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Protection of Vulnerable Protection of Vulnerable Subjects in ResearchSubjects in Research

Melody Lin, Ph.D.Melody Lin, Ph.D.

December 2012December 2012

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ObjectivesObjectives

What ? Why ?What ? Why ?

Background for additional protectionsBackground for additional protections

US requirements for protection of US requirements for protection of vulnerable subjects in researchvulnerable subjects in research

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“ “Vulnerable” SubjectVulnerable” Subject

Ethical principlesEthical principles─ Respect for personsRespect for persons─ BeneficenceBeneficence─ JusticeJustice

Respect for personsRespect for persons─ AutonomousAutonomous─ Decreased AutonomyDecreased Autonomy

Vulnerable subjects are those with Vulnerable subjects are those with diminished autonomydiminished autonomy

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AutonomyAutonomy

CapacityCapacity─ Ability to understand and process informationAbility to understand and process information

VoluntarinessVoluntariness─ Freedom from the control or influence of othersFreedom from the control or influence of others

Full autonomy Full autonomy ─ Capacity to understand and process informationCapacity to understand and process information─ Freedom to volunteer without coercion or undue Freedom to volunteer without coercion or undue

influence influence

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What subjects are vulnerable?What subjects are vulnerable?

A limitation of capacity or voluntarinessA limitation of capacity or voluntariness─ CapacityCapacity

children children subjects who are mentally disabledsubjects who are mentally disabled

─ VoluntarinessVoluntariness in emergency situationsin emergency situations in hierarchical social structuresin hierarchical social structures who are economically or educationally disadvantagedwho are economically or educationally disadvantaged who are marginalized in societywho are marginalized in society with fatal or incurable diseasewith fatal or incurable disease

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Vulnerable PopulationsVulnerable Populations

Children, minorsChildren, minors Pregnant womenPregnant women PrisonersPrisoners Fetuses Fetuses Cognitively impaired Cognitively impaired

personspersons Economically Economically

disadvantaged personsdisadvantaged persons Educationally Educationally

disadvantaged personsdisadvantaged persons

MilitaryMilitary StudentsStudents ElderlyElderly WorkersWorkers VeteransVeterans

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What are subjects What are subjects vulnerable to?vulnerable to?

Physical control Physical control ─ Nazi hypothermia experimentsNazi hypothermia experiments

Coercion: threat of harm or force to Coercion: threat of harm or force to control anothercontrol another

─ Nursing home resident forced to choose research Nursing home resident forced to choose research study or leaving nursing homestudy or leaving nursing home

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What are subjects What are subjects vulnerable to?vulnerable to?

Undue Influence: misuse of power or position Undue Influence: misuse of power or position to lead someone to make a decision that would to lead someone to make a decision that would not otherwise be madenot otherwise be made

─ Entering research study, in spite of knowing that this Entering research study, in spite of knowing that this is not in patient’s best interestis not in patient’s best interest

Manipulation: intentional management of Manipulation: intentional management of conditions or information that leads another to conditions or information that leads another to make decision not otherwise mademake decision not otherwise made

─ Lying, withholding information, exaggerationLying, withholding information, exaggeration

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Why Study Vulnerable Subjects?Why Study Vulnerable Subjects?

Improve diagnosis and treatment of the Improve diagnosis and treatment of the disease & conditiondisease & condition

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Special ProtectionsSpecial Protections

Why?Why?─ Past abuses of the rights of subjects, Past abuses of the rights of subjects,

especially vulnerable subjectsespecially vulnerable subjects─ Ethical principles of justice and respect of Ethical principles of justice and respect of

personspersons

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Additional ProtectionsAdditional Protections

What?What?─ Federal regulationsFederal regulations─ State statutesState statutes─ Special review by IRBSpecial review by IRB─ Risk/benefit of the studyRisk/benefit of the study─ Researcher sensitivity to the particular Researcher sensitivity to the particular

category of vulnerabilitycategory of vulnerability

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Research Involving Research Involving Vulnerable SubjectVulnerable Subject

Important to conduct ethical research into Important to conduct ethical research into conditions affecting vulnerable individualsconditions affecting vulnerable individuals

Be certain information provided is Be certain information provided is understandableunderstandable

Protection of human rightsProtection of human rights

Above all – do no harmAbove all – do no harm

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VulnerabilityVulnerability

If vulnerable once – Is subject vulnerable If vulnerable once – Is subject vulnerable forever?forever?

When is a child not a child?When is a child not a child?

Are emotionally disabled persons always Are emotionally disabled persons always vulnerable?vulnerable?

Where does vulnerability start and end?Where does vulnerability start and end?

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DefinitionDefinition

VulnerabilityVulnerability – susceptible to harm – susceptible to harm─ ““those who are relatively (or absolutely those who are relatively (or absolutely

incapable of protecting their own interests.” incapable of protecting their own interests.” (Levine, 1986 p.72)(Levine, 1986 p.72)

HarmHarm – social, economic, legal, – social, economic, legal, psychological, and physical psychological, and physical (Belmont Report)(Belmont Report)

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Specific VulnerabilitySpecific Vulnerability

Cognitive or communicative –diminished Cognitive or communicative –diminished capacity to understandcapacity to understand

Institutional – subject to formal authority of Institutional – subject to formal authority of othersothers

Deferred – subordinate to others Deferred – subordinate to others ─ cultural or societal normscultural or societal norms─ physician and patientphysician and patient

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Specific VulnerabilitySpecific Vulnerability

Medical – serious illness; research may be Medical – serious illness; research may be believed to be offering ‘hope’believed to be offering ‘hope’

Economic – benefits offered by researchEconomic – benefits offered by research Social – participant groups may subject Social – participant groups may subject

participants to risk/benefit unacceptable to participants to risk/benefit unacceptable to other groupsother groups

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US RegulationsUS Regulations

45 CFR 46 & 21 CFR 56 – Subparts B-D45 CFR 46 & 21 CFR 56 – Subparts B-D─ Subpart B: women, fetuses and neonatesSubpart B: women, fetuses and neonates─ Subpart C: prisonersSubpart C: prisoners─ Subpart D: childrenSubpart D: children

State RegulationsState Regulations

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Requirements for Requirements for Research Involving Research Involving Pregnant Women and Pregnant Women and FetusesFetuses

45 CFR 46 Subpart B

FR 66, No. 219, 11/13/01

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RequirementsRequirements

Appropriate pre-clinical studies have been Appropriate pre-clinical studies have been completed on pregnant animals and non-completed on pregnant animals and non-pregnant women.pregnant women.

The risk to the fetus is caused The risk to the fetus is caused solelysolely by by interventions that offer direct benefit for the interventions that offer direct benefit for the woman woman oror fetus fetus

ororIf there is If there is nono prospect of benefit prospect of benefit

– The risk to the fetus is not greater than minimal.The risk to the fetus is not greater than minimal.– The purpose of the study is to develop important The purpose of the study is to develop important

biomedical knowledgebiomedical knowledge– The knowledge cannot be obtained by any other meansThe knowledge cannot be obtained by any other means

45 CFR 46.204

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Requirements cont’dRequirements cont’d

Any risk to the pregnant woman or the Any risk to the pregnant woman or the fetus is the fetus is the leastleast possible to achieve the possible to achieve the research objective.research objective.

Consent of the pregnant woman and Consent of the pregnant woman and father (if available) is required if the father (if available) is required if the research may research may onlyonly benefit the fetus. benefit the fetus.

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Consent of the pregnant woman Consent of the pregnant woman onlyonly is is required for research whichrequired for research which─ May benefit the woman onlyMay benefit the woman only─ May benefit the woman and fetusMay benefit the woman and fetus─ Will not benefit the woman or fetus but Will not benefit the woman or fetus but

there is minimal risk to the fetusthere is minimal risk to the fetus The purpose of the research is to develop The purpose of the research is to develop

important biomedical knowledgeimportant biomedical knowledge The data cannot be obtained by any other meansThe data cannot be obtained by any other means

Requirements cont’dRequirements cont’d

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The consent form must fully disclose The consent form must fully disclose reasonably foreseeable risks to the fetusreasonably foreseeable risks to the fetus

There are no inducement offered to There are no inducement offered to terminate a pregnancyterminate a pregnancy

The investigator will not be involved in any The investigator will not be involved in any decisions to terminate a pregnancydecisions to terminate a pregnancy

Requirements cont’dRequirements cont’d

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Requirements for Research Requirements for Research Involving PrisonersInvolving Prisoners

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IRB CompositionIRB Composition §46.304§46.304

Majority have no association with the Majority have no association with the prisonprison

One member must be a prisoner or One member must be a prisoner or prisoner representativeprisoner representative

All other requirements under All other requirements under §§46.10746.107

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Additional dutiesAdditional duties§§46.30546.305

(1) Approved categories(1) Approved categories

(2) No undue influence (2) No undue influence

(3) Risks are same as non-prisoners(3) Risks are same as non-prisoners

(4) Fair subject selection(4) Fair subject selection

(5) Understandable language(5) Understandable language

(6) No impact on parole (6) No impact on parole

(7) Follow-up care(7) Follow-up care

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Subpart DSubpart D

Additional DHHS Protections for Additional DHHS Protections for Children Involved as Subjects in Children Involved as Subjects in

ResearchResearch

March 8, 1983March 8, 1983

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IRB DutiesIRB Duties

Not greater than minimal risk. (Not greater than minimal risk. (§§46.404)46.404) Greater than minimal risk, prospect of direct Greater than minimal risk, prospect of direct

benefit. (benefit. (§§46.405)46.405) Greater than minimal risk, no prospect of Greater than minimal risk, no prospect of

direct benefit but generalizable knowledge. direct benefit but generalizable knowledge. ((§§46.406)46.406)

Not otherwise approvable. Further Not otherwise approvable. Further understanding, prevent or alleviate. understanding, prevent or alleviate. ((§§46.407)46.407)

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Assent of ChildrenAssent of Children

IRB determines when children are capable IRB determines when children are capable of assent based on age, maturity, and of assent based on age, maturity, and psychological state. psychological state. §46.408(a)§46.408(a)

IRB determines whether and how assent IRB determines whether and how assent is to be documented is to be documented §46.408(e)§46.408(e)

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Parental PermissionParental Permission

Adequate provisions are made to solicit Adequate provisions are made to solicit permission of each child’s parent or permission of each child’s parent or guardian.guardian.

Under Under §§46.404 and 46.404 and §§46.405, one parent46.405, one parent

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Parental Permission, cont.Parental Permission, cont.

Under Under §§46.406 and 46.406 and §§46.407, two parents 46.407, two parents unless one is deceased, unknown, unless one is deceased, unknown, incompetent or not reasonably available. incompetent or not reasonably available. Or in case of sole custody.Or in case of sole custody.

Waiver of parental consent (Waiver of parental consent (§§46.116, 46.116, Subpart A) Abused or neglected childrenSubpart A) Abused or neglected children

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SummarySummary

What ? Why ?What ? Why ?

Background for additional protectionsBackground for additional protections

US requirements for protection of US requirements for protection of vulnerable subjects in researchvulnerable subjects in research

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SummarySummary

Ethical research is guided by principles of Ethical research is guided by principles of justice, respect for persons, and justice, respect for persons, and beneficencebeneficence

Vulnerable subjects should be included Vulnerable subjects should be included but also deserve special protectionsbut also deserve special protections

Take steps to ensure their rights and Take steps to ensure their rights and welfare are protectedwelfare are protected