IRB Member Orientation

1. IRB Member Orientation Human Studies Program University of Hawai`i November 2010

2. Purpose of this Tutorial This tutorial has been developed to: • Provide members of a UH Institutional Review Board (IRB) with an orientation to the UH Human Studies Program and their role as IRB members, • Summarize applicable federal regulations and the principles on which they are based, • Describe the purpose, role, and authority of the UH IRBs, • Describe central elements and considerations in the IRB review and decision making process, and • Direct UH IRB members to available resources.

3. Purpose of the Human Studies Program The purpose of the Human Studies Program is to assure that: • Only ethically sound human subjects research is performed at UH, • The safety, welfare, and rights of research participants are protected throughout every study, • UH research is performed in compliance with applicable federal regulations and institutional policies, • UH maintains IRBs that operate according to federal regulations, and that these IRBs receive necessary institutional support, and • Investigators, IRB members and others are educated on applicable regulations and policies.

4. Why be a UH IRB Member • If you volunteer as a member of a UH IRB, you can expect to: • Expand your understanding of how research is designed and conducted; • Learn about specific research projects being conducted at UH; • Learn and apply ethical principles and government regulations to UH research; • Participate in lively and interesting discussions with other committee members at monthly IRB meetings; and • Achieve the satisfaction of knowing that you are playing an important role in supporting research at UH.

5. Role of the IRB The IRB: • Determines whether proposed research can be conducted at UH or by UH researchers and under what conditions; • Requires changes in the protocol, consent form or other documents in response to new risks identified during the study; • Monitors approved research until it is complete, paying special attention to minimizing risk and assuring participant safety, welfare, and rights throughout the study; • Makes decisions based on ethical considerations and local standards; and • Makes study-related decisions free from undue influence or coercion from investigators, sponsors, and UH.

6. Ethical Foundations The basic ethical principles that must guide the protection of research participants are described in The Belmont Report. They are: Respect for Persons: Requiresrecognition of the personal dignity and autonomy of individuals and the need for special protections for people with diminished autonomy (e.g., vulnerable populations) Beneficence: Requires that all appropriate steps be taken to protect potential research volunteers by minimizing possible risks of harm and maximizing potential benefits Justice: Requires that the benefits and burdens of research be distributed fairly among potential research participants All IRB members must read and understand The Belmont Report.

7. What is Human Subjects Research? • Federal regulations define research as a “systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” • Human subjects are defined as living individuals about whom an investigator obtains data through intervention or interaction with them or by using their identifiable private information. This extends to biological materials that are identifiable as well as graphic, written or recorded information that can be linked to identifiable individuals. • Some types of inquiry are neither designed nor intended to contribute to generalizable knowledge, and are therefore not subject to human subjects research regulations or IRB review. • Only studies that fall within these definitions of human subjects research require review and oversight by the UH Human Studies Program.

8. Federal Human Subjects Regulations The U.S. government has issued regulations that govern the protection of “human subjects” who volunteer to participate in research studies (human subjects are usually referred to in this tutorial as “participants”). These regulations establish rules that govern IRB composition, IRB function and operations, recordkeeping, and informed consent. They provide specific requirements on how IRBs must review research. Regulations also establish special protections that must be provided for vulnerable populations, including prisoners, pregnant women, fetuses, and children. Following is a summary of the federal regulations.

9. Federal Regulations: DHHS Department of Health and Human Services (DHHS) regulations (45 CFR 46) apply to research involving human subjects that is funded by a federal agency. Many universities apply these regulations to all research performed by the institution. The main component of these regulations (Subpart A) is referred to as the Common Rule. Subparts B, C and D are specific to the protection of pregnant women, fetuses, prisoners, and children. The federal Office for Human Research Protections (OHRP) is responsible for implementation and enforcement of these regulations. UH Human Studies Program is required to comply with these regulations, and a copy can be found on the IRB website.

10. Federalwide Regulations: FDA • U.S. Food and Drug Administration (FDA) regulations (21 CFR 50 & 56) are similar to the Common Rule in most respects and apply whenever an investigational agent (drug, device,or biologic) is being evaluated for safety and efficacy or when an FDA-approved agent is being evaluated for a new indication. • FDA regulations incorporate international quality standards for clinical trials known as the Guideline for Good Clinical Practice (GCP). • The Biomedical and Cooperative IRBs review research to which FDA regulations may apply. • These regulations can be found on the IRB website.

11. Other Research Regulations Beyond the Scope of the Human Studies Program • There are many other federal regulations that apply to research. Some of the topics addressed by these regulations include: • Scientific Misconduct (falsification, fabrication or plagiarism) • Care and Use of Animals in Research • Environmental Health and Safety (use of RDNA, etc.) • Administration of federal funds • Transporting hazardous materials • Privacy and Security (HIPAA) • Objectivity in Research… and others Implementation of these regulations is generally outside the scope of the UH Human Studies Program

12. Research Participant Protection at UH • As required of all research institutions, UH has entered into a Federalwide Assurance (FWA) with OHRP, which provides assurance to the federal government that all human subjects research performed by UH investigators (faculty and students) or using UH facilities will be conducted in compliance with the Common Rule. • The UH FWA stipulates that “human subjects research is not permitted until an appropriate IRB has reviewed and prospectively approved the research.” • The UH Human Studies Program is largely responsible for implementing the terms of the UH FWA in collaboration with the IRB Chairs, IRB members, and investigators.

13. Policies and Procedures • The Human Studies Program is required to develop and comply with policies and procedures that reflect applicable federal and state regulations and institutional (UH) policies. • Federal regulations and the UH FWA require that policies and procedures be developed to address specific topics. • The Human Studies Program has developed policies, procedures, forms and instructions to facilitate consistent application of federal regulations and institutional rules. • Human Studies Program policies and procedures are posted on the IRB website at http://www.hawaii.edu/irb

14. Authority of the IRB • The IRB has the authority to: • Approve or disapprove proposed research • Require modifications in proposed research as a condition of approval • Require modifications to ongoing research and/or to research documents based on considerations of participant protection • Suspend or terminate ongoing research as necessary to protect current or potential participants • Requirethat specific information be provided to participants to fully inform them of study procedures, risks, and benefits that may affect their willingness to participate in the research • Require, waive, or alter informed consent (or documentation thereof) consistent with federal regulation • Monitor any part of the research process

15. UH IRBs • The Human Studies Program administers three IRBs: • The Social and Behavioral Sciences IRB reviews and monitors research in the social and behavioral sciences performed by UH faculty and students. • The Biomedical IRB reviews and monitors clinical trials and other biomedical and epidemiologic research performed primarily by faculty at the John A. Burns School of Medicine and the Cancer Research Center of Hawaii. • The Cooperative IRB reviews multi-institutional, federally-funded research performed by UH, Queen’s Medical Center, Castle Medical Center, and/or Hawaii Pacific Health hospitals. These institutions are represented by members of the Cooperative IRB.

16. Role of the IRB Chair The primary responsibility of the IRB Chair is to: • Direct the proceedings of IRB meetings, assuring that there is adequate opportunity for open discussion among members; • Be knowledgeable of applicable regulations and policies, and partner with the CHS Director to ensure compliance with them; • Assure that voting and other IRB protocols are followed; • Review and respond to investigator responses to stipulations imposed by the committee; • Perform expedited reviews of qualified research, and designate other experienced CHS members to perform expedited reviews; and • Assist in recruiting and training new CHS members.

17. Role of the IRB Member • Members of a UH IRB have responsibility to: • Participate in education & training activities as required by UH; • Attend and participate in most IRB meetings ; • Vote on proposed research according to their conscience, free from coercion or undue influence from investigators, sponsors, UH, or other members of the IRB; • Apply the ethical principles articulated in The Belmont Report; • Understand and comply with applicable federal, state and UH requirements and make the protection of research participants the focus of all decisions and votes; • Participate in the expedited review process, as appropriate; (continued on next page)

18. Role of the IRB Member (continued) • Review materials received prior to the IRB meeting with sufficient attention to be able to vote on the research under consideration by the IRB; • Complete a comprehensive review, prior to the IRB meeting, of all relevant aspects of the study(ies) to which they have been assigned as primary reviewer; • Identify personal conflicts of interest in connection with studies under review, and refrain from voting on these studies in the event of any such conflict; • Communicate their needs for additional information to the Human Studies Program Director; and • Communicate about planned absences to the IRB staff.

19. Role of the Human Studies Program Staff • There are currently six members of the Human Studies Program staff. Their duties include to: • Review and approve applications for exempt status; • Screen non-exempt research applications to determine if they meet the criteria for expedited review; • Prepare meeting agendas and meeting minutes; • Prepare meeting packets (with protocols for review at upcoming meetings) for IRB members; • Prepare correspondence communicating IRB decisions and requirements to investigators; (cont. on next slide)

20. Role of the Human Studies Program Staff (continued) • Maintain the Human Studies Program database and files; • Respond to questions from investigators (faculty and students); • Respond to questions and complaints from research participants; • Communicate problems and complaints to the IRB Chairs, and work with the Chairs to address them; • Support the IRB Chairs and members at IRB meetings; • Maintain communication with the UH FWA Official (the VP for Research) and other institutional leaders; and • Communicate changes and problems to OHRP.

21. Types of Research Review • There are several types of research reviews, and the mechanisms for conducting these reviews vary across institutions. Included are: • Scientific Review: Determines if the design, methodology, and procedures of proposed research will produce valid results • Ethical Review: Determines whether proposed research meets ethical standards • Other Reviews: May be required by regulation for particular studies or by the sponsor, department or institution The primary role of the IRB is to conduct ethical review of research. However, research that is not scientifically valid cannot be ethically justified.

22. Exempt and Expedited Review • Federal regulations allow some human subjects research to be exempt from IRB review. Exempt determinations are made by the Human Studies Program staff, and exempt research is not presented to the IRB for review. • Federal regulations allow some research to be approved by the IRB under an expeditedreview procedure. This research must meet minimal risk and other criteria established by DHHS and the FDA. • Expedited review rules allow the IRB Chair, or another qualified member(s) of the IRB designated by the Chair, to approve research outside a convened IRB meeting. Research may not be disapproved by expedited review. • If a study (or minor study modification) is approved or re-approved by expedited review, all members of the IRB must be notified. At UH, a report is appended to the meeting minutes.

23. The IRB Meeting • Each IRB meets once a month, on a published schedule. • A written agenda is prepared for each IRB meeting. A list of protocols approved since the last meeting by expedited review is appended. • The agenda, minutes from the prior meeting, and all protocols to be reviewed at the upcoming IRB meeting are available to IRB members for review approximately one week prior to the meeting. • A primary reviewer is assigned for each protocol-related item requiring review by the IRB, including new submissions, progress reports, modification requests, protocol violation reports, and adverse event reports.

24. Preparing for the IRB Meeting • To prepare for IRB meetings, members should: • Review the meeting agenda; • Review the minutes from the prior meeting; • Perform a comprehensive review of protocol-related items assigned to the member as primary reviewer; • It is acceptable and often helpful to contact the PI prior to the meeting to get answers to your questions about the protocol • Be prepared to present a summary of the protocol and issues / concerns to the other committee members; and • Be prepared to make a recommendation to the committee on the action to be taken.

25. Role of Primary Reviewer • For each protocol being reviewed at an IRB meeting, a primary reviewer is assigned from among the members. • The primary reviewer: • Is expected to conduct a comprehensive review of the application, protocol/project description, and all documents submitted for review by the committee. • May be asked to complete a “Primary Reviewer Worksheet” on their assigned applications. • Should come to the meeting prepared to present the protocol to the committee. • Should be prepared to recommend an action on the proposed study or study changes to the committee.

26. Primary Reviewer Recommendations The Primary Reviewer will recommend one of four possible actions for IRB discussion and vote: 1. Approve the application as submitted; 2. Approve the application with stipulations (specific changes); 3. Defer action on the application, pending receipt and review by the committee of additional information to be supplied by the researcher; or 4. Disapprove the research. The primary reviewer should present his/her recommendations succinctly and concretely to the IRB. If the recommendations are substantive or detailed, it is helpful if the primary reviewer types them up for distribution at the meeting. These recommendations will form the basis of the IRB discussion; however, the ultimate decision of the IRB may or may not align with the recommendations of the primary reviewer.

27. Confidentiality • All aspects of IRB review, including deliberations at meetings about specific protocols, must be kept confidential. • It is not appropriate to discuss IRB business with individuals who are not members of the IRB. • UH does not publish the names of its IRB members, and it does not release the names of primary or expedited reviewers of specific protocols to investigators.

28. Initial Review of Proposed Research • In reviewing a proposed study, the IRB must determine whether: • Risks to participants are minimized • Risks to participants are reasonable in relation to anticipated benefits • The selection of participants is equitable • Provisions are in place to assure informed consent is obtained and documented as appropriate to the study and required by regulation • The research plan makes adequate provisions to monitor and assure the safety, welfare, and rights of participants • Provisions are in place to protect the privacy of participants and the confidentiality of their health information • Special protections are provided for vulnerable populations, as needed to protect their safety, welfare, and rights • Investigators are qualified to conduct the research • Potential conflicts of interest are avoided

29. Initial Review Decisionmaking • The IRB has several decisionmaking options following review of a proposed research project. These include: • Approve the research (all determinations on page 18 must be met) • Disapprove the research (if this action is taken by the IRB, the research cannot be conducted by UH researchers regardless of other approvals) • Approve the research with stipulations, requiring specific modifications • Defer action on the research, pending receipt and review of additional information, consultation with experts, etc. • To approve research with stipulations, the stipulations should require only “simple concurrence” by the investigator to accept them. If substantive changes are required (e.g., to the study plan, consent form, etc.) or the IRB has substantive questions about the protocol, the IRB should defer action on the research until the investigator’s response is reviewed.

30. Protocol Risk Assessment A primary responsibility of the IRB is to assess the degree of risk of a proposed study to potential participants. • Minimal Risk: The probability and magnitude of physical, psychological, social, legal, or economic harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Most minimal risk studies can be approved under an expedited review procedure. • Greater than Minimal Risk: For studies that do not qualify as minimal risk, careful consideration must be paid to the information provided to participants about the study and its risks. The IRB should consider requiring additional safeguards for participants and/or increased data and safety monitoring.

31. Vulnerable Populations • Federal regulations and ethical principles require the IRB to consider and require, as appropriate, special protections for research participants who may be vulnerable to coercion or undue influence. • Federal regulations mandate special requirements for the IRB when reviewing studies that will involve children; pregnant women, fetuses or neonates; or prisoners. However, other populations may require special protections as well. • Other vulnerable populations may include people who are institutionalized or have communication or decisional impairments (e.g., cognitive deficits), grave illness, mental illness, lack of education, etc. • When vulnerable populations will be represented among study participants, the IRB is required to follow federal regulations, UH policies, community standards, and the ethical principles documented in The Belmont Report.

32. FDA-Regulated Research • The FDA regulates research that involves the evaluation ofinvestigational agents (drugs, devices and biologics) or the evaluation of approved agents for unapproved indications. • FDA-regulated research is not minimal risk and cannot be approved under an expedited review procedure. • A minor modification to a FDA-regulated study may qualify for expedited review. • The “additional” consent form elements, explained later in this tutorial, should be considered for all FDA-regulated research. • Safety monitoring is particularly important for FDA-regulated research. Prompt review of unanticipated serious adverse events is required.

33. Informed Consent • Informed consent is the process by which potential participants learn about the risks, benefits, procedures, and alternatives to research and decide whether or not to participate. • Informed consent is fundamental to the system of protecting research participants. • Informed consent is a process that begins when participants first learn about a study (a flyer, a phone call, etc.) and continues until the study is complete. • Informed consent usually involves use of a consent form that must be signed by research participants before they can be involved in any study-related activities. • The IRB must review the entire informed consent process, including the recruitment strategy and documents, not just the consent form.

34. Informed Consent (continued) • Federal regulations allow the IRB to waive informed consent or to waive documentation of informed consent (a signature on a consent form) if the study meets certain criteria defined by DHHS. Regulations also allow the IRB to alter the usual informed consent procedures or documents if specific conditions are met. • Unless waiver or alteration criteria are met, the IRB must approve a consent form that contains all required elements and, as appropriate, additional elements as described on the next two slides. • As required by our hospital affiliates and some sponsors, the IRB may approve consent forms with privacy language required by the Health Insurance Portability and Accountability Act (HIPPA) Privacy Rule.

35. The Consent Form • Unless an alteration is approved by the IRB, all consent forms must include the following elements: • A statement that the study involves research • An explanation of the purposes of the research • The expected duration of the participants’ participation • A description of the procedures to be followed • Identification of any procedures that are experimental • A description of any potential risks or discomforts to participants • A description of any possible benefits to participants or others • A disclosure of appropriate alternative procedures or treatments • A statement addressing confidentiality of research records • A description of any compensation to be provided and the availability of medical coverage for research-related injuries (continued on next slide)

36. The Consent Form (continued) • Whom to contact for answers to questions about the research and participants’ rights, and whom to contact if there is an injury • A statement that participation is voluntary and that refusal to participate will involve no penalty or loss of benefits • A statement that participation may be discontinued at any time without penalty or loss of benefits Additional elements (when appropriate for the study): • A statement that there may be risks that are unforeseeable • Circumstances under which participation may be terminated by KP • Additional costs to participants • Consequences of participants’ decision to withdraw from the study • A statement that new findings will be provided to participants • The approximate number of participants to be enrolled in the study

37. Privacy and Confidentiality • The IRB must assure that proposed research is designed to assure privacy and confidentiality for research participants. • Privacy: Having control over the extent, timing, and circumstances of sharing oneself physically, behaviorally or intellectually with others • Confidentiality: Pertaining to the treatment of information that an individual has disclosed in a relationship of trust and with the expectation that it will not be divulged to others in ways that are inconsistent with the understanding of the original disclosure without permission

38. Privacy & Confidentiality (continued) • The IRB should consider: • What confidential information is being accessed, recorded, and/or shared in the proposed research • Whether access to confidential information is necessary to answer the research question • How participants are identified • Who has access to identifiable information • Who invites participants to enroll in a study • The sensitivity of the information to be accessed in a study • Whether confidentiality agreements signed by non-UH researchers should be required • Whether a Certificate of Confidentiality (from the NIH) should be required • What other special protections should be in place to assure privacy and confidentiality for research participants

39. Conflicts of Interest • A conflict of interest exists when an investigator (or IRB member) stands to benefit financially from the outcome of a study or when a researcher’s or relationship with or investment in a company creates a divided loyalty between UH and the sponsor. • Even the appearance of a conflict of interest must be avoided. • A significant financial interest exists when an investigator (or a member of his or her immediate family) holds or receives: • Equity interests >$10,000 or 5% ownership interest in a company that may benefit financially from the outcomes of the research, or • Aggregate payments (to the investigator and/or family members) from the sponsor >$10,000 in a calendar year (payments could include salary, royalties, consulting fees, honoraria, etc.)

40. Conflicts of Interest (continued) • IRB members must: • Not deliberate or vote on studies in which they have a conflicting interest • If IRB members have a direct role in the performance of the project, they should leave room during IRB deliberation and vote on the conflicting study; they may be present prior to the deliberation and vote to provide information and answer questions posed by IRB members • Consider whether researchers (UH or external) involved in the studies under review have a conflict of interest • Take all steps necessary to eliminate, minimize or disclose to participants, potential conflicts of interest • Sign an IRB Member Conflict of Interest form.

41. Safety Monitoring • A primary mechanism that the IRB uses to monitor participant safety is the review of unanticipated problems (UPs) experienced by research participants. • UH has written policies, consistent with federal regulations, requiring researchers to report certain UPs to the IRB. • When a UP report is submitted to the IRB, the IRB may take the following (or other) actions: • Revise the protocol / study procedures to minimize risks, • Approve a revised consent form or letter to participants, describing new risks, • Require investigators to re-consent currently-enrolled participants, providing them with information on the newly-identified risks, • Require more careful monitoring and /or additional reporting, or • Suspend or terminate a study to protect participant safety.

42. Continuing Review • The IRB is required by federal regulation to review all research operating under its approval at least annually. • The IRB should require progress reports at an interval appropriate to the degree of risk to participants in each study. This process of continuing review is the primary monitoring mechanism of research approved by the IRB. • In continuing review, the IRB is required to: • Conduct reviews that are substantive and meaningful • Review the entire study and interim findings – not just the progress report • Focus on whether risks to participants have changed and IRB conditions have been met • Reassess the risk/benefit ratio of the research • Only re-approve the study if the IRB has determined that risks continue to be minimized and reasonable

43. Resources • Many UH resources are available to IRB members on the IRB web site at: http://www.hawaii.edu/irb • CHS members are encouraged to review the following on-line training resources: • http://ohsr.od.nih.gov/IRBCBT/intro.php • http://ohrp-ed.od.nih.gov/CBTs/Assurance/default.asp • http://www.hhs.gov/ohrp/irb/irb_guidebook.htm • http://phrp.nihtraining.com/users/login.php • IRB members are encouraged to request information and/or resources on topics of interest to them that are relevant to their role. Questions may be directed to the UH Human Studies Program 808.956.5007

44. Mahalo! Thank you for agreeing to participate as a member of a UH IRB. Please let us know how we can help to make your experience stimulating and rewarding.