IRB Discussion

Consent and Assent Issues in Vulnerable Populations

December 2008irb@umn.edu

perke001@umn.edu 612-626-5922

History of Research Using History of Research Using Vulnerable PopulationsVulnerable Populations

Nazi Experiments with Jewish and Nazi Experiments with Jewish and mentally ill inmatesmentally ill inmates

Willowbrook trials with Willowbrook trials with institutionalized children with mental institutionalized children with mental retardationretardation

Tuskegee syphilis study of poor and Tuskegee syphilis study of poor and poorly educated African American poorly educated African American menmen

The Nuremberg Code (1947)The Nuremberg Code (1947)As part of the verdict, the Court enumerated some As part of the verdict, the Court enumerated some

rules for "Permissible Medical Experiments", now rules for "Permissible Medical Experiments", now known as the “Nuremberg Code”. These ten rules known as the “Nuremberg Code”. These ten rules include:include:

Voluntary consentVoluntary consent Yield fruitful results otherwise unobtainableYield fruitful results otherwise unobtainable Based on animal experimentsBased on animal experiments Avoid physical and mental sufferingAvoid physical and mental suffering Not done if injury expectedNot done if injury expected Risk less than importance of problemRisk less than importance of problem Protect subject from injuryProtect subject from injury Conducted by qualified peopleConducted by qualified people Termination by subjectTermination by subject Termination by investigatorTermination by investigator

Principle 1The 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.

The Belmont ReportThe Belmont ReportEthical Principles and Guidelines for the Ethical Principles and Guidelines for the

Protection of Human Subjects of Protection of Human Subjects of ResearchResearch

The National Commission for the Protection of The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Human Subjects of Biomedical and Behavioral

ResearchResearch

April 18, 1979April 18, 1979

The Belmont ReportThe Belmont ReportBasic Ethical Principles:Basic Ethical Principles:

Respect for PersonsRespect for Persons– Individual autonomyIndividual autonomy– Protection of individuals with reduced Protection of individuals with reduced

autonomyautonomy BeneficenceBeneficence

– Maximize benefits and minimize harmsMaximize benefits and minimize harms– Do good, not just avoid harmDo good, not just avoid harm

JusticeJustice– Equitable distribution of research costs and Equitable distribution of research costs and

benefitsbenefits

45 CFR 46 – DHHS Policy for Protection of Human Research Subjects- Subpart A

Originally adopted January 13, 1981Revised June 18, 1991

“The Common Rule” –Federal Policy for Protection of Human Subjects, June 18, 1991 –adopted by 17 federal agencies

Federal Regulations and PolicyFederal Regulations and Policy

Additional Protections Included in 45 CFR 46:Additional Protections Included in 45 CFR 46:

Subpart B- Subpart B- Additional DHHS Protections Additional DHHS Protections Pertaining to Research, development, and Related Pertaining to Research, development, and Related Activities Involving Pregnant Women, Fetuses, Activities Involving Pregnant Women, Fetuses, and Neonates (non-viable and those of uncertain and Neonates (non-viable and those of uncertain viability)viability)

Subpart C- Subpart C- Additional DHHS Protections Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Pertaining to Biomedical and Behavioral Research Involving Prisoners as SubjectsInvolving Prisoners as Subjects

Subpart D-Subpart D-Additional DHHS Protections for Additional DHHS Protections for Children Involved as Subjects in ResearchChildren Involved as Subjects in Research

Authority:Authority:– Federal Food, Drug, and Cosmetic Act (1962)Federal Food, Drug, and Cosmetic Act (1962)

Regulations:Regulations:– IRB: 21 CFR 56IRB: 21 CFR 56– Informed Consent: 21 CFR 50Informed Consent: 21 CFR 50

Adopted Sub Part D --- April 2001Adopted Sub Part D --- April 2001

– Investigational Drugs: 21 CFR 312Investigational Drugs: 21 CFR 312– Investigational Devices: 21 CFR 812Investigational Devices: 21 CFR 812

Inclusion of children:Inclusion of children:45 CFR 46 Subpart D45 CFR 46 Subpart D 21 CFR 50 Subpart D 21 CFR 50 Subpart D

• Guidelines expand inclusion Guidelines expand inclusion requirementsrequirements

• Exclusion must be justifiedExclusion must be justified • Guidelines do not relax requirement Guidelines do not relax requirement

of benefitof benefit• Issues of parental permission and Issues of parental permission and

child assent present challengeschild assent present challenges

Federal Regulations: Federal Regulations: ChildrenChildren

Category Requirements

45 CFR 46.404

21 CFR 50.51• Minimal risk • Parental Permission

• Child’s assent

Federal Regulations: Federal Regulations: ChildrenChildren

Category Category RequirementsRequirements45 CFR 46. 40545 CFR 46. 40521 CFR 50. 5221 CFR 50. 52

• Greater than minimal Greater than minimal risk; direct benefitrisk; direct benefit

• Risk justified by benefit Risk justified by benefit

• Risk/benefit is as Risk/benefit is as favorable as the favorable as the alternative alternative

• Parental permissionParental permission

• Child’s assent/as Child’s assent/as required by IRBrequired by IRB

Federal Regulations: Federal Regulations: ChildrenChildren

Category Category RequirementsRequirements45 CFR 46.40645 CFR 46.40621 CFR 50.5321 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

Federal Regulations: Federal Regulations: ChildrenChildren

Category Category RequirementsRequirements45 CFR 46.40745 CFR 46.40721 CFR 50.5421 CFR 50.54

•Otherwise not approvable

•opportunity to understand, prevent or alleviate serious problem affecting children

•HHS/FDA consultation panel of experts

•Public comment

AssentAssent• Affirmative agreement: failure to Affirmative agreement: failure to

object is not assentobject is not assent• Required except whenRequired except when

• child not capable; age, maturity, child not capable; age, maturity, psychological statepsychological state

• research presents direct benefit, research presents direct benefit, important to child’s well being and important to child’s well being and available only in context of researchavailable only in context of research

Age not specified in regulationsAge not specified in regulationsIRB determines whether and how to IRB determines whether and how to documentdocument

IRBs give special consideration to IRBs give special consideration to populations not protected with specific populations not protected with specific

regulatory sub parts:regulatory sub parts:

Vulnerable Subjects (regs take group Vulnerable Subjects (regs take group approach):approach):

– decisionally impaired including persons decisionally impaired including persons with physical handicaps and mental with physical handicaps and mental disabilitiesdisabilities

– economically disadvantaged personseconomically disadvantaged persons– educationally disadvantaged personseducationally disadvantaged persons

Other considerations when Other considerations when defining “Vulnerable”:defining “Vulnerable”:

LanguageLanguage CultureCulture Current Events or Incidents Current Events or Incidents Age (elderly)Age (elderly) Age (adolescents)Age (adolescents) Transient Cognitive ImpairmentTransient Cognitive Impairment Chemical UseChemical Use Health StatusHealth Status

IRB also understandsIRB also understands

Definition of vulnerable is not black Definition of vulnerable is not black and whiteand white

People can go in and out of People can go in and out of vulnerabilityvulnerability

Regulations are vague on this issue. Regulations are vague on this issue. Bottom Line: The IRB must ensure Bottom Line: The IRB must ensure

that there are additional safeguards to that there are additional safeguards to protect the rights and welfare of these protect the rights and welfare of these participants participants

Targeting/Including Vulnerable Targeting/Including Vulnerable Populations; Appendix IPopulations; Appendix I

Though not specifically referenced in Though not specifically referenced in the federal regulations, the targeting the federal regulations, the targeting or inclusion of potentially vulnerable or inclusion of potentially vulnerable populations (other than children, populations (other than children, pregnant women/fetuses and pregnant women/fetuses and prisoners) in research requires prisoners) in research requires special considerationsspecial considerations

Appendix I of IRB Appendix I of IRB ApplicationApplication

Mentally/Emotionally/Mentally/Emotionally/Developmentally Disabled/Impaired Developmentally Disabled/Impaired Decision Making CapacityDecision Making Capacity

TargetedTargeted IncludedIncluded Provide justificationProvide justification

Explain how competency to provide Explain how competency to provide consent will be determined and plan for consent will be determined and plan for obtaining surrogate consentobtaining surrogate consent

How to consentHow to consent

Combination of “permission” from a Combination of “permission” from a legally authorized representative and legally authorized representative and the “assent” of potential participantsthe “assent” of potential participants

Witnesses to consent processWitnesses to consent process Periodic “re-consent”Periodic “re-consent” Formal checks of comprehensionFormal checks of comprehension

Legally Authorized Legally Authorized RepresentativeRepresentative

..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)

For Further information:For Further information:

Email UMN RSPP Office: Email UMN RSPP Office: irb@umn.eduirb@umn.edu

UMN IRB Web Site:UMN IRB Web Site:

http://www.research.umn.edu/subjectshttp://www.research.umn.edu/subjects

Questions ?Questions ?