CDR Timothy Donahue, MC, USN - Chair Vincent B. Ho, MD, MBA – Vice Chair

National Naval Medical CenterDirectorate for Professional EducationClinical Investigation DepartmentRESEARCH COURSE THE IRB PROCESS • CDR Timothy Donahue, MC, USN - Chair • Vincent B. Ho, MD, MBA – Vice Chair • Dr. Donna Kahn, CPNP, CAPT, NC, USNR-Ret – Vice Chair

Disclosure Statement This CE/CME activity does not have commercial support, and has no conflicts of interest

Learning Objectives • Introduction • IRB • Membership • Functions, operations, & regulations • Navigation through the IRB process • Success & failure indicators • Focused areas of review • Basic core elements of research proposal • Informed consent • Helpful tips for successful transitioning through the IRB process

Learning objective one • Introduction • IRB • Membership • Functions, operations, & regulations

What is the IRB? • The Institutional Review Board (IRB) is a committee established to review and approve research involving human subjects • The primarypurpose of the IRB: Protect the rights, safety, & welfare of human subjects participating in biomedical research • Functions independently but in coordination with the Scientific Review Panel (SRP)

Responsibilities of the IRB • Conducts initial & continuing reviews of research • Reports findings & actions to both the investigator & the institution • Determine which projects need review more often than annually • Proposed modifications in a research activity are promptly submitted to the IRB & are approved by the IRB before such changes are made except when such changes are for the immediate safety of subjects

Responsibilities(cont) • Maintain appropriate records of all activities • Ensure prompt reporting to institutional official • Unanticipated problems involving risks to subjects • Serious or continuing non-compliance with requirements or determinations of the IRB • Suspension or termination of an IRB approved investigation

IRB Membership • Minimum of at least 5 members but can be increased to meet the needs of the institution • ensure that at least one member whose primary concern is in the scientific area • one member who is not scientifically trained * the layperson has to be present to hold an IRB meeting * • one member who should not be affiliated with the institution • balance IRB membership to include a wide variety of gender, ethnicity, & representation of specialty areas, especially as it relates to vulnerable populations and professional & social experience • Pediatrics, Obstetrics, TBI, etc.

IRB Oversight • Main goal – ensure that rights of human subjects • with emphasis on informed consent and privacy • That PI/AI’s conduct their research professionally & ethically • Potential benefits of the study outcomes outweigh the potential risks to the participant (Hood, Kaar, & Ho, 2009)

Scientific Review Panel & IRB • Two–tiered system • Adds a scientific review component step before protocol sent to IRB for review • Intended to streamline the IRB review process • Scientific Review Panel (SRP): • Scientific review by experts on subject matter • Permits IRB to focus on human use issues • IRB still needs to conduct a scientific review + review the protocol for human protection issues

IRB Operations • Basic IRB Regulations • NNMC Guidelines & DoD Requirements • Title 45 (Public Welfare) CFR Part 46 (Code of Federal Regulations) - Federal Protection of Human Subjects • Subpart A - Basic HHS Policy for Protection of Human Research Subjects • Subpart B - Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research • Subpart C - Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects • Subpart D - Additional Protections for Children Involved as Subjects in Research • Subpart E - Registration of Institutional Review Boards with the Department of Health & Human Services (HHS) & Office for Human Research Protections (OHRP) • 32 CFR 219 – DoD policy beyond 45 CFR • Additional restrictions regarding human subject research • Vulnerable population precautions • Definitions, IRB membership, functions & operations, IRB review of research, expedited review, criteria for IRB approval, review by institution, suspension or termination, cooperative research, IRB records, informed consent, human subjects, use of federal funds, early termination of research support, conditions

Learning Objective Two • Navigation through the IRB process • Success & failure indicators • Focused areas of review • Basic core elements of research proposal

Preparing Successful Proposals for SRP/IRB • Document the Scientific Validity of the Research • Justify the Selection of Intervention & Control Group Conditions • Develop Adequate Consent Procedures for Adults with Questionable Capacity to Consent • Participant Perspectives: Sound Evidence for Ethical Practices (Fisher, 2000 – Fordham University Center for Ethics Education)

Scientific Validity of the Research • Detailed theoretical and methodological rationales for the study • Failure to provide sufficient scientific background is based upon the erroneous assumption that IRBs are not responsible for evaluating scientific merit • IRB risk-benefit assessment is inextricably linked to the scientific value and validity of the study • If a study lacks methodological validity and does not provide scientific merit or social benefits, a research protocol with potential risk, should not be approved • Scanty literature review with little to no background of the problem • Goals & objectives not clearly stated • Non-validated instruments • No power analysis

Justification: Selection of Intervention and Control Group Conditions • IRBs expect PI’s to provide evidence that extant research has: • not yet confirmed that participants placed in a control group will be deprived of an intervention with empirically validated effectiveness; & that • individuals assigned to the experimental intervention will not be exposed to greater risk than if they had been assigned to the standard treatment condition • unethical to assign persons to either a treatment or control condition if one of those conditions is known to be inferior • Procedures for monitoring participant welfare during & following experimental trials • Examples of informed consent protocols that adequately describe the experimental nature of the treatments

Consent Procedures for Adults with Questionable Capacity to Consent • Cognitive impairments, differing & fluctuating levels of capacity, consent assessment methods with vulnerable populations • Provide the IRB with legal, psychological, & ethical criteria for decisions regarding when a surrogate decision-maker should be sought & who that surrogate should be • If surrogate consent is justified, IRB proposals should include procedures to insure that participant assent will be obtained whenever possible & how decisions to withdraw from the study will be honored

Participant Perspectives: Sound Evidence for Ethical Practices • IRB proposal should convey sensitivity to the rights & welfare of research participants • Enhanced sensitivity through careful consideration of the expectations, fears, & hopes that individuals bring to the research setting • Achieved through informal dialogue with participant representatives or through formal examination of prospective participant views • Pilot studies, a staple of good methodological design, when extended to preliminary exploration

Indicators for success • Research has value and should be able to stand on its own • PI/AI expertise • Supporting documents • Collaborating institutions clearly outlined • Training for all PI/AI’s completed by submission http://www.citiprogram.org • Well-written abstract • Clearly defined research question • Literature Review with background to the problem • Objectives clearly written • Conceptual framework & theoretical assumptions clearly stated

Indicators for success • Design & methodology • Sample size justification & ensure that number of subjects is c/w consent form & protocol • Describe how subjects will be recruited • Addresses protection against coercion • Inclusion/Exclusion criteria

Indicators for Success • Surveys or Questionnaires • If surveys/questionnaires are sent outside of the command, a control number needs to be issued by a higher authority (BUPERS) • While surveys/questionnaires may be expedited, if questions are of a sensitive nature – may need full IRB review

Common Pitfalls • Too long • Poorly written • Inappropriate use of technical terms • Research too ambitious • No literature review • No integration of theory in literature review • No theoretical foundation • Budget not linked to methodology • Unrealistic costs • Unclear methodology • No references or bibliography

Common Pitfalls (cont) • Consistency across IRB application, narrative & consent form • Investigator is responsible for conduct of the trial • 1572 form – Keep it up to date • A federal form • Statement of the investigator that she/he will abide by the federal guidelines set forth in the Code of Federal Regulations for the use of drugs in an investigational setting & form available at http://www.fda.gov • Adverse events not properly reported • Regulatory documents – Keep them current. • Inaccurate study records – Be audit ready

IRB Review: Basic Items • Sponsor • Investigator • Study population • Scientific Design • Informed Consent • Potential risks/discomforts to subjects • Confidentiality • Data oversight • Data analysis • Compensation & costs (Hood, Kaar, & Ho. 2009)

Core Elements for IRB Review • Idea • Background & significance • Hypothesis & objectives or aims • Design/methodology • Budget • Description of research question • Why problem is important • Review of relevant literature • Proposed methodology • Time frame

Idea • What do you want to do? • Why do you want to do it? • Why is it important? • Who has done similar work? • How are you going to do it? • How long will it take?

Background & Significance • Focus on literature review that is relevant to your study • Use simple, non-technical language • Convey: • The problem • What has been done to date to solve problem • Why existing work is insufficient to solve problem • How current study will advance knowledge or solve problem • Why current study should be done

Hypothesis • State hypothesis • Simply and clearly state what is believed to be true about the problem • State in general terms followed by a set of specific aims & objectives

Design & Methodology • Where will the study take place • Type of study • Sample • Inclusion/Exclusion criteria • Consent process • Randomization • Confidentiality • Describe protocols • Include diagrams or figures for clarification

Design & Methodology • Estimate time to complete study • Demonstrate awareness of pitfalls & suggest alternatives • Include an appropriate and coherent plan for data analysis including a power analysis

Budget • Budget accurately reflects the research proposal • Avoid expense overlap • Compensation of subjects • Justify costs • Excessive personnel • Consultant • Equipment/supply

Learning objective three Informed consent

Informed Consent • Criticalelement that the IRB must review • Language level appropriate for study population Sixth grade reading level • Must be clear to the potential participant so that decision to participate can be made freely • If research involves a medical product (device or pharmaceutical) an adequate summary of the product should be contained in document

Informed Consent • Endothelial function assessment using Digital Thermal Monitoring (DTM). This is a non-invasive study using a semi-automated sphyngomanometry method • Should explain DTM is a probe placed on the fingertip for temperature measurement purposes • Transthoracic echocardiogram is a non-invasive study with no anticipated adverse event • Should explain that the transthoracic echocardiogram is a type of an ultrasound test that uses high-pitched sound waves • Polysomnogram/Sleep Study - This is the gold standard in the diagnosis of obstructive sleep apnea with no adverse events • Should explain that this is a laboratory test that records your brain waves, heartbeat, and breathing as you sleep

Informed Consent Document • Purpose of the Study • Why is this Research • Subjects • Procedures • Potential Risks and Discomforts • Potential Benefits • Alternative to Participation • Standard of care • Deviation from the standard of care • Compensation

Informed Consent Document • Withdrawal or Termination • Confidentiality • New Findings • Other Considerations • Use of Specimens • Investigator financial Conflict of Interest • Voluntary participation • Contact information for PI • HIPAA (Health Insurance Portability and Accountability Act) Authorization Form • Given to subjects with Consent Form for release of personal health information

Informed Consent: Pregnant Women, Fetuses, and/or Neonates Must justify the need to include this vulnerable population • Describe the risks/anticipated benefits • Explain why risks involved are least possible to the pregnant woman & fetus for achieving objectives of the research • Consent of the father is also required if the risk to the fetus is increased

Informed Consent: Children • Select whether proposed research poses no greater than minimal risk to children or greater than minimal risk • Select whether parental permission will be obtained or if parental permission can be waived • Select whether assent from children will be obtained or waived * Study must show direct benefit to the child *

Informed Consent: Cognitively Impaired/Medically Incapacitated • May require use of surrogate consent • Must provide compelling & scientifically sound rationale for inclusion of this subject population • Describe in detail plan for assessing decision-making capacity & specify who will be performing the decision-making capacity evaluation • Explain how assent from cognitively impaired individuals will be solicited

Use of FDA-Approved Drugs & Investigational Drugs or Biological Products in Clinical Investigations • Elements: • Product Description • Drug Brochure • Clinical Pharmacology • Indications and Usage • Dosage and Guidelines for Administration • Toxicity and Known Side Effects • Precautions and Contraindications • IND Information (IND # and filing date)

Investigational Device • dies involving: • Device Product Name • Manufacturer • FDA Approval Status • IDE Number - not needed if there is a 510(k) • Risk Classification • Description of Device

Use of placebo • Study involving • Provide compelling and scientifically sound methodological reasons for use of placebo • Explain if subjects’ disease/condition will have potential to progress to higher risk condition if treated with placebo • Clarify if subjects in placebo group would be exposed to increased risk • Explain how study design will minimize risks to subjects

Emergency Use – HUD/HDE • HUMANITARIAN USE DEVICE (HUD): A device that is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4,000 individuals in the United States per year • HUMANITARIAN USE DEVICE EXEMPTION (HDE): Food and Drug Administration - Approval of an HDE requires evidence of safety and probable benefit but does not require establishing effectiveness • In order for a HUD to be used in treatment or diagnosis, the HUD per FDA regulations must have an approved HDE from the FDA & IRB approval • Emergency & compassionate use of a HUD may be allowed in accordance with FDA regulations

Emergency Use: HUD • Use of a HUD in an Emergency. The HUD may be used off-label (non-approved indication) or without prior IRB approval in an emergency situation • concurrence of the IRB chair or designee • informed consent from subject or legally authorized representative • independent assessment from a uninvolved physician • authorization from the HDE holder • Compassionate Use of HUD. The FDA allows the use of a HUD in circumstances where the device is the only option available for a patient faced with a serious or life-threatening condition that does not meet the criteria of an emergency • Unlike emergency use, prior FDA approval is required before compassionate use occurs

Compassionate Use: HUD • The HDE holder must submit an IDE(HDE) supplement to the FDA for approval • Once FDA approval is obtained, the investigator should submit paperwork along with documentation of FDA approval of the compassionate use to the IRB for review & approval • Paperwork - the clinician should seek approval of the HDE holder & provide: • description of the patient’s condition & circumstances • discussion why alternative therapies are unsatisfactory • identification of deviations from approved HUD labeling required to treat • patient protection measures that will be followed

SOP for HUD’s - NNMC • Standard Operating Procedure: HUD’s Applies to all who deliver health care and/or conduct human subjects research at NNMC – and applies to instances where a human use device (HUD) is used: • Must use HUD Consent Form • Sample consent forms in RCRS Office • Instruction/forms placed on IRBnet & RCRS website for investigators

Greater than minimal risk studies

If Study is greater than minimal risk ) (1) List who will conduct the safety review - name, title and experience of the individual(s) (2) Indicate how frequently the monitor will review & evaluate the accumulated study data for participant safety, study conduct, progress, and, when appropriate, efficacy (3) Explain the process by which the monitor will make recommendations concerning the continuation, modification, or termination of the trial

If study is greater than minimal risk (cont) (4) Describe the event(s) that would trigger an unscheduled review, stopping guidelines & un-blinding rules, if applicable (5) List who will be monitoring & collecting information on adverse events and/or unanticipated problems (Lead Researcher, Research Coordinator), name, title, & experience of individual(s) (6) Describe the plan for annual reporting of the participants’ safety, study’s conduct, progress, & efficacy (when appropriate)

Learning objective four Helpful tips for successful transitioning through the IRB process

Helpful Tips: IRB • Well-written proposal • Follow proposal guidelines • Clearly written hypotheses • Keep the experiment simple • Articulate pitfalls & provide alternate plans * No research can begin until Commander, NNMC approval is granted *

CDR Timothy Donahue, MC, USN - Chair Vincent B. Ho, MD, MBA – Vice Chair