Inclusion of Individuals with Impaired Decisionmaking In Research

1
Inclusion of Individuals with Impaired
Decision-making In Research
The SIIIDR Subcommittee of the Secretarys
Advisory Committee on Human Research Protections
and Jeffrey R. Botkin, MD, MPH Associate Vice
President for Research
2
Case I

• Investigators wish to study a new combination of
  radiation therapy and chemotherapy for adults
  with meduloblastoma. Consenting participants
  will be randomized to standard of care
  interventions or the experimental protocol.
• Should decision-making capacity be an inclusion
  criterion for the study?
• How should the study manage individuals who lack
  decision-making capacity?

3
Case II

• Investigators wish to study changes in brain
  structure and function during the progression of
  Alzheimer disease. Mildly affected individuals
  with newly diagnosed Alzheimer will be asked to
  consent to MRI and PET scans twice per year
  through the remainder of their lives.
• How should the consent process be managed for
  this study?

4
Individuals with Impaired Capacity

• Increasingly important area of research
• Not included in 45CFR46 explicitly as a
  vulnerable population
• Individuals with impaired capacity may be
• the specific target population for research or
• included as occasional members of other groups
  (ICU patients)

5
Regulatory Background

• 1. Legally effective informed consent
• e.g. From 45CFR46.116
• Information shall be in language
  understandable to the subject
• 2. Special protections in IRB review and approval
  (e.g. notions of acceptable risk)
• From 111
• Whensubjects are likely to be vulnerable to
  coercion or undue influence, additional
  safeguards have been included
• From 111(2)
• Risks to subjects are reasonable in relation
  to anticipated benefits, if any, to subjects,
  and the importance of the knowledge that may
  reasonably be expected to result. and
• 3. Legally authorized representative

6
Basis for Action

• Prior efforts have not been successful.
• The absence of adequate, consistent, or in many
  cases, any state law creates significant problems
  for research protections.
• Solutions must protect subjects and support
  science.

7



SIIIDR Membership



Paul Appelbaum, Jeffrey Botkin, Anne Donahue,
Laurie Flynn, David Forster, Edgar Kenton Lisa
Leiden, John Luce, John Oldham, Laura Roberts,
Gustavo Roman, David Strauss



8
Framework for SIIIDR activities
How do we identify those who have limited
ability to consent and those who are unable to
make consent decisions for themselves?
How do we define a reasonable risk/benefit balanc
e when ability to consent is limited or absent?
How do we decide who may provide consent for
those who are unable to consent for themselves?
9
The ability to consent requires

• Effective disclosure of required information,
• A capacity to understand, appreciate, and reason
  about the relevant facts and consequences related
  to participations, and
• A context which promotes voluntary choice, free
  of undue influence

10
Ability to consent

• Ability to consent occurs along a continuum.
• Some individuals will be assessed as being able
  to make a consent decision despite some
  impairment or limitation in ability.
• Others will have limitations to a degree that
  they will be assessed as unable to consent.
• Ability can be enhanced in some circumstances

11
Ability to consent occurs along a continuum
Unable Able
Increasing Ability
Unable to Consent
Able to Consent
Impairments or limitations in ability
12
Ability to Consent is Task Specific

• The ability required to make a decision about
  participation in a specific research study
  depends on the complexity, novelty, level of
  risk, and level of benefit of the proposed
  research.
• So, an individual may be assessed as being able
  to make a consent decision to participate in one
  research study, and unable to consent to others.

13
Impairments and Limitations in Ability to Consent

• Situational vs. disorder-related impairment
• (e.g. emergency room, ICU, institutions vs.
  stroke)
• Global vs. specific impairment
• (e.g. sedative overdose vs. paranoid psychosis)
• Static vs. progressive vs. episodic vs. time
  limited impairment
• (e.g. severe mental retardation vs. Alzheimers
  disease vs. manic depressive disorder vs. TBI)
• Acute vs. persistent impairment
• (e.g. hypoxia secondary to asthma or acute pain
  vs. mental retardation, autism)

14
Assessment

• No uniformly accepted tools for assessing
  capacity across the range of impairments
• Ideally, assessments of decision-making capacity
  should be independent of investigators
• All potential subjects should be assessed for
  capacity
• Can be informal
• Periodic reassessment may be appropriate to judge
  a return of capacity to consent

15
Framework for SIIIDR activities
How do we identify those who have limited
ability to consent and those who are unable to
make consent decisions for themselves?
How do we define a reasonable risk/benefit balanc
e when ability to consent is limited or absent?
How do we decide who may provide consent for
those who are unable to consent for themselves?
16
Research Advance Directives

• Can individuals with capacity consent to their
  research participation in the future when they
  have lost capacity?

17
Assent

• What is the role of assent in research with
  individuals with impaired capacity?
• Should any sign of objection to the research
  procedures be honored as a dissent?

18
LAR and the Regulatory Dead End

• The federal regulations require the subjects
  legally effective informed consent
• They also allow consent by a legally authorized
  representative (LAR) to the procedures used in
  the research.
• But, the federal regulations do not define LAR.
  This is left to applicable local (State) law.
  OHRP guidelines indicate that state laws
  governing clinical decision-making can be applied
  to research
• The States, with rare exceptions, have not
  defined LAR for research, and some do not define
  it at all.

19
SIIIDR Consensus

• A comprehensive and consistent national approach
  to the definition and use of legally authorized
  representative is necessary to provide
  protections and promote research for those who
  are unable to consent.
• SIIIDR will further consider the merits and
  practicalities of federal regulation defining
  LAR.
• SACHRP might consider an alternative approach by
  which HHS promotes the development and adoption
  of model state legislation re LAR.

20
Framework for SIIIDR activities
How do we identify those who have limited
ability to consent and those who are unable to
make consent decisions for themselves?
How do we define a reasonable risk/benefit balanc
e when ability to consent is limited or absent?
How do we decide who may provide consent for
those who are unable to consent for themselves?
21
How do we define risk of harm?
Minimal Greater than Minimal
Minor Increment
Increasing Risk
22
Approvability as per Subpart A
Risk/Benefit Ratio
Increasing Benefit Decreasing Risk Decreasing
need for external protections
Increasing Approvability
23
Subpart D Approach

• 4 categories of acceptable research
• Minimal risk
• Prospects of direct benefit
• Risks are reasonable in relation to benefits
• No better alternatives
• No prospect of direct benefit
• Minor increase over minimal risk
• Vital importance to an understanding of the
  condition
• Special review of expert panel at federal level

24
Initial Considerations

• Protections must address the nature and extent of
  subject vulnerability, the magnitude of research
  risk/benefit.
• The relative merits of categorical vs. other
  approaches to risk/benefit analysis must be
  addressed.
• Pragmatic considerationschallenges at the State
  and institutional levels, IRB and investigator
  practicemust guide recommendations.

25
Near-term Goals

• Seek additional data on current practice and
  specifically, whether subject welfare/safety
  and/or scientific progress is hampered
• Patient advocacy organizations
• Academic organizations and professional
  societies
• The IRB community

26
University of Utah Points to Consider

• Does the IRB have the expertise?
• Is it necessary to involve cognitively impaired
  individuals?
• Are there adequate procedures for evaluating
  mental status?
• Is the research more than minimal risk? If so,
  do the benefits outweigh the risks?
• Possible to identify a LAR?
• Should assent be required?
• Should an advocate or consent auditor be
  appointed?