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Protecting Human Subjects: What everyone needs to know


DF/ HCC. DANA-FARBER / HARVARD CANCER CENTER. Beth Israel Deaconess ... Dana-Farber Cancer Institute / Harvard Medical School / Harvard School of Public ... – PowerPoint PPT presentation

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Title: Protecting Human Subjects: What everyone needs to know

Protecting Human SubjectsWhat everyone needs to
  • Office for Human Research Studies (OHRS)
  • December 2009
  • (617) 632-3029 ?

  • Michele Russell-Einhorn, JD
  • Senior Director, Office for Human Research
  • Amanda Hammond, JD
  • Deputy Director, Office for Human Research Studies

Goals of Training
  • Briefly review scientific review process
  • Review regulatory issues involved in the
    protection of human subjects in research to
    ensure adequate substantive review, consistency
    and thoroughness of IRB review and approval and
    continuing oversight of research involving human

General Overview
  • The DF/HCC scientific review committees and the
    DFCI IRBs review all adult and pediatric
    cancer-related research on behalf of BIDMC BWH
    CHB DFCI and MGH.

National Cancer Center Grant
  • DF/HCC Scientific Review Committees-four
    committees and an ongoing expedited review
    process that fall under the protocol review and
    monitoring system process for oncology research
    set out in the NCI Cancer Center Support Grant.
  • The Cancer Center Grant requires that we keep the
    scientific review and IRB review functions
    separate and distinct.

National Cancer Institute
  • Cancer Center Support Guidelines require
  • 1. Scientific review for merit and progress and
  • 2. No guidelines for determining which post
    approval events such as amendments deviations
    violations or adverse events require re-review
    by a scientific review committee.

Scientific Review vs. IRB Review
  • There are differences between scientific review
    and IRB review, e.g.,
  • -conditional approvals
  • -annual progress review

Institutional Review Boards
  • DFCI IRBs operate under a Federal Wide Assurance
    that we have with the U.S. Department of Health
    and Human Services.
  • DFCI IRBs operate under Federal regulations that
    specifically dictate the operations and
    substantive review of the IRBs.
  • DFCI IRBs, on behalf of the DF/HCC, currently
    have oversight of over 1750 open research
    protocols involving human subjects.

  • Information Relating to the Operation of IRBs

  • IRBs A and B
  • meet on an alternating basis every Tuesday from
    12-2 pm.
  • expertise to review any matter, but focus on new
    protocols and amendments.

  • IRBs C and F
  • meet on an alternating basis every Thursday
    morning from 8-10 am.
  • expertise to review any matter but focus on
    continuing reviews amendments adverse events
    and other events.

  • IRB D
  • meets twice monthly on Mondays from 10-12 pm
  • was known as the social and behavioral IRB or
    the minimal risk IRB, in fact
  • reviews any research that is not technically
    clinical intervention research as well as
    research that is greater than minimal risk.
  • additional bone marrow aspirates
  • additional blood draws
  • tissue repository research etc.

  • IRB E
  • rapid response IRB
  • small number of members and can respond quickly
    to an emergent situation.

  • IRB G
  • Pediatric Panel
  • Meets 1st and 3rd Monday of each month
  • Expertise to review any pediatric matter

Institutions in the News
(No Transcript)
(No Transcript)
JHU-FDA Warning Letter to PIMarch 31, 2003
  • Our records indicate that you are aware of your
    sponsor obligationswe note that on September 15,
    1997, you submitted an IND application to the
    FDA(FDA) notified you in writing on October 24,
    1997, that you were prohibited from initiating
    any of the submitted protocols due to significant
    safety concerns and other protocol deficiencies
    including inadequate chemistry, purity, and
    pre-clinical data inadequate and confusing study
    procedures and protocols, lack of inclusion
    criteria, discontinuation criteria, and defined
    safety parameters and lack of methodology for
    adverse event monitoring, treatment, and
    follow-up of subjects.

Carle Foundation Hospital
University of Pittsburgh
Government Shutdowns
  • Massachusetts Eye and Ear Infirmary
  • UCLA
  • VA Health Sys. Greater Los Angeles
  • Rush Presbyterian St Lukes Med Ctr.
  • University of Illinois Chicago
  • Duke University Med Ctr.
  • Univ. Texas Medical Branch Galveston
  • University of Oklahoma Tulsa
  • Johns Hopkins University

Still happens Weill Medical College, May 2004
  • OHRP Findings
  • OHRPs review of IRB documents reveals
    evidence that the IRB does not always make the
    required findings when reviewing research
    involving children, and when the findings are
    made, they are sometimes inappropriate (e.g. for
    protocol 0204-165, which involved a
    dose-finding, safety study of a drug in pediatric
    hypertensive patients, the IRB found that the
    protocol was approvable under HHS regulations at
    45CFR 46.404). Based on OHRPs discussions with
    the IRB chairperson and IRB members, OHRP is
    concerned that the IRB lacks a detailed
    understanding of HHS regulations at 45 CFR part
    46, subpart D, which require specific IRB
    determinations related to the risks and potential
    benefits when children are involved as subjects
    of research.

Weill Medical College, May 2004
  • OHRP Findings
  • (a) For protocol 0296-223, subjects were
    enrolled outside the protocol age range
  • prior to IRB review and approval of the amended
  • (b) Protocol 0800-354 stated that subjects would
    be randomized between
  • metformin and placebo. During our interview, the
    investigator stated that, among
  • other things, the protocol was changed to a
    single arm study without prior IRB
  • review and approval.
  • (c) For protocol 0801-842, between August 12,
    2002 and July 22, 2003, the
  • protocol was changed from a double-blind study to
    a single blind study. OHRP
  • could find no evidence of IRB review and approval
    of this protocol modification.
  • Further, the continuing review form reviewed by
    the IRB on July 22, 2003 stated
  • no changes since last continuing review.

Weill Medical College, May 2004
  • OHRP Action
  • In view of the above determinations and in order
    to ensure adequate protections for human
    subjects, OHRP hereby restricts the WMC assurance
    (FWA 93), pending satisfactory completion of the
    required corrective actions described below.

  • Emory halts enrollment in cancer clinical trials
  • Action at Winship Cancer Institute follows
    critical audit of procedures
  • By Craig Schneider
  • The Atlanta Journal-Constitution
  • Tuesday, June 16, 2009
  • Emory Universitys Winship Cancer Institute has
    stopped accepting new patients into clinical
    trials after a critical audit, even as it seeks
    to enhance its standing in the fight against
  • The center voluntarily halted accepting new
    patients May 15 following a critical audit of
    record-keeping for research purposes. The audit
    was performed by the Eastern Cooperative Oncology
    Group, a cancer research group that works with
  • The audit found deficiencies in the research
    files regarding patients, including missing test
    results and CAT scans, unreported vital signs
    such as blood pressure and heart rate, and
    unreported logs on how often a patient took his
    or her drugs.

Historical Overview
  • The development of protections for human subjects
    in research.

Historical OverviewInternational
  • Nazi Doctor Trials
  • Nuremberg Code 1947
  • Informed Consent
  • Declaration of Helsinki
  • World Medical Association, Ethical Principles for
    Medical Research Involving Human Subjects
  • 1964 (revised 2000)

Historical Overview
  • Public Health Service (PHS) Policy
  • Prior Review of Research by Institutional
    Associates (PPO 129, February 8, 1966)
  • United States Public Health Service
  • Syphilis Study at Tuskegee (1932 -1972)

Historical OverviewUnited States -- 1974
  • Congressional Hearings
  • Senator Walter Mondale
  • Senator Edward Kennedy
  • HHS Regulations
  • National Research Act
  • National Commission for the Protection of
  • Human Subjects of Biomedical and Behavioral
    Research, July 12, 1974

Historical OverviewThe Belmont Report April
18, 1979
Federal Oversight of Human Subject Research
  • Federal Policy for the Protection of Human
    Subjects (Common Rule)
  • Adopted 1991
  • HHS Regulations
  • Revised 1981, 1991
  • FDA Regulations
  • Revised 1981, 1991
  • No Mandatory Protections if not covered by above

DHHS Federalwide Assurance (FWA)
  • FWA requires compliance with 45 CFR 46 for
    Federally Funded/Supported Research
  • All FDA regulated research must comply with
    applicable FDA regulations even in the absence of
    Federal Funding or Support

Federal Policy (Common Rule) for the Protection
of Human Subjects
  • 18 Federal Agencies Adopted DHHS Subpart A
  • Some Agencies Required Additional Protections
  • VA requires compensation for research-related
  • DoD additional level of review (e.g., HSRRB) for
    certain types of research
  • Some Agencies Never Adopted the Federal Policy
  • Department of Labor Miners and Coal Dust
  • Appalachian Regional Commission Telemedicine

DHHS Regulations45 CFR Part 46
  • Subpart A ? Core Protections ? Common Rule
  • IRB Review
  • Informed Consent
  • Subpart B ? Additional Protections
  • Pregnant Women, Fetuses, and Neonates
  • Subpart C ? Additional Protections
  • Prisoners
  • Subpart D ? Additional Protections
  • Children

Subpart A Core Human Subject ProtectionsFederal
Policy (Common Rule), DHHS, FDA
  • IRB Review (DHHS 45 CFR Part 46 and FDA 21 CFR
    Part 56)
  • Initial Review
  • Prospective Review of All Changes
  • Reporting/Review of Unanticipated Problems
  • Reporting/Review of Adverse Events
  • Continuing Review at Least Annually
  • Informed Consent (DHHS 45 CFR Part 46 and FDA 21
    CFR Part 50)
  • Eight Required Elements
  • Written Documentation
  • Language Understandable to Subjects
  • No Coercion or Undue Influence
  • No Waiver of Subjects Rights

Roles and ResponsibilitiesInstitutional
  • Institutional Commitment and Infrastructure
  • Authorized Institutional Official
  • IRB Chair, IRB Members, IRB Staff
  • Data Safety Monitoring Committees/Boards (DSMBs)
  • Other Institutional Committees (Audit)
  • Research Investigators and Co-Investigators
  • Everyone Else Involved in the Research Enterprise

Roles and ResponsibilitiesInstitutional Review
Board (IRB)
  • Review and Approve Proposed Research
  • Risks Minimized through Sound Research Design
  • Risks Reasonable Relative to Benefits
  • Subject Selection Equitable
  • Informed Consent Obtained
  • Informed Consent Documented
  • Privacy and Confidentiality Protections Adequate
  • Safety Monitoring is Adequate
  • Protections for Vulnerable Subjects are Adequate
  • Exercise Continuing Oversight of Research

Roles and ResponsibilitiesInstitutional Review
Board (IRB)
  • IRBs are also required to review HHS grants to
    ensure that the protocol submitted to the IRB is
    consistent with the grant application

Risks Minimized Through Sound Research Design
  • Family of Subject who died in Gene Therapy Trial
    sponsored by Targeted Genetics is suing the
    company, the IRB and the principal investigator.
  • The basis of the lawsuit is not so much
    objections to the informed consent document as
    the contention that someone with a mild case of
    rheumatoid arthritis should not be enrolled in a
    gene therapy trial.
  • The science of the protocol could not justify
    enrollment of this type of subject in the

Roles and ResponsibilitiesPrincipal
  • Accept responsibility for all aspects of the
  • Ensure adequate training for entire research team
  • Ensure adequate supervision of entire research
  • Know and ensure compliance with
  • All regulatory requirements
  • All IRB requirements
  • All protocol requirements
  • Ensure adherence to enrollment criteria
  • Monitor and report unanticipated problems and
    adverse events to sponsor and IRB

Roles and ResponsibilitiesPrincipal
  • University of Pittsburgh, FDA warning letter,
    September 15, 2009-John M Kirkwood
  • 1. failed to conduct procedures required by
  • 2. changed protocol without going through the IRB
    and FDA
  • 3. failed to follow-up and collect adverse event
  • 4. failed to report serious adverse events
    experienced by three subjects
  • 5. failed to prepare and maintain case histories
  • 6. failed to monitor the progress of the clinical

Applying the Regulations to Research Involving
Human Subjects
Definition of ResearchHHS, Federal Policy
(Common Rule)
  • Research means
  • A systematic investigation
  • Designed to develop or contribute to
  • Generalizable knowledge
  • Includes
  • Research development
  • Testing
  • Evaluation
  • Pilot Studies

Definition of Research
  • Research means
  • A systematic investigation designed to develop or
    contribute to generalizable knowledge
  • What does Systematic mean?
  • Carried out according to a plan
  • Permitting logical conclusions to be drawn
  • What does Generalizable mean?
  • Beyond the immediate situation
  • Beyond the institution

Manhattan Eye, Ear and Throat Hospital Incident
Definition of Human Subject
  • Human Subject means
  • a living individual
  • about whom an investigatorconducting research
  • data through intervention or interaction with the
    individual, or
  • identifiable private information
  • -- 45 CFR 46.102(f)

VCU Twin Study
Definition of Human Subject
  • Private Information means
  • Information about behavior in a context in which
    an individual can reasonably expect that no
    observation or recording is taking place
  • Information, provided for specific purposes, that
    the individual can reasonably expect will not be
    made public (e.g., a medical record)
  • -- 45 CFR 46.102(f)

IRB Requirements and Procedures
Institutional Review Board (IRB)Mission,
Duties, Authorities
  • Mission ? To protect the rights and welfare of
    individuals participating in research involving
    human subjects
  • Duties ? To approve, disapprove, modify, suspend
    research as necessary to ensure protections for
    human subjects in research
  • Authority ? To exercise final authority within
    the institution for ensuring adequate protections
    for subjects. Officials of the institution may
    not approve research if it has not been approved
    by an IRB.
  • Institutional Authority Beyond Regulations ?
    Delegated to IRB
  • Ethical Issues on behalf of institution
  • Sanctioning Investigators for noncompliance
  • Use of tainted data

IRB Review and Approval
  • Routine oversight mechanisms
  • Initial Review
  • Continuing Review
  • Review of Adverse Events
  • Review of Unanticipated Problems
  • Special oversight mechanisms
  • Data Safety Monitoring Boards (DSMBs)
  • Consent Monitors
  • Random Audits of Research
  • Continuing Education

IRB Approval (Initial or Continuing) Includes
Findings That
  • Risks are minimized through sound research design
  • Risks are reasonable relative to anticipated
  • Selection of subjects is equitable
  • Informed consent will be obtained
  • Informed consent will be documented
  • Privacy and Confidentiality provisions are
  • Data safety monitoring is adequate
  • Appropriate safeguards are included for
    vulnerable subjects

IRB Oversight Includes...
  • Continued ethical evaluation of the research
  • Monitoring of the research
  • Monitoring of the informed consent process
  • Analysis (as received) of new information,
    adverse events, and unanticipated problems
    involving risks to subjects and others
  • Formal Continuing Review at intervals appropriate
    to the degree of risk and no less than annually

Types of IRB Review
  • Determination whether activity is Human Subject
  • Verification of Exemption
  • Expedited Review
  • Convened (Full Board) Review
  • NOTE Initial and Continuing Review require
    votes of the convened IRB, meeting all quorum
    requirements, unless specific conditions for use
    of expedited review are satisfied

Institutional Review Board (IRB)Composition
  • Minimum of 5 members
  • Diverse in gender and racial background
  • Sufficiently qualified in experience and
  • (e.g., pediatric expertise required to review
    research involving children)
  • One scientific member
  • Non-scientific member
  • One member not otherwise affiliated with the
  • Expertise in vulnerable populations for regular
    review of such research

Convened (Full Board) Review
  • Majority of Total Membership Must Be Present
  • Non-Scientist Member Must Be Present (not lay
  • Approval Requires a Majority of Those Members
  • Vote Must Be Documented
  • Same Requirements for Initial and Continuing
  • Important that documentation demonstrate that the
    IRB is making the appropriate regulatory

IRB Meetings and Record Keeping
  • All members receive complete set of materials
  • Adequate time to review materials
  • Minutes of meetings must be comprehensive
  • Attendance and votes should be recorded
  • OHRP permits teleconferencing if each
    participating member (i) has received all
    pertinent material prior to the meeting and (ii)
    can actively and equally participate in the
    discussion of all protocols

Types of IRB determinations
  • Approval
  • Conditional Approval
  • Deferral
  • Disapproval

Conditional ApprovalFrom OHRP Common Findings
  • Contingent Approval of Research with Substantive
    Changes and no Additional Review by the Convened
  • OHRP finds that the IRB frequently approves
    research contingent upon substantive
    modifications or clarifications without requiring
    additional review by the convened IRB.

Expedited ReviewMinor Changes to Approved
  • MINOR changes in previously approved research
  • During the established approval period
  • Conducted by Chair or IRB member designated by
  • Must be reported to full IRB
  • No disapprovals, e.g., a decision to disapprove a
    requested deviation must be sent to the full
  • -- 45 CFR 46.110

Expedited Review ListInitial or Continuing
  • Conducted by Chair or IRB member designated by
  • Only minimal risk research
  • Must fit into a category on November 1998 list
  • All other provisions and requirements apply
  • Can only approve research -- Cannot disapprove
  • Must be reported to full IRB
  • -- 45 CFR 46.110 21 CFR 56.110

Expedited Review
  • Minimal Risk Research in the Following
  • 1) Clinical studies of drugs and medical devices
    where an IND (drugs) or IDE (devices) is not
  • 2) Collection of blood samples by finger stick,
    heel stick, ear stick, or venipuncture
  • a) from healthy, non-pregnant adults weighing at
    least 100 lbs 550 ml in 8-wk period, limited to
    2 collections per week
  • b) from other adults and children, not more than
    50 ml or 3 ml per kg in 8-wk period, limited to 2
    collections per week.

Expedited Review
  • Minimal Risk Research in the Following
  • 3) Prospective collection of biological specimens
    by noninvasive means
  • 4) Collection of data through noninvasive
    procedures (not involving general anesthesia or
    sedation) employed in clinical practice,
    excluding procedures involving x-rays or
    microwaves. Where medical devices are employed,
    they must be cleared/ approved for marketing.
    (Studies intended to evaluate the safety and
    effectiveness of the medical device are no
    generally eligible for expedited review,
    including studies of cleared medical devices for
    new indications.)

Expedited Review
  • Minimal Risk Research in the Following
  • 5) Research involving materials (data, documents,
    records, or specimens) that
  • have been collected
  • will be collected for non-research purposes
  • 6) Collection of data from voice, video, digital,
    or image recordings made for research purposes.

Expedited Review
  • Minimal Risk Research in the Following
  • 7) Research on individual or group behavior or
    characteristics -- cognition, motivation,
    identity, language, communication, cultural
    beliefs/practices, social behavior survey,
    interview, oral history, focus group, program
    evaluation, human factor, quality assurance

Expedited Review
  • Minimal Risk Research in the Following
  • 8) Continuing review of research previously
    approved by the convened IRB where
  • a) the research is permanently closed to new
    enrollments, all subjects have completed all
    research-related interventions, and research
    remains active only for long-term follow-up of
    subjects or
  • b) no subjects have been enrolled and no
    additional risks have been identified or
  • c) remaining research activities are limited to
    data analysis.

Expedited Review
  • Minimal Risk Research in the Following
  • 9) Continuing review of research where the IRB
    has determined and documented at a convened
    meeting that the research involves no greater
    than minimal risk, and no additional risks have
    been identified.
  • Critical Catchall Provision Note documentation

Expedited ReviewCompliance Problems
  • Inappropriate use of expedited review
  • greater than minimal risk
  • no appropriate category
  • failure to document category and determination
  • Greater than minor changes to approved research
  • Inappropriate use for Continuing Review

Exempt Research
Six Exemptions45 CFR 46.101(b)
  • 1) Research conducted in
  • Established or commonly accepted educational
  • Involving normal educational practices
  • Instructional strategy comparisons

Six Exemptions45 CFR 46.101(b)
  • 2) Research involving the use of
  • Educational tests (cognitive, diagnostic,
    aptitude, achievement), survey procedures,
    interview procedures, or observation of public
  • information is recorded in an (directly or
    indirectly) identifiable manner (NOTE Coded
  • AND
  • disclosure would place subject at risk of
    criminal or civil liability or be damaging to
    financial standing, employability, or reputation

Six Exemptions45 CFR 46.101(b)
  • Special Consideration involving Children
  • Survey and Interview Research Involving Children
    IS NOT Exempt
  • Passive Observation of Public Behavior Involving
    Children IS Exempt
  • Participant Observation of Public Behavior
    Involving Children IS NOT Exempt
  • IRB Needs Copy of All Surveys and Interview
    Scripts (unless standard test known to IRB)

Six Exemptions45 CFR 46.101(b)
  • 3) Research involving the use of
  • Educational tests (cognitive, diagnostic,
    aptitude, achievement), survey procedures,
    interview procedures, or observation of public
  • subjects are elected or appointed public
    officials or candidates for public office
  • or
  • Federal statutes require confidentiality without

Six Exemptions45 CFR 46.101(b)
  • 4) Research involving the collection or study of
  • existing data, documents, records, specimens, if
  • the sources are publicly available
  • or
  • the information is recorded by the investigator
    in such a manner that subjects cannot be
    identified, directly or through identifiers
    linked to the subjects.
  • NOTE Even brief recording of identifiers or
    codes disqualifies the exemption

Definition of Existing
  • Existing means
  • All data has been collected (i.e., on the shelf)
    prior to the research
  • For a purpose other than the proposed research
  • Includes data (or specimens) collected in
    research and non research activities.

Six Exemptions45 CFR 46.101(b)
  • 5) Research and demonstration programs designed
    to study, evaluate, or examine (Federal) Public
    Benefit or Service Programs
  • 6) Taste and food quality evaluation and consumer
    acceptance studies involving
  • wholesome foods without additives
  • additives, chemical, contaminants below safe
    levels determined by FDA, EPA, USDA

Informed Consent
Eight Required Elements45 CFR 46.116(a)
  • Statement that study is research and information
    on purposes/duration/procedures/experimental
  • Reasonably foreseeable risks or discomforts
  • Reasonably expected benefits
  • Alternative procedures (including availability
    off-protocol where applicable)
  • How confidentiality will be maintained
  • Information on compensation for injuries (unless
    minimal risk)
  • Contact Persons for info on research, injury,
    subjects rights
  • Voluntary participation, no penalty or loss of
    benefits for refusal or withdrawal

Six Additional Elements
  • Statement that there may be risks which are
  • Under what circumstances investigator could
    terminate subjects participation
  • Additional costs to subject
  • Consequences of subjects withdrawal from research
  • Statement that will be told of new findings
  • Approximate number of subjects in study

Informed ConsentSpecial Issues
  • There is no such thing as passive consent
  • consent is required unless formally waived
  • documentation is required unless formally waived
  • There is no such thing as a secondary subject
  • if an investigator obtains identifiable private
    information about a living individual, the
    individual is a human subject, regardless of the

Waiver of Informed Consent(Not Permitted Under
FDA Regulations)
  • IRB must find and document that 4 criteria met
  • Minimal risk research
  • Waiver or alteration will not adversely affect
    the rights and welfare of the subjects
  • Research could not practicably be carried out
    without the waiver or alteration
  • Subjects will be provided with additional
    pertinent information

Documentation of Informed Consent
  • Written consent document
  • In language understandable to the subject or the
    subjects Legally Authorized Representative (LAR)
  • Verification of translated consent document
  • Signed by subject or subjects LAR
  • Copy SHALL be given to subject
  • Opportunity to read before signing

Documentation of Informed Consent
  • Short form written consent document requires
  • oral presentation
  • witness to oral presentation
  • an IRB approved written summary
  • given to subject
  • signed by witness
  • signed by person obtaining consent
  • short form documenting oral presentation
  • signed by subject or LAR
  • signed by witness

Waiver of Documentation of Informed Consent (Not
Permitted by FDA Regs)
  • The Signed Consent Document provides the only
    link to the subjects identity and principal risk
    is breach of confidentiality
  • The research presents no greater than minimal
    risk of harm to subjects and involves no
    procedures requiring consent in a non-research
  • IRB may require a subject information sheet

After IRB Approval
Adverse Events v. UPIRSO
  • FDA Regulatory Terms
  • Adverse Events
  • Unanticipated Problems Involving Risks to
    Subjects and Others
  • Reportable events
  • HHS Regulatory Language
  • Unanticipated Problems Involving Risks to
    Subjects and Others
  • Reportable Events

Risks to Subjects
  • Adverse events vs. unanticipated problems
  • A risk or problem is unanticipated if it is not
    in the protocol or consent document.
  • Risks discussed in the protocol should be
    included in the consent document
  • Questions raised as a result of an unanticipated
  • Does the informed consent form need to be
  • Do previously enrolled subjects need to be
  • Does a report need to be made to any government

Risks to Subjects
  • If a risk is listed as rare in a protocol, and it
    becomes frequent, then it may be an unanticipated
    problem that has to be reported to OHRP.

Protocol Deviations
  • Very detailed protocol
  • Missing a dose
  • Intervention on the wrong day
  • All become protocol deviations
  • Write protocols more broadly
  • Range for dosing
  • Ranging for timing
  • Less likely that differences in regimen will
    become a protocol deviation

Protocol Deviations
  • University of Oklahoma July 2000 suspension of
  • Testing of a vaccine on subjects with melanoma
  • Three year trial
  • Numerous violations of study protocol
  • shipping vaccine to subjects for self-injection
  • inadequate staffing
  • inadequate supervision of sponsors manufacturing

Protocol DeviationsUniv. of Oklahoma
  • June 29, 2000 letter from OHRP to Univ. OK
  • OHRP finds that the principal investigator
    implemented substantive changes to the research
    project without IRB approval. The changes made
    without IRB approval included, but are not
    limited to the following
  • (a) The investigator deviated from the
    IRB-approved inclusion and exclusion criteria. In
    specific, 11 of the first 18 subjects enrolled in
    the protocol did not satisfy all IRB-approved
    inclusion/exclusion criteria. Of note, the IRB
    Chair unilaterally approved these deviations

Protocol DeviationsUniv. of Oklahoma (cont.)
  • (b) Sample size was increased above the total
    subject number approved by the IRB (15 for phase
    I and 25 for phase II) by November 17, 1999,
    total subject enrollment had increased to more
    than 90.
  • (c) The study vaccine was shipped to some
    subjects homes for self-administration by the
    subjects. Of note, the IRB-approved protocol
    prior to November 19, 1999 stated the following
  • the Nurse Coordinator will give all injections.
    She will record any transient erythematous
    reactions and refer patients with any other side
    effects to Dr. McGee Patients will be required
    to remain in the physicians office for 30
    minutes afterward.

Protocol DeviationsUniv. of Oklahoma (cont.)
  • (d) Some subjects were allowed to self-monitor
    for adverse local reactions following vaccine
  • (e) The investigator added several remote study
    sites and co-investigators.
  • (f) Non-physicians were used to perform some
    protocol-stipulated physical exams that were to
    have been performed by a physician under the
    IRB-approved protocol.

FDA Issues
FDA Regulations
  • Informed Consent - 21 CFR Part 50
  • IRB Review - 21 CFR Part 56
  • Investigational Drugs - 21 CFR Part 312
  • Marketing Approval - 21 CFR Part 314
  • Biologics - 21 CFR Part 600
  • Biologics Licensing 21 CFR Part 601
  • Investigational Devices - 21 CFR Part 812
  • Pre-Market Approval 21 CFR Part 814
  • Financial Disclosure 21 CFR Part 54
  • Electronic Records 21 CFR Part 11

FDA Regulations
  • Informed Consent -- 21 CFR 50
  • Eight Required Elements
  • Written Documentation
  • Language Understandable to Subjects
  • No Coercion or Undue Influence
  • No Waiver of Subjects Rights
  • IRB Review -- 21 CFR 56
  • Initial Review
  • Prospective Review of All Changes
  • Reporting/Review of Unanticipated Problems
  • Reporting/Review of Adverse Events
  • Continuing Review at Least Annually

FDA Regulations
  • Drugs and Biologics
  • Investigational New Drug Application (IND)
  • 21 CFR Part 312
  • Devices
  • Investigational Device Exemption (IDE)
  • 21 CFR Part 812

FDA RegulationsWhen is an IND Needed?
  • Any use in which a marketed or un-marketed drug
    is administered or dispensed to, or used
    involving, one or more human subjects, except
  • Use of a marketed drug in course of medical
    practice, or
  • Investigation of a marketed drug where there is
  • No intent to support a new indication for use or
    other significant change in labeling
  • No intent to support a significant change in
  • No factor such as route of administration,
    dosage, or patient population that increases or
    decreases the acceptability of risks associated
    with the product
  • Compliance with FDA Informed Consent and IRB
    Review requirements and
  • No promotion or representation of the drug as
    safe or effective for the purpose under

FDA RegulationsResponsibilities of Sponsors
  • Maintaining the IND
  • Obtaining Qualified Investigators and Monitors
  • Providing Necessary Information/Training for
  • Monitoring the Investigation
  • Controlling the Investigational Agent
  • Reporting Significant Adverse Events to
  • Maintaining and Retaining Accurate Records

FDA RegulationsResponsibilities of Investigators
  • Specific Responsibilities
  • Ensuring Conduct of the Research per the
    Investigator Agreement, Investigational Plan, and
    All Applicable Regulations
  • Protecting the Rights, Safety, and Welfare of the
    Research Subjects
  • Controlling access to and use of the test article
    (drug / biologic / device)
  • Monitoring and Reporting Adverse Events
  • Maintaining and Retaining Accurate Records

FDA Reporting RequirementsIND - Adverse Event
  • Investigator must report promptly (immediately if
    alarming) to the Sponsor any adverse effect that
    may reasonably be regarded as caused by the drug
    (21 CFR 312.64)
  • Sponsor must notify FDA of any adverse experience
    associated with the drug that is both serious and
  • Serious Adverse Drug Experience death,
    life-threatening, hospitalization, persistent
    /significant disability / incapacity, congenital
    anomaly / birth defect (21 CFR 312.32)
  • Unexpected Drug Experience any adverse drug
    experience, the specificity or severity of which
    is not consistent with the current investigator
    brochure or IND application (21 CFR 312.32)

FDA Reporting RequirementsIDE - Adverse Event
  • Investigator must report any unanticipated
    adverse device effect to Sponsor and the IRB as
    soon as possible and within 10 working days 21
    CFR 812.150
  • Sponsor must report any unanticipated adverse
    device effect to FDA, all reviewing IRBs, and
    investigators 21 CFR 812.150
  • Unanticipated Adverse Device Effect any serious
    adverse effect on health or safety, or any
    life-threatening problem or death, caused by or
    associated with a device if not previously
    identified in nature, severity, or degree of
    incidence in the investigational plan or
    application 21 CFR 812.3

FDA Regulation Exceptions ExemptionsEmergency
Use of a Test Article
  • Without Informed Consent 21 CFR 50.23(a)
  • Life Threatening Situation Necessitating the Use
  • Inability to Communicate with Subject for Legal
  • Insufficient Time to Obtain Consent from Legally
    Authorized Representative (LAR)
  • No Alternative Therapy Available
  • Certification in Writing from Investigator and an
    other Nonparticipating Physician of the Above
  • Report to IRB Within 5 Working Days

FDA Regulation Exceptions ExemptionsEmergency
Use of a Test Article (cont.)
  • No IRB Review 21 CFR 56.104 (c)
  • Life Threatening Situation Necessitating the Use
  • No Alternative Available
  • Insufficient time for IRB review
  • Report to IRB Within 5 Working Days
  • Subsequent Use Requires IRB Review

FDA Regulations Single Patient IND
  • Commonly referred to as compassionate use
  • Requires Informed Consent and IRB review 21 CFR
  • See OHRS website for guidance

FDA Device Regulations Compassionate Use
  • Compassionate Use of an Unapproved Device may be
    approved by FDA when it is the only option for a
    patient with a serious condition
  • Requires as many of the following as possible
  • Informed Consent
  • Institutional Approval
  • Concurrence of IRB Chair (but NOT IRB APPROVAL)
  • Independent Assessment of Uninvolved Physician
  • Authorization of the Sponsor

FDA Regulations DevicesSR Devices vs. NSR
  • IRB Must Make a Specific Determination
  • Significant Risk Device Investigational device
    that presents a potential for serious risk to the
    health, safety, or welfare of subjects, including
  • Non-Significant Risk Device Investigational
    devices that does NOT present the potential for
    serious risk to the health, safety, or welfare of
  • Non-Significant Risk is NOT the same as Minimal
  • Once IRB-approves the research as not involving a
    Significant Risk Device, the research is
    considered to have an approved IDE, unless the
    FDA has notified the sponsor otherwise.

FDA Regulations Off-Label Use
  • FDA-approved products (i.e., marketed products)
    may be used by physicians outside of labeled
  • Such use in RESEARCH (i.e., as part of a
    systematic investigation designed to develop or
    contribute to generalizable knowledge) requires
  • Such use intended to support a CHANGE in labeling
    requires IRB REVIEW and an IND / IDE

FDA Regulations Standard of Care Comparisons
  • Systematic comparison of FDA-approved products
    (i.e., marketed products) used for approved
    indications constitutes research and requires IRB
  • Systematic comparison of competing standards of
    care constitutes research and requires IRB review

FDA Regulations Humanitarian Device Exemption
  • Humanitarian Use Device (HUD)
  • Device tested but not profitable for marketing
  • Requires
  • IRB Review (Limited) and Approval
  • No Research Informed Consent

FDA Regulations Planned Emergency Research
  • Ordinarily Requires IRB Review and Informed
    Consent of Subject or Subjects Legally
    Authorized Representative (as determined by State
    Law for Research Contexts)
  • Exception from Informed Consent Requirement
    Involves Many Specific IRB Determinations and
    Approval by FDA or OHRP

Protections for Vulnerable Subjects
  • Under Sections 46.111
  • Vulnerable to Coercion or Undue Influence
  • eg Handicapped, Disabled, Economically or
    Socially Disadvantaged Persons
  • HHS Subpart B
  • Pregnant Women, Human Fetuses, and Neonates
  • HHS Subpart C
  • Prisoners
  • HHS Subpart D
  • Children

HHS Subpart B Research Involving Pregnant
Women, Human Fetuses, and Neonates
  • Subpart B -- Revised December 2001
  • Research involving pregnant women
  • Research involving fetuses
  • Research involving neonates of uncertain
    viability, nonviable neonates, or viable neonates

HHS Subpart B 45 CFR 46.204Research Involving
Pregnant Women or Fetuses
  • Any research that TARGETS pregnant women or
    fetuses requires a special and specific
    regulatory review.
  • Any such research should be submitted directly to
    senior staff at OPRS since the IRB will need
    special training for the review and approval of
    this type of research.

HHS Subpart C 45 CFR 46.303(c)Research
Involving Prisoners
  • Definition of a Prisoner
  • Any individual involuntarily confined or detained
    in a penal institution under a criminal or civil
  • Individuals detained in other facilities as an
    alternative to criminal prosecution or
    incarceration in a penal institution
  • Individuals detained pending arraignment, trial,
    or sentencing

HHS Subpart CResearch Involving Prisoners
  • Subpart C
  • Prisoner representative on OHRP approved roster
  • Additional duties under 46.305
  • Finding of permissible category under 46.306
  • Certification to OHRP
  • Concurrence from OHRP

Additional IRB DutiesHHS Subpart C 45 CFR 46.305
  • Research is permissible within a 46.306 category
  • Advantages of participating are not coercive
    given the limited choice prison environment
  • Risks commensurate with those accepted by
    nonprisoner volunteers
  • Selection procedures are fair
  • Language is understandable to the subject
  • Participation has no affect on parole, and
    prisoners are so informed
  • Adequate provisions will be made if there may be
    a need for follow-up care, and given varying
    lengths of sentences, and prisoners are so
  • If HHS-supported, institution (IRB) certifies to
    OHRP that it has carried out its duties under
    these sections

Categories of Permissible Research HHS Subpart
C 45 CFR 46.306(b)
  • The study of the possible causes, effects, and
    processes of incarceration, and of criminal
    behavior, provided that the study presents no
    more than minimal risk and no more than
    inconvenience to the subjects.
  • The study of prisons as institutional structures
    or of prisoners as incarcerated persons, provided
    that the study presents no more than minimal risk
    and no more than inconvenience to the subjects.

Categories of Permissible Research HHS Subpart
C 45 CFR 46.306(b)
  • Research on conditions particularly affecting
    prisoners as a class - ONLY AFTER DHHS
  • Research on practices, both innovative and
    accepted, which have the intent and reasonable
    probability of involving the health or well-being

Lawsuit Involving Prisoners
  • DOJ funded research in Pennsylvania prison
  • mandatory drug testing (urine vs. hair)
  • no consent
  • solitary confinement for refusal to be tested
  • facts of case not contested
  • Acres of Skin
  • Dow, U Pennsylvania, City of Philadelphia
  • Prisoners told experiments were harmless

Research involving Children
Definition of Minimal Risk
  • Definition impacts
  • Pediatric Studies
  • Important for determining whether a research
    protocol or change in research can be expedited
    or must go to the full board.
  • Waiver of Consent
  • Document of Consent

Definition of Minimal RiskFDA, HHS, Federal
  • Minimal Risk means
  • The probability and magnitude of harm or
  • Are not greater than those ordinarily encountered
    in daily life
  • or
  • During the performance of routine physical or
    psychological examinations or tests.

HHS Subpart D FDA Subpart DResearch Involving
  • Category Determinations Required
  • Specific Approval Criteria for Each Category
  • Protocol-Specific Justification Required
  • Not greater than minimal risk
  • Greater than minimal risk
  • Prospect of direct benefit
  • Greater than minimal risk
  • No prospect of direct benefit
  • Research not otherwise approvable

Subpart D 45 CFR 46.404 21 CFR 50.51 Research
involving no greater than minimal risk
  • Children may be involved in research where the
    IRB finds that
  • The research presents no greater than minimal
    risk to the child
  • Adequate provision are made for obtaining
  • The assent of the child
  • The permission of the childs parents or guardians

  • In the minutes of the NICHD IRB, they noted that
    for one protocol, there was more risk to children
    in crossing the street than in spending two days
    in the hospital hooked up to an IV line.

Subpart D 45 CFR 46.405 21 CFR 50.52Greater
than minimal risk but presenting prospect of
direct benefit to individual subjects
  • Children may be involved in research where the
    IRB finds that more than minimal risk to children
    is presented by (i) an intervention or procedure
    that holds out the prospect of direct benefit for
    the individual subject, or (ii) a monitoring
    procedure that is likely to contribute to the
    subjects well-being if
  • The risk is justified by anticipated benefit to
  • The relation of anticipated benefit to risk is at
    least as favorable as available alternatives
  • Assent of child and permission of parents are

Subpart D 45 CFR 46.406 21 CFR 50.53
Research involving greater than minimal risk and
no prospect of direct benefit to individual
  • Children may be involved in research presenting
    more than minimal risk without the prospect of
    direct benefit or increased well being for the
    subject if
  • Risk is a minor increase over minimal risk
  • Research presents situations reasonably equal to
    to those inherent in their actual situations
  • Research is likely to yield generalizable
    knowledge about disorder or condition
  • Adequate provisions for obtaining child assent
    and parental permission.

Fenfluramine Study
  • New York State Psychiatric Institute
  • Mount Sinai School of Medicine
  • Queens College
  • The study focused on 34 boys between the ages of
    6 and 10 who had brothers with violent tendencies
    as reflected in court cases.
  • The boys were given fenfluramine.
  • Did children with siblings who were juvenile
    delinquents have a greater propensity towards
    juvenile delinquency.

Fenfluramine Study
  • Since the study did not provide any benefit, was
    it likely to yield generalizable knowledge about
    an underlying condition or disorder?

Subpart D 45 CFR 46.407 21 CFR 50.54
Research not otherwise approvable but presenting
opportunity to understand, prevent, or alleviate
a serious problem affecting health or welfare of
  • IRB finds the research presents opportunity as
  • HHS Secretary, after consultation with panel of
    experts public review and comment, determines
  • The research presents reasonable opportunity as
  • The research will be conducted in accordance with
    sound ethical principles
  • Adequate provisions are made for obtaining child
    assent and parental permission

Subpart D Research Involving ChildrenParental
Permission Required
  • Permission of Both Parents Required If Greater
    than Minimal Risk, unless
  • One parent not reasonably available
  • One parent has sole custody
  • Standard HHS Waiver Not Contained in FDA
  • HHS Waiver in Interest of Child Not Contained in
    FDA Regulations
  • 45 CFR 46.408

Subpart D Research Involving Children Assent
of Child Required
  • Developmentally Appropriate as Determined by IRB
  • Documentation as Determined by IRB
  • Unless the Research Holds the Prospect of Direct
    Benefit Available Only in the Research
  • Or
  • Unless Waived by IRB per criteria at 45 CFR
  • 45 CFR 46.408

What happens if a child reaches the legal age of
  • Subject is a child enrolled in research
  • Subject reaches the age of majority
  • IRB can
  • waive informed consent if can meet 4 regulatory
  • otherwise, investigators have to re-consent the

Conflicts of Interest
Types of Conflict of Interest
  • Individual
  • Clinical investigators
  • Study coordinators
  • Research technicians
  • Research officials
  • IRB members
  • Institutional
  • Financial holdings of the institution
  • Decisions regarding research funding or
    allocation of resources for research
  • Financial
  • Consulting fees
  • Stock ownership
  • Honoraria
  • Salary
  • Intellectual property rights
  • Enrollment bonuses
  • Spouse / dependent finances
  • Professional
  • Pressure to publish
  • Professional rivalries
  • Career advancement