Human Research Protections: Historical, Ethical

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Human Research ProtectionsHistorical, Ethical
Regulatory Perspectives for Good Clinical
Practices

• Susan C. Buskirk, RN, BSN, CCRC
• Executive Director
• Human Research Protections Program

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Outline

• Definition of Good Clinical Practice
• Historical Background
• Ethical Milestones
• Basic Protections for Human Subjects
• Regulatory Oversight
• Institutional Requirements

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Good Clinical Practices (GCPs)

• International ethical and scientific quality
  standards for designing, conducting, recording,
  and reporting trials that involve the
  participation of human subjects.
• Purpose
• Protect human subjects during clinical studies
• Protect patients who might receive approved
  products in the future
• Not just one document
• Several different components which vary by
  country and research setting

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Good Clinical (Research) Practices

• Why GCPs are important
• -Insure that one can validate the human subject
  protections decided upon by the IRB and PI were
  carried out
• -Insure that data reported by research results
  can be validated
• This is an introduction and summary

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Human Subjects Research

• DEFINITION
• A human subject is a living individual about who
  an investigator obtains either
• data through interaction or intervention with the
  individual
• bodily materials (cells, blood, urine, organs,
  nail clippings, hair) even if the investigator
  did not collect these
• Private, identifiable information (Medical info)

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History

• 1948 Nuremburg Code
• Voluntary Informed Consent
• Favorable Risk/Benefit Analysis
• Right to withdraw without penalty

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History (2)

• 1964 Declaration of Helsinki
• Builds on Nuremburg Code
• Interests of subjects be given higher priority
  than those of society
• Every research subject should receive the best
  known treatment

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History (3)

• 1974 National Research Act
• Established modern IRB system
• National Commission for the Protection of Human
  Subjects of Biomedical and Behavioral Research
• Belmont Report

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Belmont Report

• Ethical Principle 1 Respect for Persons
• Treat individuals as autonomous agents
• Protect persons with reduced autonomy
• IRB Requirements
• Participants voluntary consent
• Privacy and confidentiality are protected

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Belmont Report (2)

• Ethical Principle 2 Beneficence
• Do unto others as you would have them do unto you
• IRB Requirements
• Risks of research are justified by potential
  benefits
• Study is designed to minimized risks
• Adequate data and safety monitoring
• Conflicts of Interest are managed adequately

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Belmont Report (3)

• Ethical Principle 3 Justice
• Distribute the risks and potential benefits of
  research equally among those who may benefit from
  the research.
• IRB Requirements
• Vulnerable subjects are not targeted for
  convenience
• Subject selection is equitable
• Population exclusion is justified

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Basic Protections for Human Subjects

• Ethics
• Regulations (ethics operationalized)
• Oversight (Culture of conscience)

• Science
• Design/Important question
• Conduct/Validity

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Three Levels of Protection

• Assurances/ Regulatory Oversight
• Institutional Review Board (IRB)
• Informed Consent

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Oversight Agencies

• Office of Human Research Protections
• 45 CFR 46
• Subparts A, B, C
• Food and Drug Administration
• 21 CFR 50, 56
• Office of Good Clinical Practice
• Office of Research Oversight (VA)
• DHHS Agencies (DOD)
• ICH Good Clinical Practices

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GCP Standards
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Institutional Assurances

• The Assurance formalizes the institutions
  commitment to protect human subjects. The
  requirement to file an Assurance includes both
  awardee and collaborating performance site
  institutions.

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University of Maryland Baltimore

• regardless of whether the research is subject
  to Federal regulation or with whom conducted or
  source of support (i.e., sponsorship).

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IRB/IEC

• Purpose
• To protect the rights and welfare of human
  subjects

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IRB REVIEW

• Appropriate Informed Consent
• Acceptable Risk/Benefit ratio
• Privacy and Confidentiality Protection
• Data and Safety Monitoring
• Scientific Validity
• Equitable Subject Selection

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Initial Protocol Review

• Risk/Benefit
• What are the risks?
• Is the potential knowledge important enough to
  justify the risks?
• Is subject selection equitable?

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Initial Protocol Review (2)

• Consent Process
• Are mechanisms for obtaining consent appropriate?
• All risks/benefits documented appropriately?
• Is a waiver of consent requested?
• If yes, is the waiver justified?

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Initial Protocol Review (3)

• Vulnerable Populations
• Prisoners
• Children
• Pregnant woman and Fetus
• Cognitively impaired
• Are the protections adequate? OR Why are they not?

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Initial Protocol Review (4)

• Privacy and Confidentiality
• HIPAA Is PHI involved?
• Plans to protect PHI
• Authorization to collect PHI?
• Who will have access to identifiers?
• Will the data be coded?
• Where will the data be stored?

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Review Levels

• EXEMPT
• IRB Determination
• EXPEDITED
• Not Fast
• Regulatory Definition
• FULL BOARD
• Anything greater than minimal risk

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IRB Authority

• Initial Continuing Review
• Approve
• Disapprove
• Require modifications
• Terminate

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IRB Reporting Requirements

• Unanticipated events involving risks to human
  subjects
• Serious and Ongoing non-compliance

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Continuing Review

• The guideline for continuing IRB review of
  previously approved protocols are as follows
• 1) Determine if the study is currently actively
  enrolling, treating, or following subject
• Summary of progress to date

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Continuing Review (2)

• 2) Accrual
• Equitable?
• Over enrollment?
• Unable to meet enrollment goals?

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Continuing Review (3)

• 3) Review any requested protocol revisions and
  any revisions that have been approved by the IRB
  since last continuing review.
• BRAAN Amendments
• How have these impacted the overall protocol?

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Continuing Review (4)

• 4) Determine if the study is progressing as
  planned.
• Will the study objectives be met?
• Under enrollment
• Unexpected toxicity profile
• Risk/Benefit ratio still favorable?

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Continuing Review (5)

• 5) Determine if unexpected events have occurred
  that may indicate a need for a change in the
  protocol or consent document.
• Review DSM reports
• SAE reports in BRAAN
• Subject Complaints
• Unexpected rate of withdrawals

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Continuing Review (6)

• 6) Determine if information has become available
  since the study that indicates a need to make
  modifications.
• Interim Analyses
• SAEs

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Amendments

• Federal Regulations require that all revisions be
  approved by the IRB prior to their implementation
• Revisions that increase the risk of research
  participation must be approved by the full IRB
  committee.

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Amendments (2)

• Guidelines for the review of protocol amendments
• Identify the part of the research proposal being
  revised.
• Determine if the revision increases risk for
  currently enrolled subjects.

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Amendments (3)

• 3) Determine if the revision increases risk for
  future subjects.
• 4) Determine if the consent form should be
  revised or if the proposed revision to the
  consent form is adequate.

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Amendments (4)

• 5) Determine if currently enrolled subjects
  should be re-consented.
• 6) If the revision increases risk to current or
  future subjects, determine if the protocol still
  meets the criteria that are used to evaluate new
  studies.

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Unanticipated Problems

• Include Serious Adverse Events
• Not necessarily adverse events
• Expedited reporting
• UMB policy
• Sponsor policy

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Deviations

• Deviation Any difference in study conduct from
  the criteria or procedures prescribed in the
  approved protocol may constitute a deviation.
  Deviations may result from the action of the
  participant, investigator, or staff.
• Expedited reporting vs. Continuing Review
• Affect risk and/or study integrity
• Do not affect risk and/or study integrity

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Exception Request

• An exception is an anticipated departure from
  approved protocol procedures
• Requested by the investigator and are usually
  specific to an individual subject.
• Exceptions are also approved by the sponsor.

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Study Monitoring Oversight

• Sponsor or Sponsor/PI is responsible for
  continued monitoring of the study
• Auditing by IRB/Sponsor
• Inspections by FDA and other oversight agencies

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Investigator Responsibilities

• Scientific validity
• Research design
• Ethical principles upheld
• Quality of study conduct (GCPs)
• Compliant with federal, state, institutional
  requirements

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Conclusion

• Know your responsibilities
• Educate others
• Be Accountable
• PI, Coordinator, Nurse, IRB, Institution
• Education and Training
• CITI University of Miami
• Utilize Resources

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Human Research Protections Office

• Emergency 410-963-1237 (Chair)
• Direct Access to Analyst/Staff
• Email
• HRPO_at_som.umaryland.edu
• Website (New July 1, 2005)
• http//medschool1.somweb.som.umaryland.edu/orags/h
  rpo/default.asp
• New Content, Navigation, Layout