Intro to Research Design and Application Part 3: Demystifying the IRB M. Ammar Hatahet, MD, MPH, FACP Director of Clinical Research, McLaren Oakland Chair, McLaren Health Care IRB Associate Clinical Professor, Michigan State University August 24th, 2012 Ammarhat@medicalpmc.com

Objectives Review common study designs for residents and students Review IRB history and role Exemption, expedition and full board review Where do I start

Cohort Studies (observational) exposed develop disease don’t develop disease not exposed develop disease don’t develop disease Framingham study population

Case-Control Studies exposed not-exposed exposed not-exposed Diseased individuals (cases) Non-diseased individuals (controls)

Cross-sectional studies defined population Exposure + Disease + Exposure + Disease - Exposure - Disease + Exposure - Disease - gather data on exposure and disease

Writing up the Study, IRB concerns Introduction: Description of the problem, what is known about it. Hypothesis: The question being asked Data: Inclusion criteria Exclusion criteria Measurements

Federal Regulations and Policy 45 CFR 46 - Basic DHHS Policy for Protection of Human Research Subjects Originally adopted May, 1974, Revised January 13, 1981, Revised June 18, 1991 Federal Policy for the Protection of Human Subjects - “The Common Rule” June 18, 1991 Departments of Agriculture, Energy, Commerce, HUD, Justice, Defense, Education, Veterans Affairs, Transportation, and HHS. NSF, NASA, EPA, AID, Social Security Administration, CIA, and the Consumer Product Safety Commission.

Federal Regulations and Policy Additional Protections Included in 45 CFR 46: Subpart B - Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research (revised December 13, 2001) Subpart C - Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D - Additional DHHS Protections for Children Involved as Subjects in Research

Common Rule vs. FDA Regulations Basic requirements for Informed Consent and IRB oversight are the same. However applicability is different Common Rule applies to protocols funded by federal funds. FDA regulations apply when the research is related to FDA regulated product: drugs, devices, or biologics

Current Situation Other relevant entities Human Research Protections Program AAHRPP Accreditation Higher standards for IRB review Criteria for Approval Required Findings Post-approval monitoring Higher standards for investigator responsibility

The Secret The secret to getting research approved by the IRB is knowing what issues the IRB has to address in order approve research and giving them the information that they need. IRB is required to establish findings and determinations 11

45 CFR 46/21 CFR 56 “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. 12

45 CFR 46/21 CFR 56 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 When appropriate: data collection is monitored to ensure subject safety privacy and confidentiality of subjects is protected additional safeguards are included for vulnerable populations 13

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 Associates, Inc. 14

Risk Assessment Assessing the level of risk involves taking into account Magnitude of harm Probability of harm IRB Responsibilities: Identify Risks Determine that risks are minimized Determine that “risks to subjects are reasonable in relation to anticipated benefits” Determine that subjects are adequately informed about “any reasonably foreseeable risks or discomforts” Comes from Common Rule Sections 111 (Criteria for IRB Approval of Research) and 116 (General Requirements for Informed Consent) IRB cannot rely on the investigator to identify risk. “Dr. Frankenstein” Example - Achievement Motivation in Black Children IRB can call on outside experts to advise on determinations. 15

Risks Assessment The IRB has to do an independent evaluation of the risks because no investigator can be objective about their own work When the IRB does not have the necessary scientific expertise to determine risks it must use outside consultants. 16

How to minimize risks Alternatives If known, using other procedures that are less risky (not recording identifiers) Precautions Additional steps taken to decrease the likelihood that harms will occur (exclusion criteria, safety monitoring) Contingencies procedures to deal with harms if they occur (compensating patients, treatment of complications) Precautions: Steps which can be taken to prior to the subjects’ participation to minimize risk Pre-screening subjects Pre-testing materials Subject warnings Coding data Certificates of confidentiality Safeguards: Steps which can be taken during the subjects’ participation to minimize risk Frequent monitoring of subject reactions Active listening Extended debriefing Referrals 17

Risk vs. Benefit IRB must decide whether the anticipated benefit justifies asking subjects to undertake the risks, often it is a subjective call Unique to the different populations and individual differences among subjects There are two kinds of benefits: Benefits to subjects Benefits to society Risk threshold where benefits to society not sufficient to outweigh risks. 18

Subject Selection Justice requires equitable distribution of both the burdens and benefits of research Individuals and groups that bear the burden should share in the benefits Individuals and groups that benefit from research should share in the burden Selection of subjects should be justified by the science IRBs should not overprotect vulnerable populations so that they are excluded from participating in beneficial research If the study is funded by NIH, exclusions of women, minorities or children MUST be justified. © HRP Associates, Inc. 19

Subject Recruitment Subject recruitment (should not be coercive in any way) Where When How Conditions of recruiters Material used in recruitment should be Consistent with protocol Simple and clearly indicates that it is for research (ie; end-result is not known, that is why the research is done) 20

The Consent Process The basic elements of the consent process include: Only the subjects can fully evaluate the degree of risk in any given situation but that is only if they have sufficient information to determine so, hence, the consent must have educational component that allows the subjects to do just that. The basic elements of the consent process include: Research details and what the subject's participation entails (what and for how long) Full understanding by the subjects of risks and benefits, 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. 21

Obtaining Consent Subject has the legal and mental capacity to give consent, otherwise a legally authorized representative; Sufficient opportunity (time and place) is provided Minimizing the possibility of coercion or undue influence Simple understandable language suitable to the subject No “exculpatory” language 22

Form vs. Informed Consent For the informed consent to be legally effective it is usually documented in a form that is signed by the subject or the subject’s legal representative. The form itself is not an informed consent. The subject could withdraw his/her consent at anytime Sometimes, a new consent and a new form is required if additional risks have been identified. 23

Data Safety Monitoring Research that involves more than minimal risk must have a Data Safety Monitoring Plan Monitoring data collection, subject reactions, new findings. A plan for an unanticipated problem. 24

Definitions Privacy - having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others. Confidentiality - methods used to ensure that information obtained by researchers about their subjects is not improperly divulged. © HRP Associates, Inc. 25

Confidentiality Confidentiality and anonymity are not the same Anonymous means no one, anywhere, ever can identify individual subjects Names are not the only identifiers Subjects’ participation in the research may need to be kept confidential as well as their data © HRP Associates, Inc. 26

Confidentiality More elaborate procedures may be necessary for studies in which data are collected on sensitive matters such as sexual behavior or criminal activities. Any written record linking subjects to the study can create a threat to confidentiality, including consent forms © HRP Associates, Inc. 27

Some Vulnerable Groups Additional Protections Included in 45 CFR 46: Subpart B - Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research (revised December 13, 2001) Subpart C - Additional DHHS Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects Subpart D - Additional DHHS Protections for Children Involved as Subjects in Research 28

Other Vulnerable Populations Cognitively impaired (permanent or transient) Non-English speaking Desperately ill (but may be justified at time) Economically and educationally disadvantaged Students and employees if there is authority imbalance and the risk of coercion. 29

FDA Guidance 10/2009 It is the the investigator responsibility to protect the rights, safety, and welfare of the study subjects. Conducts all research according to the IRB approved protocol and complies with all IRB determinations. Ensures that each potential subject understands the nature of the research and of the subject's participation and takes appropriate steps to gain that comprehension. 30 © HRP Consulting Group 30

Investigator Responsibilities Protecting the rights, safety and welfare of human subjects Providing adequate supervision Complying with IRB requirements Complying with provisions of FDA-1572 or clinical trials agreement Controlling test articles 31 © HRP Consulting Group 31

IRB Determination Is it research? Is it human subject under FDA or DHHS? Does it qualify for an exemption? Initial review Continued review Expedited or full board Additional reports Amendments

Types of Reviews Application for initial review: The first request for approval of a specific project is the application for initial review. Application for continuing review: The IRB must re-review studies at a minimum of once every 365 days. An IRB may require review more frequently depending on the IRB's assessment of the study's risk/benefit ratio. The review may be a full or expedited review. Amendments or modifications: Changes can not be made to approved studies, including the informed consent document, without prior IRB review and approval. The review may be full or expedited, depending on the magnitude of the change and the effect of the change on the risks / benefit ratio.

Types of Reviews (cont’d) 4. Reports: The IRB may require a report for: Adverse events or unanticipated problems involving risks to subjects or others. Incidents of noncompliance. Deviations from an approved study protocol and violations of the terms of approval. Data Safety and Monitoring Report summaries.

IRB Exemption Federal Guidance indicates that applying exempt status to a project is a decision to be made by the IRB and that investigators should not make this determination for themselves.

IRB Exemption (cont’d) Research conducted in established or commonly accepted educational settings, involving normal educational practices. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior. Some studies that employ observation, survey, or interview procedures do not qualify for exemption. Research not exempt under "2" above, may still qualify for an exemption if the human subjects are elected or appointed public officials or candidates for public office.

IRB Exemption (cont’d) Research involving the collection or study of freely available de-identified existing data, documents, records, pathological specimens, or diagnostic specimens. Research and demonstration projects conducted by heads of government departments or agencies which are designed to evaluate public programs. Taste and food quality evaluation and consumer acceptance studies