IRB Review: Beyond the Basics

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IRB Review Beyond the Basics

• Kevin L. Nellis, M.S., M.T. (A.S.C.P.)
• Program Analyst
• Program for Research Integrity Development and
  Education (PRIDE)
• March 23, 2011

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Goal

• Applying
• The Belmont Report
• Common Rule
• VHA Handbook 1200.05
• to VA IRB Review

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The Belmont Report
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The Belmont Report

• Boundaries Between Practice and Research
• Principles
• Respect for persons
• Beneficence
• Justice

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The Common Rule
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Common Rule IRB Approval Criteria38 CFR 16.111

• 38 CFR 16.111 criteria must be met before the IRB
  can grant approval
• Expedited review
• Convened initial review
• Continuing review
• Amendments

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Common Rule IRB Approval Criteria38 CFR 16.111

• Risks are minimized
• Risk/benefit balance is reasonable
• Subject selection is equitable
• Appropriate informed consent will be sought
• Informed consent will be appropriately documented
• Safety will be appropriately monitored
• Privacy and confidentiality will be protected
• Additional safeguards included for vulnerable
  subjects
• VHA Handbook 1200.05, Paragraph 17

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Additional Requirements of VHA Handbook 1200.05
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Additional Criteria for IRB ApprovalVHA Handbook
1200.05, Paragraph 17(i-k)

• Conflicts of interest must be managed or
  eliminated
• Investigator must have appropriate background and
  experience
• Ensure consistency of
• Protocol
• Informed consent form
• HIPAA authorization
• When applicable, comply with other VA regulations

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Applying Belmont Principles to IRB Review
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Home Telemonitoring Case Study

• Veterans over the age 60 with multiple chronic
  illnesses and at risk for worsening medical
  status are randomized
• 100 provided with home telemonitoring device
• 100 placed in a usual care arm
• Make appointments when problems arise
• Use the 24 hr nurse hotline and My HealtheVet
  that is available to all patients at the XYZ VAMC
• Outcomes are assessed by hospitalizations and ER
  visits over 1 yr

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Boundaries Between Practice and ResearchThe
Belmont Report

• Research and clinical practice can be blurred
  when they occur together
• Practice provides diagnosis, preventive
  treatment or therapy
• Research designates an activity designed to
  develop or contribute to generalizable knowledge
• VHA Handbook 1200.05 differentiates usual care
  from research

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How Are Boundaries Between Practice and Research
Applied to IRB Review of Home Telemonitoring
Study?

• IRB ensures
• Protocol clearly differentiates the usual care
  (appointments and 24 hr nurse hotline) from the
  research (home telemonitoring arm)
• Informed consent defines risks related to the
  research
• Risks associated with reliance on telemonitoring
  (versus the usual care risks from appointments
  and 24 hr hotline)

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Principle of Respect for PersonsThe Belmont
Report

• IRB review must ensure
• Persons are treated in an ethical manner
• Respect their decisions
• Protect them from harm
• Individuals are treated as autonomous agents
• Provide potential subjects with sufficient
  information so they are free to make their own
  decisions

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Principle of Respect for PersonsThe Belmont
Report

• IRB review must ensure the immature and the
  incapacitated are respected and protected
• Some may need to be excluded
• Others require little protection beyond making
  sure they undertake activities freely and are
  aware of possible risks
• Extent of protection varies based on
• Person or population
• Circumstances

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How is the Principle for Respect for Persons
Applied to IRB Review?

• Ensure full disclosure of information
• Debrief subjects involving incomplete disclosure
• Manner and context is important
• Adapt process to subjects ability to comprehend
  information
• May be suitable to give oral or written tests of
  comprehension

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How is the Principle for Respect for Persons
Applied to IRB Review?

• Ensure that informed consent process is
• Voluntary
• Without undue influence
• Ensure additional protections described for
  vulnerable populations
• Required additional findings
• Provisions for surrogate consent

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How is Respect Applied to IRB Review of Home
Telemonitoring Study?

• IRB should ensure full disclosure of information
  in the informed consent process
• IRB may require testing subjects to ensure they
  understand how to operate home telemonitoring
  equipment
• IRB may require investigator to exclude certain
  populations (e.g., patients with certain
  diseases, persons who lack decision-making
  capacity, etc)
• IRB ensures privacy is maintained

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Principle of BeneficenceThe Belmont Report

• Make efforts to secure subjects well-being
• Do not harm - fundamental principle of medical
  ethics
• Benefits must outweigh the risks
• Risks must be justified

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Principle of BeneficenceHow is This Applied to
IRB Review?

• Ensure that science is valid
• Ensure protocol and informed consent process
  distinguish and clarify risks as much as possible
• Psychological
• Physical
• Legal
• Social
• Economic

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How is the Principle of Beneficence Applied to
IRB Review?

• IRB cannot permit brutal or inhumane treatment of
  subjects
• IRB ensures that benefits and risks are
  balanced and shown to be in a favorable ratio
• IRB ensures justification of
• Significant risks
• Appropriateness of involving vulnerable
  populations
• IRB can add protections to minimize the
  significant risks

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How is the Principle of Beneficence Applied to
IRB Review?

• IRB ensures appropriate safety monitoring
• Privacy Officer and ISO ensure appropriate
  protections for
• Privacy
• Confidentiality
• Information security

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How is Beneficence Applied to IRB Review of Home
Telemonitoring Study?

• IRB must ensure that the risks are reasonable in
  relationship to the potential benefits of the
  research
• IRB determines whether the subjects are
  vulnerable and if additional protections are
  needed
• Privacy Officer and ISO evaluate protections for
  privacy, confidentiality, and information
  security

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A Closer Look at Beneficence

• Principle of Therapeutic Misconception
• Principle of Equipoise

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Principle of Therapeutic Misconception

• Subjects misunderstand the primary purpose of the
  research as therapeutic
• Fail to appreciate the difference between
  research and treatment
• Underestimate risk
• Overestimate benefit
• Undermines informed consent
• Investigators can be susceptible to believing
  research offers a direct benefit

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How is Therapeutic Misconception Avoided?

• IRB should evaluate quality of protocol and
  informed consent process to ensure they do not
  promote potential therapeutic misconception
• In Phase I trials (e.g., first time testing in
  humans to assess safety and tolerability), IRB
  should insist on clarity for
• Proposed dosing strategy
• How investigators plan to assure that subjects
  understand the nature of the purpose of the study

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How is Therapeutic Misconception is Avoided in
the Home Telemonitoring Study?

• IRB may ensure that telemonitoring is fully
  described as a research intervention in the
  protocol and informed consent
• IRB may ensure home telemonitoring is not
  described as a standard clinical intervention for
  this entity

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Principle of Equipoise

• Genuine uncertainty as to whether the outcomes of
  the research will be beneficial
• If the answer to the research question is known,
  the research is not in equipoise
• Subjects may participate in a randomized
  controlled research study only when uncertainty
  surrounds which arm they should be in

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How is Equipoise applied to IRB Review of
Telemonitoring Study?

• There must be a genuine uncertainty as to whether
  the outcomes of telemonitoring are different than
  the outcomes of usual care
• There are no data demonstrating home
  telemonitoring is or is not equivalent to usual
  care

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Principle of JusticeThe Belmont Report

• Distribute the burdens and benefits of research
  equally
• Ensure subjects are selected for reasons directly
  related to the problem being studied
• Do not select subjects because they are
• Readily availability
• In a compromised position
• Easy to manipulate

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Principle of JusticeThe Belmont Report

• Advances resulting from research should provide
  advantages to everyone affected
• Research should not unduly involve persons from
  groups unlikely to benefit from the research

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How is the Principle of Justice Applied to IRB
Review?

• Select classes of subjects in an order of
  preference (e.g., adults before children)
• Be cognizant of biases
• Social
• Racial
• Sexual
• Cultural

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How is the Principle of Justice Applied to IRB
Review?

• Ensure that researchers exhibit fairness
• Should not offer research to only favored
  individuals or populations
• Should not select only "undesirable" persons for
  risky research
• Should not focus on vulnerable populations for
  convenience
• IRB must consider the individuals access to
  research participation and the impact on groups

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How is This Applied to IRB Review of Home
Telemonitoring Study?

• IRB should determine if the right group of
  subjects are selected for the study
• Are the inclusion criteria appropriate?
• Are others appropriately excluded?
• Is it appropriate to exclude homeless Veterans?
• Does the recruitment strategy select Veterans at
  risk for worsening medical status because they
  are easy to approach in clinics?

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Applying 111 Criteria to IRB Review
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How are Minimization of Risks and Risks and
Benefits Analysis Applied to IRB Review?

• IRB needs to understand the research
• Science can be evaluated by Scientific Review
  Committee
• IRB needs to evaluate ALL the risks
  (psychological, physical, legal, social,
  economic) of research and ensure that risks are
  minimized
• Apply the Belmont principle of beneficence
• 38 CFR 16.111(a)(1)-(2)

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How does Equitable Selection of Subjects Apply to
IRB Review?

• IRB must take inclusion and exclusion criteria
  into account, based on
• Purpose of the research
• Research setting
• Vulnerabilities
• If non-Veterans are to be recruited the must be
  justification
• Apply the Belmont principle of justice
• 38 CFR 16.111(a)(3)

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How does the IRB Evaluate the Informed Consent
Process?

• Ensure that legally effective informed consent is
  obtained from each prospective subject or the
  subjects LAR
• Ensure that Informed consent form 10-1086 meets
  all the requirements of VHA Handbook 1200.05
• Ensure that information exchanged before the
  study is appropriate (e.g., recruitment process
  and advertising)
• Ensure the process avoids overly optimistic
  language
• Provide genetic counseling, access to social
  worker, referrals, or other support, as
  appropriate
• 38 CFR 16.111(a)(4-5)
• 38 CFR 16.111(a)(4)-(5)

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How Does the IRB Apply Safety Monitoring to IRB
Review?

• Ensures the research plan must make adequate
  provisions for monitoring the data collected to
  ensure the safety of subjects, when applicable
• Research plan may include
• Establishing a Data Monitoring Committee (DMC)
• Plan for reporting DMC findings to the IRB and
  the sponsor
• IRB can witness the consent process
• 38 CFR 16.111(a)(6)

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How Does the IRB Ensure Privacy and
Confidentiality?

• The IRB must determine there are adequate
  provisions to protect privacy of subjects and
  maintain the confidentiality of data, taking into
  consideration
• HIPAA Privacy Rule
• Privacy Act of 1974
• VA Claims Confidentiality Statute
• Confidentiality of Drug Abuse, Alcoholism and
  Alcohol Abuse, Infection with Human
  Immunodeficiency Virus (HIV), and Sickle Cell
  Anemia Medical Records
• Confidentiality of Healthcare Quality Assurance
  Review Records
• VHA Handbook 1200.05, Paragraph 17(f)

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How Does the IRB Ensure Privacy and
Confidentiality?

• ISO ensures
• Implementation of applicable VHA and VA
  information security policies pertaining to
  research (VA Directive 6500 and its Handbooks)
• 38 CFR 16.111(a)(7)

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How Does the IRB Ensure Vulnerable Subjects are
Protected?

• Ensure all required determinations are made
• Ensure additional safeguards outlined in the
  protocol are appropriate
• Ensure adequate plans are in place if subjects
  are likely to
• Loose decision-making capacity
• Become pregnant
• Become incarcerated
• 38 CFR 16.111(b)

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Applying Additional Criteria of
VHA Handbook 1200.05 to IRB Review
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Conflict of Interest (COI)VHA Handbook 1200.05,
Paragraph 17(i)

• IRB ensures COI does not undermine credibility of
  the research
• IRB ensures all COI is Managed, reduced, or
  eliminated
• Financial
• Role (investigator-patient
• relationships)
• Professional
• Institutional
• Personal roles

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Conflict of Interest (COI)Considerations

• IRB ensures disclosure of COI within the 10-1086
  is done in an obvious and meaningful manner, when
  appropriate
• IRB considers whether the COI impacts
• Risks of the study
• Study design or Procedures
• Monitoring
• Reporting
• Data analysis
• Recruitment or enrollment

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Investigator QualificationsVHA Handbook 1200.05,
Paragraph 17(j)

• Ensure that investigators have the appropriate
  background and experience to conduct the research
• NOTE The IRB is not responsible for confirming
  that the investigator or other research team
  members have met current credentialing,
  privileging, and training requirements

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IRB Must Ensure Consistent DocumentationVHA
Handbook 1200.05, Paragraph 17(k)

• IRB ensures the following are consistent with the
  protocol and IRB application
• Informed consent document
• Waiver (or alteration) of informed consent
• Waiver of documentation of informed consent
• HIPAA authorization
• Waiver of HIPAA authorization

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Key Points

• The IRB makes specific findings to grant IRB
  approval in consideration with
• The principles of the Belmont Report
• The Common Rule
• VHA Handbook 1200.05 and other VA requirements

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QUESTIONS