1. Protection of Vulnerable Subjects in Research Tracy Rightmer, J.D. Compliance Manager Human Investigation Committee Yale University School of Medicine

2. Objectives Discuss categories of vulnerable subjects & why they are vulnerable Discuss categories of vulnerable subjects & why they are vulnerable Points to consider for protection of these subjects Points to consider for protection of these subjects Struggle to balance ethical principles with the conduct of research and protection of the rights and welfare of human subjects Struggle to balance ethical principles with the conduct of research and protection of the rights and welfare of human subjects

3. Ethical Principles of Research Justice Justice Respect of Persons Respect of Persons Beneficence Beneficence

4. Special Protections Why? Why? –Past abuses of the rights of subjects, especially vulnerable subjects –Ethical principles of justice and respect of persons What? What? –Federal Regulations –State Statutes –Special Review by HIC –Risk/Benefit of the study –Researcher Sensitivity to the particular category of vulnerability

5. Vulnerable Populations Cognitive or Communicative Cognitive or Communicative –Decisionally impaired individuals, Children, Non-English speaking individuals, Fetuses and neonates (includes pregnant women) Institutional or Deferential Institutional or Deferential –Prisoners, students and employees Medical Medical –Terminally ill individuals Economic Economic –Dependent or impoverished individuals Social Social –Minorities (includes non-English speaking persons)

6. Categories of Vulnerable Subjects Cognitive or Communicative Cognitive or Communicative –Decisionally impaired persons, Children, Fetuses and Neonates, Seriously ill persons, Non-English speakers, Individuals with substance abuse problems, Adults in ER Protections Protections –Surrogate consent from LAR, subject assent –Pay close attention to non-verbal behavioral cues indicating their wishes re: participation –Delay enrollment until situation causing the impairment has passed or consent prior to the situation causing impairment –Use translated consent forms and translator during IC process (not a family member) & include provision for ongoing communication –Carefully consider the risk/benefit ratio of the study and the appropriateness of the population being studied

7. Decisionally Impaired Have diminished capacity for decision-making and may be unable to fully understand the risks of research Have diminished capacity for decision-making and may be unable to fully understand the risks of research Capacity must be assessed by trained clinician Capacity must be assessed by trained clinician LAR must consent and subject assent LAR must consent and subject assent Regulations governing inclusion of decisionally impaired subjects §45 CFR 46.102 and §45 CFR 46.116 Regulations governing inclusion of decisionally impaired subjects §45 CFR 46.102 and §45 CFR 46.116 Special regulations prohibit court-appointed guardians of mentally retarded individuals to give permission for participation in research unless very stringent terms and conditions are met Special regulations prohibit court-appointed guardians of mentally retarded individuals to give permission for participation in research unless very stringent terms and conditions are met

8. Current Controversies No law in CT that confers the right to consent to medical procedures on the patient’s Next of Kin (NOK) No law in CT that confers the right to consent to medical procedures on the patient’s Next of Kin (NOK) Current practice in research: surrogate consent of LAR or NOK Current practice in research: surrogate consent of LAR or NOK Recent OHRP interpretation of federal regs indicate law authorizing NOK to consent to medical procedures may translate to research context Recent OHRP interpretation of federal regs indicate law authorizing NOK to consent to medical procedures may translate to research context

9. Children Regulations §45 CFR 46.404-408 mandate favorable risk/benefit ratio for research with children Regulations §45 CFR 46.404-408 mandate favorable risk/benefit ratio for research with children Permission from parent or legal guardian & assent from child Permission from parent or legal guardian & assent from child Information must be presented in language appropriate for the age of the child Information must be presented in language appropriate for the age of the child Explicitly delineate steps of the research Explicitly delineate steps of the research Length of each visit or procedure should be minimized and frequent breaks should be offered Length of each visit or procedure should be minimized and frequent breaks should be offered Preparation for procedures e.g. practice MRI Preparation for procedures e.g. practice MRI

10. Difficult/Sensitive Matters Involving Children or Elderly In the course of research with children or other vulnerable subjects like the elderly, researchers may discover sensitive information about subjects that is not research related e.g., sexual activity, STDs, use of illegal substances and child or elder abuse. In the course of research with children or other vulnerable subjects like the elderly, researchers may discover sensitive information about subjects that is not research related e.g., sexual activity, STDs, use of illegal substances and child or elder abuse. Investigators need to think about how they will handle such situations should they arise Investigators need to think about how they will handle such situations should they arise Permission/assent forms should describe plans for disclosure or non-disclosure of such information to parents, legal authorities and subjects themselves Permission/assent forms should describe plans for disclosure or non-disclosure of such information to parents, legal authorities and subjects themselves Reporting requirements apply whenever child or elder abuse is discovered and for certain diseases Reporting requirements apply whenever child or elder abuse is discovered and for certain diseases

11. Categories of Vulnerable Subjects Institutional or Deferential Institutional or Deferential –Prisoners, students and employees Protections Protections –No inappropriate or excessive incentives to enroll –Keep institution from knowing identity of participants –Informed consent state clearly that participation is voluntary, without authority figures present, protections in place to prevent retaliation –Recruitment procedures should not involve direct solicitation by superiors

12. Categories of Vulnerable Subjects Medical Medical –Terminally ill subjects Protections Protections –Consent form states clearly the potential risks and benefits and characterizes the potential benefits appropriately –Impartial third party perform IC and/or use patient advocate, consent monitor –Potential subjects should not be approached re: participation immediately after diagnosis or after they’ve learned a standard treatment has failed

13. Categories of Vulnerable Subjects Economic Economic –Dependent or impoverished subjects Protections Protections –Set economic compensation at meaningful level that compensates subject for his/her time, but not so great it becomes unduly influential –Consider alternatives to economic compensation –Make the risks to the subjects clear in the consent form

14. Categories of Vulnerable Subjects Social Social –Minorities (includes non-English speaking persons) Protections Protections –Keep data strictly confidential –Consider whether study design could incorporate participants from all segments of society –Consult with community and include representatives of this group in study design and oversight to reduce potential for stereotyping and stigmatization –Translated ICF, and translator present for IC process (not family member), & include provisions for continued communication

15. Re-consent Process Consent is an ongoing process Consent is an ongoing process Reassess vulnerability and take steps to protect subjects Reassess vulnerability and take steps to protect subjects Reassess capacity Reassess capacity

16. Conclusion Ethical research is guided by the principles of justice, respect for persons, and beneficence. Vulnerable subjects should be included but also deserve special protections. Think carefully about the populations you plan to include in your research and take steps to ensure their rights and welfare are protected.

17. Further Guidance For the Code of Federal Regulations see: http://www.hhs.gov/ohrp/humansubje cts/guidance/45cfr46.htm For the Code of Federal Regulations see: http://www.hhs.gov/ohrp/humansubje cts/guidance/45cfr46.htm http://www.hhs.gov/ohrp/humansubje cts/guidance/45cfr46.htm http://www.hhs.gov/ohrp/humansubje cts/guidance/45cfr46.htm For other guidance regarding human subject protections see: http://www.hhs.gov/ohrp/ For other guidance regarding human subject protections see: http://www.hhs.gov/ohrp/ http://www.hhs.gov/ohrp/ Human Subjects Protection Training: http://info.med.yale.edu/irbtraining/ Human Subjects Protection Training: http://info.med.yale.edu/irbtraining/

18. References OHRP http://www.hhs.gov/ohrp/ OHRP http://www.hhs.gov/ohrp/ http://www.hhs.gov/ohrp/ University of Connecticut http://www.uconn.edu/ University of Connecticut http://www.uconn.edu/ http://www.uconn.edu/ University of Michigan http://www.umich.edu/ University of Michigan http://www.umich.edu/