What is an IRB (Institutional Review Board)?

What is an IRB (Institutional Review Board)?

The Belmont Report The Belmont Report on the Ethical Principles and Guidelines for the Protection of Human Subjects of Research was prepared by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1979.

The Belmont Report Three ethical principles are outlined in the Belmont Report: Respect for Persons = voluntary informed consent Acknowledges the subject s s autonomy Those with diminished capacity are entitled to extra protections Children Pregnant women and fetuses Prisoners Subjects with diminished cognitive capacity Temporary (trauma, drug or alcohol related) Permanent (Neurodegenerative disorders Alzheimer s) Non-English speaking subjects Illiterate Surrogate consent

The Belmont Report Beneficence = Do no harm, maximize benefits and minimize harm Risk/Benefit ratio This is very difficult to establish. Often new interventions have a relatively limited history of use and therefore many potential risks and the level of benefit are unknown. Requires a constant reassessment of the study in light of evolving efficacy and safety data IRBs Data Safety Monitoring Boards Investigators FDA

The Belmont Report Justice = Equitable distributions of the burdens and benefits of research. Is the study sufficiently representative of the society as a whole? Diverse representation is a goal of the NIH and FDA Improves the generalizability of findings Distributes potential benefits Shares potential risks

Federal Policy and Regulations Used the Belmont Report as a framework The Common Rule is a federal policy regarding Human Subjects Protection that applies to 17 Federal agencies and offices. It does not apply to federal agencies that have not signed the agreement (e.g., Department of Labor), however most agencies that are involved in human subject research are bound by the common rule. The main elements of the Common Rule include: Requirements for assuring compliance by research institutions Federal Wide Assurance

Federal Policy and Regulations Requirements for researchers to obtain and document voluntary informed consent Requirements for Institutional Review Boards (IRBs) Membership Function Operations Review of research Record keeping

Federal Policy and Regulations The Common Rule includes additional protections for certain vulnerable research subjects. Subpart B provides additional protections for pregnant women, in vitro fertilization, and fetuses Subpart C contains additional protections for prisoners Subpart D contains additional protections for children

Federal Policy and Regulations Agency Regulations DHHS Regulations are detailed in 45 CFR, Part 46. http://www.access.gpo.gov/nara/cfr/waisidx_99/45cfr 46_99.html FDA Regulations are detailed in 21 CFR, Part 50, and 21 CFR, Part 56. http://www.access.gpo.gov/cgi- bin/cfrassemble.cgi?title=199945

Federal Policy and Regulations The common rule only applies to research for FDA approval process and federally funded research, however: DHHS Federal Wide Assurance (FWA) An institution with a DHHS approved Federal Wide Assurance typically agrees to apply DHHS regulations to all research regardless of the funding source (checking the box) includes research that is internally initiated and funded international research collaborative research across institutions.

Federal Policy and Regulations FDA Regulations FDA regulations apply to clinical investigators and regulates products, drugs, devices, food and color additives. FDA generally regulates, but does not support or conduct research. FDA regulations for informed consent are codified in 21 CFR, Part 50. Note: There are subtle or not so subtle differences between DHHS and FDA regulations particularly with regards to investigational devices and conflicts of interest.

What are the responsibilities of the researcher, sponsor, subject and IRB? All four are responsible for insuring subject safety IRB evaluates the study for: Scientific soundness Consent readability and completeness of disclosure Monitors adverse events (side effects) both individually at the local level (internal adverse events) and through monitoring of MedWatch reports, CTSU action letters, FDA drug updates and DSMB reports etc. Insures or attempts to insure the following parties are monitoring safety

What are the responsibilities of the researcher, sponsor, subject and IRB? Researcher Insures the subject understands the proposed study and risks (truly informed consent) Monitors subjects on an individual and aggregate basis for emerging safety issues Keeps the subject informed about changes related to safety, efficacy and other findings that occur during the study (participants may withdraw from a study without prejudice at any time) Insures that any conflicts of interest are disclosed and meet federal guidelines. If they exist they are managed appropriately

What are the responsibilities of the researcher, sponsor, subject and IRB? Sponsor Discloses all relevant information relating to the study Previous human trials Phase 1 Phase 2 Phase 3 In vitro studies (i.e. cell cultures) Animal trials if any Pharmacologic studies Monitors the trial on an ongoing basis through Data Safety Monitoring Board (DSMB) or other alternative monitor Subject Yes that s s right subjects are an active participants Should know what side effects might occur Report any potential side effects promptly to the researcher Ask lots of questions to insure understanding

So what is an IRB? Institutional Review Board (Ethics Review Boards in other countries) A quasi-regulatory body Originally designed to address research design and ethics within specific institutions Not originally designed with a regulatory function in mind Co-opted opted by the government to fulfill the regulatory function of the Common Rule (45 CFR: 46, 21 CFR:20 and 26)

So what is an IRB? Research protection is only one of the functions of the IRB Addresses issues of research design (A well designed study to answer a question that is not worth asking is not worth doing). Not having a Joe Biden moment here, I just can t t remember where I heard this, but it s s not my brilliant revelation Risk/benefit analysis. What is Minimal Risk? Minimal risk is a term that is critical to the way IRBs evaluate proposed research means the risks of harm anticipated in the proposed research are not greater, considering both probability and magnitude, than those ordinarily encountered in daily life, or during routine physical examinations What does this concept mean to a critically ill cancer patient? As you might imagine this is one of the more difficult concepts to apply

So what is an IRB? Asks the question is this really human subject research? This is the most important question to ask if the answer is yes common rule applies, if no the common rule does not and the IRB does not have jurisdiction What is research? Research means: A A systematic investigation designed to develop or contribute to generalized knowledge It It includes research, development, testing, evaluation and pilot studies

So what is an IRB? What is a human subject? Also very important Human Subject means: a living human individual about whom an investigator conducting research obtains data through intervention or interaction with the individual identifiable private information (health data and demographic data)

So what is an IRB? Often the IRB acts as the Privacy Board for Health Insurance Portability and Accountability Act (HIPAA) related issues Since human research may and often does involve disclosure of protected health information, the IRB provided a convenient way to insure the disclosure to the subject of what information is being collected, by whom, for what purpose, who will be looking at the information and what the subjects rights are regarding use of their information.

So What is an IRB? Informed Consent Required elements of the Informed Consent from the Common Rule A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. A description of any reasonably foreseeable risks or discomforts to the subject. Discloses that unexpected and unknown side effects may emerge (adverse events include not only physical effects, but also adverse social, financial and psychological effects)

So What is an IRB? A description of any benefits to the subject or to others which may reasonably be expected from the research. This is difficult to address for the individual and is often poorly fleshed out in consent forms. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration and other regulatory bodies and industry sponsors may inspect the records.

So What is an IRB? For research involving more than minimal risk (almost all research), an explanation as to whether there is any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. An explanation of whom to contact for answers to questions about the research and research subjects' rights, and whom to contact in the event of a research-related related injury. Make sure that the local IRB is listed

So What is an IRB? A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. A statement that by signing the consent the subject does not waive any legal rights.

So What is an IRB? Optional but usual elements of the Informed Consent A statement that the particular intervention or procedure may involve risks to the subject or to the embryo or fetus, if the subject is or may become pregnant which are currently unforeseeable. Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent or wishes. Any additional costs to the subject that may result from participation in the research and the consent is free of exculpatory language.

So What is an IRB? The consequences of a subjects' decision to withdraw from the research and the procedures for orderly termination of participation by the subject. Intended to protect the participant A statement that significant new findings developed during the course of the research which may relate to the subject s s willingness to continue participation will be provided to the subject. This is an important point! The approximate number of subjects involved in the study.

So What is an IRB? The Informed Consent Process Informed consent is more than just a signature on a form.

Conflicts of Interest Recent research scandals brought to light the corrupting influence conflicts of interest can have on research Jesse Gelsinger The NIH and FDA have rules regarding what constitutes a conflict of interest that emphasize financial conflicts of interest However, COIs can take many forms other than financial conflicts Reputation Power Tenure Blind enthusiasm Etc.

Conflicts of Interest IRBs must insure that at a minimum the federal requirements relating to conflict of interest are addressed Further IRB members should be free of interests in the studies in question or recuse themselves from deciding the disposition of a study that they are directly involved

Composition of the IRB No set number of members Required composition Scientific members Lay members (Community members, nonscientific) Unaffiliated members Quorum At least one scientific member At least one community member (nonscientific) Over 50% of the board must be present for any vote Members with conflicts of interest may not participate in the vote Recuss Physically leave the room Additional members or consultants with specialized knowledge are retained as appropriate (i.e. pediatrics, criminal justice, women s s issues, community/cultural issues)

Role of the IRB chair Do not impose a personal agenda Facilitate discussion Minimize unnecessary delays Engage all members in the discussion Provide scientific leadership

Role of the scientific members Evaluate the scientific rationale Evaluate the study for potential risks Evaluate the study for potential benefit Risk/Benefit ratio

Role of community members Evaluate the understandability of the consent Ask any and all questions Evaluate the risks vs. expected benefit Evaluate the study from the standpoint of community standards (ex. Research conducted in a Native American Community, research involving vulnerable populations etc.) Community members are often research activists, former subjects, family members of former subjects, lawyers, clergy, business people Community members play a key role in IRB deliberations

Special Consultants When an IRB evaluates a study in a field where the members have limited or no expertise it is expected that the IRB will engage an expert in the field who advises but usually does not vote on the study and who has no conflicts of interest Vulnerable populations Prisoners Children Pregnant women Others Note: The IH-DM IRB #1 considers pediatric studies and therefore must have members who are experienced in pediatric research and care

Required reviews Initial review Exempt Expedited Full board review Continuing reviews At least yearly May be more frequent depending on the risk level Should be as rigorous as the initial review Special attention should be paid to new information relating to the study and safety reviews

Required reviews Amendments, revisions and addenda All changes to studies must be reviewed and approved by the IRB If the change represents a change in the risk profile recruitment is suspended and current participants must be notified in a prompt fashion. Recruitment can only continue after IRB approval (OHRP and CTSU), although at times the approval may be expedited

The power of the IRB An IRB can demand substantive changes to a protocol. Vote down a protocol. Table a protocol if there are substantive issues to be resolved. The IRB is expected to report suspected misconduct or other unanticipated problems that emerge during the course of a study to FDA, OHRP and others. Iowa Health may not approve a study over the objection of the IHDM - IRBs

Questions and further guidance IRBs #1 and #2 515-241 241-5790 Jane Spencer IRB #1 chair Dr. Drevyanko drevyatf@ihs.org IRB #2 chair Dr. Drevyanko drevyatf@ihs.org