1. IRB Discussion Consent and Assent Issues in Vulnerable Populations December 2008 irb@umn.edu perke001@umn.eduperke001@umn.edu 612-626-5922

2. History of Research Using Vulnerable Populations Nazi Experiments with Jewish and mentally ill inmates Nazi Experiments with Jewish and mentally ill inmates Willowbrook trials with institutionalized children with mental retardation Willowbrook trials with institutionalized children with mental retardation Tuskegee syphilis study of poor and poorly educated African American men Tuskegee syphilis study of poor and poorly educated African American men

3. The Nuremberg Code (1947) As part of the verdict, the Court enumerated some rules for "Permissible Medical Experiments", now known as the “Nuremberg Code”. These ten rules include: Voluntary consent Voluntary consent Yield fruitful results otherwise unobtainable Yield fruitful results otherwise unobtainable Based on animal experiments Based on animal experiments Avoid physical and mental suffering Avoid physical and mental suffering Not done if injury expected Not done if injury expected Risk less than importance of problem Risk less than importance of problem Protect subject from injury Protect subject from injury Conducted by qualified people Conducted by qualified people Termination by subject Termination by subject Termination by investigator Termination by investigator

4. Principle 1 The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice without the intervention of any element of force, fraud, deceit, duress, over- reaching or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision.

5. The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979

6. The Belmont Report Basic Ethical Principles: Respect for Persons Respect for Persons –Individual autonomy –Protection of individuals with reduced autonomy Beneficence Beneficence –Maximize benefits and minimize harms –Do good, not just avoid harm Justice Justice –Equitable distribution of research costs and benefits

7. 45 CFR 46 – DHHS Policy for Protection of Human Research Subjects- Subpart A Originally adopted January 13, 1981 Revised June 18, 1991 “The Common Rule” –Federal Policy for Protection of Human Subjects, June 18, 1991 –adopted by 17 federal agencies

8. Federal Regulations and Policy Additional Protections Included in 45 CFR 46: Subpart B- Additional DHHS Protections Pertaining to Research, development, and Related Activities Involving Pregnant Women, Fetuses, and Neonates (non-viable and those of uncertain viability) Subpart C- Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D- Additional DHHS Protections for Children Involved as Subjects in Research

9. Authority: –Federal Food, Drug, and Cosmetic Act (1962) Regulations: –IRB: 21 CFR 56 –Informed Consent: 21 CFR 50  Adopted Sub Part D --- April 2001 –Investigational Drugs: 21 CFR 312 –Investigational Devices: 21 CFR 812

10. Inclusion of children: 45 CFR 46 Subpart D 21 CFR 50 Subpart D Guidelines expand inclusion requirements Guidelines expand inclusion requirements Exclusion must be justified Exclusion must be justified Guidelines do not relax requirement of benefit Guidelines do not relax requirement of benefit Issues of parental permission and child assent present challenges Issues of parental permission and child assent present challenges

11. Federal Regulations: Children Category Requirements 45 CFR 46.404 21 CFR 50.51 Minimal risk Parental Permission Child’s assent

12. Federal Regulations: Children Category Requirements 45 CFR 46. 405 21 CFR 50. 52 Greater than minimal risk; direct benefit Greater than minimal risk; direct benefit Risk justified by benefit Risk justified by benefit Risk/benefit is as favorable as the alternative Risk/benefit is as favorable as the alternative Parental permission Parental permission Child’s assent/as required by IRB Child’s assent/as required by IRB

13. Federal Regulations: Children Category Requirements 45 CFR 46.406 21 CFR 50.53 Greater than minimal risk/ no direct benefit/ will yield generalizable knowledge Minor increase over minimal risk Experiences commensurate with inherent, actual, or expected situations Yield knowledge of vital importance Both parents give permission Child assent

14. Federal Regulations: Children Category Requirements 45 CFR 46.407 21 CFR 50.54 Federal Regulations: Children Category Requirements 45 CFR 46.407 21 CFR 50.54 Otherwise not approvable opportunity to understand, prevent or alleviate serious problem affecting children HHS/FDA consultation panel of experts Public comment

15. Assent Affirmative agreement: failure to object is not assentAffirmative agreement: failure to object is not assent Required except whenRequired except when child not capable; age, maturity, psychological statechild not capable; age, maturity, psychological state research presents direct benefit, important to child’s well being and available only in context of researchresearch presents direct benefit, important to child’s well being and available only in context of research Age not specified in regulations IRB determines whether and how to document

16. IRBs give special consideration to populations not protected with specific regulatory sub parts: Vulnerable Subjects (regs take group approach): Vulnerable Subjects (regs take group approach): –decisionally impaired including persons with physical handicaps and mental disabilities –economically disadvantaged persons –educationally disadvantaged persons

17. Other considerations when defining “Vulnerable”: Language Language Culture Culture Current Events or Incidents Current Events or Incidents Age (elderly) Age (elderly) Age (adolescents) Age (adolescents) Transient Cognitive Impairment Transient Cognitive Impairment Chemical Use Chemical Use Health Status Health Status

18. IRB also understands Definition of vulnerable is not black and white Definition of vulnerable is not black and white People can go in and out of vulnerability People can go in and out of vulnerability Regulations are vague on this issue. Regulations are vague on this issue. Bottom Line: The IRB must ensure that there are additional safeguards to protect the rights and welfare of these participants Bottom Line: The IRB must ensure that there are additional safeguards to protect the rights and welfare of these participants

19. Targeting/Including Vulnerable Populations; Appendix I Though not specifically referenced in the federal regulations, the targeting or inclusion of potentially vulnerable populations (other than children, pregnant women/fetuses and prisoners) in research requires special considerations Though not specifically referenced in the federal regulations, the targeting or inclusion of potentially vulnerable populations (other than children, pregnant women/fetuses and prisoners) in research requires special considerations

20. Appendix I of IRB Application Mentally/Emotionally/Developmentally Disabled/Impaired Decision Making Capacity TargetedIncluded TargetedIncluded Provide justification Provide justification Explain how competency to provide consent will be determined and plan for obtaining surrogate consent Explain how competency to provide consent will be determined and plan for obtaining surrogate consent

21. How to consent Combination of “permission” from a legally authorized representative and the “assent” of potential participants Combination of “permission” from a legally authorized representative and the “assent” of potential participants Witnesses to consent process Witnesses to consent process Periodic “re-consent” Periodic “re-consent” Formal checks of comprehension Formal checks of comprehension

22. Legally Authorized Representative..an individual, or judicial or other body, under applicable law to consent on behalf of the prospective subject to the subject’s participation in the procedures involved in the research. 45 CFR 46.102 (c) and 21 CFR 50.3 (25) (l)

23. For Further information: Email UMN RSPP Office: irb@umn.edu irb@umn.edu UMN IRB Web Site: http://www.research.umn.edu/subjects

24. Questions ?