Research Involving Vulnerable Populations ‘Beyond’ the Regulations

1. Research Involving Vulnerable Populations ‘Beyond’ the Regulations Monika S. Markowitz, MSN, RN, MA, PhD Director, Office of Education and Compliance Oversight Office of the Vice President for Research Virginia Commonwealth University 3/09

2. Objectives • Describe what it is to be ‘vulnerable’ in the research setting • Identify potentially vulnerable research subjects, beyond those with federally regulated protections • Assess risks of harm that might result from vulnerabilities • Describe investigator- and IRB-managed protections for vulnerable populations

3. What does it mean to be Vulnerable? • Webster’s: open to attack or damage • Roget’s Thesaurus: susceptible or prone; unprotected; fragile Who is vulnerable in research? The research involves VULNERABLE research participants any time some or all of the subjects are likely to be susceptible to coercion or undue influence.

4. The Range of Vulnerabilities in Research Populations • Spectrum of vulnerability Powerless/ Decisional incapacity Inadequate information Voluntariness decreasesincreases • Vulnerability may be relative or absolute • Vulnerability may be a permanent or temporary condition • Vulnerability is affected by the research context • Level of duress • Level of coercion • Level of comprehension about research **Research design and procedures may exacerbate condition or may reduce aspects of vulnerability

5. Special Protections Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequence. The Belmont Report

6. The Belmont Report Respect for Persons Promote autonomy and protect those with diminished autonomy Beneficence Maximize benefit, minimize risk Justice Equitable distribution of research costs and benefit

7. Federal Regulations and Policystemming from Belmont Principles 45 CFR 46 – DHHS Policy for Protection of Human Research Subjects 21CFR50, 56, etc. – drugs, devices, biologics ‘The Common Rule’ 45CFR46 Subpart A - adopted by 17 federal agencies, including FDA, in 1991

8. Populations specifically protected in federal regulations 45CFR46 • Pregnant women - Subpart B Fetuses & Neonates • Prisoners – Subpart C • Children – Subpart D

9. Others Identified as Vulnerable in Regulations 45CFR46.111(b) 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 subjects.

10. IRB considerations per regs “If an IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects.” (45 CFR 46.107(a) “IRB shall determine that…. Selection of subjects is equitable. In making this assessment the IRB should … be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.” (45 CFR 46.110(a)(3) and 21 CFR 56.111)

11. Sources of ‘coercion and undue influence’ • Power differential • Easily suggestible cognitive state • Research subject ‘benefits’ – cash or equivalent; ‘free’ medical care • Search for a cure; ‘last hope’ – therapeutic misconception may be fostered by researcher

12. Who may be subject to coercion or undue influence (in addition to those groups protected in regs)? • Acutely or chronically ill • Students: • college students • adult learners • Employees, workers • Military personnel • Non-English speakers • Decisionally-impaired • Substance abuse • Mentally ill • Impaired cognition due to illness/injury states • Elderly • Cognitive disability

13. Terminally ill • Institutionalized • Individuals/groups socially stigmatized by • Age • Gender • Ethnicity • Religion • Behavior (sex, alcohol, drug use, group membership) • Type of disease • Those engaged in non-legal behavior • gang members • drug-users • under-age alcohol and tobacco use • criminal activity • Survivors of traumatic event(s)

14. Assessing “the magnitude and probability” of harm and discomfort in order to minimize vulnerability • Identify possible source(s) of harm • Recruitment • Increase feelings of stigmatization? • Research procedures • Exacerbate condition? • Breach of identifiable data • Increase stigmatization? • Cause economic or political harm? • Decrease self-worth, self-image? • Evaluate remediability of harms

15. Decisionally impaired subjectsInvestigator builds in protections • Expected range of decisional impairment. How will it be assessed, especially if fluctuating? • If relevant, justify why cognitively impaired individuals may be enrolled to study their comorbid conditions • When will a legally authorized representative (LAR) be used? • Will the subject be asked to assent? • Plans for obtaining consent for continued participation if, and when, decisional capacity returns • Not just consent/assent issues – additional protections, i.e. research setting, special qualifications of investigator/ research team, etc.

16. NHRPAC Workgroup– beyond NBAC:recommendations apply to all subjects in BMR or SBR who lack decisional capacity for any reason Persons who lack decisional capacity may participate in: • Research that is no greater than minimal risk and if LAR has given permission; consent waived on subject • Research greater than minimal risk but presents prospect of direct benefit, if: risk justified; favorable risk benefit relation; LAR permits • Research with minor increase over min risk and no prospect of direct benefit if likely yield generalizable knowledge about condition/disorder if: interventions reasonably commensurate with others; LAR permits • Research not otherwise approvable, Secretary determines: IRB sees as reasonable research opportunity; adheres to sound ethical principles; LAR permits

17. Virginia Code § 32.1-162.16. Hierarchy of LAR in Research (i) the parent or parents having custody of a prospective subject who is a minor (ii) the agent appointed under an advance directive, as defined in § 54.1-2982, executed by the prospective subject, provided the advance directive authorizes the agent to make decisions regarding the prospective subject's participation in human research, (iii) the legal guardian of a prospective subject, (iv) the spouse of the prospective subject, except where a suit for divorce has been filed and the divorce decree is not yet final, (v) an adult child of the prospective subject, (vi) a parent of the prospective subject when the subject is an adult, (vii) an adult brother or sister of the prospective subject or (viii) any person or judicial or other body authorized by law or regulation to consent on behalf of a prospective subject to such subject's participation in the particular human research.

18. Conditions Limiting LAR Use in VirginiaCode of Virginia § 32.1-162.18. Informed consent A legally authorized representative may not consent or give permission: • That forces the subject to participate. • To nontherapeutic unless the IRB determines that such nontherapeutic research presents no more than a minor increase over minimal risk to the human subject. 3. To participation in human research on behalf of a prospective subject if the LAR knows, or ought to know, that any aspect of the human research protocol is contrary to the religious beliefs or basic values of the prospective subject, whether expressed orally or in writing.

19. Conditions Limiting LAR Use in Virginia A legally authorized representative may not consent or give permission: 4. To participation in human research involving nontherapeutic sterilization, abortion, psychosurgery or admission for research purposes to a facility or hospital as defined by the Code of Virginia at § 37.2-100. 5. If two or more persons who qualify as LARs and have equal decision-making priority inform the PI or attending physician that they disagree as to participation of the prospective subject in human research, the subject shall not be enrolled in the human research that is the subject of the consent.

20. VCU Informed Consent Evaluation Instrument • Do you understand that your research study participation is voluntary? ____Yes ____No ____Unsure 2.Do you understand the difference between treatment and research? ____Yes ____No ____Unsure ____N/A (Skipped) • Can you describe the alternative(s) to participation in this research? ____Yes ____No ____Unsure ____N/A (Skipped) • Can you name at least two possible risks of study participation? ____Yes ____No ____Unsure • Can you name at least two things that you will be expected to do as part of your participation in this research study? ____Yes ____No ____Unsure 6.Do you understand that you have a right to stop participating in this research study at any time? ____Yes ____No ____Unsure 7. Can you tell me what you would do if you experience physical, emotional, or other symptoms that were not expected as a result of your study participation? ____Yes ____No ____Unsure

21. Economically- and/or Educationally Disadvantaged Subjects Information provided by investigator: • Population of convenience or focus of research? • Considerations about ‘coercion and undue influence’ –incentives/compensation, power differential, etc. • Informed consent process – issues of comprehension and voluntariness • Practical considerations of study compliance, accessibility

22. Involving Non-English Speaking Participants (LEP)Info provided by investigator: • Considerations for involvement based on level of risk and prospect for direct benefit, unless population of focus • Informed consent process - Careful consideration of short form - If deemed to provide prospect of benefit, use certified verbal interpreter - Obtain ICF translation to be approved by IRB • Consider provisions for on-going communication and IC process – eg. Understanding study interventions; how will ‘unanticipated problems involving risk to subjects or others’ be reported?

23. Employees and studentsInfo providedby investigator: • Are employees, students eligible even if not the target population? • Voluntariness - No grade, extra credit, or ‘bonus’ for research participation unless a comparable activity is available • Strategies to minimize employee or student identification • Minimize sense of ‘exploitation’

24. IRB considerations for protecting vulnerable subjects • Study design • Inclusion/exclusion criteria; equitable selection • Stopping rules • Additional data monitoring efforts • How, when, and to whom data will be released • Training and availability of staff; qualifications in working with ‘vulnerable’ groups • Additional Informed Consent safeguards - Use of Waiting Periods - Use of LAR and assent/consent process - Use of Informational/Educational Techniques - Use of an Independent Monitor or Advocate - IRB observes obtaining of consent/assent - Advanced Directive for Research

25. IRB considerations for protecting vulnerable subjects • Study procedures • Recruitment • Ongoing involvement of family, LARs, significant others • Payment to subjects • Debriefing • Providing benefits back to subjects • Competence of IRB members • IRB membership reflects experience with vulnerable group • Using consultants • Gathering data on vulnerability and associated harm in research • Policies of the IRB and HRPP re: managing vulnerability

26. AAHRPP standards and elements for protection of vulnerable subjects II.4.C. The Research Review Unit has and follows written policies and procedures for determining the risks to vulnerable populations as defined in applicable federal regulations, and specifically for determining the required risk categories in protocols involving children and prisoners. II.7.B. The Research Review Unit has and follows written policies and procedures requiring that prospective participants whose decision-making capacity is in question be appropriately protected. III.1.D. The Investigator or research staff recruits participants in a fair and equitable manner, weighing the potential benefits of the research to the participants against their vulnerability and the risks to them.

27. Resources • Research Involving Individuals with Questionable Capacity to Consent: Points to Consider, NIH OER, 1999 http://grants.nih.gov/grants/policy/questionablecapacity.htm • Final Report to NHRPAC from the Workgroup on Informed Consent and the Decisionally Impaired, National Human Research Protections Advisory Committee. Federal Register, Sept. 5, 2002http://www.hhs.gov/ohrp/nhrpac/documents/nhrpac10.pdf • Research Involving Persons with Mental Disorders that May Affect Decision Making Capacity, NBAC, September 1998 http://bioethics.georgetown.edu/nbac/capacity/TOC.htm • Wall, A., Including Persons with Alzheimer Disease in Research on Comorbid Conditions, IRB: Ethics and Human Research, 31 (1), Feb. 2009

28. Thank You Questions? Feel free to access: - VCU IRB website http://www.research.vcu.edu/irb/index.htm