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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