Ethical Principles of Human Subjects Protection The Belmont Report The Common Rule University of Pennsylvania School of Medicine.

Ethical Principles of Human Subjects Protection

• The Belmont Report

• The Common Rule

University of PennsylvaniaUniversity of Pennsylvania

School of MedicineSchool 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 PennsylvaniaUniversity of Pennsylvania

School of MedicineSchool 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 RULEAdditional 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…

Funding

Sponsor

Subjects

Institution

Investigator

FederalAgencies

IRB

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 JUSTICE

RESPECT FOR PERSONS

Privacy & ConfidentialityProtection of subjects

(especially vulnerable populations)

Informed consentSurrogate consent

Assent

Risk/Benefit AnalysisExperimental DesignQualifications of PI

Subject selectionInclusion/exclusion

Recruitment

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 21Parts

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

• Scientific validity

• Fair subject selection

• Favorable risk benefit ratio

• Independent review

• Informed consent

• Respect for autonomy

• 21 CFR

– 50 Informed Consent

– 56 IRB Regulations

– 54 Financial Disclosure

– 312 Investigational New Drug

– 314 New Drug Application

– 600 Biological Products

– 812 Investigational Device Exemptions