COLUMBUS CHILDREN

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COLUMBUS CHILDRENS RESEARCH INSTITUTEand
Columbus Childrens Hospital, Inc.

• Institutional Review Board Tutorial
• Protection of Human Research Subjects

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INTENDED AUDIENCE Physicians, PhDs, nurses, and
other key personnel who conduct research
involving human subjects. JOINT
SPONSORS Childrens Hospital, Inc. and
Childrens Research Institute
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CONTINUING EDUCATION CREDIT This activity has
been planned and implemented in accordance with
the Essential Areas and Policies of the
Accreditation Council for Continuing Medical
Education (ACCME) through the joint sponsorship
of Childrens Hospital, Inc. and the Childrens
Research Institute. Childrens Hospital is
accredited by the ACCME to provide continuing
medical education for physicians. Childrens
Hospital designates this continuing medical
education activity for a maximum of 2.0 credits
in Category I of the Physicians Recognition
Award of the American Medical Association. Each
physician should claim only those hours of credit
that he/she actually spent in the educational
activity.
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CME CERTIFICATE FEE CME Credit transcripts are
provided annually to all members of the
Childrens Hospital Medical staff free of charge.
The CME office must be notified that a passing
score was achieved on the activity post-test and
be in receipt of a completed and signed CME
evaluation form before credit will be issued.
Notification will be sent electronically to the
CME office at the time of completion of the quiz.
The evaluation form will also be sent
electronically to the CME office. Any
non-Childrens Hospital employees may request a
CME Certificate at a cost of 10.00. Payment
(along with the completed post-test and completed
evaluation form) must be made at the time of the
request. Please send the check (payable to
Childrens Hospital) to the CME Office,
Childrens Hospital, 700 Childrens Drive,
Columbus, OH 43205.
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FACULTY DISCLOSURE OF COMMERCIAL
RELATIONSHIPS Faculty for this activity are
expected to disclose any economic or other
personal interests that create or may be
perceived as creating, a conflict related to the
material discussed. This policy is intended to
make you aware of faculties interests, so you
may form your own judgements about such material.
Full disclosure of faculties relationship(s)
will be included in the next section. FACULTY/AUTH
OR John Barnard, M.D. Dr. Barnard has no
conflict of interest relevant to this
presentation.
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INTRODUCTION
This presentation fulfills the human subjects
protection training requirement mandated by the
Department of Health and Human Services (OCTOBER
2000). Completion of this slide presentation and
the accompanying quiz is a requirement for all
key personnel involved in human subject
research at Columbus Childrens Hospital. A quiz
score of 80 or better must be achieved. If there
are questions or problems completing the quiz,
please contact the Institutional Review Board
office at 722-2708 during regular office hours.
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TUTORIAL OUTLINE
History Regulatory Standards and Codes
Good Clinical Practices in Conduct of Human
Research Special Requirements for Vulnerable
Subjects, Including Children The Institutional
Review Board Investigator Responsibilities Informe
d Consent Scientific Integrity and Misconduct
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HISTORY
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HISTORY

• Principles of modern human research protections
  are derived in large part from a storied history
  of indiscretions in the name of biomedical or
  behavioral research.
• Two seminal events are reviewed here
• Trial of Nazi war criminals
• Tuskegee Syphilis Experiments

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NAZI DOCTORS TRIAL

• The Nuremberg Code was one of the first documents
  to address the ethical conduct of human subjects
  research. The Code was recorded as part of the
  judgment against Nazi doctors who committed war
  crimes and murder in the course of human
  experimentation during World War II.

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THE NUREMBERG CODE

• Identified the following basic principles
• voluntary informed consent is essential
• research should give useful results
• research should be based on animal work and prior
  knowledge
• all unnecessary harm should be avoided
• should be no expectation of disability or death
• risk should never exceed benefit
• safeguards to protect subjects should be in place
• only qualified persons should perform research
• subjects may withdraw from research at any time
• researcher must be prepared to stop at any stage

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TUSKEGEE SYPHILIS STUDY

• From the 1930s to the 1973, African-American men
  in Tuskegee, Alabama were unwitting subjects in a
  study of the natural history of syphilis.
  Certain treatments were withheld and subjects
  were not properly informed of their
  participation. This study was sponsored by the
  U.S. Public Health Service and full disclosure of
  this experiment did not occur until the early
  1970s. The Belmont Report and federal regulation
  of human subjects research were a direct result
  of a Congressional investigation of the Tuskegee
  study.

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REGULATORY STANDARDS AND CODES
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THE BELMONT REPORT

• This document was published in 1979 by the
  Belmont Commission in the aftermath of the
  Tuskegee Syphilis Study investigation. The
  Belmont Report remains a cornerstone document in
  human subjects research in the United States.
  The report is entitled Ethical Principles and
  Guidelines for the Protection of Human Subjects
  of Research and emphasizes the following three
  principles1) Respect for persons, 2)
  Beneficence, and 3) Justice

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THE BELMONT REPORT (Cont.)

• Respect for persons individuals should be
  treated as autonomous those with diminished
  autonomy (e.g. children) are entitled to extra
  protection
• Beneficence benefits should be maximized and
  risks minimized human subjects should not be
  harmed
• Justice benefits and risks of research should
  be distributed fairly among participants

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THE BELMONT REPORT(Cont.)

• All persons at Columbus Childrens Hospital who
  seek certification by the Institutional Review
  Board must read the Belmont report. Questions on
  the mandatory quiz are taken from the Belmont
  Report.
• The Belmont Report can be accessed by visiting
  the IRB websites links section.

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REGULATORY CODES

• Code of Federal Regulations Title 21
• FDA regulations regarding human subjects research
  and IRBs
• Part 50 Protection of Human Subjects
• Part 56 Institutional Review Boards
• Part 312 Investigational New Drug Application
• Part 600 Biological Products
• Part 812 Investigational Device Exemptions

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REGULATORY CODES (Cont.)

• Code of Federal Regulations Title 45
• DHHS regulations regarding human subjects
  research and IRBs
• The Office for Human Research Protections (OHRP)
  at DHHS oversees research funded by almost every
  federal agency
• Part 46 Protection of Human Subjects, often
  referred to as the The Common Rule

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REGULATORY CODES (Cont.)

• Columbus Childrens Hospital, its investigators,
  and IRB are responsible to
• The FDA (21 CFR 50) in the case of research
  involving most drugs, biologics or medical
  devices
• OHRP (45 CFR 46) for all research activities
• Both agencies may perform an on-site audit of the
  IRB and/or activities related to individual
  studies

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GUIDELINES

• International Conference on Harmonizations
  Guideline for Good Clinical Practice (1990)
• An international ethical and scientific
  quality standard for designing,
  conducting, recording and reporting trials that
  involve participation of human subjects
• World Medical Association Declaration of Helsinki
  (amended October 2000)An outline of ethical
  principles for medical research involving human
  subjects

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HIPAA

• Health Insurance Portability and Accountability
  Act
• Effective April 14th, 2003
• Strict regulations on use and disclosure of an
  individuals Protected Heath Information (PHI),
  including in research
• Includes all subject data collected during
  research studies
• HIPPA compliance forms must be submitted with
  every IRB application these can be found on the
  IRB website

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• GOOD CLINICAL PRACTICES IN THE CONDUCT OF HUMAN
  RESEARCH

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WHAT IS GOOD CLINICAL PRACTICE (GCP)?

• A standard developed by the International
  Conference on Harmonization by which clinical
  trials are designed, conducted, recorded, and
  reported so that there is public assurance that
  the data are credible, and that the rights,
  welfare, safety and well being of subjects are
  protected.
• Most FDA-regulated industry trials are designed
  to meet GCP guidelines

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SELECTED ELEMENTS OF GOOD CLINICAL PRACTICE

• Investigators should notify the subjects primary
  care physician, preferably in writing, that the
  subject is participating in a clinical study.
• If subjects are given a drug designed to prevent
  disease or progression of disease, they should be
  informed of the chances, in the absence of study
  drug, of acquiring the disease or having the
  disease progress.

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SELECTED ELEMENTS OF GOOD CLINICAL PRACTICE

• If conducting more than one study at the same
  time, a fair and equitable method for spreading
  patients across studies should exist.
• Medical records for serious adverse events should
  be thoroughly reviewed.
• Investigators should not rely on patient
  completed history forms to determine study
  eligibility.
• A physician should be involved in the consenting
  process.

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SPECIAL REQUIREMENTS FOR VULNERABLE SUBJECTS,
INCLUDING CHILDREN
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FEDERAL REGULATIONS MANDATE ADDITIONAL
PROTECTION FOR

• Children
• Prisoners
• Fetuses
• Genetic research
• Pregnancy
• In vitro fertilization

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ADDITIONAL PROTECTIONS MANDATED FOR CHILDREN

• Specifically outlined in subpart D of 21 CFR
  50-56 45 CFR 46.401-408
• Adequate provisions must be made for assent, a
  childs affirmative agreement, to participate
  in research
• Permission of parents or guardians is required
• Risk benefit categories for children must be
  identified by the IRB

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ASSENT

• Assent must be obtained from children when the
  IRB deems the subjects are capable (21 CFR 50)
• Age, maturity, and psychological state of the
  child must be accommodated in the decision to
  obtain assent
• Columbus Childrens Hospital IRB requires assent
  from children 9 years of age or older, in most
  circumstances
• If assent is not obtained, the reason should be
  documented in case records

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PARENTAL PERMISSION

• Must be obtained (except as in 45 CFR 46.408(c)
• Under certain conditions (see Risk and Benefit
  Categories) the IRB may mandate that permission
  be obtained from both parents, unless one is
  deceased, unknown, incompetent or reasonably
  unavailable, a fact that must be documented in
  case records
• Wards of the state can be included only in
  special situations the IRB office should be
  contacted to determine eligibility of wards of
  the state

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RISK AND BENEFIT CATEGORIES FOR RESEARCH IN
CHILDREN

• TYPE OF RESEARCH1. No greater than minimum
  risk (45 CFR 46.404)

• REQUIREMENTSAssent of child and permission of
  at least one parent

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RISK AND BENEFIT CATEGORIES FOR RESEARCH IN
CHILDREN

• TYPE OF RESEARCH
• Greater than minimal risk and a prospect of
  direct benefit or a monitoring procedure exits
  that contributes to well being (45 CFR 46.405)
• If 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 research, the assent of the
  children is not a necessary condition for
  proceeding with the research.

• REQUIREMENTS
• Assent of child and permission of at least one
  parent
• Anticipated benefit justifies the risk, AND the
  anticipated benefit is at least as favorable as
  that of alternative approaches

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RISK AND BENEFIT CATEGORIES FOR RESEARCH IN
CHILDREN

• REQUIREMENTS
• Assent of child and permission of BOTH
  parents,Only a minor increase over minimal
  risk,Likely to yield generalizable knowledge
  about the childs disorder or condition that is
  of vital importance for the understanding or
  amelioration of the disorder or condition, and
  the intervention or procedure presents
  experiences to the child that are reasonably
  commensurate with those in the childs actual or
  expected medical, dental, psychological, social,
  or educational situations

• TYPE OF RESEARCH3. Greater than minimum risk
  and no prospect of direct benefit(45 CFR 46.406)

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RISK AND BENEFIT CATEGORIES FOR RESEARCH IN
CHILDREN

• TYPE OF RESEARCH4. Any other research in
  children (45 CFR 46.407)

• REQUIREMENTSAssent of child and permission of
  BOTH parentsIRB finds that the research
  presents a reasonable opportunity to further the
  understanding , prevention, or alleviation of a
  serious problem affecting the health or welfare
  of children, ANDThe DHHS Secretary approves,
  after consultation with a panel of experts

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• THE INSTITUTIONAL REVIEW BOARD

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WHAT IS AN IRB?

• An appropriately constituted group formally
  designated to review and monitor biomedical
  behavioral research involving human subjects
• The IRB as authority to approve, require
  modifications in, or disapprove research
• Research disapproved by an IRB cannot be approved
  by other institutional officials
• The IRB has a formal assurance with the federal
  government (NIH, FDA) that it will function in
  accordance with regulations at 21 CFR 50, 21 CFR
  46, and 45 CFR 46

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IRB MEMBERSHIP

• Minimum of five members with varying backgrounds
• diversity of membership with regard to race,
  gender, cultural background, and community
  sensitivity
• professional competence as well as knowledge of
  regulations and applicable laws
• if special categories of patients are involved in
  research (pregnant women, prisoners, children) at
  least one member serves as expert
• Every nondiscriminatory effort should be made to
  ensure no IRB consists entirely of women or men

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IRB MEMBERSHIP (Cont.)

• At least one member with scientific concerns, and
  one whose primary concerns are non-scientific
• At least one member not affiliated with
  Childrens Hospital, Inc.
• Members with conflict of interest may not vote or
  provide initial or continuing review they may be
  called upon to provide pertinent information

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WHAT IS THE PURPOSE OF AN IRB?

• To assure, both in advance and by periodic
  review, that study subjects rights are protected
  by assuring that
• Risks are minimized
• Risks are reasonable
• Subject selection is equitable
• Informed consent obtained for each study subject
• Data will be monitored to assure subject safety
• Subject privacy and confidentiality is protected
• Additional safeguards are in place for vulnerable
  subjects
• Detailed records are kept of all meetings,
  communications and actions

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THE IRB AND NONCOMPLIANCE

• IRB may suspend study based upon seriousness of
  Noncompliance.
• Examples
• Purposefully not following protocol
• Repeated failure to provide requested or
  required information to IRB
• Publication without IRB approved protocol
• Complaint from research subject

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IRB REVIEW AND APPROVAL

• IRB approval is required for
• Initial protocol and consent/assent forms
• Advertisements
• Any amendments/changes to protocol, consent, etc.
• Annual protocol renewals the IRB may require
  more frequent reviews under certain
  circumstances.
• Adverse event reports
• Protocol deviations and violations

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TYPES OF RESEARCH THAT REQUIRE IRB REVIEW

• Any human research study that involves
• An investigational drug, device or procedure
• Unapproved use of an FDA approved drug
• Data intended for publication or public
  presentation
• Tissue studies, blood studies, genetic studies
• Review of medical records, including case reports
  (if gt5 subjects)
• Surveys

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CATEGORIES OF IRB REVIEW

• EXEMPT REVIEW
• EXPEDITED REVIEW
• FULL REVIEW

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EXEMPT REVIEW

• Research must fulfill one of the six categories
  in 45 CFR 46.101 (see IRB web site, Exempt
  Policy)
• Research must involve little or no risk
• Data may not be recorded from medical records so
  that subjects are identified in any manner
• Only the IRB can determine research is exempt
• Reviewed by IRB Chairperson or designee
• Very few medical research projects are eligible
  for exempt review

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EXPEDITED REVIEW

• Research must fulfill one of the ten categories
  in 45 CFR 46.110 (see IRB web site, Forms)
• Research involves no more than minimal risk
• May be reviewed by IRB Chairperson or designee
• The full IRB membership must be notified of all
  expedited approvals
• IRB may not disapprove a protocol by expedited
  review
• May be used to review minor changes in previously
  approved research

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FULL REVIEW

• Used for all protocols not eligible for exempt or
  expedited review
• Applications must be submitted in the required
  format and correct number of copies
• Receipt deadlines are posted on the IRB website
• The Columbus Childrens Hospital IRB uses a
  primary and secondary reviewer system
• Investigators are permitted to attend meetings to
  answer questions after IRB review in closed
  session

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• INVESTIGATOR RESPONSIBILITIES

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INVESTIGATOR RESPONSIBILITIES

• Staff Management
• Advertising
• Confidentiality

• Reporting
• Amendments
• Protocol Deviations/Violations
• Conflict of Interest
• Adverse Events
• Record Keeping
• Informed Consent

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MANAGING RESEARCH STAFF

• Goes far beyond authorizing or delegating study
  tasks to study personnel.
• The PI is fundamentally and ultimately
  responsible for adherence to the study protocol
  and clinical care of the study subjects.

• It is incumbent that the PI maintain oversight of
  staffs activities and provide guidance,
  clinical training and Good Clinical Practices
  training.
• Research staff should not perform beyond their
  scope of practice or expertise.

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ADVERTISING

• IRB must review and approve all advertisements
• Advertisements are considered part of the
  informed consent process
• Information must not be misleading or coercive
• If investigator decides to begin advertising
  after study has received IRB approval, an study
  amendment must be submitted to the IRB

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ADVERTISING
FDA guidance suggests advertising be limited to

• Name and address of investigator and research
  facility
• Research purpose
• Eligibility criteria
• Reasonable benefits
• expected

• Reasonable reimbursement (no amount) for
  expenses, time and inconvenience
• Time commitment required
• Contact information

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CONFIDENTIALITY

• There should be adequate provisions to protect
  the privacy of the subject and to maintain
  confidentiality of data collected
• Consent forms should discuss any processes in
  place which provide confidentiality
• Consent forms should state who will review the
  subjects data
• HIPPA regulations must be followed during the
  conduct of human subjects research.

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REPORTING AMENDMENTS

• Any change to the protocol
• Any change to the consent/assent forms
• Any change to advertising
• Must be reviewed/approved by the IRB BEFORE
  change is implemented

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REPORTING PROTOCAL DEVIATIONS/VIOLATIONS

• Any action which is outside specific protocol
  guidelines
• Must be reported within 72 hours of discovery
• Minor vs. major violations depend on risk/benefit
  ratio and ethical principles as defined by the
  IRB (see IRB website)

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REPORTING CONFLICT OF INTEREST

• Conflict of Interest A set of conditions
  involving judgment concerning primary interest
  (subject welfare, research integrity, etc.) that
  may be biased by a secondary interest, (personal
  gain, financial gain, desire for promotion and
  tenure, authorship, finders fees, patents, etc.)
• Perception of conflict is as important as actual
  conflict
• If conflict cannot be eliminated, it should be
  disclosed in the consent document

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REPORTING CONFLICT OF INTEREST (Cont.)

• Conflicts of interest must be disclosed on the
  IRB application form
• Conflicts of interest must be described in the
  appropriate area of the research abstract
  submitted to the IRB

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REPORTING CONFLICT OF INTEREST

• Reporting Financial Disclosure
• Since 1998, FDA has expected both PIs
  sub-investigators to complete a financial
  disclosure form
• At CCRI conflicts of interest statements must be
  disclosed at least annually to the Legal
  Services Office at Columbus Childrens Hospital
• FDA may inspect sites where investigators are
  financially linked to a sponsor
• Columbus Childrens Hospital requires disclosure
  of more than 10,000 holdings (investigator or
  immediate family member) in a potentially
  conflicting entity (for example, a pharmaceutical
  company)
• Our IRB requires disclosure of any payments,
  bonuses or other inducements from sponsors

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REPORTING ADVERSE EVENTS

• Adverse Event An undesirable clinical event.
  May or may not be related to study drug or
  participation.
• Serious Adverse Event (SAE) An event which is
  fatal or life-threatening or has resulted in
  hospitalization (initial or prolonged),
  disability, congenital anomaly, or requires
  intervention to prevent permanent impairment or
  damage. Report deaths to IRB within 24 hrs.
  Report others to IRB within 72 hrs. Follow
  individual sponsors guidelines when reporting
  SAEs to them.
• SAEs are considered serious, unexpected (not
  listed as a risk on the consent form) and
  possibly related to study drug or study
  participation, and must be reported to the IRB.

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RECORD KEEPING

• Maintain adequate records of study, including
• - Accurate case histories
• - Medical history
• - Physical, lab results, x-rays, progress notes,
  consults
• - Concomitant medications
• - Correspondence between investigator and
• Sponsor/IRB
• - Case Report Forms/Data Collection Forms

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RECORD KEEPING (Cont.)

• Retention of accurate and complete records is
  essential to validity and completeness of data
• investigator, not sponsor, is responsible for
  accuracy and completeness
• Investigator may maintain own study records, or
  may be part of hospital or clinical records.
• IRB retains records indefinitely
• Records may be in original form, in a computer
  database or on microfilm

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INFORMED CONSENT
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INFORMED CONSENT

• Is much more than just a signature on a form.
• Is a PROCESS designed to give subjects all the
  information necessary to voluntarily decide to
  participate in a clinical trial without coercion
  or undue influence. The process must allow the
  subject sufficient opportunity to ask questions
  and to consider participation in the study
  (initially and ongoing) as well as other options
  available.

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INFORMED CONSENT (Cont.)

• Is the process of information exchange between
  subject and investigator, including written
  materials, verbal instructions, question/answer
  sessions, and measures of subject understanding.

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INFORMED CONSENT (Cont.)

• Must provide information in a manner
  understandable to the study subject
• Written in 6th 8th grade reading level
• Non-technical/non-medical
• Provided in subjects language (may be oral in
  certain circumstances approved by the IRB)
• Must not use any coercive language
• Must be IRB approved prior to beginning the
  study. Revised consents must also be IRB approved
  prior to implementation

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INFORMED CONSENT (Cont.)

• Must be obtained BEFORE a subject participates in
  any clinical investigation, including BEFORE any
  screening procedures that are performed solely
  for the purpose of determining eligibility for
  research.
• Should be revised whenever important new
  information becomes available that may be
  relevant to the subjects participation e.g.
  updated adverse effects. In some cases, current
  subjects must be notified of new information
  (re-consented) that might affect their decision
  to continue study participation.

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EIGHT BASIC ELEMENTS OF INFORMED CONSENT

• 1. Statement that study involves research
  explanation of purpose and duration of study,
  procedures to be followed and experimental-only
  procedures outlined
• 2. Risks and discomforts
• 3. Expected benefits
• 4. Disclosure of alternative procedures or
  treatments
• 5. Statement of confidentiality and who may
  inspect records

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EIGHT BASIC ELEMENTS OF INFORMED CONSENT (Cont.)

• Availability of compensation and treatment if
  injury occurs
• 7. Name and telephone number of persons or
  offices to contact regarding research rights,
  research-related injury, or the study itself
• Statement that participation is voluntary and
  subject may withdraw at anytime without penalty
• 21 CFR 50.25(a) and 45 CFR 46.116(a)

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SIX ADDITIONAL ELEMENTS OF INFORMED CONSENT

• These items are desirable in most instances
• 1. Research may involve unforeseeable risks
• 2. Investigator may terminate subjects
  participation
• without subject consent
• 3. Disclosure of additional costs that may
  result from participation

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SIX ADDITIONAL ELEMENTS OF INFORMED CONSENT
(Cont.)

• Consequences of early subject withdrawal
• Statement that significant new findings which may
  relate to the subjects willingness to participate
  will be provided
• Number of subjects involved in study
• 21 CFR 50.25(b) and 45 CFR 460116(b)

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WHO MUST SIGN THE INFORMED CONSENT DOCUMENT?

• Study subject (gt18 years) or legal representative
  (parent or guardian)
• A copy must be given to the person signing the
  document
• Signature on the consent document should be dated
  at the time of the signature
• Our IRB requires investigator signature
• Subjects age 9-17 should assent to participate by
  signing an assent form presented in language
  appropriate for the age of the subject if not
  obtained, the reason should be documented in case
  records

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SCIENTIFIC INTEGRITY AND MISCONDUCT
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SCIENTIFIC INTEGRITY AND MISCONDUCT
Scientific Misconduct FALSIFICATION,
FABRICATION, PLAGIARISM or other practice that
seriously deviates from common research practices
(does not include honest errors) Institution
should conduct a careful inquiry which could
result in an investigation and possible
disciplinary action (see CRI policy on Scientific
Misconduct)
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WHISTLEBLOWER

• Someone who brings charges of scientific
  misconduct against an individual
• The institution will protect, to the maximum
  extent possible, the confidentiality of those
  who, in good faith, report apparent scientific
  misconduct

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YOU MAY NOW PROCEED TO THE QUIZ