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Welcome to the IRB

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Title: Welcome to the IRB


1
Welcome to the IRB
2
NYU School of Medicine INSTITUTIONAL REVIEW BOARD
IRB ORIENTATION New Member
Helen Panageas, CIP Associate Director
www.med.nyu.edu/irb
3
What we will Cover Today
  • What is the IRB
  • and how does the IRB work?
  • Mechanics the process
  • 10 minute BREAK
  • Mechanics how to review a protocol, review
    strategies and meeting time
  • 10 minute BREAK
  • History and Regulations
  • Research ethics essence/spirit a bit distilled
  • Commonly Vexing Details
  • Wrap Up Questions, issues, considerations, and
    last words.

4
What is an IRB?
  • An Institutional Review Board (IRB) is a group of
    people formally designated (by feds and
    Institution) to review and monitor research
    involving human subjects.
  • Direct arm of the federal government when it
    comes to protection of human subjects
  • New York University School of Medicine
  • has three IRBs

5
What is the IRB?
  • The purpose of the IRB is to protect the rights
    and welfare of individuals who are participating
    as subjects in research.
  • The IRB has the authority to approve, disapprove,
    and require modifications to research projects
    involving human subjects.

6
What is an IRB?
  • Federal Government says
  • An Institutional Review Board is a federally
    mandated group required to review and approve
    human research projects in accordance with Title
    45 Public Welfare DHHS, PART 46 PROTECTION OF
    HUMAN SUBJECTS and FDA regulated studies in
    accordance with TITLE 21 FOOD AND DRUGS, PART 50
    PROTECTION OF HUMAN SUBJECTS, PART 56
    INSTITUTIONAL REVIEW BOARDS

7
Federal Wide Assurance
  • NYU SoM holds a Federal wide Assurance (FWA)
    00004952
  • The FWA assures that the Institution will be
    compliant with the federal regulations for the
    protection of human subjects for all research
    regardless of funding source
  • The FWA is also approved by OHRP

8
IRB Membership
  • At least 5 members
  • IRB shall include at least one member whose
    primary concerns are in scientific areas and at
    least one member whose primary concerns are in
    nonscientific areas.
  • Federal Regulations at 45 CFR 46.107

9
IRB Membership (Continued)
  • IRB shall include at least one member who is not
    otherwise affiliated with the institution and who
    is not part of the immediate family of a person
    who is affiliated with the institution.
  • Federal Regulations at 45 CFR 46.107(d)

10
IRB Membership (Continued)
  • Consultant as Reviewers
  • An IRB may, in its discretion, invite
    individuals with competence in special areas to
    assist in the review of issues which require
    expertise beyond or in addition to that available
    on the IRB. These individuals may not vote with
    the IRB.
  • Federal regulations at 45 CFR 46.107(f)

11
The Individual IRB Member
  • Its tough job but you add to the process
  • Your unique professional and personal
    perspective.
  • This includes your scientific, social, ethical,
    community, minority, legal, administrative or
    operational perspectives, maybe all of these.

12
The Individual IRB Member
  • Members must attend a minimum of ten meetings
    annually,
  • should attend all meetings for which they are
    scheduled.
  • If a member is unable to attend a scheduled
    meeting, that member should inform the IRB Chair,
    Vice Chair, or an IRB Office staff member.

13
The IRB as a Privacy Board
  • At NYU SoM
  • The IRB is the Privacy Board
  • What does that mean?
  • The IRB makes all HIPAA findings

14
How does it Work?
15
Human Subjects Protection is a Shared
Responsibility
Investigator/Researcher
IRB
Institution
16
Team Approach
17
Institutional Official obligations
  • Sets tone for culture for respect of human
    subjects
  • Serves as Signatory official on Federa-lwide
    Assurance
  • Is Knowledgeable contact for OHRP/FDA
  • Ensures effective communication and access to
    human subject information
  • Ensures investigators fulfill responsibilities
  • Facilitates educational activities
  • Holds administrative responsibilities which
    include
  • appoint IRB members and chair
  • provide IRB with resources and staff
  • support IRB authority and decisions

18
Institutional Obligations
  • Assure that the IRB has necessary resources to
    support the review of human subject research at
    the institution
  • Assure autonomy of IRB decision making process
  • Provide education and training in the responsible
    conduct of research for all researchers and key
    personnel
  • Develop policies and procedures to administer
    human subject program
  • Ensure assurances are in place and certification
    of IRB review submitted (include collaborating
    performance sites)
  • Implement oversight to ensure compliance with
    regulations
  • Promptly correct any situations of non-compliance
    with rules and regulations which could jeopardize
    research, funding, or reputation

19
IRB Chair role
  • Full knowledge of regulations and their
    application
  • Maintain current knowledge of trends and changes
    in protection requirements
  • Convene IRB meetings
  • Perform review functions as needed for new, and
    continuing research
  • Assist institution in review of non-compliance
  • Perform expedited review and/ or designate
    experienced reviewers
  • Assist in the education and development of IRB
    members
  • Assure that documentation (minutes etc.) adhere
    to regulatory requirements
  • Assure that all members have equal voice in
    meeting deliberations and voting
  • Keep deliberations of IRB confidential

20
IRB panel obligations
  • Apply the rules and regulations to specific
    projects/protocols
  • Provide constructive review of research proposals
    (in a timely manner)
  • Assist with education of research community
  • Respond to staff requests for attendance and
    information
  • Communicate new developments to research
    community
  • Seek outside consultation when lacking expertise
  • Model exemplary research behavior

21
IRB member roles
  • Full knowledge of regulations and their
    application
  • Maintain current knowledge of trends and changes
    in protection requirements
  • Attend IRB meetings
  • Perform review functions as needed for new, and
    continuing research
  • Perform expedited review if designated
  • Keep deliberations of IRB confidential

22
Principal Investigator Obligations
  • Protect Human Subjects
  • Know and apply rules and regulations
  • Apply for prospective IRB approval
  • Follow dictates of IRB
  • Report unanticipated problems to IRB
  • Report changes in research activities and ensure
    changes not initiated without IRB approval
    (except to eliminate immediate hazard to subject)
  • Provide continuing reports of research
  • Obtain informed consent/assent
  • Retain records as required by regulation
  • Train and supervise research team and associates

23
IRB Autonomy and Support
  • Autonomy of IRB decision making is mandated by
    regulation and assured by the institution through
    the Federalwide assurance. (FWA)
  • In essence, the IRB is a franchise of the federal
    agencies, OHRP and FDA when operating as a duly
    constituted IRB.

24
Review by Institution 45 CFR 46.112 and 21 CFR
56.112
  • Research may be subject to further appropriate
    review and approval or disapproval by officials
    of the institution. However, these officials may
    not approve the research if it has not been
    approved by an IRB.

25
System Integrity
  • Team system is based on trust and open
    communication
  • Issues and problems should be openly reviewed and
    addressed
  • Complaints or problems should be handled fairly
    and efficiently
  • The Primacy of the Rights and Welfare of subjects
    should guide us all decisions

26
How does it work?
  • Basically
  • Protocols submitted for review
  • IRB Admin Office processes review
  • Reviews to ensure conformity to regulations and
    NYU policy
  • Forwards all full board reviews up to board
  • IRB meets once a month (sometimes more by
    teleconference) to review and make decisions on
    new research and the continuation of research
  • IRB also may, at times, have to make tough
    decision disapprove, suspend, terminate etc..

27
How does it work?
  • In detail
  • That is what we will discuss today
  • How this IRB works
  • Your responsibilities as a member
  • History of research and the development of
    regulations and ethical principles

28
Mechanics
  • Background
  • Types of review
  • How Review is determined
  • Some IRB speak
  • The Process
  • Meeting materials
  • What happens at the meeting
  • Meeting Time
  • Quorum
  • Voting and COIs
  • Review Process at the meeting and the Belmont

29
Types of IRB Review
Exempt
Expedited
Full
30
How is Review Type Determined?
  • Four Basic Questions
  • Is the Proposed project Research?
  • Does the proposed project involve Human Subjects?
  • What type of Risk is involved in the proposed
    project?
  • Does the proposed project meet the criteria for
    the Review Category?

31
Is the Proposed Project Research?
Research is defined as a systematic
investigation, including research development,
testing and evaluation, designed to develop or
contribute to generalizable knowledge.
32
Are Human Subjects involved ?
  • Human subject means a living individual about
    whom an investigator (whether professional or
    student) conducting research obtains
  • Data through intervention or interaction with the
    individual, or
  • Identifiable private information.

33
What is the Type of Risk?
  • Minimal Risk is defined as
  • the probability and magnitude of harm or
    discomfort anticipated in the proposed research
    are not greater, in and of themselves than those
    ordinarily encountered in daily life or
  • during the performance of routine physical or
    psychological examinations or tests.

34
Review Categories
  • Three Review Types
  • Full, Expedited, Exempt
  • Only
  • Expedited
  • Exempt
  • have Review Categories

35
The level of review depends on the risk to the
human participants.
Review Continuum
Risk Low Minimal
Higher
Review Exempt Expedited
Full
Informed Consent
None May be Waived Required
36
Review Determinations
  • Who makes it?
  • PI
  • Designees of the Chair
  • What does it mean?
  • Exempt- review by designee
  • Expedited- review by designee
  • Full Board- IRB meeting review

37
And then theres
HIPAA
38
PHI 18 Identifiers
  • Names/Initials
  • Postal Address
  • Dates (DOB, DOA, DOD)
  • Telephone numbers
  • Fax numbers
  • E-mail address
  • Social Security Number
  • Medical Record Number
  • Health Plan Numbers
  • Account Numbers
  • Certificate/License numbers
  • VIN including license plate numbers
  • Device identifiers
  • Web URLs
  • Internet Protocol address
  • Biometric identifiers
  • Photographs and comparable images
  • Any other unique identifying number,
    characteristic, or code

39
Some IRB Speak
  • AE- Adverse Event
  • CFR - Code of Federal Regulations
  • CIP- Certified IRB Professional
  • COG- Childrens Oncology Group
  • COI- Conflict of Interest
  • DSMB - Data Safety Monitoring Board
  • GOG- Gynecologic Oncology Group
  • HDE- Humanitarian Device Exemption
  • HIPAA- Health Insurance Portability and
    Accountability Act
  • UAP- Unanticipated Problem
  • PHI Private/Protected/Public Health Information

40
The Process
41
Mechanics of the process
  • About 2 weeks prior to the meeting, an RSVP is
    sent via email.
  • If you dont use your email, give us an
    alternative method by which to communicate with
    you.
  • If you are an alternate you are expected to
    attend if the member you are assigned, can not
    attend.

42
Your Review Materials
  • Applications, attestations, signatures
  • Protocol summary lay summary
  • Detailed protocol typically authored by sponsor
    or the PI
  • Recruitment materials ads, letters, flyers
  • Diaries, information sheets
  • Consent and assent documents
  • NIH grant document
  • Drug/device brochures
  • Additional review requirements Nursing,
    Biomedical Engineering, Radiation Safety

43
Your Review Materials
  • Initially daunting but youll soon be able to
    move through them quickly.
  • Check your assignments.
  • If you are primary or secondary read in depth.
  • Otherwise, review the protocol summary, the
    consent forms and any advertisements.
  • Feel free to add to any discussion regardless of
    your assignment.

44
Your Review Materials
  • The Reviewers Checklist
  • Why was it created?
  • Function
  • Do you need to fill it out?
  • Do you need to hand it in?

45
  • BREAK

46
How to Prepare
47
Who Is the IRB Again?
  • Human subjects protection committee
  • Scientific review
  • Ethical review
  • NOT A DSMB
  • NOT the OCT or SPA
  • NOT Research Compliance

48
Do a little Quality Control
  • The IRB, reviewing from the principal perspective
    of human protection, begins with a scientifically
    sound clinical trial
  • Bad science bad clinical trial
  • Good science ? good clinical trial

49
Who is Vulnerable?
The research involves VULNERABLE research
participants any time some or all of the subjects
are likely to be vulnerable to coercion or undue
influence.
  • Populations
  • Pregnant women, Prisoners, Children,
  • Mentally Disabled persons, Economically or
    educationally disadvantaged persons
  • What about limited English proficiency,
    employees, students, end-of life cases, etc. ???
  • What Must be Done?
  • Always consider vulnerability of
    individuals/groups (PI protocol/application and
    IRB review)
  • Document considerations where practical/notable
    (PI protocol/application and IRB review)
  • Document required findings (IRB level only)
  • Pregnant women
  • Prisoners
  • Children

50
IRB Review Requirements
  • In order for a project to receive IRB approval
    the IRB Board and reviewers must review and
    document certain findings according to the
    Federal Regulations.
  • Research CANNOT be approved unless these
    findings can be made.

51
Regulatory Requirements For IRB Approval 45 CFR
46.111
  • Minimized risks
  • Reasonable risk/benefit ratio
  • Equitable subject selection
  • Informed consent process
  • Informed consent documentation
  • Data monitored for safety
  • Confidentiality/privacy maintained
  • Vulnerable populations protected

52
Regulations and Guidelines
  • HHS Regulations 45 CFR Part 46
  • FDA CFR 21 Parts 50, 56, 312, 812
  • ICH Good Clinical Practice
  • The regulations are open to interpretation
  • 45 CFR 46, OHRP is the interpreter
  • 21 CFR and it subparts are interpreted by the FDA

53
Subparts
  • Three subparts under HHS regulations
  • Subpart B Fetus, Pregnant Women, In Vitro and
    neonates of uncertain viability
  • Subpart C - Prisoners
  • Subpart D Children
  • Subparts under FDA regulations
  • Subpart D - Children

54
Consent
  • Informed Consent Documents
  • NYU SoM IRB standard template
  • Title
  • Purpose
  • of Subjects to participate at NYU and in
    total (multicenter)
  • Description of Procedures
  • Costs
  • Risks
  • Benefits
  • Alternatives
  • Confidentiality including Authorization to use
    PHI
  • Treatment for injury
  • Voluntary Participation and Withdrawal
  • Permission to contact for future research
  • Contact information for more information or
    question on rights
  • HIV Reporting Disclosure

55
Consent
  • Research that Requires Consent
  • Greater than minimal risk
  • Practicable to obtain consent
  • Identifiers being collected- Authorization
  • Research that May Not Require Consent
  • Minimal Risk
  • Impracticable to obtain consent
  • Anonymous information collected
  • No identifiers collected

56
HIPAA
  • The Authorization is combined with the consent
    form
  • What does that mean?
  • Subject sign only one document not two

57
Elements of a Protocol
  • Background
  • Project Description including Specific Aims
  • Literature Review
  • Rationale
  • Inclusion/Exclusion Criteria
  • Methods
  • Risks and Benefits
  • Primary and Secondary Outcomes
  • Statistical Analysis
  • Informed Consent Process or Waiver info

58
Background and Specific Aims
  • Should contain a summary of previous work and
    rationale for the study
  • May be a cut and paste from the NIH grant
  • References should be included
  • Feel free to make use of the references
  • There should be clear aims and endpoints

59
Subject Selection and Enrollment
  • How are subjects identified?
  • charts, referrals, PIs own clinic, support
    groups, public records.
  • How, when and by whom are subjects for contacted
    about study?
  • In person? Should be by someone who has reason to
    know confidential medical information.
  • Letters? Letters should be co-signed by the MD
    know to the patient-subject.
  • No cold calls.

60
Subject Selection and Enrollment
  • Advertising for subjects?
  • Radio scripts, web page content, advertisements,
    etc.. All need IRB approval
  • Content for ads must meet IRB requirements
  • Cannot be coercive
  • No amounts listed

61
Subject Selection and Enrollment
  • Inclusion/Exclusion Criteria
  • Should be a detailed list
  • Should include appropriate laboratory parameters
  • Should include appropriate medical exclusions
  • Should not/rarely exclude non English speakers
  • Who obtains consent? Who gives consent?

62
Study Procedures
  • Should include sufficient detail to ascertain
    what subjects will actually experience while in
    study.
  • Time commitment.
  • Setting or site where study procedures occur.
  • Any routine agents to be used such as
    sedation.
  • ALL this should also be in the Consent form with
    detail in lay terms.

63
Biostatistics
  • A formal sample size is generally necessary.
  • Why does the PI need this many subjects?
  • Are there enough subjects to answer the study
    question?
  • How are the data to be analyzed?
  • Just because the PI says it is a pilot study
    doesnt mean they dont need statistics.

64
Risks and Discomforts
  • Should be listed clearly, quantitatively and in
    order of seriousness.
  • Should include risks of withdrawal from current
    medications.
  • Non medical risks? Social, legal, financial or
    psychological risks?
  • Is loss of confidentiality a legitimate risk or
    concern?
  • What about loss of privacy?
  • Is there a complete list of adverse events in the
    drug or device brochure?
  • Any foreseeable but maybe still theoretical risks
    for example tumorigenesis?

65
Benefits
  • Compensation is not a benefit.
  • If there are benefits to the individual subjects
    these should be discussed first, then any
    potential benefits to future society.
  • A common error we see is the overstatement of
    benefits.
  • Example of good benefit statement
  • There is no direct health benefits to you as a
    result of your participation in this study.
    However we hope to find information that will
    help improve treatment of your condition in the
    future.

66
Safety Monitoring
  • How are the data to be monitored and by whom?
  • All studies involving more than minimal risk
    require a data and safety monitoring plan.
  • Not all studies require a DSMB but if one is
    necessary who does it involve? Is it independent?
    Should it be?
  • Are there objective criteria for withdrawal of
    subjects when safety is in question?
  • Are there stopping rules?
  • Is there a plan for reporting to the IRB?
  • Does the PI state that NYU SoMs IRB Reportable
    Events guidelines will be followed?

67
Review Strategies
68
Suggested Review Strategy
  • Review application
  • Look for special issues such as kids, radiation,
    emergency use issues, new drugs/devices,
    genetics, storing samples for future use
  • Read protocol summary
  • Look for site specific issues can we
    logistically perform the study here?
  • Read detailed protocol
  • Look also at any study specific tools, letters,
    ads, extras

69
Suggested Review Strategy
  • Prepare your comments
  • Written and submitted are wonderful
  • Emailed is even better
  • Editing the consent form
  • Edit right on the document
  • Use legible handwriting
  • Submit marked up document
  • NIH grant
  • Review for consistency
  • Is the study captured in the grant
  • If PI says study pays, are there funds to pay

70
Suggested Review Strategy
  • Scientific Reviewers
  • 1. Read protocol jot down comments, thoughts
    suggestions etc..
  • 2. Read Consent Mark it up!
  • 3. Look at any additional info (ads, scripts,
    etc..)
  • 4. Think about 45 CFR 46.111 can you make the
    findings?
  • If yes, be prepared to explain how
  • If no, be prepared to explain how
  • Come to the meeting ready
  • to state your opinion and be able to justify it

71
Suggested Review Strategy
  • Non- Scientific Reviewers
  • 1. Read protocol summary
  • 2. Read Consent Mark it up!
  • 3. Think about one important question before you
    come to the meeting Do I know what this study
    is ALL about?
  • 3. Look at any additional info (ads, scripts,
    etc..)
  • 4. Think about 45 CFR 46.111 do you think the
    findings can be made?
  • 5. jot down comments, thoughts suggestions etc..

72
Its Meeting Time
73
How Our IRB System Works
  • Primary and Secondary Reviewers
  • Assignments made 1 week ahead of meeting
  • Discussion by Full Committee
  • Reviewers lead discussion
  • Everyone contributes
  • Committee Vote
  • Approve
  • Conditional Approval
  • Deferral
  • Disapprove
  • One year maximum approval

74
At the Meeting
  • Primary reviewer, present a 2-3 minute summary of
    the study
  • Present clear, concise, well defined review
  • Focus on major consent form issues, leave grammar
    and typos to the consent team
  • Assume everyone else has read their assignments
  • Present your recommended disposition
  • Secondary reviewer, add anything that the Primary
    didnt touch on

75
Quorum
  • 45 CFR 46.108 IRB functions and operations.
  • In order to fulfill the requirements of this
    policy each IRB shall
  • (b) Except when an expedited review procedure
    is used, review proposed research at convened
    meetings at which a majority of the members of
    the IRB are present, including at least one
    member whose primary concerns are in
    nonscientific areas.

76
Quorum
  • Regulations require we meet quorum.
  • We define quorum as more than half the members
    present.
  • Since we cant cut anyone in two, this means if
    there are 22 people on the board, we cant start
    the meeting until 12 people are present.
  • We need your expertise.
  • Meetings begin 900 AM Please be on time.

77
At Convened Meetings
  • A majority of members must be present
  • Nonscientist must be present
  • No nonscientist ---gt no meeting
  • Community member not always nonscientist
  • Meeting must stop whenever number present drops
    below quorum or nonscientist leaves
  • 45 CFR 46.108

78
At Convened Meetings
  • IRB Meeting Convened without Quorum
  • (Scientist or Nonscientist Absent or a majority
    of member not present)
  • When no scientist or nonscientist member is
    present during the course of the meeting or the
    quorum fails during a meeting (e.g., those with
    conflicts being excused, early departures), the
    IRB may not take further actions or votes until a
    nonscientist member returns.
  • OHRP guidance

79
At Convened Meetings Review of Protocols
  • Members must receive protocols PRIOR to the
    meeting, with sufficient time to review.
  • Protocols may not be distributed at the meeting
    for review at the meeting.

80
Convened Meetings Vote
  • We do a show of hands to record vote
  • for, against, abstain
  • Record in minutes (Example)
  • Total 8
  • For 6 Against 1Abstain 1

81
Convened Meetings Vote (Continued)
  • Total number present is important especially if
    anyone has left the room
  • Must vote separately on each protocol

82
IRB Members and CONFLICT OF INTEREST
83
Regulations...
  • DHHS and FDA regulations 45CFR 46.107(e) 21CFR
    56.107(e) prohibit members from participating in
    IRB reviews if they have a conflict of interest.
  • No IRB may have a member participate in the IRB's
    initial or continuing review of any project in
    which the member has a conflicting interest,
    except to provide information requested by the
    IRB.

84
NYU SoM Policy for Conflict of Interest Disclosure
  • It is the expectation of the University that IRB
    members will voluntarily recuse themselves from
    review and discussion of research protocols if
    they have a conflict of interest.
  • Members of the IRB must disclose to the IRB Chair
    or Administrator any conflict of interest that
    may arise in the review of research or compliance
    matters for the IRB.
  • Members should not divulge the details of their
    conflict - just that one exists

85
Risk of Non-Recusal
  • Compromised Objectivity
  • Biased opinion of the merit of the study
  • Biased opinion of whether IRB criteria for
    approval have been met
  • Undue influence on other IRB members
  • Appearance of impropriety loss of public trust

86
Conflicts of Interest that Require Member Recusal
  • Members who are an investigator or faculty
    sponsor on the project under review, or whose
    spouse or child is an investigator or faculty
    sponsor
  • Members who have any financial interests (i) that
    would reasonably appear to be affected by the
    research or (ii) in entities whose financial
    interests would reasonably appear to be affected
    by the research
  • Members who believe existing circumstances may
    directly affect their objectivity should recuse
    themselves from the review

87
At Convened Meetings
  • You have a conflicting interest in a proposal
    under review.
  • How should the IRB handle this?

88
At Convened Meetings
  • Recusal
  • If an IRB member has a conflicting interest in a
    project under review, the member MUST leave the
    room during the discussion and vote of the
    project.

89
Recusal
  • The member may be present if the IRB requests
    clarifications from the member.
  • Vote is not valid if member does not leave the
    room.
  • There can be no exceptions.

90
Recusal
  • What if quorum is lost if the member with the
    conflict leaves the room for the discussion and
    vote on the proposal?

91
Recusal
  • The proposal must wait for the next convened
    meeting for which there will be a quorum without
    the conflicted member.

92
Other Responsibilities of the IRB
  • Annual review and re-approval (Continuing Review)
  • Observe, Monitor and Audit
  • Suspend or Terminate Approval

93
IRB Approved Research what happens next
  • Continuations - usually require full board review
  • Modifications major modifications require full
    board review
  • Reportable events
  • Unanticipated problems causing risk of harm to
    subject or other
  • Unanticipated adverse events (not in original
    proposal)
  • Deviations/violations
  • Patient Complaints
  • Imprisonment of subjects

94
Continuing Review
  • Reporting on study to date
  • Reality check on how it is really going
  • Any new developments in alternatives?
  • Risks and discomforts havent changed?
  • Benefits havent changed?
  • Any new risks identified?
  • Are the initial statistical assumptions still
    valid

95
Continuing Review
  • Have any/all amendments been incorporated into
    the protocol document?
  • Have any/all amendments been incorporated into
    the consent document?
  • If NIH funded, is the progress report consistent
    with the continuing review report?

96
  • BREAK

97
History of Protection of Human Subjects
  • Nuremberg Code (1947)
  • Unethical Research in the U.S.
  • Regulations
  • Modern Day Problems
  • Declaration of Helsinki (1964,75,83,89,2000,200
    8)

98
Nuremberg
  • During the Nuremberg War Crimes Trials
  • 23 German doctors were charged with crimes
    against humanity for performing medical
    experiments upon concentration camp inmates and
    other living human subjects, without their
    consent, in the course of which experiments the
    defendants committed the murders, brutalities,
    cruelties, tortures, atrocities, and other
    inhuman acts.

99
Nuremberg
  • As part of the verdict, the Court enumerated some
    rules for "Permissible Medical Experiments", now
    known as the Nuremberg Code. These rules
    include
  • voluntary consent
  • experiment yielded results for good of society
  • benefits outweigh risks
  • ability of the subject to terminate participation

100
Nuremberg
  • Creation of the Nuremberg Code (1947)
  • Although it did not carry the force of law, the
    Nuremberg Code was the first international
    document which advocated voluntary participation
    and informed consent.
  • 10 principles includes informed consent and
    absence of coercion properly formulated
    scientific experimentation and beneficence
    towards experiment participants.

101
  • SUCH CONDUCT COULD NOT OCCUR IN THE U.S.
  • RIGHT?

102
Well Known Major Cases Involving Unethical
Research in the U.S.
  • Willowbrook (1956 -1965)
  • Jewish Chronic Disease (1963)
  • USPHS Syphilis Study (aka Tuskegee Study)
    (1932-72)
  • And More modern day problems.

103
The Willowbrook Hepatitis Study
  • New York (1963-1966)
  • Conducted on mentally retarded, institutionalized
    children
  • Involved systematically infecting the children
    with hepatitis
  • Parents were coerced into consenting

104
Jewish Chronic Disease Hospital
  • New York (1963)
  • Cancer Experiments
  • Injection of live cancer cells
  • Hospitalized elderly patients
  • Indigent subjects were injected with live cancer
    cells without their knowledge or consent

105
US Public Health Services Study of Untreated
Syphilis in the Negro Male
  • American medical research project conducted by
    the U.S. Public Health Service from 1932 to 1972
  • Tuskegee syphilis study
  • examined the natural course of untreated
    syphilis in black American men when there was no
    effective treatment
  • subjects all poor sharecroppers - unknowing
    participants
  • subjects not told that they had syphilis - nor
    offered effective treatment once it came
    available

106
US Government Regulation
  • After problems in US Medical Research were
    highlighted, the US government decided to look
    into government regulation of human
    experimentation and develop ethical guidelines
    for such research.

107
US Government Response
  • 1973 Kennedy Hearings
  • Quality of Health Care Human
    Experimentation
  • 1974 National Research Act
  • Established the National Commission for the
  • Protection of Human Subjects of Biomedical and
  • Behavioral Research
  • Required IRBs at institutions receiving federal
  • support for human subjects research

108
National Research Act 1974
  • Established the National Commission for the
    Protection of Human Subjects of Biomedical and
    Behavioral Research (i.e., The National
    Commission)
  • Initially met over a four-day period in 1976
  • Met at the Smithsonian Institute's Belmont
    Conference Center (thus The Belmont Report)
  • Monthly deliberations over the next four years
  • Resulted in The Belmont Report

109
Respect for Persons informed consent , respect
for privacy

Beneficence(nonmalficence) first do no harm, good
research design, competent investigators,
favorable risk/benefit analysis maximize
benefits, minimize risks.
Justice equitable selection of subjects
appropriate inclusion and exclusion criteria.
110
The Federal Government and the IRB
DHHS
Office of Human Research Protection
NIH
FDA
21 CFR 50,56
45 CFR 46
Institutional Review Board
111
Regulations and Guidelines
  • HHS Regulations 45 CFR Part 46
  • FDA CFR 21 Parts 50, 56, 312, 812
  • ICH Good Clinical Practice
  • The regulations are open to interpretation
  • 45 CFR 46, OHRP is the interpreter
  • 21 CFR and it subparts are interpreted by the FDA

112
Subparts
  • Three subparts under HHS regulations
  • Subpart B Fetus, Pregnant Women, In Vitro and
    neonates of uncertain viability
  • Subpart C - Prisoners
  • Subpart D Children
  • Subparts under FDA regulations
  • Subpart D - Children

113
Modern Day Problems
  • The public, congress, and universities react to
  • Ethical and scientific mistakes
  • September 1999, University of Pennsylvania,
    18-yearold volunteer named Jesse Gelsinger died
    from drugs administered as part of a gene therapy
    study
  • June 2001, Johns Hopkins, Ellen Roche, a
    24-year-old volunteer, died one month after
    inhaling an unapproved drug as part of a study
    into the causes of asthma.

114
Declaration of Helsinki
  • At the conclusion of the Nuremberg Trials it was
    decided that as biomedical research efforts
    expanded, there was an international need for a
    more specific code of ethics to review research.
  • This specific code was formulated in 1964 and
    called the Declaration of Helsinki.

115
Declaration of Helsinki
Recommendations Guiding Medical Doctors in
Biomedical Research Involving Human Subjects
Adopted by the 18th World Medical Assembly,
Helsinki, Finland, 1964 and as revised by the
World Medical Assembly in Tokyo, Japan in 1975,
in Venice, Italy in 1983, and in Hong Kong in
1989 and the 48th General Assembly, Somerset
West, Republic of South Africa, October 1996,
52nd General Assembly, Edinburgh, Scotland in
2000, Note clarification on paragraph 29 added by
WMA, Washington 2002, Note clarification on
paragraph 30 added by WMA, Tokyo 2004, 2008
Cairo/Sao Paulo. Concern for the interests of
the subject must always prevail over the
interests of science and society.
116
Declaration of Helsinki
  • In cases of incompetence informed consent should
    be obtained from legal guardian or responsible
    relative
  • Some risks justified by potential therapeutic or
    diagnostic value to the patient

117
The Belmont Report as a Review Tool
118
Belmont Principles
  • Are general prescriptive judgments (Other
    principles may also be relevant)
  • Cannot always be applied so as to resolve beyond
    dispute particular ethical problems
  • But the objective is to provide an analytical
    framework that will guide the resolution of
    ethical problems arising from research involving
    human subjects.

119
The Belmont Report
  • Boundaries Between Practice and Research
  • IRB must determine that the researcher (and
    through informed consent, the subject)
    distinguishes practice from experiment in both
    social science and medical science research

120
Respect for Persons
  • Treat individuals as autonomous agents
  • Do not use people as means to an end
  • Allow people to choose for themselves
  • Give extra protection to those with limited
    autonomy

121
Beneficence
  • Acts of kindness or charity that go beyond duty
  • Obligations derived from beneficence
  • Do no harm
  • Prevent harm
  • Prevent evil
  • Promote good

122
Justice
  • Treat people fairly
  • Fair sharing of burdens and benefits of research
  • Distinguish procedural justice from distributive
    justice

123
Protocol Design Respect for Persons
  • Consider
  • How can the consent process maximize autonomy?
  • How can the protocol maximize autonomy?
  • What additional protections can be in place for
    protected populations?
  • How can this study maximally protect subject
    privacy?

124
Protocol Design Beneficence
  • Consider
  • Can the research design be improved to enhance
    safety and benefit ?
  • What are the risks? How can they be minimized?
  • What are the benefits? How can they be maximized?

125
Protocol Design Justice
  • Consider
  • How can you ensure that recruitment targets the
    population that will benefit from the research?
  • How can you ensure that recruitment will not
    unfairly target a population? (avoid exploitation
    of population of convenience)
  • How can the inclusion/exclusion criteria be made
    fair?

126
Other Commonly Vexing Details
  • Or things that will make you tear your hair out

127
Investigator Conflicts of Interest
  • All PIs must be in compliance with the NYU SoM
    rules.
  • IRB can and must flag any conflicts we become
    aware of during our reviews.
  • IRB can refer PIs to COIC and or Research
    Compliance Office.

128
Short Forms
  • Use when non English speaking subjects are
    unexpectedly eligible for the study.
  • Short form must be written in the subjects
    native language.
  • Needs an attestation of accuracy of translation,
    where no funding is available for certified
    translations.
  • Impartial witness signature
  • Family member of the subject
  • Member of staff not related to the project
  • Translator
  • Does not require prior IRB review

129
Consent Process and Forms
  • Consent is a process and not just a form.
  • The form is the document that captures the
    signature and records the process of agreement to
    participate.
  • Timing is important Protocol should give us
    details regarding the consent process
  • Once consent is signed, person is considered
    enrolled in study those who do not meet
    inclusion are screen failures

130
Consent and Assent
  • In NY Adults age 18 and up.
  • Anyone under 18 must have a parent or guardians
    permission (at least one) in order to
    participate.
  • Sophisticated teens (15-17) can use the adult
    consent form for assent purposes
  • NYU SoM has research assent form templates for
    kids 7-11 and 12-14.
  • Assent may be obtained verbally.
  • Emancipated Minors A pregnant teen or child.

131
Emancipated Minor
  • Nikki is 15 years old, and she has a
    2-month- old daughter. She visits the doctor with
    her daughter and her mother. During the visit,
    the doctor keeps talking to Nikkis mother about
    the baby. The doctor wants the baby to be put on
    an investigational drug. Who can consent?
  • As the parent, Nikki has the right to make all
    treatment decisions for her child including
    research as treatment option. Nikki can seek
    the advice of her own mother in making those
    decisions but Nikki can consent to her
    daughters health care and any research options
    with or without her mothers input.

132
Assent
  • Assent means a childs affirmative agreement to
    participate in research, (45 CFR 46.402(b). The
    child must actively show his or her willingness
    to participate in the research, rather than just
    complying with directions to participate and not
    resisting in any way.
  • When judging whether children are capable of
    assent, the ages, maturity, and psychological
    state of the children involved must be taken into
    account.

133
Assent (cont.)
  • At the IRB meeting if the board determines that
    assent is not required, one of these findings
    must be met
  • (1) capability of some or all of the children is
    so limited that they cannot reasonably be
    consulted or (2) the intervention or procedure
    involved in the research holds out a prospect of
    direct benefit that is important to the health or
    well-being of the children and is available only
    in the context of the research.

134
Who May Obtain Consent?
  • People can obtain consent for activities
    commensurate with their usual clinical practice
    in medicine
  • Mammogram technologist
  • BA study coordinator
  • RN DPP GTT, lab work
  • RNP DM, study initiation and education for FDA
    approved drugs
  • Licensed MD investigational drugs and device
    studies

135
Surrogate Consent
  • Why cant the subject give consent?
  • NEW YORK law doesnt cover research but we have
    guidance see our web page policies.
  • How do we consider when surrogate consent is
    appropriate?
  • Potential/likely benefit is required and/or risk
    must be very small indeed.
  • Who can be a surrogate? Spouse? Children?
    Siblings?

136
Study Staff
  • Their qualifications should match their
    responsibilities.
  • PIs can delegate but must be specific.
  • When someone is assigned as back up, what does
    this mean to us?

137
WHO MAY BE PRINCIPAL INVESTIGATOR ?
FACULTY
138
OTHER APPROVALS
  • Conflict of Interest Committee (COI)
  • Radiation Safety Committee
  • Institutional Bio-safety Committee
  • Protocol Reviewing and Monitoring Committee
    (PMRC)
  • Bellevue Hospital Committee
  • BHC Drug and Formulary
  • General Clinical Research Center (GCRC)
  • Approvals are pre-requisite for IRB approval

139
International Research
  • OHRP says if the study is federally funded, then
    our rules prevail.
  • Do we know enough about the local situation to
    review the study?
  • Can we get the information if needed?
  • Is there an IRB or ethics committee over there?
  • Can we get things translated?
  • Do we have an expert on this area/population?
  • Can be an IRB member or the PI or a consultant.

140
Prisoners
  • To review prisoner research IRB must have a
    prisoner advocate on the board we do
  • Must review research with Subpart C regulations
    see reviewers checklist for details
  • If a subject is imprisoned during participation
    in research that was not reviewed and approved to
    include research the IRB must revisit the study

141
Treatment IND/IDE and Other Expanded Access To
Investigational Drugs and Devices
142
Treatment IND/IDE
  • A Treatment Use is implemented when a patient
    does not meet the eligibility requirements of any
    other clinical trial, and the drug or device is
    not approved for marketing but is under a
    clinical investigation. Treatment Uses are
    approved to treat a serious or immediately life
    threatening condition.

143
Treatment IND
  • Treatment IND 21 CFR 312.34 and 312.35 is a
    mechanism for providing eligible subjects with
    investigational drugs for the treatment of
    serious and life-threatening illnesses for which
    there are no satisfactory alternative treatments.
  • FDA requires the following to issue
  • The drug is intended to treat a serious or
    immediately life-threatening disease
  • There is no comparable or satisfactory
    alternative drug or other therapy available to
    treat that stage of the disease in the intended
    patient population
  • The drug is under investigation in a controlled
    clinical trial under an IND in effect for the
    trial, or all clinical trials have been
    completed and
  • The sponsor of the controlled clinical trial is
    actively pursuing marketing approval of the
    investigational drug with due diligence.

144
Treatment IND
  • Treatment IND studies require prospective IRB
    review and informed consent.
  • A sponsor may apply for a waiver of local IRB
    review under a treatment IND if it can be shown
    to be in the best interest of the subjects, and
    if a satisfactory alternate mechanism for
    assuring the protection of human subjects is
    available, e.g., review by a central IRB. Such a
    waiver does not apply to the informed consent
    requirement.
  • NYU requires IRB review before a treatment IND is
    used, even in cases where FDA has granted a
    waiver.

145
Others
  • Compassionate Use Treatment IND
  • Humanitarian Device Exemption
  • Other FDA approved expanded access use for a
    drug/biologic/device 

146
Wrap Up
147
General Pointers/considerations
  • The committee system exists to keep you out of
    the hot seat
  • We do not post IRB member rosters but it is
    public information and researchers, sponsors and
    anyone else can get this information
  • We do not post nor do we release reviewer
    assignments
  • Individuals vote by name is not recorded
  • You may contact the PI prior to the meeting if
    you wish OR you can let the IRB office be the
    middle man at your discretion entirely.

148
IRB Review As Peer Review
  • Strives for consistency but different reviewers
    can and do have different opinions.
  • Staff meets with the IRB chair in order to create
    and communicate consistent approaches,
    requirements, regulations.
  • The system is not perfect but it is effective.

149
Determining an Action
  • Approval the criteria for approval are met.
  • Conditional approval IRB stipulates specific
    revisions requiring simple concurrence by the
    investigator, then the IRB Chair or another IRB
    member designated by the Chair subsequently
    approve the revised research protocol on behalf
    of the IRB.
  • Deferral - substantive clarifications or
    modifications required that are directly relevant
    to the criteria for approval.
  • Disapproval major ethical or scientific issues
    PI can respond to the IRB or start over.

150
Common Review Issues
  • PI has failed to provide information about
    reasonable clinical context or apparent
    withholding of standard of care.
  • Failure to minimize risk.
  • Inadequate information about collaborating sites,
    especially when international sites are involved.
  • Poor preparation of materials cutting and
    pasting errors.
  • Poor writing skills, no proof reading.

151
Dos
  • Do feel free to answer questions and provide
    information about the study if you are a
    co-investigator
  • Do remove yourself from the room if you are a
    co-investigator or have any other conflict with a
    study under review
  • Do vote your conscience
  • Do keep reviews confidential it protects you
    and the Board

152
Donts
  • Dont discuss IRB meetings outside the meeting or
    with any one other than the PI
  • IRB meetings are confidential
  • They include confidential sponsor information
  • Discussions could lead to scientific disputes,
    competition issues

153
Bottom Line
  • It is not ethical to subject people to risks,
    discomforts or inconveniences for research that
    cannot contribute meaningfully to science!
  • If the IRB cant understand the submission, then
    the PI hasnt done a good job.

154
Last Words
  • Dont hesitate to communicate with our office or
    the IRB Chair/Vice Chairs directly.
  • Dont hesitate to ask for advice at the meetings.
  • If you find things missing from your materials,
    contact the IRB office prior to the meeting so we
    can get the material to you.
  • Again we welcome you
  • thank you for joining the IRB
  • and thank you for giving us your time today

155
Key Reading
  • The Belmont Report
  • Our IRB policies and procedures
  • The regulatory criteria for IRB approval
  • The regulatory criteria for the elements of
    consent
  • The FDAs information sheets

156
2008/2009 MEETING DATES
Go To http//www.med.nyu.edu/irb/schedule/index.h
tml
IRB Web site Go To http//www.med.nyu.edu/irb.ht
ml IRB Staff Contact Info IRB Policies, Forms ,
Guidelines etc.. Information for Research
Volunteers IRB Course Calendar IRB Consent Tool
Kit IRB Newsletter
157
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