reason for pro-tection, concerned with the fairness of participant re-cruitment and of the distribution of research burdensand benefits [12, 13]. Others ground vulnerability in aprinciple of autonomy or respect for persons, suggestingthat persons who cannot provide informed and volun-tary consent are susceptible to harm because they arenot able to protect their interests [5, 13]. These ap-proaches are not mutually exclusive, but we must atleast be able to identify which ethical principles define towhom we owe special consideration. In research, thereare often gaps between the rules intended to govern andthe practices at hand, requiring those tasked with theimplementation of these rules to interpret and applythem in their specific context [3]. An ethical foundationis needed for these interpretations; otherwise, it is difficultto understand the intentions of the authoring parties orapply the rule to the situation at hand [3]. In this context,a better understanding of the justifications of vulnerabilitybecomes a crucial goal of scholarly work in this area.The application of vulnerability and its scope in re-

search has also been a subject of much debate. In par-ticular, vulnerability has been charged with being bothtoo broad and too narrow. An overly broad concept cap-tures all research participants, creating conceptual con-fusion over the meaning of ‘special protections’, while anoverly narrow concept may leave some vulnerable partic-ipants at risk and without the needed protection [5, 11,12, 14]. Practically, a definition of vulnerability must becomprehensive enough to capture those in need of add-itional protections without overburdening participantsfor whom protection beyond the norm is unnecessary.Further, it must provide researchers and research ethicsboards with the information necessary to identify thosewho are vulnerable, as well as what they might be vul-nerable to. There are compelling arguments against nar-row definitions of vulnerable groups that support the

identification of specific factors within the research con-text and the participants’ personal situation that createpossible vulnerabilities [6].The foundational debate about the concept of vulner-

ability revolves around its definition, with various pro-posals made for its delineation in the literature. Arguingthat vulnerability lacks an organising principle, Hurst [5]suggests that vulnerable persons are properly conceivedof as those who have “an identifiably increased likeli-hood of incurring additional or greater wrong”. This ac-count emphasises that both individual and situationalfactors must be evaluated in defining vulnerability be-cause being overly focused on individual characteristicscan obscure features of the research protocol or environ-ment that may harm participants. Luna [6] argues thatvulnerability must be conceived of as ‘relational’, in thatvulnerabilities can only be discovered by examining anindividual in context, and ‘dynamic’, since one’s vulner-ability depends on one’s context. Luna and Vanderpoel[14] describe layers of vulnerability which arise from inter-actions between an individual’s characteristics and theirenvironment, and which interact with one another to cre-ate an inextricably context-dependent vulnerability.To our knowledge, an in-depth analysis of the concept

of vulnerability as it exists in the policies and guidelinesthat govern research on human subjects has not beenconducted. This is an important gap because, at present,the scholarly literature seeks to advance the conceptwithout an understanding of the full scope of the regula-tory context. Without a clear understanding of the con-ceptualisation and operationalisation of vulnerability incurrent research ethics, recommendations for its refine-ment risk being disconnected from the range of policyoptions. To explore the diversity of options with respectto the enshrinement and application of the concept ofvulnerability in research ethics guidelines, we conductedan in-depth analysis of major national and internationalresearch ethics policies and guidelines.

MethodsSamplingInspired by previous research ethics policy analyses [3, 15],we compiled a sample of internationally- and nationally-adopted research ethics guidelines and policies, focusing onCanada (the authors’ own regulatory context) and regionswith similar demographic and legal structures to Canada,including Australia, the European Union, the United King-dom, and the United States [15]. We began our searchusing a compilation of international human research stan-dards produced by the Office for Human Research Protec-tions of the United States Department of Health andHuman Services [16]. Additionally, we performed second-ary searches of the references of any included guidelinesand policies for relevant, non-duplicated documents.

Bracken-Roche et al. Health Research Policy and Systems (2017) 15:8 of 18

Our primary goal was to build a sample of guidelinesand policies that discussed or referenced vulnerability ingeneral health research. As such, we excluded those inwhich vulnerability was not explicitly discussed (e.g. theNuremberg code) as well as those focused on specificareas of or issues within research (e.g. paediatric research,genetic research), put forward by professional organisa-tions, or published as working papers, drafts, commentar-ies, or otherwise less broadly adopted documents. Ourfinal sample included 11 guidelines and policies, six ofwhich are internationally-adopted (i.e. across multiplecountries) [17–22] and five of which are nationally-adopted (i.e. within individual countries) [23–27]. All doc-uments were downloaded and saved for data extraction.See Table 1 for an overview of our sample and the keycharacteristics of included policies.

Inter-policy component analysisThis stage of analysis consisted of an inter-policy analysis,allowing us to capture and explore patterns in the dataacross our sample. Given our specific interest in under-standing how guidelines and policies employ the conceptof vulnerability, each document was word-searched forthe term ‘vulnerab’. Using this truncated keyword allowedus to identify all uses of the terms ‘vulnerability’ or ‘vul-nerable’. We read the broader sections of text surroundingthe key terms to facilitate a contextual understanding ofhow the notion of vulnerability was used.We employed a content analysis strategy, developing an

initial coding guide deductively and refining it inductively.We hypothesised, based on the literature (as described inthe Background section), that research ethics guidance onvulnerability should include at least the following basic con-tent: (1) a definition of vulnerability, (2) a discussion of thesources or circumstances from which vulnerability can ariseand/or identification of groups likely to be in thosecircumstances, (3) an explanation of the ethical justificationof the concept to aid in its application. A preliminarycoding guide was created to capture these content areas.This preliminary guide was applied to a subset of the sam-ple (n = 3). Through this ‘piloting’ stage, the coding schemewas refined inductively by three authors (DBR, EB, ER) toensure other major areas of content were captured. This re-sulted in the addition of a fourth content category, ‘implica-tions of vulnerability’, which captures responses tovulnerable participants laid out within the guidelines andpolicies. Definitions and rules for the application of eachcode were developed to ensure rigor and thoroughness.Throughout the coding process, three authors (DBR, EB,ER) engaged in open discussions in order to account forany biases of the primary coder (DBR) and to ensure thefull depth of the data would be represented through thisanalytic strategy. Once final coding was complete, it was

reviewed by other authors (EB, ER, MEM) and consensuswas achieved through team discussions.The results of our comparative data analysis are pre-

sented in tables, with direct excerpts from the guidelinesand policies provided where possible. Two codes (groupsand sources of vulnerability, and implications) includedmore data than others and thus the text has been con-densed (i.e. direct citations are not provided). To ensurefidelity to the data, one author (DBR) condensed thistext and another (ER) reviewed it to ensure accurate rep-resentation of the guidelines and policies.

Intra-policy holistic analysisAfter the inter-policy comparative analysis, we examinedthe conceptualisation and operationalisation of vulnerabil-ity within each policy. Building on the structure developedin our comparative analysis, we assessed the logicalconsistency between the four content areas of vulnerabil-ity. More specifically, we analyzed each policy and guide-line in isolation to examine (1) which major content areasare lacking, (2) whether the four content areas (definitions,justifications, groups and sources, and implications) are con-sistent (e.g. in their meaning) with one another, and (3) whatoverall impression a guideline or policy user might haveabout the concept of vulnerability within the document.

ResultsInter-policy comparative analysisDefining vulnerabilityAll policies in our sample reference vulnerability and/orvulnerable subjects, but only three out of eleven expli-citly define these terms (Table 2). Of these, the Councilfor International Organizations of Medical Sciences(CIOMS) and the Tri-Council Policy Statement: EthicalConduct for Research Involving Humans (TCPS2) guide-lines define vulnerability itself, while the InternationalConference on Harmonisation, Good Clinical Practice(ICH GCP) instead provides a definition of vulnerablesubjects. These definitions share similar structures, all de-fining vulnerability or vulnerable subjects and identifyingparadigmatic sources (or causes) of vulnerability. The ICHGCP definition focuses on issues of consent, where a lackof voluntariness in a subject’s decision to participate estab-lishes their vulnerability. The CIOMS and TCPS2 guide-lines employ broader language, both stating thatvulnerability arises from a subject’s lack of ability toprotect their own interests. Both identify sources of vul-nerability located within the subject (e.g. a lack ofdecision-making capacity) and in their environment (e.g. alack of access to medical care). Only the definition pro-vided by the TCPS2 makes explicit reference to anothercentral ethical concept – that of autonomy. This referencesuggests an important link between vulnerability and au-tonomy, though this connection is not further explained.


Table 1 Key characteristics of guideline and policy sample

Guideline/Policy Date Adopted Abbreviation Status Intended Users Guiding Ethical Framework/Principles

Declaration of Helsinki 2013 Intl Declarationof Helsinki

A statement of ethicalprinciples proposing howphysicians should act inresearch; not legally binding

Primarily physicians; othersinvolved in medical researchwith human subjects areencouraged to adopt itsprinciples

Articles of the Declarationitself are intended asguiding ethical principles forresearch

Council for InternationalOrganizations of MedicalSciences, InternationalEthical Guidelines forBiomedical ResearchInvolving Human Subjects

2002 Intl CIOMS A guidance documentintended to guide theeffective application of theDeclaration of Helsinki’sethical principles inresearch, especially in low-resource countries; notlegally binding

CIOMS member bodies,which include internationaland national biomedicalorganisations (e.g. WorldMedical Association)

Cites three guiding ethicalprinciples: respect forpersons, beneficence, andjustice

UNESCO UniversalDeclaration on Bioethicsand Human Rights

2005 Intl UNESCODeclaration

A universal framework ofprinciples to guide States informulating legislation andpolicies, as well as to guidethe actions of individuals,groups, communities,institutions andcorporations, public andprivate

Addressed to States, butalso provides guidance forindividuals, groups,communities andcorporations, public andprivate

Articles of the UNESCODeclaration itself areintended as guidingbioethical principles

Directive of 4 April 2001 N°2001/20/EC

2001 EU EU ClinicalTrialsDirective

A legislative act thatestablishes specificprovisions for good clinicalpractice in clinical trials; EUMember States must meetthese provisions though theDirective does not legislatehow

EU member states Not explicitly provided;states that “[t]he acceptedbasis for the conduct ofclinical trials in humans isfounded in the protection ofhuman rights and the dignityof the human being… as forinstance reflected in the 1996version of the HelsinkiDeclaration” [20]

Regulation of 16 April2014 N°536/2014

2014 EU EU ClinicalTrialsRegulation

A binding legislative actapplying to all clinical trialsconducted in the EU

EU member states Not explicitly provided

International Conferenceon Harmonisation, GoodClinical Practice

1996 US, EU,JP, AUS,CA

ICH GCP An ethical and scientificquality standard fordesigning, conducting,recording, and reportinghuman subject researchtrials; serves as a unifiedstandard for CA, the EU,JPN, and US to facilitate themutual acceptance ofclinical data by theregulatory authorities inthese jurisdictions

Targeted at those involvedin the generation of clinicaltrial data intended to besubmitted to regulatoryauthorities, especially in CA,the EU, JPN, and US; canalso be used by othersinvolved in clinicalinvestigations “that mayhave an impact of the safetyand well-being of humansubjects” [22]

Not explicitly provided;states that “clinical trialsshould be conducted inaccording with the ethicalprinciples that have theirorigin in the Declaration ofHelsinki” ([22], Art. 2.1)

National Statement onEthical Conduct in HumanResearch

2007 AUS AustralianNationalStatement

Must be used to inform thedesign, ethical review, andconduct of human researchfunded by or taking placeunder the auspices of thebodies that have developedthe Statement (i.e. NationalHealth and MedicalResearch Council, AustralianResearch Council, AustralianVice-Chancellors’Committee)

Researchers, members ofethical review bodies, andthose involved in researchgovernance, as well aspotential researchparticipants

Describes four guidingvalues and principles:research merit and integrity,justice, beneficence, andrespect

Tri-Council PolicyStatement, 2nd edition

2014 CA TCPS2 To be eligible to receiveand administer researchfunds from the federalresearch agencies

All those involved in theconduct and review ofresearch funded by thefederal research agencies,

Sets out three coreprinciples: respect forpersons, concern forwelfare, and justice


The definition provided by the TCPS2 is distinct fromthe others because it explicitly states that vulnerability iscontext-dependent, and is experienced “to differentdegrees and at different times, depending on [an individ-ual’s or group's] circumstances” ([24], p. 210) . However,qualifying language employed in other policies implicitlysuggests a similar view that vulnerability exists on aspectrum or as a matter of degree (Table 2). The Declar-ation of Helsinki, Australian National Statement, andBelmont Report, for example, discuss participants whoare “particularly vulnerable” [17], “more-than-usuallyvulnerable” [23], or “especially vulnerable” [26], re-spectively. Unlike the TCPS2, no other guidelines inour sample state explicitly that vulnerability should be

thought of as existing on a spectrum, or as a featurethat can vary between circumstances.

Ethical justifications for the concept of vulnerabilityMany guidelines and policies (CIOMS, UNESCODeclaration, Declaration of Helsinki, Australian NationalStatement, TCPS2, Belmont Report) provide explicit ethicalargumentation relating to vulnerability and/or vulnerablesubjects. There is significant overlap across the sample be-tween the principles from which obligations or consider-ations relating to vulnerability arise (see Table 3 for anoverview). In all cases where guiding ethical principles areprovided by a policy or guideline, vulnerability-related con-cerns are discussed in the application of each principle.

Table 1 Key characteristics of guideline and policy sample (Continued)

responsible for this policy(i.e. Canadian Institutes ofHealth Research, NaturalSciences and EngineeringResearch Council of Canada,Social Sciences andHumanities ResearchCouncil), institutions mustagree to comply with it;while not required to do so,other organisations andentities are encouraged toadopt this Policy to guidethe ethical aspects of thedesign, review and conductof research involvinghumans

e.g. institutions, researchers,ethics review boards, etc.

Research GovernanceFramework for Health andSocial Care, 2nd edition

2005 UK UK ResearchGovernanceFramework

Sets out a framework ofprinciples, requirements,and standards for thegovernance of research inhealth and social care andapplies to all researchrelating to theresponsibilities of theSecretary of State for Health

Intended for all those whodesign research studies,participate in research, hostresearch in theirorganisation, fund researchproposals or infrastructure,manage research, andundertake research

Not explicitly provided

The Belmont Report 1979 US BelmontReport

A statement of basic ethicalprinciples and guidelinesintended to assist inresolving the ethicalproblems that surround theconduct of research createdby the National Commissionfor the Protection of HumanSubjects of Biomedical andBehavioral Research for theDepartment of Health,Education, and Welfare

Those involved in thereview and conduct ofresearch

Lays out three basic ethicalprinciples: respect forpersons, beneficence, andjustice

Title 45 Code of FederalRegulations, Part 46

1991 US CommonRule

Serves as a federal policy forhuman subjects research,and applies to all researchconducted or supported byor affiliated with the federalagencies by which is hasbeen adopted

Those involved in thereview and conduct ofresearch associated with thefederal agencies by whichthe Common Rule has beenadopted

Not explicitly provided, butthe Regulations werecreated on the basis of theBelmont Report

Intl international, EU European Union, AUS Australia, CA Canada, JP Japan, UK United Kingdom, US United States


The normative status of the concept of vulnerability isinconsistent across policies and guidelines. In certaincases (CIOMS, Australian National Statement, TCPS2,Belmont Report), obligations towards vulnerable re-search participants arise from the application of otherfundamental principles. For example, in the TCPS2, obli-gations towards those in circumstances of vulnerabilityare entailed by the policy’s core principles of Respect forPersons, Concern for Welfare, and Justice. In others,

concerns or obligations related to vulnerability are them-selves characterised as fundamental principles. Specific-ally, principles 19 and 20 of the Declaration of Helsinkifocus on vulnerability, with 19 stating that “[s]ome groupsand individuals are particularly vulnerable and may havean increased likelihood of being wronged or of incurringadditional harm” [17]. Similarly, Article 8 of the UNESCODeclaration promotes “[r]espect for human vulnerabilityand personal integrity” [19] as a principle in and of itself.

Table 2 Content regarding definitions of vulnerability and detailing the use of qualifying language

Policy/Guideline

Explicit definition of vulnerability or vulnerable subjects Use of qualifying languagea

Intl

Intl Declaration ofHelsinki

– • Some groups and individuals are “particularly vulnerable”([17], Art. 19)

CIOMS “‘Vulnerability’ refers to a substantial incapacity to protect one’sown interests owing to such impediments as lack of capability togive informed consent, lack of alternative means of obtainingmedical care or other expensive necessities, or being a junior orsubordinate member of a hierarchical group” ([18], p. 18)

• Persons with serious, potentially disabling or life-threatening diseases are “highly vulnerable” ([18], p. 65)• Selection of the “least vulnerable” subjects required forresearch ([18], p. 18)

UNESCODeclaration

– • Certain individuals and groups are of “specialvulnerability” ([19], Art. 8)

EU Clinical TrialsDirective

– –

Clinical TrialsRegulation

– –

US,EU, JP,AUS, CA

ICH GCP Glossary defines vulnerable subjects as “[i]ndividuals whosewillingness to volunteer in a clinical trial may be unduly influencedby the expectation, whether justified or not, of benefits associatedwith participation, or of a retaliatory response from senior membersof a hierarchy in case of refusal to participate” ([23], Art. 1.61)

–

National

AUS NationalStatement

– • Where “potential participants [in dependent or unequalrelationships] are especially vulnerable” special measuresmay be required ([23], p. 53)• Neonates in intensive care have a “unique developmentalvulnerability” ([23], p. 56)• People with a cognitive impairment, intellectualdisability, or mental illness have “distinctive vulnerabilitiesas research participants” and are “more-than-usuallyvulnerable to various forms of discomfort or stress” ([23], p. 58)

CA TCPS2 “Vulnerability – A diminished ability to fully safeguard one’s owninterests in the context of a specific research project. This may becaused by limited decision-making capacity or limited access tosocial goods, such as rights, opportunities and power. Individualsor groups may experience vulnerability to different degrees andat different times, depending on their circumstances. See also ‘Au-tonomy’” ([24], p. 210)

• Participants, researchers, and research ethics boardmembers may be rendered “more vulnerable” duringpublicly declared emergencies ([24], p. 90)• “The least organisationally developed communities are themost vulnerable to exploitation” ([24], p. 130)• Participants may be “in highly vulnerable circumstances”because of social or legal stigmatisation ([24], p. 141)

UK ResearchGovernanceFramework

– –

US BelmontReport

– • “Also, inducements that would ordinarily be acceptablemay become undue influences if the subject is especiallyvulnerable” ([26], Part C.1)

CommonRule

– –

aQualifying language captures nuances about degrees or types of vulnerabilityIntl international, EU European Union, AUS Australia, CA Canada, JP Japan, UK United Kingdom, US United States, CIOMS Council for International Organizations ofMedical Sciences, TCPS2 Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, ICH GCP International Conference on Harmonisation, GoodClinical Practice


The CIOMS guidelines are a unique case in our samplebecause they characterise vulnerability as both a principleand as a consideration derived from other principles. Inthe introduction to the CIOMS guidelines, issues ofhuman rights are described as relating to two principles,one of which is the “protection of dependent or vulnerablepersons and populations” ([18], p. 11), while the principleof Respect for Persons is described as entailing “at leasttwo fundamental ethical considerations”, including “pro-tection of persons with impaired or diminished autonomy,which requires that those who are dependent or vulnerablebe afforded security against harm or abuse” ([18], p. 17).In the remaining guidelines (ICH GCP, EU Clinical

Trials Directive, EU Clinical Trials Regulation, UnitedKingdom Research Governance Framework, CommonRule), vulnerability is not explicitly discussed in relationto any ethical principles, nor is it described as a guidingprinciple itself. In these cases, concerns relating to vul-nerable persons seem to serve the role of considerationfor ethics review or ethical research with no explicitethical status.

Identifying vulnerable groups and individualsAll guidelines and policies in the sample provide meansthrough which vulnerability can be identified. The ma-jority identify subject groups who are likely to be

vulnerable. Vulnerable groups identified in our sampleare captured in Table 4, along with the correspondingexplanations of why a subject group is considered vul-nerable or what they are vulnerable to, when these de-tails are available. Notably, while the EU Clinical TrialsDirective and Clinical Trials Regulation, as well as theUnited Kingdom Research Governance Framework, allidentify vulnerable subject groups, none of these policiesprovide any supporting explanation. Further, only fourpolicies (CIOMS, Australian National Statement, TCPS2,and the Common Rule) provide any explanations ofwhat certain identified groups are vulnerable to.Across the sample, a great number of groups are iden-

tified as vulnerable. Counting only those broad groupsidentified in our table (i.e. excluding the examples ofsubgroups discussed in the footnote to Table 4), 32groups were identified; when these subgroups are in-cluded, the total number of groups identified as vulner-able expands to 51. Groups most frequently identifiedare children, minors or young people (discussed in sevenpolicies), prisoners (discussed in five policies), as well aspersons with mental health issues, patients in emergencysettings, and certain ethnocultural, racial or ethnic mi-nority groups (each discussed in four policies). Concernsfor the vulnerability of children centre around consent,with both the CIOMS and TCPS2 guidelines positing a

Table 3 Content on the ethical justification of vulnerability and its normative status in each policy

Policy/Guideline Justification for vulnerability Normative status of vulnerability

Intl

IntlICH GCP – Consideration for ethics review

CIOMS The protection of dependent or vulnerable persons and populations is described itself as aprinciple; additionally, concerns relating to vulnerability are grounded in both the principlesof respect for persons and justice

Fundamental principle/application of other principles

UNESCODeclaration

Respect for human vulnerability and personal integrity is itself a fundamental principle inthis framework

Fundamental principle

Declaration ofHelsinki

Concerns related to vulnerability are themselves principles in this framework Fundamental principle

EUClinical TrialsDirective

– Consideration for ethics review

Clinical TrialsRegulation


National

AUSAustralian NationalStatement

Considerations related to vulnerability are discussed in relation to the principles of principlesof respect for persons, research merit and integrity, justice, and beneficence

Application of other principles

CATCPS2 The principles of respect for persons, justice (fairness and equity), and concern for welfare all

entail special obligations regarding vulnerabilityApplication of other principles

UKResearchGovernanceFramework


USBelmont Report The principles of respect for persons, beneficence, and justice all entail special obligations

relating to vulnerabilityApplication of other principles

Common Rule – Consideration for ethics review

Intl international, EU European Union, AUS Australia, CA Canada, JP Japan, UK United Kingdom, US United States, CIOMS Council for InternationalOrganizations of Medical Sciences, TCPS2 Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, ICH GCP International Conferenceon Harmonisation, Good Clinical Practice


Table 4 Vulnerable groups identified in our sample, as well as explanations for this designation, where available

Vulnerable Group (Mentioned in) Explanation

Grouped by social status or situation

Prisoners (CIOMS, ICH GCP, Aus. NationalStatement, TCPS2, Common Rule)

Vulnerable because:• Historically considered vulnerable and “have, at times,been treated unfairly and inequitably in research, or havebeen excluded from research opportunities”a ([24], p. 8)

• Explanation unclear [18, 22]Vulnerable to:• Coercion or undue influence [27]

Certain ethnic, racial minority, or ethnoculturalgroups (CIOMS, ICH GCP, TCPS2, Belmont Report)

Vulnerable because:• Historically considered vulnerable and “have, at times,been treated unfairly and inequitably in research, orhave been excluded from research opportunities”a ([24], p. 8)

• May continually be sought as research subjects due to readyavailability and administrative convenience; have a dependentstatus and, frequently, compromised capacity for free consent;are easy to manipulate as a result of their illness or socioeconomiccondition b[26]

• Explanation unclear [18, 22]

Patients in emergency settings, prospectiveparticipants for emergency research (CIOMS,Clinical Trials Regulation, ICH GCP, TCPS2)

Vulnerable because:• Their incapacity to make decisions creates vulnerablecircumstances [24]

• No explanation [21]• Explanation unclear [18, 22]

Subordinate members of hierarchies or relationshipsc

(CIOMS, ICH GCP, Aus. National Statement)Vulnerable because:• Voluntary consent may be compromised by expectationsof benefit or repercussions from superiors [18, 22]

• Pre-existing relationships may compromise the voluntarinessof consent because they typically involve unequal status, whereone party has influence or authority over the other [23]

Vulnerable to:• Being over-researched [18, 23]

Economically disadvantaged persons(Belmont Report, Common Rule)

Vulnerable because:• Dependent status, impaired capacity to consent, easy tomanipulate as a result of their illness [26]

Vulnerable to:• Coercion or undue influence [27]

Homeless persons (CIOMS, ICH GCP) • Explanation unclear [18, 22]

Institutionalized persons (TCPS2, Belmont Report) Vulnerable because:• Historically considered vulnerable and “have, at times, been treatedunfairly and inequitably in research, or have been excluded fromresearch opportunities”a ([24], p. 8)

• Their ability to fully safeguard their own interests in research maybe limited, and their situation may compromise the voluntarinessof consent in other ways [24]

• May continually be sought as research subjects due to ready availabilityand administrative convenience; have a dependent status and, frequently,compromised capacity for free consent; are easy to manipulate as a resultof their illness or socioeconomic conditionb [26]

Nomads (CIOMS, ICH GCP) • Explanation unclear [18, 22]

Persons in nursing homes (CIOMS, ICH GCP) • Explanation unclear [18, 22]

Persons lacking political or social power (CIOMS) • Explanation unclear [18]

Refugees or displaced persons (CIOMS, ICH GCP) • Explanation unclear [18, 22]

Women (CIOMS, TCPS2) Vulnerable to:• In some parts of the world, they may be vulnerable to neglect or harmin research “because of their social conditioning to submit to authority,to ask no questions, and to tolerate pain and suffering” ([18], p. 73)

Vulnerable because:• Historically considered vulnerable and “have, at times, been treatedunfairly and inequitably in research, or have been excluded fromresearch opportunities”a ([24], p. 8)


Table 4 Vulnerable groups identified in our sample, as well as explanations for this designation, where available (Continued)

Countries or communities with limited resources (CIOMS) Vulnerable to:• Exploitation by sponsors and investigators who are relatively wealthy [18]

Educationally disadvantaged persons (Common Rule) Vulnerable to:• Coercion or undue influence [27]

Members of communities unfamiliar with modernmedical concepts (CIOMS)

• Explanation unclear [18]

Neonates in intensive care (Aus. National Statement) Vulnerable because:• Developmental vulnerability (potential for long-range impacts onhealth and development) [23]

Patients in terminal care (Aus. National Statement) Vulnerable to:• Unrealistic expectations of benefit [23]

Participants and researchers in research that uncoversillegal activities (Aus. National Statement)

Vulnerable because:• Vulnerability may arise because of discovery of participants’illegal activity [23]

Those with diminished capacity for self-determination (TCPS2) • Historically vulnerable and “have, at times, been treated unfairlyand inequitably in research, or have been excluded from researchopportunities”a ([24], p. 8)

The least organizationally developed communities (TCPS2) Vulnerable to:• Exploitation [24]

Grouped by patient/participant condition

Children, minors, or young people (CIOMS, ClinicalTrials Directive, Clinical Trials Regulation, Aus. NationalStatement, TCPS2, Common Rule)

Vulnerable because:• Limited freedom or capacity to consent [18, 24]• Vulnerability arising from developmental stage [24]• No explanation [20, 21]• Explanation unclear [23]

Vulnerable to:• Coercion or undue influence [27]

Persons with mental illness or mental health problems(Clinical Trials Regulation, Aus. National Statement,TCPS2, UK Research Governance Framework)

Vulnerable because:• Historically considered vulnerable and “have, at times,been treated unfairly and inequitably in research, orhave been excluded from research opportunities”a ([24], p. 8)• Unclear [21, 25]

Vulnerable to:• Various forms of discomfort and stress [23]

Elderly persons (CIOMS, Clinical Trials Regulation, TCPS2) Vulnerable because:• Likely to acquire “vulnerability-defining” traits (e.g., institutionalization,dementia) ([18], p. 65]

• Historically considered a group in vulnerable circumstances “have, attimes, been treated unfairly and inequitably in research, or have beenexcluded from research opportunities”a ([24], p. 8)

• No explanation [21]

Persons with limited (or no) freedom or capacityto consent (CIOMS, Clinical Trials Regulation, ICH GCP)

Vulnerable because:• Relatively (or absolutely) incapable of protecting their own interests [18]• No explanation [21]• Explanation unclear [22]

Vulnerable to:• Exploitation for financial gain by guardians [18]

Pregnant or breastfeeding women (Clinical TrialsRegulation, Common Rule)

Vulnerable to:• Coercion or undue influence [27]• No explanation [21]

Adults with learning difficulties (UK ResearchGovernance Framework)


Handicapped persons (Common Rule) • No explanation [27]

Mentally disabled persons (Common Rule) Vulnerable to:• Coercion or undue influence [27]

Persons who have serious, potentially disabling orlife-threatening diseases (CIOMS)

Vulnerable because:• May be treated with drugs or other therapies with unprovensafety and efficacy [18]


vulnerability arising from their limited freedom or cap-acity to consent and the Common Rule emphasisingchildren’s vulnerability to coercion or undue influence.The Australian National Statement similarly positionsthe vulnerability of young people relative to capacity andconsent, though it is unclear how this policy conceivesof the relationship between these concepts. It outlinesvarious scenarios regarding the vulnerability of youngpeople: in some cases, young people may be able tounderstand information but their “relative immaturitymeans they remain vulnerable” ([23], p. 50); in othercases they may be “mature enough to understand andconsent [though] not vulnerable through immaturity inways that warrant additional consent” ([23], p. 50); andin yet other cases, young people may be “mature enoughto understand the relevant information and to give con-sent, although vulnerable because of immaturity in otherrespects” ([23], p. 50). The ‘other respects’ in which im-maturity can render young people vulnerable are notmade explicit, leaving the designation of vulnerabilityopen to interpretation in this case. Other policies employsimilarly open-ended strategies, the CIOMS guidelinesmost explicitly by listing vulnerable groups and sources ofvulnerability, and adding that “[t]o the extent that theseand other classes of people have attributes resemblingthose of classes identified as vulnerable, the need for spe-cial protection of their rights and welfare should bereviewed and applied, where relevant” ([18], p. 65).There is little overlap between the explanations provided

by policies and guidelines for other frequently-identifiedvulnerable groups, and there was a lack of explanation fromat least two of them for prisoners, patients in emergencysettings, and ethnocultural and racial minorities. For overhalf of the groups identified across our sample, an explan-ation of their vulnerability was unclear or lacking entirely.

The EU Clinical Trials Directive and Clinical Trials Regula-tion and United Kingdom Research Governance Frame-work provide no explanation or justification for any of thegroups they designate as vulnerable, and while the Com-mon Rule specifies that it is concerned with vulnerability tocoercion or undue influence, it does not address 'handi-capped persons' in this explanation despite also identifyingthem as a vulnerable subject group. The CIOMS and ICHGCP guidelines, on the other hand, provide definitions ofvulnerable subjects and explanations for some vulnerablegroups. However, both of these policies include categoriesof 'other vulnerable groups' and fail to provide any connec-tion between these other groups and their overarching def-inition of vulnerability. As such, it is unclear whether theyare designated as vulnerable on some other unstatedgrounds.Some policies and guidelines identify sources or

circumstances of vulnerability independently, i.e. withoutany relation or association to a specific vulnerable group.For example, neither the Declaration of Helsinki nor theUNESCO Declaration identifies any particular subjectgroups as vulnerable. Instead, they identify characteris-tics of vulnerable participants or key sources of vulner-ability (Table 5). It is important to note that, while theTCPS2 does identify certain groups as likely to be in vul-nerable circumstances, it qualifies any such labels,emphasising that “[i]ndividuals should not automaticallybe considered vulnerable simply because of assumptionsmade about the vulnerability of the group to which theybelong” ([24], p. 54).

Implications of vulnerability in researchAll policies in our sample identify practical implicationsof vulnerability in research, i.e. responses to vulnerabilityin the design and review of research and to vulnerable

Table 4 Vulnerable groups identified in our sample, as well as explanations for this designation, where available (Continued)

Very sick persons (Belmont Report) Vulnerable because:• May continually be sought as research subjects due to readyavailability and administrative convenience; have a dependent statusand, frequently, compromised capacity for free consent; are easy tomanipulate as a result of their illness or socioeconomic conditionb [26]

People suffering from multiple chronic conditions (Clinical TrialsRegulation)


Persons with a cognitive impairment or intellectual disability(Aus. National Statement)

Vulnerable to:• Various forms of discomfort and stress [23]

aIt is not clear whether the TCPS2 intends these groups it refers to as having been historically in vulnerable circumstances as still at risk of this. Given that this ismentioned but not negated, we included these groups in our tablebThe Belmont Report lists a number of vulnerable groups and a series of explanations of their vulnerability. It is unclear whether certain groups were intended tobe linked to certain explanations, so all have been includedcWithin this category, specific subject groups are provided as examples. For the CIOMS these are “medical and nursing students, subordinate hospital andlaboratory personnel, employees of pharmaceutical companies, and members of the armed forces or police” ([18], p. 65). The ICH GCP adds pharmacy and dentalstudents and persons kept in detention to this list [18]. The Australian National Statement lists “carers and people with chronic conditions or disabilities, includinglong-term hospital patients, involuntary patients, or people in residential care or supported acumination; health care professionals and their patients or clients;teachers and their students; prison authorities and prisoners; governmental authorities and refugees; employers or supervisors and employees (includingmembers of the Police and Defence forces); service-providers (government or private) and especially vulnerable communities to whom the service is provided”([23], p. 53).The table is grouped by category, and organized by the number of times a group is mentioned in the policies and guidelines


participants themselves. A wide range of implicationswere identified, some directed explicitly towards REBsand/or investigators but the majority formulated morebroadly with no specific group targeted. Further, theseimplications span the research process, from consider-ations important in the design of research to actions thatmust be taken when vulnerable persons are participatingin research (Table 6).A majority of policies and guidelines identify implica-

tions relating to restrictions for research with vulnerablegroups or individuals, but these entail both negative andpositive duties. Overall, these policies and guidelinespropose that the involvement of vulnerable groups in re-search ought to be restricted to some extent; vulnerablepersons ought to be involved only when the researchcannot be carried out with persons who are less vulner-able and special justification is required for their involve-ment. However, when these persons are involved inresearch, additional actions are required, such as the de-sign of research that is responsive to their needs or pri-orities and the provision of benefits relevant to theirgroup/subject population. Across our sample, a commonunderlying assumption seems to be that vulnerablegroups can and should be involved in research, but thatadditional measures are required to ensure this involve-ment occurs in an ethical manner. In fact, several pol-icies (CIOMS, EU Clinical Trials Directive, AustralianNational Statement, and TCPS2) assert that vulnerablegroups have a right to participate in research and accessits benefits, and while the others do not identify such anentitlement, none go so far as to state that the outrightexclusion of vulnerable groups from research best servesto protect them.The implications of vulnerability all tend towards careful

inclusion rather than outright exclusion of vulnerablegroups from research. However, there is more variability re-garding the extent to which these protections afford agencyto vulnerable subjects. The majority specify considerationsand actions for researchers and REBs, with few explicitlyidentifying the desires of these individuals as relevant in theapplication of these measures. The TCPS2 in particular

puts forth numerous measures intended to promote theagency of those in vulnerable circumstances. For example,it is suggested that they should be afforded opportunities toinfluence research and that research ought to enhance vul-nerable persons’ capacity for participation. Furthermore,the TCPS2 guidance states more broadly that vulnerablegroups may need or desire special measures to ensure theirsafety, suggesting a role for participants in the design andimplementation of their protections.In addition to conditions and restrictions for research

involvement, the process of informed consent is a majorarea of focus in the policies and guidelines. Here in par-ticular there is an emphasis on the provision of mean-ingful support to enable vulnerable persons to offer afully informed consent to research. Mechanisms of sup-port include ensuring adequate time and an appropriateenvironment (CIOMS), as well as ensuring that informa-tion is fully explained and understood (United KingdomResearch Governance Framework). Additionally, theAustralian National Statement uniquely suggested thatparticipants be given the option of using a participantadvocate within the consent process.

Holistic policy analysisOf the 11 policies and guidelines in our sample, onlytwo, the CIOMS guidelines and TCPS2, meet our cri-teria for a full conceptualisation of vulnerability, ad-dressing all content areas (Table 7). In this section, wepresent the results of our intra-policy analysis of vulner-ability with a narrative about each policy statement, ad-dressing (1) which major content areas are lacking, (2)whether the content areas are consistent (i.e. in theirmeaning) with one another, and (3) what overall impres-sion a guideline or policy user might have about theconcept of vulnerability within the document.

International policies and guidelines

Declaration of Helsinki The Declaration conveys aharm/wrong-based conceptualisation of vulnerabilitythat is internally coherent due to its broad language. Itdoes not identify what these wrongs or harms mightconsist of and, because concern for vulnerability is pre-sented as a fundamental principle, interpretation cannotbe guided by other ethical principles. Implications ofvulnerability focus on the need for responsive research,special justification for involving vulnerable persons, andto-group benefits, suggesting these harms include theunfair distribution of the risks and benefits of research.

CIOMS These guidelines present an autonomy-basedconceptualisation of vulnerability that is comprehensivein scope but lacks internal clarity in its discussion of

Table 5 Sources of vulnerability identified independently fromvulnerable groups

Policy/Guideline Sources of vulnerability


An increased likelihood of being wronged or ofincurring harm

UNESCODeclaration

Persons may be rendered vulnerable by disease ordisability or other personal, societal or environmentalconditions

TCPS2 Persons may be in vulnerable circumstances becauseof social or legal stigmatisation associated with theiractivity or identity

TCPS2 Tri-Council Policy Statement: Ethical Conduct for ResearchInvolving Humans


Table 6 Implications of vulnerability, grouped by theme

Restrictions for research with vulnerable groupsor individuals

Policy/Guideline

When research is carried out with vulnerableparticipants it should be responsive to theneeds, conditions, or priorities of thevulnerable group involved

Declaration of Helsinki;CIOMS

Vulnerable subjects should be involved inresearch only when it cannot be carried outwith less vulnerable subjects

CIOMS

Special justification is required for involvingvulnerable groups in research andappropriateness ought to be demonstrated

CIOMS;Belmont Report

Children should not be included in early-phaseresearch until therapeutic effects have beenshown in adults

CIOMS

Opportunities to participate in and influenceresearch affecting their welfare should not bewithheld from vulnerable groups

TCPS2

Members of vulnerable groups are entitled toaccess the benefits of research

CIOMS

Children must be involved in studies ofmedicinal products likely to be of value tothem


People with a cognitive impairment,intellectual disability, or mental illness areentitled to participate in research, which neednot be limited to their particular impairment,disability, or illness

Australian NationalStatement

Research with communities vulnerable toexploitation should strive to enhance capacityfor participation

TCPS2

Patients receiving high-risk clinical care shouldnot be inappropriately included in or excludedfrom research

TCPS2

Risk to vulnerable subjects is justified when itarises from interventions that will provide adirect health benefit, or when it will benefitthe subject’s population group

CIOMS

Special protections and obligations

Individuals and groups of specialvulnerability should be protected

UNESCO Declaration

Special ethical obligations exist towardsvulnerable subjects

TCPS2

Vulnerable subjects should receive special/specific protections

Declaration of Helsinki

Groups or individuals in vulnerablecircumstances may need or desire specialmeasures to ensure their safety in a specificresearch project

TCPS2

Vulnerable subjects should be affordedsecurity against harm or abuse

CIOMS

Special (or additional) protections for therights and welfare of vulnerable subjectsshould be applied

CIOMS; Common Rule

Attention and consideration

Special attention should be paid to trialsinvolving vulnerable subjects

ICH GCP

Table 6 Implications of vulnerability, grouped by theme(Continued)

Special attention or regard should be paidto vulnerable communities, groups, or persons

UNESCO Declaration;TCPS2

Researchers and REBs should recognise andaddress changes in participants’ circumstancesthat may impact their vulnerability

TCPS2

Research ethics board composition

REBs reviewing research with vulnerablesubjects should include members withexpertise on these populations

Common Rule;EU Clinical TrialsRegulation

Community members on REBs ought toreflect participant’s perspectives, particularlyimportant when participants are vulnerableand/or risks are high

TCPS2

Assessing harms, risks and benefits

For those gauging the severity of harm inresearch, the vulnerability of a population willbe relevant


The existence of vulnerable circumstancesmay require greater effort to minimise risks/maximise benefits to participants

TCPS2

Care must be taken to ensure the risks andburdens of proposed research with personswith a cognitive impairment, intellectualdisability, or mental illness are justified bypotential benefits


Recruitment practices

The vulnerability of persons in unequal,dependent relationships must be taken intoaccount when considering recruiting thesepersons

National Statement

Process of informed consent

Consent may need to be re-confirmed in re-search where participants are vulnerable

National Statement

The method of consent in qualitativeresearch depends, in part, on the vulnerabilityof the research participant; the method mustbe tailored for their protection

National Statement;TCPS2

When requirements of free, informed,ongoing consent cannot be met, vulnerableparticipants ought to be involved in decision-making, i.e. obtaining assent, asking abouttheir feelings regarding participation

TCPS2

Clinician-researchers must take care not tooverplay the benefits of research participationto vulnerable patients, who may be misled toenter research with false hope

TCPS2

Inducements that may not be excessive orinappropriate for other participants may beundue influences if the subject is especiallyvulnerable

Belmont Report

Care should be taken in the informedconsent process to ensure that womenvulnerable to coercion have adequate timeand a proper environment in which to takedecisions

CIOMS


vulnerable groups. While the provided definition fo-cuses on vulnerability as stemming from an incapacityto protect one’s own interests owing to both individualand environmental features, vulnerability is also expli-citly linked to justice-based concerns about the distri-bution of the risks and benefits of research. Theidentified implications of vulnerability thus correspondto concerns relating to participants’ ability to providefree and informed consent and relating to the appropri-ateness of involving vulnerable participants in research.There is a lack of clarity and consistency, however, inthe discussion of vulnerable groups. The CIOMSguidelines distinguishes between three types of vulner-able groups – those who are “conventionally consideredvulnerable”, those who are vulnerable due to socialpressures (i.e. persons in dependent relationship withresearchers, such as students or pharmaceutical em-ployees), and “other groups or classes” ([18], p. 64) forwhom no explanation is provided and who do not, ontheir face, bear a significant resemblance to these othergroups.

UNESCO Declaration The Declaration is concernedwith both a general “human vulnerability” and a moreparticular “special vulnerability” ([19], Art. 8), neither ofwhich are defined. Its identification of personal, societaland environmental conditions as sources of vulnerabilitysuggests a concept with wide-ranging concerns. The

Table 6 Implications of vulnerability, grouped by theme(Continued)

Care should be taken in the informedconsent process for adults with mental healthproblems or learning difficulties to ensure thatinformation is provided in the appropriateformat and that the roles and responsibilitiesof those involved are clearly explained andunderstood

UK ResearchGovernance Framework

Additional consent from a parent orguardian may be required for young peoplewho are vulnerable through immaturity inways that warrant this

National Statement

Researchers should invite participants independent or unequal relationships to discusstheir participation with someone who cansupport them in making their decision;especially vulnerable participants in thesecircumstances should be offered participantadvocates

National Statement

Debriefing

REBs must assess risks and benefits ofdebriefing participants and whether debriefingplan is appropriate for participants, especiallywhen they are vulnerable

TCPS2

REB research ethics board, CIOMS Council for International Organizations ofMedical Sciences, TCPS2 Tri-Council Policy Statement: Ethical Conduct forResearch Involving Humans, ICH GCP International Conference on Harmonisation,Good Clinical Practice

Table 7 Major content areas of vulnerability addressed within each policy/guideline

Policy/Guideline Definition: What isvulnerability?

Groups/Sources: Who isvulnerable and why?

Justifications: What ethicalconcern(s) does vulnerability reflect?

Implications: How should we respondto vulnerability in research?

International


– X X X

CIOMS X X X X

UNESCODeclaration

– X X X


– X – X

EU Clinical TrialsRegulation

– X – X

ICH GCP X X – X

National


– X X X

TCPS2 X X X X

UK ResearchGovernanceFramework

– X – X

Belmont Report – X X X

Common Rule – X – X

CIOMS Council for International Organizations of Medical Sciences, TCPS2 Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, ICH GCPInternational Conference on Harmonisation, Good Clinical Practice


Declaration identifies respecting the personal integrity ofvulnerable groups as a key implication, suggesting thatvulnerability may consist, at least in part, of risks to one’spersonal integrity. Since concerns relating to vulnerabilityare presented as fundamental principles, their interpret-ation cannot be guided by other ethical principles.

EU Clinical Trials Directive The Clinical Trials Direct-ive conveys a primarily consent-based vulnerability, withchildren as the focus of its vulnerability-related regula-tions. The implications it identifies focus on obtainingproxy consent and assent, but also on the need to avoid fi-nancial inducements for participation, suggesting a con-cern for a risk of exploitation. Other implications includea need to perform research with children in which groupbenefits will be obtained and ensuring the interests of thepatient prevail over those of society. As such, in additionto concerns relating to consent, the Directive implicitly re-lates vulnerability to concerns with the distribution of thebenefits and burdens of research. The Directive does notprovide an ethics framework, so interpretation of thisguidance cannot be guided by ethical principles.

EU Clinical Trials Regulation The Clinical Trials Regu-lation conveys a mixed concept of vulnerability, concernedboth with issues of consent and increased health risks.While vulnerability is not defined and no explanation forthe vulnerability of listed groups is provided, they can begrouped by those assumed to face issues of consent in re-search (people affected by mental health disorders, mi-nors, and incapacitated subjects) and those who may be atgreater physical (i.e. health) risks in research (frail or olderpeople, people suffering from chronic conditions, andpregnant or breastfeeding women). The implications iden-tified do not fall along this consent/health risk distinction,however, with a need for research to improve treatments akey implication for frail or older people, people withchronic conditions, and people affected by mental healthdisorders, and the need for special expertise in researchethics review identified as a specific consideration for mi-nors, incapacitated subjects, and pregnant or breastfeed-ing women. No ethical framework is provided in theRegulation to facilitate interpretation of this guidance.

ICH GCP These guidelines present a consent-basedconcept of vulnerability that lacks internal clarity due toits broad scope of vulnerable groups. Vulnerable subjectsare defined as those whose ability to provide voluntaryconsent may be compromised by social pressures, andthe first category of groups listed is clearly linked to thisdefinition. However, it is not clear how the wide range of'other vulnerable groups' relates to this definition orwhich characteristics are thought to render them

vulnerable. The guidelines do not provide an ethicalframework to facilitate interpretation of the concept ofvulnerability.

National policies and guidelines

Australian National Statement The National State-ment suggests a comprehensive conceptualisation of vul-nerability relating to concerns about consent, fairinvolvement in research, and a balance of risks and ben-efits to participants. It favours a group-specific approachto vulnerability, where this concept is discussed largelyin reference to specific groups. General statements aboutvulnerability suggest that it is an important factor whenconsidering the appropriate method of consent. Whilevulnerability is not defined, explanations for the vulner-ability of all identified groups are provided and are dis-cussed with reference to the Statement’s guiding ethicalprinciples. Interestingly, explanations of the vulnerabilityof identified groups the principles from which obliga-tions to those groups stem do not always line up. Insome cases, the relationship is clear; the vulnerability ofyoung persons originates in their lack of ability to pro-vide consent and is linked to respect for persons, andthe vulnerability of neonates in intensive care originatesin the risks of long-term harms and is linked to benefi-cence. However, while persons in pre-existing/dependentrelationships with researchers are said to face issues pro-viding voluntary consent, the key implication relating tothis group is grounded in the principle of justice (i.e. en-suring they are not over-researched). Similarly, whilepersons with terminal illness are said to be vulnerable tounrealistic expectations of benefit (i.e. may have a com-promised ability to consent), the key response to this isto balance the benefits and burdens of research and isgrounded in beneficence.

TCPS2 The TCPS2 presents an autonomy-based con-ceptualisation of vulnerability that is comprehensive inscope. The provided definition of vulnerability statesthat it stems from a diminished ability to protect one’sown interests caused by both individual (e.g. lack ofdecision-making capacity) and environmental (e.g. lackof access to social goods) factors. Importantly, vulner-ability is said to be context-specific and dynamic, dis-couraging assumptions of vulnerability based on groupmembership. However, the policy still relies on theidentification of groups likely to be vulnerable, as well asthe identification of circumstances that can createvulnerability for a participant. While the definition ofvulnerability itself is implicitly linked to the principle ofautonomy, obligations towards participants in vulnerablecircumstances are more comprehensive and are


grounded in the principles of respect for persons, con-cern for welfare and justice.

United Kingdom Research Governance FrameworkThe framework conveys a consent-based conceptualisa-tion of vulnerability that is narrow in scope, labellingadults who may have issues with understanding anddecision-making as vulnerable. Consistent with this, theimplications of vulnerability focus on providing partici-pants with the necessary support in the informed con-sent process. Since no ethical framework or principlesare discussed relative to vulnerability, these cannot beused to facilitate interpretation of the guidance.

Belmont Report The Report conveys a consent-basedconceptualisation of vulnerability that lacks clarity in thefeatures of vulnerability it aims to target. It is assumedthat vulnerable subjects have a “dependent status and fre-quently compromised capacity for free consent” ([26], PartC. 3), which seems to form the basis of their vulnerability.Special considerations about vulnerable subjects are dis-cussed in reference to respect for persons (ordinary in-ducements may be come undue influences for vulnerablepopulations), beneficence (special justification is requiredfor research with vulnerable subjects) and justice (vulner-able subjects must be protected from over-recruitment toresearch).

Common Rule The Common Rule conveys a consent-based conceptualisation of vulnerability that lacks internalclarity regarding its scope. A number of groups are identi-fied as vulnerable, including handicapped persons, butwhile the other groups are said to be vulnerable to coer-cion or undue influence, no explanation is provided forhandicapped persons. Similarly, the implications of vul-nerability include concern for equitable subject selectionand the provision of additional safeguards, but handi-capped persons are never associated with these protec-tions. Without a definition of vulnerability, it is not clearwhat special vulnerability handicapped persons may befaced with in research.

DiscussionThe objective of this analysis was to describe the conceptof vulnerability in research ethics policies and guidelines,and to assess how it is conceptualised and operationalised.All policies and guidelines employed the concept of vul-nerability but very few define it. Instead, vulnerability ismost frequently discussed in terms of vulnerable groups,with some attention given to the sources of vulnerability,and the implications of conducting research with vulner-able participants. In many respects the policies come out,on the whole, as richer and more complex than somescholarly analyses of the concept of vulnerability suggest

[6, 28, 29]. For example, the policies and guidelines iden-tify sources of vulnerability that are both individual andsituational [29]; vulnerability can stem from a lack of cap-acity or from one’s health status, but also from social pres-sures that may impact one’s ability to make a free andinformed decision, consistent with some scholarly per-spectives [30]. Responding to vulnerability requires cau-tion and special consideration on the part of researchersand REBs but, ultimately, the implications identified inour study suggest that participant vulnerability need notsignal a need for exclusion from research. The few explicitdefinitions in our sample define vulnerability as a defi-ciency of the participant, as an inability to protect one’s in-terests in research. The majority of other guidelines andpolicies implicitly convey a similar conceptualisation ofvulnerability as a deficiency in a participant’s ability toprovide voluntary informed consent. Accordingly, eventhough there is some diversity and richness in policies, ittends to be scattered across multiple policies and relies onimplicit assumptions about the definition and nature ofvulnerability. Indeed, a significant analytic effort was re-quired to bring structure to the data and yield the guid-ance captured in this paper. We further discuss how ourfindings relate to (1) previous critiques found in the schol-arly literature and (2) the role of stakeholder engagementin the process of refining the concept of vulnerability inresearch ethics policies and guidance.

Previous critiques from the scholarly literatureWithin the scholarly literature several critiques of vul-nerability in research ethics guidelines have been voiced.First, concerns have been raised that the manner inwhich vulnerability is defined and operationalised in re-search ethics governance stereotypes and reinforcesstigma about whole categories of individuals [9, 12, 31].Our results reinforce these concerns, as the reliance onlisting groups of vulnerable persons is rampant. This la-belling [6] or sub-population [30] approach does little tobring attention to the importance of context and ofassessing the characteristics of individual research par-ticipants beyond their membership in a group [5, 6, 9].It is important to note that research protocols creategroups through sampling “regardless of whether the sam-ple is drawn from a naturally occurring community” ([9],p. 2221). Understanding this point underscores the factthat group membership in this context may not wellcapture the various relevant aspects (and potential vul-nerabilities) in an individual participant’s situation. Thismay result in inappropriate and ineffective protectionsbeing applied in some protocols. Group listings may alsocause confusion due to the broadness of some labels(e.g. persons with mental illness or mental health prob-lems). Furthermore, it seems that the designation ofsome groups as vulnerable may be based on


assumptions not supported by evidence (e.g. the designa-tion of pregnant women as vulnerable to coercion or undueinfluence in the Common Rule).Another major concern has been that vulnerability, as

conceived of in the guidelines, focuses overwhelminglyon a lack of ability to consent [10], blinding researchersand REBs to other relevant types of vulnerability, relat-ing, for example, to an increased risk of exploitation [32]or a lack of basic rights [33]. While vulnerability is rarelydefined, the majority of policies and guidelines conveyimplicitly that vulnerability is fundamentally an inabilityto provide free and informed consent. However, the im-plications of vulnerability often move beyond consent,addressing issues of fair subject selection and favourablerisk benefit assessments. In addition to providing explicitdefinitions for what, exactly, is meant when the term‘vulnerability’ is used, the clarity and usability of policiesand guidelines could be improved by ensuring that thesedefinitions clearly relate to the concerns with which vul-nerability is associated.Though they recognise both individual and contextual

sources of vulnerability, all policies and guidelines con-veyed that vulnerability is a personal characteristic. Eventhe TCPS2, with its notable emphasis on vulnerability asa context-dependent feature, ultimately defines it as aperson’s inability to protect their own interests in re-search. In contrast, a growing body of scholarly literatureconverges around the notion that vulnerability is a rela-tional feature, borne of power asymmetries between par-ticipants and research staff, investigators and institutions[10, 31, 34]. Adopting such a view in research ethics guide-lines may better serve participants, encouraging measuresthat would empower and promote their agency in the re-search context [34]. Furthermore, the focus on researchparticipants neglects how research environments (e.g. theexistence of conflicts of interest) can actively contribute todisempowering research participants/research subjects andthus create the need for remediation that does not neces-sarily concern the research participant per se [6, 10].

A need for evidence and stakeholder engagement torefine research ethics policies and guidance onvulnerabilityResearch ethics guidelines and policies typically stress theimportance of vulnerability. However, it has been arguedthat vulnerability is not a substantive ethical concept in it-self, serving only as a marker of other research ethics con-cerns already captured by existing concepts such as harmor consent [35]. This is certainly an important conceptualconcern, but what may be of greater relevance in the realmof policy development is the degree to which the conceptof vulnerability is a useful, effective tool for those designing,reviewing and conducting research [5, 6]. It may be the casethat vulnerability merely serves to signal concerns relating

to other pre-existing ethical concepts, but if these concernswould be otherwise missed, the concept would then beproven to have a vital practical function in research ethics.A few authors have made explicit claims to that effect. Forexample, Kipnis argues that vulnerability stems from im-pairments to one’s ability to provide voluntary informedconsent. He identifies six types of vulnerability which allsignal potential issues with a participant’s ability to consent:cognitive, deferential and medical vulnerability, all of whichrelate to characteristics of the participant themselves, andjuridic, allocational and infrastructural vulnerability, all ofwhich relate to factors in the participant’s environment[30]. These categories help bring attention to more specificaspects that generate vulnerability. Luna argues that vulner-ability, when conceived of as dynamic, flexible and inessen-tial, can serve as “a fine grain tool to analyze, interpret, andevaluate the research situation” ([6], p. 130). She proposesthat vulnerability be conceived of through the metaphor oflayers, in which different layers of vulnerability can operateand interact within a given participant’s circumstances.Luna’s account of vulnerability thus provides researchersand REBs with a conceptual tool with which to examine aresearch participant’s circumstances, identify potential vul-nerabilities (e.g. relating to capacity or social pressure in theconsent process), and develop targeted strategies for theirremediation.In spite of these more sophisticated proposals, there is

a dearth of empirical evidence on the functioning of re-search ethics committees and outcomes of research eth-ics policies and, to our knowledge, few studies haveexamined the impact or understandings of the conceptof vulnerability based on research ethics guidelines and/or more elaborate scholarly accounts. Empirical evidencehas shown that an understanding of vulnerability in thecontext of research cannot be assumed to be universal –in a study with Russian and Romanian research ethicstrainees, Loue and Loff [36] found that, at the initiationof their training, their existing understanding of vulner-ability varied considerably from conceptualisations inthe international guidelines. A study by Sengupta et al.[37] gathered researchers’ perspectives on vulnerabilityin HIV/AIDS clinical trials and on the Common Ruleguidance related to vulnerability and found that re-searchers assessed vulnerability in relation to situationalfactors that can render participants vulnerable, and thatthey emphasised the need to assess vulnerability on acase-by-case basis (i.e. rather than relying on a group-based strategy). Taken together, these studies underscorethe need for policymakers to clearly delineate and definethe concerns vulnerability is intended to encompass, andto assess the alignment of these views with those of re-search stakeholders. Further, there is a need to assess theoutcomes of vulnerability-related guidance and policyand to understand whether protections are actually


effective and their impact on vulnerable participantsthemselves. For example, there are crucial questionsabout the actual usability and impact of such guidelinesas well as the potential need for mid-level guidance be-tween general guidelines and the actual analyses of REBs[38]. It has been suggested that more elaborate, on-the-ground guidance on vulnerability would be beneficial tohelp REBs direct their attention to the most pertinentconcerns [30]. In the process of developing such guid-ance, the voices of those concerned by the application ofwhat sometimes appears as a label of vulnerability couldbe instrumental in moving forward and avoiding the per-petuation of stereotyping or stigmatising accounts ofvulnerability [34]. In this endeavour, the perspectives ofresearchers and REBs, but also of research participants,who seem to have been largely left out of the develop-ment of research ethics guidelines, could be investigated.

ConclusionOur in-depth analysis of human research ethics guidelinesand policies allowed us to analyse different perspectives onthe concept of vulnerability, including the definitions, justi-fications, sources, and implications of vulnerability for re-searchers and REBs. In some respects, this syntheticaccount yielded a richer perspective than sometimes admit-ted in scholarly literature. At the same time, there are con-ceptual gaps within individual guidelines and policies thatrequire the attention of those charged with their develop-ment. This lack of clarity could diminish the usability of theguidance put forth in policies and therefore undermine itsimpact on research practices. Policymakers should revisitthe concept of vulnerability to ensure each of its key com-ponents is spelled out, and that these components are in-ternally consistent (i.e. within individual guidelines).Practically-oriented refinement of vulnerability could be fa-cilitated by engaging research stakeholders and examiningthe concrete impact of guidance and policy related tovulnerability.

AcknowledgementsThe authors would like to thank Michael McDonald for his feedback on anearlier version of this manuscript, as well as the members of the NeuroethicsResearch Unit for their feedback throughout the conduct of this research.

FundingFunding for this study was provided by a CIHR grant held by EB, ER andMEM, an FRQ-S career award held by ER, and graduate scholarships from theIRCM and McGill University held by DBR. No funding body played any role inthe design of the study or collection, analysis, interpretation of the data, orin the writing of the manuscript.

Availability of data and materialsThe datasets used and/or analysed during the current study are availablefrom the corresponding author on reasonable request.

Authors’ contributionsEB and ER developed the idea of conducting a review of research ethicspolicies and guidelines. DBR developed the search strategy and inclusionand exclusion criteria and gathered the sample with input from EB and ER.

DBR developed the coding strategy and conducted the data analysis and EBand ER reviewed. DBR drafted the manuscript and ER served as the primaryreviewer and editor, with EB and MEM providing feedback. DBR drafted thefinal version of the manuscript and all authors agreed on the final version.

Competing interestsThe authors have no competing interests to declare.

Consent for publicationNot applicable.

Ethics approval and consent to participateNot applicable.

Author details1Neuroethics Research Unit, Institut de recherches cliniques de Montréal, 110Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada. 2Biomedical EthicsUnit and Division of Experimental Medicine, McGill University, Montréal, QC,Canada. 3Faculty of Dentistry, Oral Health and Society Research Unit, McGillUniversity, 2001 McGill College, Suite 500, Montréal, QC H3A 1G1, Canada.4Department of Medicine and Department of Social and PreventiveMedicine, Université de Montréal, Montréal, QC, Canada. 5Department ofNeurology and Neurosurgery, McGill University, Montréal, QC, Canada.

Received: 26 October 2016 Accepted: 14 December 2016

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