1. 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

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

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

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

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

6. 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

7. 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.

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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.

34. 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.

35. 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.

36. 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.

37. 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