Download The Belmont Report

Ethical Principles of Human
Subjects Protection
• The Belmont Report
• The Common Rule
University of Pennsylvania
School of Medicine
The Belmont Report
• Purpose of the report is to provide three principles
(prescriptive judgments) that will ‘assist researchers,
subjects, reviewers and interested citizens with an
understanding of the ethical issues inherent in HSR’
• Statement consists of 3 parts
– Distinction between research and medical practice
– Establishment of 3 ethical principles
– Remarks regarding application of the principles
University of Pennsylvania
School of Medicine
The Belmont Report
• Practice
– Interventions designed solely to enhance the
wellbeing of the patient and that have a reasonable
expectation of success
• Research
– An activity designed to test an hypothesis, permit
conclusions to be drawn, develop or contribute to
generalizable knowledge
The Belmont Report
Three Ethical Principles
• Principle of respect for persons autonomy
• Principle of beneficence
• Principle of justice
Respect for Persons Autonomy
• Enters research voluntarily and with adequate information
• Implies everyone is capable of self determination
– Matures during life span
– May be lost in whole or in part as a result of illness, mental disability or
circumstances that restrict liberty
– Cannot exclude those incapable of self determination
• Respect for such situations requires protection
– Explicit requirement that each class of incompetent patient be
considered on its own terms
– Third parties whose primary goal is to protect the subject from harm
should be used and that these individuals be allowed to observe the
research
The Belmont Report - Three Ethical Principles
• Principle of respect for persons
– Individual autonomy
– Protection of individuals with reduced autonomy
• Principle of beneficence
– Requires a risk benefit assessment be made
– Maximize benefits and minimize harms
• Principle of justice
– Equitable distribution of research costs and
benefits
Beneficence
• Acts of kindness or charity that go beyond strict
obligation
• Strict sense of obligation
–
–
–
–
–
Do not harm
Maximize possible benefits
Minimize possible harms
Seek benefit despite certain risks
Benefits should be forgone because of the risk
The Belmont Report - Three Ethical Principles
• Principle of respect for persons autonomy
• Principle of beneficence
– Requires a risk benefit assessment be made
• Principle of justice
– Fairness in selection of subjects
– Benefit is denied or burden is imposed
How to Apply the 3 Principles
• Autonomy - Informed consent
– Information
– Comprehension
– Voluntariness
• Beneficence – determination of the risk and benefits
– Peer review – risks are justified
– Investigator – study design
– Subject – the determination to participate
• Justice
– Selection of subjects described by the researcher
– Reviewed during the peer review process
– Determined to be equitable
Pillars of Protection for Human
Subjects Research
•
•
•
•
Consent
Peer Review
Research Integrity
Conflict of Interest
– Disclose COI to employer, IRB, and subject
• COI committee
• Thresholds
• Management plan
Pillars of Protection for Human
Subjects Research
• Consent
• Peer Review
• Research Integrity
– Duty to protect subjects
– Carry out studies per protocol
– Communicate with subjects
– Report findings honestly
• Conflict of Interest
The Common Rule
• Further review by the president’s commission 1980-1983
and other panels
• Mid 1980’s no standard government policy that coordinated
the diverse regulations of all federal agencies
• 1986 the “Common Rule” proposed and then codified in
1991
• Essentially identical to the 1981 DHHS policy
– CFR 46 Subpart A
• But by executive order extended that basic structure to the
regulations of all 15 federal agencies and the CIA
The Common Rule
• Comprehensive regulatory framework that formally governs
all HSR conducted by the federal government or in facilities
receiving federal funds
• Requires the establishment of a HSR Protection Program
– If meets the federal standard institutional assurance of
compliance is issued
– Any institution that receives federal funding must have a
Federalwide Assurance (FWA) Cert
• Mandates role of the IRB
• Defines requirements for informed consent
• Codifies special requirements for vulnerable populations
THE COMMON RULE
Additional Protections Included in 45 CFR 46
• Subpart B
– Additional Protections for Pregnant Women, Human
Fetuses and Neonates Involved in Research (revised
December 13, 2001)
• 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
Note: Each agency decides which Subpart, if any, to
adopt
Basic Elements of a Program for
Human Subject Protection in Research
• Institution
• IRB
• Subject
• Investigator
• Regulatory Sponsor
• Funding Source
• Federal Agencies (FDA/OHRP)
NOTE:
The Regulatory
Sponsor is
often the funding
source, but not
to be
assumed
Human Subject Protection…
Sponsor
IRB
Institution
Subjects
Investigator
Federal
Agencies
Funding
Institution Responsibility
– Protect the rights and welfare of research subjects
– Qualified IRBs appropriate to review research
– Human Protection Training
– HIPAA training
– Qualified administrative IRB support staff
– Operational space
– Budget to support the IRB operations
– Budget to support HSRP Program
Investigator Responsibility
– Protect the rights and welfare of research subjects
– Practice of ethics and professional standards
appropriate to type of research
– Maintenance of IRB approval
– Adhere to protocol
– Comply with ALL applicable regulations
– Comply with ALL institutional requirements
Subject Responsibility
– Ask questions to obtain clear understanding of what
is expected
– Comply with protocol requirements
– Report adverse events and unanticipated outcomes
to investigator
Responsibility of the Regulatory Sponsor
– Protect the rights and welfare of research subjects
– Comply with ALL applicable regulations
– Provide data safety monitoring according to
research risk level
– Appropriate safety reporting to IRB and associated
regulatory agencies
– Ensure appropriate investigator/staff qualifications
Responsibility of Funding Source
– Protect the rights and welfare of research subjects
– Appropriate funding
– Ethical considerations
– Assurance from institution to comply with
appropriate regulations
Responsibility of Federal Agencies
(FDA, OHRP, etc.)
– Protect the rights and welfare of research subjects
– Ethical considerations
– Research approval
– Assurance from institution to comply with
appropriate regulations
– Inspections of IRBs, Investigators and Sponsors
– Suspension or termination of research
Responsibility of the IRB
– Protect the rights and welfare of research subjects
– Oversight of the conduct of ALL human research
– Guidance and support to research staff through
IRB review and administrative IRB support staff
– Ensures compliance with all federal, state, local
and institutional requirements in human subject
research
3 Ethical Principles
• Autonomy - Informed consent
– Information
– Comprehension
– Voluntariness
• Beneficence – determination of the risk and benefits
– Peer review – risks are justified
– Investigator – study design
– Subject – the determination to participate
• Justice
– Selection of subjects described by the researcher
– Reviewed during the peer review process
– Determined to be equitable
IRB Decision Matrix
BENEFICENCE
Risk/Benefit Analysis
Experimental Design
Qualifications of PI
JUSTICE
Subject selection
Inclusion/exclusion
Recruitment
RESPECT FOR PERSONS
Informed consent
Surrogate consent
Assent
Privacy & Confidentiality
Protection of subjects
(especially vulnerable
populations)
What does the IRB do?
• Approves or Disapproves “human research”
• Requires modifications to approve “human research”
• Conducts continuing review and re-approval
• Observes/Monitors/Audits aspects of the research
• Suspends/terminates the research - initiated by
– Sponsor
– Investigator
– IRB
What are the IRB regulations?
• Title 45 of the Code of Federal Regulations, part 46 (45 CFR 46)
– Applies to all federally funded human research
– Includes federally funded research outside the US
• Title 21 of the Code of Federal Regulations, part 56 (21 CFR 56)
– Applies to all human research of FDA-regulated products
– Includes research outside the US conducted under an FDA filing
• IRB review is required of all human research
– Federally funded research
– Research involving FDA regulated products
– Research not federally funded or not involving FDA regulated products
Which Regulations Apply and When?
FDA: research involves products regulated by FDA
Common Rule: Federally supported or conducted or
conducted in an institution that agrees to review all
research under the Common Rule
Both: if Federally funded research involves FDA regulated product or FDA
regulated research conducted in an institution that agrees to review all
research under the Common Rule
FDA REGULATIONS - Title 21
Parts
11 – Electronic records; electronic signatures
50 – Protection of Human Subjects
54 – Financial Disclosure by Clinical Investigators
56 – Institutional Review Boards
312 – Investigational New Drug
314 – New Drug Application
600 – Biological Products: General
812 – Investigational Device Exemptions
814 – Pre-market Approval of Medical Devices
Your Responsibility as an Investigator
• 45 CFR Part 46
– DHHS Human Subjects
Regulations Social or
scientific value
• 21 CFR
– 50 Informed Consent
• Scientific validity
– 56 IRB Regulations
• Fair subject selection
– 54 Financial Disclosure
• Favorable risk benefit ratio
– 312 Investigational New Drug
• Independent review
• Informed consent
• Respect for autonomy
– 314 New Drug Application
– 600 Biological Products
– 812 Investigational Device
Exemptions