1. VA Requirements for Vulnerable Subjects Kevin L. Nellis, M.S., M.T. (A.S.C.P.) Program Analyst Program for Research Integrity Development and Education (PRIDE)

2. 2 Overview Vulnerable Subjects Populations Considered Categorically Vulnerable Pregnant Women Prisoners Children Persons Who Lack Decision-Making Capacity Surrogate Consent 2

3. 3 Vulnerable Subjects Common Rule: When some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these [38 CFR 16.111(b)] 3

4. 4 IRB Must Document Deliberations Reasons why IRB considers population or individual to be vulnerable That adequate safeguards protect the rights and welfare of subjects likely to be vulnerable That the VA criteria are met to approve inclusion of individuals who lack decision-making capacity 4

5. 5 Individuals or Populations Which May Be Temporarily or Permanently Vulnerable Those who are susceptible to coercion or undue influence (e.g., homeless, students, patients with limited treatment options, socially or economically disadvantaged) Those who lack comprehension of research or potential risks (e.g., educationally disadvantaged, dementia, schizophrenia, depression) 5

6. 6 Those who have increased susceptibility to harm (e.g., individuals answering questions about traumatic events such as sexual assault, or combat experiences) Those who are at risk for physical, psychological, economic, social, legal consequences (e.g., Individuals answering questions about drug use or HIV status) 6 Individuals or Populations Which May Be Temporarily or Permanently Vulnerable

7. 7 Research Involving Pregnant Women VA Requirements Adequate provisions has been made to monitor risk to subject and fetus Women of child bearing potential may not be entered into studies involving Category D or X drugs without a waiver from the Chief Research and Development Officer (CRADO) 7

8. 8 Research Involving Pregnant Women 45 CFR 46, Subpart B Requirements Prior studies must assess potential risks to pregnant women and fetuses (preclinical studies, clinical studies, studies on pregnant animals, studies on non-pregnant women), when scientifically appropriate [45 CFR 46.204(a)] 8

9. 9 Research Involving Pregnant Women 45 CFR 46, Subpart B Requirements Risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, If there is no such prospect of benefit: the risk to the fetus is not greater than minimal, and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means [45 CFR 46.204(b)] 9

10. 10 Research Involving Pregnant Women 45 CFR 46, Subpart B Requirements Any risk is the least possible for achieving the objectives of the research [45 CFR 46.204(c)] If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, the pregnant woman’s informed consent is obtained in accord with the informed consent provisions of 38 CFR 16.116 [45 CFR 204(d)] 10

11. 11 Research Involving Pregnant Women 45 CFR 46, Subpart B Requirements Subject is fully informed regarding the reasonably foreseeable impact of the research on the fetus [45 CFR 46.204(f)] 11

12. 12 Research Involving Pregnant Women 45 CFR 46, Subpart B Requirements No inducements, monetary or otherwise, are to be offered to terminate a pregnancy [45 CFR 46.204 (h)] Individuals engaged in the research have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy [45 CFR 46.204(i)] determining the viability of a fetus [45 CFR 46.204 (j)] 12

13. 13 Research Involving Prisoners IRB Approval Must Comply 45 CFR 46, Subpart C Waiver from Chief of Research and Development Officer (CRADO) OHRP FAQs: http://www.hhs.gov/ohrp/policy/populations/index.html http://www.hhs.gov/ohrp/policy/populations/index.html 13

14. 14 Research Involving Prisoners Incarceration During Study Investigators must notify the IRB as soon as they become aware that the subject has been incarcerated Investigator determines whether or not it is the best interests of the subject to remain in the study, or if the subject can be safely withdrawn from the study Continued participation is contingent on the IRB’s reviewing and approving such participation Waiver must be obtained from the CRADO Follow all requirements (court, penal system, local VA, Federal) 14

15. 15 Research Involving Children VA Requirements VA Research must support mission of VA and enhance quality of health care delivery to veterans CRADO Waiver (see VHA Handbook 1200.05) must be obtained to conduct VA research involving children Interventions Interactions Data or specimens Meet requirements of 45 CFR 46, Subpart D 15

16. 16 Research Involving Persons Who Lack Decision-Making Capacity Individual is presumed to have decision-making capacity unless: Documented by a qualified practitioner* in the medical record Ruled incompetent by a court of law If there is any question whether a potential adult subject has decision-making capacity, the investigator must consult with a qualified practitioner* about the individual’s decision-making capacity before proceeding with the informed consent process *May be a qualified member of the research team

17. 17 Research Involving Persons Who Lack Decision-Making Capacity Individuals at high risk for temporary (e.g., head trauma) or fluctuating (e.g., schizophrenia) lack of decision-making capacity must be evaluated to determine the ability to provide informed consent Evaluation must be performed as described in the IRB- approved protocol If individual is deemed to lack decision-making capacity, a legally authorized representative (LAR) must provide informed consent If subject regains decision-making capacity, repeat informed consent process with subject, and obtain subject’s permission to continue

18. 18 Criteria for Enrolling Persons Who Lack Decision-Making Capacity Risk, Harm, & Direct Benefit of Proposed Research* Additional Requirements* No greater than minimal riskNo additional requirements Some probability of harmProbability of direct benefit must be greater than probability of harm Greater than minimal risk with no prospect of direct benefit to subject Research is likely to lead to generalizable knowledge about subject’s disorder or condition that is of vital importance for understanding or amelioration of subject’s disorder or condition *VHA Handbook 1200.05, Paragraph 49(d)(1)(a), or (b), or (c)

19. Criteria for Enrolling Persons Who Lack Decision-Making Capacity * 19 Type of Study*Additional Requirements Example Disorder leading to individual’s lack of decision-making capacity is being studied; whether or not the lack of decision-making itself is being evaluated The study cannot be performed with only persons who have decision-making capability Individual who lacks decision making capacity as the result of stroke can participate in study of cardiovascular effects of stroke * Also need VHA Handbook 1200.05, Paragraph 49(d)(1)(a), or (b), or (c)

20. 20 Criteria for Enrolling Persons Who Lack Decision-Making Capacity Type of Study*Additional Requirements Example Study is not directly related to individual’s lack of decision- making capacity Compelling argument for including individuals who lack of decision-making capacity Study the transmission of MRSA infection in nursing home where both individuals with, and those without, decision making capacity are affected * Also need VHA Handbook 1200.05, Paragraph 49(d)(1)(a), or (b), or (c)

21. 21 IRB Determinations for Research Involving Persons Who Lack Decision-Making Capacity Ensure the study includes appropriate procedures for respecting dissent Consider whether or not the study needs to include procedures for obtaining assent Determine whether any additional safeguards need to be used (e.g., consent monitoring)

22. 22 IRB Determinations for Research Involving Persons Who Lack Decision-Making Capacity IRB must document Reasons why IRB considers subject to be vulnerable That adequate safeguards protect subjects VA criteria are met to approve include individuals who lack decision-making capacity

23. 23 Surrogate Consent Legally Authorized Representative (LAR) Health care agent Legal or special guardian Next of kin in this order: Spouse, child, parent, sibling, grandparent, grandchild Close friend LAR is not synonymous with HIPAA’s “personal representative”

24. 24 Surrogate Consent If feasible, the investigator must explain the proposed research to the prospective research subject Some persons may resist participating in a research (i.e., dissent) Under no circumstances may a subject be forced or coerced to participate in a research study even if the LAR has provided consent For subjects with fluctuating decision-making capacity or those with decreasing capacity to give consent, a re-consenting process with surrogate consent may be necessary 24

25. 25 Key Points Understand who is categorically vulnerable Understand which individuals or populations may be vulnerable Understand the protections afforded to vulnerable subjects in a study 25

26. 26 Key Points IRB must document Reasons why IRB considers to be vulnerable That adequate safeguards protect subjects VA criteria are met to approve include individuals who lack decision-making capacity 26

27. 27 Key Points Protecting vulnerable populations is a shared responsibility among: Investigators IRB Legally Authorized Representative 27

28. 28