1. Investigator Responsibilities in Human Subjects Research
Jeffrey M. Cohen, Ph.D. CIP
Chief Executive Officer
HRP Consulting Group
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2. Overview History Human Research Protection Program
Investigator Responsibilities
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History
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National Research Act
1973 Kennedy Hearings “Quality of Health Care - Human Experimentation”
1974 National Research Act
Established the “National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research”
Required IRBs at institutions receiving HEW support for human subjects research
1974 Federal Regulations
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Recent History
1974 – 1995
IRBs fulfill ethical responsibility
“Sniff Test”
1995
President’s Commission
GAO & HHS Investigation
1998
Jesse Gelsinger death
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Current Situation
IRBs not enough
Human Research Protections Program
Accreditation
Higher standards for IRB review
Criteria for Approval
Required Findings
Post-approval monitoring
Increased responsibility for investigators
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What is an HRPP?
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What is an HRPP?
An HRPP is a comprehensive and organized system to ensure the protection of human volunteers participating in research.  The objective of this system is to assist the institution in meeting ethical principles and regulatory requirements for the protection of human subjects in research. 
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Components of an HRPP
Institutional Officials
Investigators
IRB – Members/Chair
HRPP Administrator
Other Units
Departments/Chairs
Sponsored Programs
Pharmacy
Other Research Compliance Committees
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10. HRPP Responsibility
Human Research Protections is a Shared Responsibility
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11. Investigator Responsibilities
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12. FDA Guidance
Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects
October 2009
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13. Investigator Responsibilities
Protecting the rights, safety and welfare of human subjects
Complying with IRB requirements
Providing adequate supervision
Complying with provisions of FDA-1572 or clinical trials agreement
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14. Protecting Human Subjects
Design and implement ethical research, consistent with three ethical principles delineated in the Belmont report
Respect for Persons
Informed Consent
Beneficence
Risk/Benefit Analysis
Justice
Equitable Subject Selection
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15. Protecting Human Subjects
Comply with all applicable federal regulations impacting the protection of human subjects
45 CFR 46 - Basic DHHS Policy for Protection of Human Research Subjects
Federal Policy for the Protection of Human Subjects - “The Common Rule” June 18, 1991
21 CFR 50 & 56 Food and Drug Administration regulations
21 CFR 312 & 812 FDA Investigational Drug and Device Regulations
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16. HHS vs. FDA Regulations
Basic requirements for IRBs and for Informed Consent are congruent
Differences center on differences in applicability
HHS regulations based on federal funding of research
FDA regulations based on use of FDA regulated product: drugs, devices, or biologics
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17. Protecting Human Subjects
Obtain informed consent and assent in accord with federal regulations and as approved by the IRB
Ensure that each potential subject understands the nature of the research and of the subject's participation and takes appropriate steps to gain that comprehension.
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18. Beyond the Consent Form
Informed Consent
Beyond the Consent Form
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19. The Consent Process
Informed consent is not a single event or just a form to be signed -- rather, it is an educational process that takes place between the investigator and the prospective subject.
The basic components of the consent process include:
full disclosure of the nature of the research and the subject's participation,
adequate comprehension on the part of the potential subjects, and
the subject's voluntary choice to participate.
Adequate Informed Consent. Only the subjects can evaluate the degree of risk in a given situation. The IRB must ensure that subjects are given sufficient information regarding the study to determine for themselves what the risks are and whether they want to assume those risks.
Must be understandable to subjects: Risks described in terms that the subjects can understand. Comparisons to everyday risks.
Avoid Bias and Creation of Negative Mindsets: Consent process should not increase the likelihood of harm.
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20. Procedures for Obtaining Consent
Subject has the legal and mental capacity to give consent
legally authorized representative;
Sufficient opportunity is provided to consider
The possibility of coercion or undue influence is minimized
Language understandable to the subject
No “exculpatory” language
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21. Protecting Human Subjects
Document informed consent and assent in accord with federal regulations and as approved by the IRB
Provide a copy of the IRB-approved informed consent document to each subject at the time of consent, unless the IRB has specifically waived this requirement.
Retain all signed consent documents according to institutional policies, but at least three years beyond the completion of the research.
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22. Documentation of Consent
It is recommended that consent forms meet four criteria:
Be brief, but have complete basic information.
Be readable and understandable to most people.
Be in a format that helps people comprehend and remember the information.
Serve as a script for the face-to-face discussions with the potential subjects.
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23. Documentation of Consent
Format can help comprehend and remember complex material. Good format uses: headings; indents; bolded type; lists; extra spacing between sub-topics; repetition; reasonable-size type; and plenty of margins and empty space in general.
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24. Documentation of Consent
Format can help comprehend and remember complex material. Good format uses:
headings;
indents;
bolded type;
lists;
extra spacing between sub-topics;
repetition;
reasonable-size type; and
plenty of margins and empty space in general.
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25. Protecting Human Subjects
Report adverse events to sponsor
Report unanticipated problems involving risk to subjects or others to the IRB
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26. Adverse Events are not an IRB issue!!!
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27. IRBs only review “Unanticipated Problems”
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28. New Guidance
FDA: “Guidance for Clinical Investigators, Sponsors, and IRBs - Adverse Event Reporting to IRBs - Improving Human Subject Protection” January 2009
OHRP: “Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events” January 2007
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29. Adverse Events “Adverse Events” only appears in the FDA Regulations
Investigational New Drugs 21 CFR 312
Investigational Devices 21 CFR 812
Describe what Investigators report to Sponsors and what Sponsors report to FDA (and IRBs for devices)
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30. IRB Regulations HHS Regulations: 45 CFR 46 FDA Regulations: 21 CFR 56
IRBs must have and follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of …any unanticipated problems involving risks to subjects or others (b)(5)/56.108(b)(1)
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31. Unanticipated Problems
Not all Adverse Events are unanticipated
Not all Adverse Events are related to the research
Not all Unanticipated Problems are Adverse Events
Determined by risk of harm, not actual harm
Not all Unanticipated Problems involve the subjects – “…risk to subjects or others.”
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32. IRB Review
Ensure that all research involving human subjects is submitted to and approved by the appropriate institutional review board
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33. IRB Review
Institutional Review Board (IRB): A institution-wide committee charged with the review of human participants research to assure that the rights and welfare of human participants are adequately protected.
Why do we need IRB review?
No one can be objective about their own work
People underestimate the risks involved in things they are very familiar with
People overestimate the benefit of things that are important to them
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34. Criteria for IRB Approval
45 CFR 46/21 CFR 56 §111(a) “In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied”
These are the IRB’s “Marching Orders”
The IRB cannot approve research until it is satisfied that all of these criteria are met.
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35. Criteria for IRB Approval
When appropriate:
data collection is monitored to ensure subject safety
privacy and confidentiality of subjects is protected
additional safeguards are included for vulnerable populations
Risks to subjects are minimized
Risks are reasonable in relation to anticipated benefits
Selection of subjects is equitable
Informed consent is appropriately sought from each subject
Informed consent is appropriately documented
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36. Criteria for IRB Approval
46.111
BENEFICENCE
JUSTICE
RESPECT FOR PERSONS
Subject selection
Inclusion/exclusion
Recruitment
Risk/Benefit Analysis Data Safety
Experimental Design
Qualifications of PI
Privacy & Confidentiality Vulnerable Populations
Informed consent
Surrogate consent
Assent
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37. Investigator Responsibilities
Conduct all research according to the IRB approved protocol and reports any deviations from the protocol to the IRB
Comply with all IRB determinations.
Do not initiate any changes in the research without IRB review and approval, except where necessary to eliminate apparent immediate hazards to the subjects.
Report progress of approved research to the IRB, as often as and in the manner prescribed by the IRB on the basis of risks to subjects, but not less than once per year.
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38. Investigator Responsibilities
Have sufficient resources to conduct the research in a manner that protects human subjects
a potential for recruiting the required number of suitable subjects within the agreed recruitment period.
sufficient time to properly conduct and complete the trial within the agreed trial period.
an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.
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39. Supervision
When tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated.
The investigator is accountable for regulatory violations resulting from failure to adequately supervise the conduct of the clinical study.
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40. Supervision
PI must insure that individuals are qualified to perform tasks
PIs must ensure that staff
Know the protocol
Understand regulatory requirements
Understand ethical and IRB requirements
Are competent to perform tasks
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41. Supervision
PI is responsible for qualifications, training and competency of staff at all performance sites
PI must have sufficient time to oversee the conduct of research at all sites and/or have adequate oversight procedures in place
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42. Supervision of Student Research
Faculty advisor/instructor is responsible for providing adequate supervision of student research
Faculty advisor/instructor is responsible for qualifications, training and competency of students conducting research
Faculty advisor/instructor is accountable for regulatory violations resulting from failure to adequately supervise the conduct
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43. FDA 1572
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44. FDA 1572
Form FDA 1572 (1572) is an agreement signed by the investigator to provide certain information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation
The investigator’s signature on this form constitutes the investigator’s affirmation that he or she is qualified to conduct the clinical investigation and constitutes the investigator’s written commitment to abide by FDA regulations in the conduct of the clinical investigation.
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45. Commitments PI personally conducts or supervises investigation
Obtain informed consent and inform subjects about investigational nature of drugs
Report adverse events to sponsor
Report unanticipated problems to IRB
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46. Commitments Ensure that colleagues and staff understand obligation
Keep adequate records
Obtain IRB approval
Comply with all regulatory requirements
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49. Conclusion
Investigators must understand their responsibilities in conducting clinical research
Investigators must comply with regulations, IRB determinations, FDA commitments
Noncompliance can have serious consequenses
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