1. 1 Protection of Vulnerable Subjects in Research Melody Lin, Ph.D. December 2012

2. 2 Objectives What ? Why ? What ? Why ? Background for additional protections Background for additional protections US requirements for protection of vulnerable subjects in research US requirements for protection of vulnerable subjects in research

3. 3 “Vulnerable” Subject “Vulnerable” Subject Ethical principles Ethical principles ─ Respect for persons ─ Beneficence ─ Justice Respect for persons Respect for persons ─ Autonomous ─ Decreased Autonomy Vulnerable subjects are those with diminished autonomy Vulnerable subjects are those with diminished autonomy

4. 4 Autonomy Capacity Capacity ─ Ability to understand and process information Voluntariness Voluntariness ─ Freedom from the control or influence of others Full autonomy Full autonomy ─ Capacity to understand and process information ─ Freedom to volunteer without coercion or undue influence

5. 5 What subjects are vulnerable? A limitation of capacity or voluntariness ─ Capacity children children subjects who are mentally disabled subjects who are mentally disabled ─ Voluntariness in emergency situations in emergency situations in hierarchical social structures in hierarchical social structures who are economically or educationally disadvantaged who are economically or educationally disadvantaged who are marginalized in society who are marginalized in society with fatal or incurable disease with fatal or incurable disease

6. 6 Vulnerable Populations Children, minors Children, minors Pregnant women Pregnant women Prisoners Prisoners Fetuses Fetuses Cognitively impaired persons Cognitively impaired persons Economically disadvantaged persons Economically disadvantaged persons Educationally disadvantaged persons Educationally disadvantaged persons Military Students Elderly Workers Veterans

7. 7 What are subjects vulnerable to? Physical control Physical control ─ Nazi hypothermia experiments Coercion: threat of harm or force to control another Coercion: threat of harm or force to control another ─ Nursing home resident forced to choose research study or leaving nursing home

8. 8 What are subjects vulnerable to? Undue Influence: misuse of power or position to lead someone to make a decision that would not otherwise be made Undue Influence: misuse of power or position to lead someone to make a decision that would not otherwise be made ─ Entering research study, in spite of knowing that this is not in patient’s best interest Manipulation: intentional management of conditions or information that leads another to make decision not otherwise made Manipulation: intentional management of conditions or information that leads another to make decision not otherwise made ─ Lying, withholding information, exaggeration

9. 9 Why Study Vulnerable Subjects? Improve diagnosis and treatment of the disease & condition Improve diagnosis and treatment of the disease & condition

10. 10 Special Protections Why? Why? ─ Past abuses of the rights of subjects, especially vulnerable subjects ─ Ethical principles of justice and respect of persons

11. 11 Additional Protections What? What? ─ Federal regulations ─ State statutes ─ Special review by IRB ─ Risk/benefit of the study ─ Researcher sensitivity to the particular category of vulnerability

12. 12 Research Involving Vulnerable Subject Important to conduct ethical research into conditions affecting vulnerable individuals Important to conduct ethical research into conditions affecting vulnerable individuals Be certain information provided is understandable Be certain information provided is understandable Protection of human rights Protection of human rights Above all – do no harm Above all – do no harm

13. 13 Vulnerability If vulnerable once – Is subject vulnerable forever? If vulnerable once – Is subject vulnerable forever? When is a child not a child? When is a child not a child? Are emotionally disabled persons always vulnerable? Are emotionally disabled persons always vulnerable? Where does vulnerability start and end? Where does vulnerability start and end?

14. 14 Definition Vulnerability – susceptible to harm Vulnerability – susceptible to harm ─ “those who are relatively (or absolutely incapable of protecting their own interests.” (Levine, 1986 p.72) Harm – social, economic, legal, psychological, and physical (Belmont Report) Harm – social, economic, legal, psychological, and physical (Belmont Report)

15. 15 Specific Vulnerability Cognitive or communicative –diminished capacity to understand Cognitive or communicative –diminished capacity to understand Institutional – subject to formal authority of others Institutional – subject to formal authority of others Deferred – subordinate to others Deferred – subordinate to others ─ cultural or societal norms ─ physician and patient

16. 16 Specific Vulnerability Medical – serious illness; research may be believed to be offering ‘hope’ Medical – serious illness; research may be believed to be offering ‘hope’ Economic – benefits offered by research Economic – benefits offered by research Social – participant groups may subject participants to risk/benefit unacceptable to other groups Social – participant groups may subject participants to risk/benefit unacceptable to other groups

17. 17 US Regulations 45 CFR 46 & 21 CFR 56 – Subparts B-D 45 CFR 46 & 21 CFR 56 – Subparts B-D ─ Subpart B: women, fetuses and neonates ─ Subpart C: prisoners ─ Subpart D: children State Regulations State Regulations

18. 18 Requirements for Research Involving Pregnant Women and Fetuses 45 CFR 46 Subpart B FR 66, No. 219, 11/13/01

19. 19 Requirements Appropriate pre-clinical studies have been completed on pregnant animals and non-pregnant women. Appropriate pre-clinical studies have been completed on pregnant animals and non-pregnant women. The risk to the fetus is caused solely by interventions that offer direct benefit for the woman or fetus The risk to the fetus is caused solely by interventions that offer direct benefit for the woman or fetusor If there is no prospect of benefit – The risk to the fetus is not greater than minimal. – The purpose of the study is to develop important biomedical knowledge – The knowledge cannot be obtained by any other means 45 CFR 46.204

20. 20 Requirements cont’d Any risk to the pregnant woman or the fetus is the least possible to achieve the research objective. Any risk to the pregnant woman or the fetus is the least possible to achieve the research objective. Consent of the pregnant woman and father (if available) is required if the research may only benefit the fetus. Consent of the pregnant woman and father (if available) is required if the research may only benefit the fetus.

21. 21 Consent of the pregnant woman only is required for research which Consent of the pregnant woman only is required for research which ─ May benefit the woman only ─ May benefit the woman and fetus ─ Will not benefit the woman or fetus but there is minimal risk to the fetus The purpose of the research is to develop important biomedical knowledge The purpose of the research is to develop important biomedical knowledge The data cannot be obtained by any other means The data cannot be obtained by any other means Requirements cont’d

22. 22 The consent form must fully disclose reasonably foreseeable risks to the fetus The consent form must fully disclose reasonably foreseeable risks to the fetus There are no inducement offered to terminate a pregnancy There are no inducement offered to terminate a pregnancy The investigator will not be involved in any decisions to terminate a pregnancy The investigator will not be involved in any decisions to terminate a pregnancy Requirements cont’d

23. 23 Requirements for Research Involving Prisoners

24. 24 IRB Composition §46.304 Majority have no association with the prison Majority have no association with the prison One member must be a prisoner or prisoner representative One member must be a prisoner or prisoner representative All other requirements under §46.107 All other requirements under §46.107

25. 25 Additional duties §46.305 (1) Approved categories (2) No undue influence (3) Risks are same as non-prisoners (4) Fair subject selection (5) Understandable language (6) No impact on parole (7) Follow-up care

26. 26 Subpart D Additional DHHS Protections for Children Involved as Subjects in Research March 8, 1983

27. 27 IRB Duties Not greater than minimal risk. (§46.404) Not greater than minimal risk. (§46.404) Greater than minimal risk, prospect of direct benefit. (§46.405) Greater than minimal risk, prospect of direct benefit. (§46.405) Greater than minimal risk, no prospect of direct benefit but generalizable knowledge. (§46.406) Greater than minimal risk, no prospect of direct benefit but generalizable knowledge. (§46.406) Not otherwise approvable. Further understanding, prevent or alleviate. (§46.407) Not otherwise approvable. Further understanding, prevent or alleviate. (§46.407)

28. 28 Assent of Children IRB determines when children are capable of assent based on age, maturity, and psychological state. §46.408(a) IRB determines when children are capable of assent based on age, maturity, and psychological state. §46.408(a) IRB determines whether and how assent is to be documented §46.408(e) IRB determines whether and how assent is to be documented §46.408(e)

29. 29 Parental Permission Adequate provisions are made to solicit permission of each child’s parent or guardian. Adequate provisions are made to solicit permission of each child’s parent or guardian. Under §46.404 and §46.405, one parent Under §46.404 and §46.405, one parent

30. 30 Parental Permission, cont. Under §46.406 and §46.407, two parents unless one is deceased, unknown, incompetent or not reasonably available. Or in case of sole custody. Under §46.406 and §46.407, two parents unless one is deceased, unknown, incompetent or not reasonably available. Or in case of sole custody. Waiver of parental consent (§46.116, Subpart A) Abused or neglected children Waiver of parental consent (§46.116, Subpart A) Abused or neglected children

31. 31 Summary What ? Why ? What ? Why ? Background for additional protections Background for additional protections US requirements for protection of vulnerable subjects in research US requirements for protection of vulnerable subjects in research

32. 32 Summary Ethical research is guided by principles of justice, respect for persons, and beneficence Ethical research is guided by principles of justice, respect for persons, and beneficence Vulnerable subjects should be included but also deserve special protections Vulnerable subjects should be included but also deserve special protections Take steps to ensure their rights and welfare are protected Take steps to ensure their rights and welfare are protected