Investigator Responsibilities in Human Subjects Research Jeffrey M. Cohen, Ph.D. CIP Chief Executive Officer HRP Consulting Group © HRP Consulting Group

Overview History Human Research Protection Program Investigator Responsibilities © HRP Consulting Group

© HRP Consulting Group, Inc. History © HRP Consulting Group, Inc.

© HRP Consulting Group, Inc. 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 © HRP Consulting Group, Inc.

© HRP Consulting Group, Inc. Recent History 1974 – 1995 IRBs fulfill ethical responsibility “Sniff Test” 1995 President’s Commission GAO & HHS Investigation 1998 Jesse Gelsinger death © HRP Consulting Group, Inc.

© HRP Consulting Group, Inc. 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 © HRP Consulting Group, Inc.

© HRP Consulting Group, Inc. What is an HRPP? © HRP Consulting Group, Inc.

© HRP Consulting Group, Inc. 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.  © HRP Consulting Group, Inc.

© HRP Consulting Group, Inc. Components of an HRPP Institutional Officials Investigators IRB – Members/Chair HRPP Administrator Other Units Departments/Chairs Sponsored Programs Pharmacy Other Research Compliance Committees © HRP Consulting Group, Inc.

HRPP Responsibility Human Research Protections is a Shared Responsibility © HRP Consulting Group, Inc.

Investigator Responsibilities © HRP Consulting Group

FDA Guidance Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects October 2009 © HRP Consulting Group

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 © HRP Consulting Group

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 © HRP Consulting Group

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 © HRP Consulting Group

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 © HRP Consulting Group

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. © HRP Consulting Group

Beyond the Consent Form Informed Consent Beyond the Consent Form © HRP Consulting Group

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. © HRP Consulting Group

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 © HRP Consulting Group

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. © HRP Consulting Group

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. © HRP Consulting Group

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. © HRP Consulting Group

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. © HRP Consulting Group

Protecting Human Subjects Report adverse events to sponsor Report unanticipated problems involving risk to subjects or others to the IRB © HRP Consulting Group

Adverse Events are not an IRB issue!!! © HRP Consulting Group

IRBs only review “Unanticipated Problems” © HRP Consulting Group

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 © HRP Consulting Group

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) © HRP Consulting Group

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. 45.103(b)(5)/56.108(b)(1) © HRP Consulting Group

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.” © HRP Consulting Group

IRB Review Ensure that all research involving human subjects is submitted to and approved by the appropriate institutional review board © HRP Consulting Group

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 © HRP Consulting Group

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. © HRP Consulting Group

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 © HRP Consulting Group

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 © HRP Consulting Group

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. © HRP Consulting Group

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. © HRP Consulting Group

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. © HRP Consulting Group

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 © HRP Consulting Group

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 © HRP Consulting Group

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 © HRP Consulting Group

FDA 1572 © HRP Consulting Group

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. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM214282.pdf © HRP Consulting Group

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 © HRP Consulting Group

Commitments Ensure that colleagues and staff understand obligation Keep adequate records Obtain IRB approval Comply with all regulatory requirements © HRP Consulting Group

Conclusion Investigators must understand their responsibilities in conducting clinical research Investigators must comply with regulations, IRB determinations, FDA commitments Noncompliance can have serious consequenses © HRP Consulting Group