Ethical Issues in Research with “Vulnerable” and “Hard‐to‐Reach” 

PopulationsPopulations

Emily E. Anderson, PhD, MPHAssistant Professor

Neiswanger Institute for BioethicsL l U i it ChiLoyola University Chicago

May 15, 2014UIC Institute for Health Research and Policy TalkUIC Institute for Health Research and Policy Talk

“Bioethical Trump Card”?Bioethical Trump Card ?

• “The concept of vulnerability appears to haveThe concept of vulnerability appears to have been grandfathered into the lexicon, lore, and literature of research ethics without undergoing g gstringent certification. And yet the need for some such notion has long been appreciated.”

‐Ken Kipnis, 2001Ken Kipnis, 2001“Vulnerability in Research Subjects: A Bioethical Taxonomy”Taxonomy

Definitions/InterpretationsDefinitions/Interpretations

• Vulnerable means “subject to exploitation”Vulnerable means  subject to exploitation

• Unequal power relationships between potential subjects and investigators/sponsors create the potential for exploitation

• Exploitation is wrong, and therefore we want t t/ id it i hto prevent/avoid it in research

Or… are we all at risk?Or… are we all at risk?

• We are all vulnerable although some may beWe are all vulnerable although some may be more “predisposed” to additional harm than othersothers

• Vulnerability is inevitable because people are interdependentinterdependent 

• One can be vulnerable w/o being harmed or d ( d i )wronged (and vice versa)

2 Ways of Looking at Vulnerability2 Ways of Looking at Vulnerability

• A characteristic inherent to an individual orA characteristic inherent to an individual or group

• A characteristic inherent in a situation

KEY RESEARCH ETHICS GUIDANCEKEY RESEARCH ETHICS GUIDANCE DOCUMENTS

Belmont ReportBelmont Report

• A reaction to historical abuses perpetratedA reaction to historical abuses perpetrated against certain groups in certain settings

• Principle of JUSTICE fair selection of subjects• Principle of JUSTICE, fair selection of subjects• Presumption: Certain categories of people are 

d lik l b i dpresumed more likely to be mistreated, misled, or otherwise taken advantage of

• Vulnerability generates a duty for “special protections” (for researchers, regulators, IRBs)

Belmont ReportBelmont Report

• Vulnerability results fromVulnerability results from – “dependent status and frequently compromised capacity for free consent”capacity for free consent  

combined withcombined with 

“ready availability in settings where research is– ready availability in settings where research is conducted”

CIOMS (2002)CIOMS (2002)

• Vulnerable persons defined as “those who areVulnerable persons defined as  those who are relatively (or absolutely) incapable of protecting their own interests because theyprotecting their own interests because they may have insufficient power, intelligence, education resources strength or othereducation, resources, strength or other needed attributes to protect their own interests”interests

“A MOTLEY COLLECTION OFKipnis

A MOTLEY COLLECTION OF VULNERABLE SUBPOPULATIONS”

Belmont Report (1979)Belmont Report (1979)

• racial minoritiesracial minorities• economically disadvantaged

i k• very sick• institutionalized

45 CFR 4645 CFR 46

“vulnerable category of subjects”g y j“special problems of research involving vulnerable populations”“vulnerable to coercion or undue influence”

ADD’L PROTECTIONS CODIFIED• Pregnant women (Subpart B)

ADDITIONAL SAFEGUARDS?• handicapped persons 

• Prisoners (Subpart C)• Children (Subpart D)

• mentally disabled persons• economically disadvantaged 

personspersons• educationally disadvantaged 

persons

OHRP Guidance (Website)OHRP Guidance (Website)

• “Vulnerable populations” has its own headingVulnerable populations  has its own heading– ChildrenPeople with HIV/AIDS– People with HIV/AIDS

– PrisonersP i t ti / C tifi t f C fid ti lit– Privacy protections/ Certificates of Confidentiality

– A video that I could not bring myself to watch

OHRP IRB Guidebook (2001)OHRP IRB Guidebook (2001)• Cognitively impaired• Traumatized• ComatoseT i ll ill• Terminally ill

• Elderly/aged• MinoritiesMinorities• Students• Employees• “normal” volunteers• Participants in international research (anyone not American?)American?)

CIOMS (2002)CIOMS (2002)

• Residents of nursing  • Nomads, refugees, es de s o u s ghomes

• People receiving welfare 

o ads, e ugees,displaced persons

• Prisonersbenefits & social assistanceU l d

• Patients with incurable disease

• Unemployed• Other poor people• People in emergency

• Individuals who are politically powerless

• Members of communities• People in emergency rooms

• Homeless

• Members of communities unfamiliar with modern medical conceptsHomeless p

Does the concept help us protect participants?

• “So many groups are now considered to be So a y g oups a e o co s de ed to bevulnerable in the context of research, particularly international research, that the concept has lost f ” ( l)force.” (Levine, et al)

• Obsession with  adding groups to the list• Little talk of appropriate protections• Stereotyping versus actually protecting? (doesn’t distinguish between individuals in a group)

RECOMMENDED SAFEGUARDS,RECOMMENDED SAFEGUARDS, “EXTRA” & “SPECIAL” PROTECTIONS

Declaration of Helsinki (2013)Declaration of Helsinki (2013)19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being wronged or of incurring additional harm.

• All vulnerable groups and individuals should receive specifically considered protection.

20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of this group and the research cannot be carried out in a non‐of this group and the research cannot be carried out in a nonvulnerable group. In addition, this group should stand to benefit from the knowledge, practices or interventions that result from the research.

45 CFR 46.111(a)(3) ‐ approval45 CFR 46.111(a)(3)  approval

• Selection of subjects is equitable. In makingSelection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly 

i f h i l bl f hcognizant of the special problems of research involving vulnerable populations, such as children prisoners pregnant womenchildren, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged personseducationally disadvantaged persons.

45 CFR 46.111(7)(b)‐approval45 CFR 46.111(7)(b) approval

• When some or all of the subjects are likely toWhen some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children prisoners pregnant womensuch as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged personseducationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare ofthe study to protect the rights and welfare of these subjects.

Types of SafeguardsTypes of Safeguards

• IRB membership/representation in ethicsIRB membership/representation in ethics review 

• Specific regulations• Specific regulations• Restrictions/limitations on participation 

i ( i )prisoners (prisoners)• “Add‐ons” to or replacements for individual informed consent (children)  

• Processes for community input (EFIC)y p ( )

45 CFR 46.107a – IRB membership45 CFR 46.107a  IRB membership

• If an IRB regularly reviews research thatIf an IRB regularly reviews research that involves a vulnerable category of subjects, such as children prisoners pregnant womensuch as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion ofconsideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced inknowledgeable about and experienced in working with these subjects.

Specific SubpartsSpecific Subparts

• 45 CFR 4645 CFR 46 – Subpart A) prisonersSubpart B) children– Subpart B) children

– Subpart C) pregnant women

• 21 CFR 50.24 (FDA)– Exception from informed consent requirements for emergency research

Prisoners 46.304 (representation)Prisoners 46.304 (representation)

• (a) A majority of the Board (exclusive of prisoner ( ) j y ( pmembers) shall have no association with the prison(s) involved, apart from their membership on the Boardon the Board.

• (b) At least one member of the Board shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than oneresearch project is reviewed by more than one Board only one Board need satisfy this requirement.

Restrictions on Participation: PrisonersRestrictions on Participation: Prisoners

• Studies of causes/effects/processes ofStudies of causes/effects/processes of incarceration or of prisons as institutions that are < minimal riskare < minimal risk

• Research on conditions that particularly affect prisoners as a classprisoners as a class

• Research with strong possibility of direct b fibenefit

Children (Subpart D) 46.408Children (Subpart D) 46.408

• Parental consent a e ta co se t– 1 or both parents – depends on risk, benefit, and reasonableness

– Waivers of parental consent allowable provided “an appropriate mechanism for protected the children who will participate” is in place….p p p

• Child assent– Rule of 7s– When to require assent/take dissent seriously– Always inform

EFICEFIC

• A different way of looking at vulnerability?A different way of looking at vulnerability?• Consultation

bli di l• Public disclosure• Independent data monitoring• LAR or contact within “therapeutic window” with a family membery

• Inform subject as soon as possible

“RECONNOITERING THE TERRAINRECONNOITERING THE TERRAIN OF VULNERABILITY”

Kipnis (2001)Kipnis (2001)

• Analyzed categories of vulnerability notAnalyzed categories of vulnerability, not subpopulations

• Defined vulnerability as limit on ability to• Defined vulnerability as limit on ability to provide informed consentWh h i i• What characteristics are common among disparate groups?

• What should researchers do?

Cognitive VulnerabilityCognitive Vulnerability

• Does the individual have the capacity to oes t e d dua a e t e capac ty todeliberate about and decide whether or not to participate in the study?– Immaturity, dementia, mental illness, mental retardationEducation language– Education, language

– Individuals in situations where there’s not enough time

• Plain language forms, advance directives, supplementary education, surrogates/advocates

Juridic VulnerabilityJuridic Vulnerability

• Is the person liable to the authority of others who may p y yhave an independent interest in that participation?

• Formal authority relationships– Prison– Military– Children/parentsChildren/parents– Students– Institutionalized – Women subjected to husbands’ authority

• How to devise a consent procedure that adequately protects the individual from the hierarchical systemprotects the individual from the hierarchical system

Deferential VulnerabilityDeferential Vulnerability

• Is the individual given to patterns ofIs the individual given to patterns of deferential behavior that may mask an underlying unwillingness to participate?underlying unwillingness to participate?

I f l l i hi ( d j idi )• Informal relationships (as opposed to juridic)• IC process should eliminate pressure

Medical VulnerabilityMedical Vulnerability

• Has the individual been selected in partHas the individual been selected, in part, because she has a serious health‐related condition for which there are no satisfactorycondition for which there are no satisfactory remedies?

Allocational VulnerabilityAllocational Vulnerability 

• Is the person seriously lacking in importantIs the person seriously lacking in important social goods that will be provided as a consequence of his or her participation inconsequence of his or her participation in research?

Infrastructural VulnerabilityInfrastructural Vulnerability

• Does the political organizational economicDoes the political, organizational, economic, and social context of the research setting possess the integrity and resources to managepossess the integrity and resources to manage the study?

Social VulnerabilitySocial Vulnerability

• Does the individual belong to a sociallyDoes the individual belong to a socially undervalued group?

Kipnis’ ConclusionsKipnis  Conclusions

• Some individuals/populations will exhibitSome individuals/populations will exhibit multiple vulnerabilities

• More attention to medical vulnerability• More attention to medical vulnerability• Need to consider “fair entitlements of 

h bj h di d d iresearch subjects who are disadvantaged in economic and others ways”

• Need for more resources to help guide decision‐making re: appropriate protections

Criticisms of Kipnis (Levine et al)Criticisms of Kipnis (Levine et al)• Leads to problematic inferences

– Everyone who fits into any of these categories is vulnerable– Anyone who is capable of free consent is NOT

• More focus needed on– Features of the research– Institutional environmentInstitutional environment– Social/economic context– Timing of research

• Women in labor, right after a natural disasterWomen in labor, right after a natural disaster– Emotional factors

• Disease that killed a loved one– Prior personal experiencep p

Are we all vulnerable?Are we all vulnerable?

• Benefits of research can never be guaranteedBenefits of research can never be guaranteed in advance 

• Much clinical research is combined with careMuch clinical research is combined with care (i.e. participants are sick)

• If it applies to everyone, “every researchIf it applies to everyone,  every research protocol requires some type of special attention and IRBs have no guidance on where to concentrate their limited attention and resources” (Levine et al)

“Special Scrutiny” (Levine et al)Special Scrutiny  (Levine et al)

• Translates new scientific advances to humansTranslates new scientific advances to humans for the 1st time (especially when intervention is novel and/or irreversible)is novel and/or irreversible)

• Known/credible risk of significant harm AND NO potential of direct medical benefitNO potential of direct medical benefit

• Raises ethical questions about research design i l i f hi h h ior implementation for which there is no 

consensus

Challenges to Traditional Conceptions f l b lof Vulnerability

• NIH policy on inclusion of women andNIH policy on inclusion of women and  minorities (1994, updated 2001)

• NIH policy on inclusion of children (1998)• NIH policy on inclusion of children (1998)• Increased funding for health disparities 

h h i i h l hresearch, research on minority health

Question for DiscussionQuestion for Discussion

• If the research is minimal risk, should t e esea c s a s , s ou dextra/special protections, safeguards be required? Why or why not? Does your answer d ff d d h l ?differ depending on the population?

• “Minimal riskmeans that the probability and it d f h di f t ti i t d imagnitude of harm or discomfort anticipated in 

the research are not greater in and of themselves than those ordinarily encountered in daily life orthan those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

WHAT ARE APPROPRIATEDISCUSSION/BRAINSTORM

WHAT ARE APPROPRIATE PROTECTIONS?

• You’ve been funded to conduct a survey withYou ve been funded to conduct a survey with LGBT teens on drug and alcohol use. You assumed you’d request a waiver of parentalassumed you d request a waiver of parental consent, but you’ve heard from others that your IRB doesn’t like to waive parentalyour IRB doesn t like to waive parental consent.

• You’re planning research at a health clinic that ou e p a g esea c at a ea t c c t atinvolves a survey, an intervention, a post‐test, and an in‐depth interview. You’re told that the l h l h h l hclinic has a policy that research involving their patients can only pay $10 per research interaction You expect the interviews to last aninteraction. You expect the interviews to last an hour and have paid $30 for other similar research. When you ask for an exception, the y padministration tells you that the subjects are vulnerable and that more than $10 is coercive. 

• A tornado touches down in the middle ofA tornado touches down in the middle of Logan Square. Perfect timing for your dissertation! You want to study the effects ofdissertation! You want to study the effects of social networks on coping with natural disasters Time is of the essence and youdisasters. Time is of the essence, and you really want your protocol to be approved the first time aroundfirst time around. 

Category 2 ExemptionCategory 2 Exemption

Research involving the use of educational tests g(cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior unless: (i)observation of public behavior, unless: (i) information obtained is recorded in such a manner that human subjects can be identified, directly or th h id tifi li k d t th bj t d (ii)through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the y psubjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability or reputationemployability, or reputation.

• For patients with Alzheimer’s disease it’sFor patients with Alzheimer s disease, it s highly likely that their LAR is going to be a child – possibly someone with an increasedchild  possibly someone with an increased risk (real or perceived) of developing the disease themselves Does anyone else thinkdisease themselves. Does anyone else think these individuals should be prohibited from giving consent for parental participation ingiving consent for parental participation in research that is greater than minimal risk?