the IRB.ppt - NYU Langone Medical Center

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					Welcome to the IRB
 NYU School of Medicine

  New Member

    Helen Panageas, CIP
     Associate Director
         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….
              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
            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
           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,
 FDA regulated studies in accordance with TITLE
        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
                   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
                IRB Membership

   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)
                 IRB Membership

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)
       The Individual IRB Member
     It‟s tough job but you add to the process

   Your unique professional and personal

          This includes your scientific, social, ethical, community,
           minority, legal, administrative or operational
           perspectives, maybe all of these.
      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.
        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
How does it Work?
Human Subjects Protection
is a Shared Responsibility

   IRB                 Investigator/

Team Approach
    Institutional Official obligations:
   Sets tone for culture for respect of human
   Serves as Signatory official on Federa-lwide
   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
            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
            IRB Chair role:
   Full knowledge of regulations and their application
   Maintain current knowledge of trends and changes in protection
   Convene IRB meetings
   Perform review functions as needed for new, and continuing
   Assist institution in review of non-compliance
   Perform “expedited review” and/ or designate experienced
   Assist in the education and development of IRB members
   Assure that documentation (minutes etc.) adhere to regulatory
   Assure that all members have equal voice in meeting
    deliberations and voting
   Keep deliberations of IRB confidential
    IRB panel obligations:
   Apply the rules and regulations to specific
   Provide constructive review of research proposals (in a
    timely manner)
   Assist with education of research community
   Respond to staff requests for attendance and
   Communicate new developments to research community
   Seek outside consultation when lacking expertise
   Model exemplary research behavior
            IRB member roles:
   Full knowledge of regulations and their
   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
    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
   Train and supervise research team and
    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.
        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.
            System Integrity
   Team system is based on trust and open
   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
                 How does it work?
   Basically:
     Protocols submitted for review
     IRB Admin Office processes review
         Reviews to ensure conformity to regulations and NYU
         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..
              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
   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
  Types of IRB Review



     How is Review Type Determined?
             Four Basic Questions:

1.   Is the Proposed project Research?
2.   Does the proposed project involve Human
3.   What type of Risk is involved in the
     proposed project?
4.   Does the proposed project meet the
     criteria for the Review Category?
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.
      Are Human Subjects involved ?

Human subject means a living individual about
      whom an investigator (whether professional
      or student) conducting research obtains

(1)   Data through intervention or interaction with
      the individual, or
(2)   Identifiable private information.
     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.
 Review Categories
  Three Review Types:
Full, Expedited, Exempt

       & Exempt
 have Review Categories
           Review Continuum

 The level of review depends on the
   risk to the human participants.
Risk:        Low     Minimal       Higher

Review:     Exempt   Expedited      Full
Consent:     None    May be Waived Required
        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
And then there‟s ………

                                 18 Identifiers

   Names/Initials              Certificate/License numbers
   Postal Address              VIN including license plate
   Dates (DOB, DOA, DOD)        numbers
   Telephone numbers           Device identifiers
   Fax numbers                 Web URLs
   E-mail address              Internet Protocol address
   Social Security Number      Biometric identifiers
   Medical Record Number       Photographs and comparable
   Health Plan Numbers          images
   Account Numbers             Any other unique identifying
                                 number, characteristic, or
                 Some IRB Speak
   AE- Adverse Event
   CFR - Code of Federal Regulations
   CIP- Certified IRB Professional
   COG- Children‟s 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
The Process
         Mechanics of the process
   About 2 weeks prior to the meeting, an
    RSVP is sent via email.
       If you don‟t 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.
          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
          Your Review Materials
   Initially daunting but you‟ll soon be able to
    move through them quickly.
   Check your assignments.
   If you are primary or secondary – read in
   Otherwise, review the protocol summary,
    the consent forms and any advertisements.
   Feel free to add to any discussion regardless
    of your assignment.
         Your Review Materials
   The Reviewer‟s Checklist
     Why was it created?
     Function

     Do you need to fill it out?

     Do you need to hand it in?
How to Prepare
         Who Is the IRB Again?

   Human subjects protection committee
     Scientific review
     Ethical review

   NOT the OCT or SPA
   NOT Research Compliance
  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
                  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:                    What Must be Done?
   Pregnant women,                Always consider vulnerability
    Prisoners, Children,            of individuals/groups (PI
   Mentally Disabled               protocol/application and IRB
    persons, Economically           review)
    or educationally               Document considerations
    disadvantaged persons           where practical/notable (PI
                                    protocol/application and IRB
   What about: limited            Document required findings
    English proficiency,            (IRB level only):
    employees, students,              Pregnant women
    end-of life cases, etc.           Prisoners
    ???                               Children
  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.
      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
       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

   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
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
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
   The Authorization is combined with the
    consent form

   What does that mean?
        Subject sign only one document not two
         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
    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

   References should be included
       Feel free to make use of the references
Subject Selection and Enrollment
   How are subjects identified?
      charts, referrals, PI‟s 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
      Letters? Letters should be co-signed by the
       MD know to the patient-subject.
      No cold calls.
Subject Selection and Enrollment
   Advertising for subjects?
      Radio scripts, web page content,
       advertisements, etc.. All need IRB approval
         Content for ads must meet IRB
             Cannot be coercive

             No $ amounts listed
           Subject Selection and
   Inclusion/Exclusion Criteria
       Should be a detailed list
       Should include appropriate laboratory
       Should include appropriate medical exclusions
       Should not/rarely exclude non English

   Who obtains consent? Who gives consent?
               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
       ALL this should also be in the Consent form
        with detail in lay terms.
   A formal sample size is generally necessary.

   Why does the PI need this many subjects?

   Are there enough subjects to answer the study

   How are the data to be analyzed?

   Just because the PI says it is a pilot study doesn‟t
    mean they don‟t need statistics.
            Risks and Discomforts
   Should be listed clearly, quantitatively and in
    order of seriousness.
       Should include risks of withdrawal from current
       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?
   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

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.
                Safety Monitoring
   How are the data to be monitored and by
       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 SoM‟s IRB Reportable
        Events guidelines will be followed?
Review Strategies
        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
     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
     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
     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
It‟s Meeting Time
     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
              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
   Present your recommended disposition
   Secondary reviewer, add anything that the
    Primary didn‟t touch on
45 CFR 46.108 IRB functions and operations.
In order to fulfill the requirements of this policy each IRB

 … (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….

   Regulations require we meet quorum.
   We define quorum as more than half the
    members present.
       Since we can‟t cut anyone in two, this means if
        there are 22 people on the board, we can‟t start
        the meeting until 12 people are present.
   We need your expertise.
   Meetings begin 9:00 AM Please be on time.
      At Convened Meetings

 A majority of members must be present
 Nonscientist must be present
    No nonscientist ---> no meeting
    Community member: not always =
 Meeting must stop whenever number present
  drops below quorum or nonscientist leaves

45 CFR 46.108
           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
         At Convened Meetings
            Review of Protocols

   Members must receive protocols PRIOR to
    the meeting, with sufficient time to

   Protocols may not be distributed at the
    meeting for review at the meeting.
          Convened Meetings
   We do a show of hands to record
      for, against, abstain

   Record in minutes (Example):
     Total = 8 ;

     For = 6; Against = 1;Abstain = 1
           Convened Meetings

   Total number present is important
    especially if anyone has left the room

   Must vote separately on each protocol
   IRB Members and
   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.
      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
           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
     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
  At Convened Meetings

You have a conflicting interest in a
     proposal under review.

How should the IRB handle this?
           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.

   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.

What if quorum is lost if the member
with the conflict leaves the room for
the discussion and vote on the

The proposal must wait for the next
 convened meeting for which there
 will be a quorum without the
 conflicted member.
Other Responsibilities of the IRB

    Annual review and re-approval
     (Continuing Review)

    Observe, Monitor and Audit

    Suspend or Terminate Approval
         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
             Continuing Review

   Reporting on study to date
     Reality check on how it is really going
     Any new developments in alternatives?

     Risks and discomforts haven‟t changed?

     Benefits haven‟t changed?

     Any new risks identified?

     Are the initial statistical assumptions still valid
           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
    History of Protection of Human
   Nuremberg Code (1947)
   Unethical Research in the U.S.
   Regulations
   Modern Day Problems
   Declaration of Helsinki
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.”

   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
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.

           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….
    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
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
                            US Public Health
                            “Study of Untreated
                            Syphilis in the Negro
  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
  subjects all poor sharecroppers - unknowing participants
  subjects not told that they had syphilis - nor offered
  effective treatment once it came available
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
         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
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
       Monthly deliberations over the next four years
       Resulted in The Belmont Report
  Respect for Persons
  informed consent ,
  respect for privacy

first do no harm,
good research design,
competent investigators,
favorable risk/benefit analysis:
maximize benefits,
minimize risks.

 equitable selection of subjects
 appropriate inclusion and
 exclusion criteria.
         The Federal Government
               and the IRB

               NIH      Office of Human
FDA                    Research Protection

21 CFR 50,56               45 CFR 46

     Institutional Review Board
       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

   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
           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.
           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.
                      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.”
              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
The Belmont Report
 as a Review Tool
          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
          The Belmont Report

   Boundaries Between Practice and
       IRB must determine that the researcher
        (and through informed consent, the
        subject) distinguishes practice from
        experiment in both social science and
        medical science research
          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

   Acts of kindness or charity that go beyond
   Obligations derived from beneficence
     Do no harm
     Prevent harm

     Prevent evil

     Promote good

   Treat people fairly
   Fair sharing of burdens and benefits of
   Distinguish procedural justice from
    distributive justice
            Protocol Design:
           Respect for Persons
   Consider:
     How can the consent process maximize
     How can the protocol maximize autonomy?

     What additional protections can be in place
      for protected populations?
     How can this study maximally protect subject
                  Protocol Design:
   Consider:
       Can the research design be improved to
        enhance safety and benefit ?
     What are the risks? How can they be
     What are the benefits? How can they be
                  Protocol Design:
   Consider:
     How can you ensure that recruitment targets
      the population that will benefit from the
     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?
Other Commonly Vexing Details

   Or things that will make you tear your
                hair out…
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.
                       Short Forms
   Use when non English speaking subjects are
    unexpectedly eligible for the study.
   Short form must be written in the subject‟s
    native language.
   Needs an attestation of accuracy of translation,
    where no funding is available for certified
   Impartial witness signature
          Family member of the subject
          Member of staff not related to the project
          Translator
   Does not require prior IRB review
        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
             Consent and Assent
   In NY Adults = age 18 and up.
       Anyone under 18 must have a parent or
        guardian‟s permission (at least one) in order to
       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.
      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 Nikki’s 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
daughter’s health care and any research options
with or without her mother’s input.
   Assent means a child‟s 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
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.
        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
             Surrogate Consent
   Why can‟t the subject give consent?
   NEW YORK law doesn‟t cover research but
    we have guidance – see our web page
   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?
                Study Staff

   Their qualifications should match their
   PIs can delegate but must be specific.
   When someone is assigned as “back up”,
    what does this mean to us?

   Conflict of Interest Committee (COI)*
   Radiation Safety Committee*
   Institutional Bio-safety Committee*
   Protocol Reviewing and Monitoring Committee*
   Bellevue Hospital Committee
   BHC Drug and Formulary
   General Clinical Research Center (GCRC)

* Approvals are pre-requisite for IRB approval
             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.
   To review prisoner research IRB must
    have a prisoner advocate on the board –
    we do
       Must review research with Subpart C
        regulations – see reviewer‟s checklist for
       If a subject is imprisoned during participation
        in research that was not reviewed and
        approved to include research the IRB must
        revisit the study
 Treatment IND/IDE and
Other Expanded Access To
Investigational Drugs and
      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.
                 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

FDA requires the following to issue:
  The drug is intended to treat a serious or immediately life-threatening
  There is no comparable or satisfactory alternative drug or other therapy
   available to treat that stage of the disease in the intended patient
  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.
                  Treatment IND
  Treatment IND studies require prospective IRB review and informed

  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

NYU requires IRB review before a treatment IND is used, even
  in cases where FDA has granted a waiver.

   Compassionate Use = Treatment IND
   Humanitarian Device Exemption
   Other FDA approved expanded access use
    for a drug/biologic/device
Wrap Up
    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
     Individual‟s 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.
     IRB Review As Peer Review
   Strives for consistency but different
    reviewers can and do have different
   Staff meets with the IRB chair in order to
    create and communicate consistent
    approaches, requirements, regulations.
   The system is not perfect but it is
            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
   Disapproval – major ethical or scientific issues – PI
    can respond to the IRB or start over.
          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
   Poor preparation of materials – cutting and
    pasting errors.
   Poor writing skills, no proof reading.
   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

   Don‟t 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
                Bottom Line

   It is not ethical to subject people to risks,
    discomforts or inconveniences for research
    that cannot contribute meaningfully to
   If the IRB can‟t understand the
    submission, then the PI hasn‟t done a
    good job.
                    Last Words
   Don‟t hesitate to communicate with our office or
    the IRB Chair/Vice Chairs directly.
   Don‟t 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
                Key Reading

   The Belmont Report
   Our IRB policies and procedures
   The regulatory criteria for IRB approval
   The regulatory criteria for the elements of
   The FDA‟s information sheets
                  2008/2009 MEETING DATES
                   Go To:

IRB Web site

Go To:

IRB Staff Contact Info
IRB Policies, Forms , Guidelines etc..
Information for Research Volunteers
IRB Course Calendar
IRB Consent Tool Kit
IRB Newsletter

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