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APPROVAL PROCESS

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Research should be based on prior animal work. Anticipated benefits should justify the risks ... Data Collection Worksheets. Sign by the PI accepting responsibility ... – PowerPoint PPT presentation

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Title: APPROVAL PROCESS


1
APPROVAL PROCESS
  • MYTHS and MYSTERIES
  • Presenters Nasim Mirkiani and Barrie Pitts

2
Clinical Research Whats the Big Deal???
  • Nuremberg
  • Tuskegee
  • The Belmont Report
  • Recent issues
  • U Penn Gene Therapy
  • Johns Hopkins

3
Nuremberg
  • Research experiments on concentration camp
    inmates by the Nazis during WWII
  • Nuremberg code
  • Informed consent is essential
  • Research should be based on prior animal work
  • Anticipated benefits should justify the risks
  • Should not conduct research in which suffering,
    disabling injury or death is expected.
  • Code restated in the Declaration of Helsinki
  • Set the stage for implementation of the IRB
    process

4
Tuskegee and Others
  • US Public Health Service Syphilis Study
  • 1932-1971 (yes, 1971)
  • Withheld effective Rx from black men
  • No informed consent, deception, exploitation
  • Willowbrook Hepatitis Study (New York, 1956)
  • Study the natural history of hepatitis
  • Mentally retarded children deliberately infected
    with hepatitis
  • Coercion declined enrollment in school to
    non-participants
  • San Antonio Contraception Study
  • Randomized Hispanic Americans seeking
    contraception to placebo without their knowledge

5
The Belmont Report
  • Report of the National Commission for the
    Protection of Human Subjects in Biomedical and
    Behavioral Research (1976)
  • Principles
  • Respect for Persons
  • Beneficence
  • Justice

6
U. Penn Gene Therapy
  • Jesse Gelsinger
  • Ornithine transcarbamylase deficiency
  • Unable to process ammonia normally
  • Entered a gene therapy trial in which an
    adenovirus vector delivered the defective enzyme
    - 1999
  • Died 4 days after treatment of multi-organ
    failure
  • So what? The patient signed informed consent!

7
The Belmont Report
  • Respect for Persons
  • Voluntariness, ability to understand the
    information
  • Requirement for informed consent
  • Beneficence
  • Minimize harms and maximize benefits
  • Justice
  • Select subjects equitably
  • Avoid exploitation of vulnerable populations

8
Yes, but
  • The patient was a substitute for another
    volunteer who dropped out of the study and did
    NOT meet eligibility criteria (ammonia level too
    high)
  • The investigators did not report that two other
    prior patients had suffered serious side effects
  • Failure to report the deaths of monkeys who were
    given similar treatment

9
Johns Hopkins
  • Ellen Roche, a 24 year old healthy volunteer
    enrolled on an asthma study in June, 2001
  • Study involved inhalation of a nerve blocker
    called hexamethonium
  • She developed a cough after inhaling the drug,
    was hospitalized 5 days later, and died 3 weeks
    after that

10
What did they do wrong?
  • They used drug obtained from a chemical company
    labeled for laboratory use only
  • The informed consent minimized the potential side
    effects, completely ignoring known pulmonary side
    effects of the drug
  • The informed consent made the drug sound like
    something that was routinely in clinical use it
    had been removed by the FDA from use in 1972. In
    the consent form, it was not termed
    experimental.

11
Still more
  • The IRB was criticized for not providing
    substantive and meaningful review
  • Many protocols were being approved by IRB
    subcommittees with no full committee review or
    discussion
  • Ellen Roche was an employee of the Department
    which conducted this research (did she feel
    pressure to participate?)

12
Presentation Agenda
  • Path for Study Submission
  • Tutorials Requirement
  • Scientific Review Committees
  • Documents for IRB Submission
  • Master Protocol
  • Protocol Narrative
  • Consent Form
  • Other Forms
  • IRB Application
  • IRB Appendices
  • Sponsor Documents

13
Agenda Continued
  • 1572 Form
  • Renewals
  • Modifications
  • Adverse Events Other Reporting
  • Clinical Trials.gov
  • Site Qualification
  • Site Initiation Meeting
  • Trouble Spots
  • Useful Links
  • QA

14
The Path
  • SCIENTIFIC COMMITTEE APPROVAL
  • IRB APPROVAL
  • CONTRACT APPROVAL

15
Human Research HIPAA Tutorials
  • Human Research Tutorial
  • HIPAA Research Tutorial
  • All members of study team must take both
    tutorials for credit to be listed on the IRB
    application

16
Scientific Review Committees
  • Clinical Trials Protocol Review and
  • Monitoring Committee (CTPRMC)
  • Deans Scientific Review Committee (DSRC)
  • Institute for Clinical Translational Science
    (ITCS)

17
Starting April 1, 2008
  • The Deans Scientific Review Committees
  • duties have been assumed
  • by the ICTS

18
Documents for IRB Submission
  • Master Protocol
  • Protocol Narrative
  • Consent Form(s)
  • Other Forms
  • IRB Application Applicable
  • Appendices
  • Sponsor Documents

19
Master Protocol
  • State Hypothesis
  • Provide Power/Sample Size Analysis
  • Include Statistical Section
  • Provide Background
  • Specify Aims/Objectives
  • Provide Methodology
  • Provide Measures and Outcomes

20
Protocol Narrative
  • Non-Technical Summary
  • Purpose and Background
  • Expertise of Study Team
  • Research Methodology/Study Procedures
  • Subjects
  • Inclusion/Exclusion Criteria
  • Recruitment Methods

21
Protocol Narrative Continued
  • Informed Consent Process
  • Risk Assessment and Possible Benefits
  • Alternatives To Participation
  • Adverse Event Reporting
  • Compensation for Injury
  • Participant Costs
  • Compensation and Reimbursement
  • Confidentiality

22
Consent Form
  • Purpose of the Study
  • Why is this Research
  • Subjects
  • Procedures
  • Risks and Discomforts
  • Benefits
  • Alternative to Participation
  • Compensation, Costs and Reimbursement

23
Consent Form Continued
  • Withdrawal or Termination
  • Confidentiality
  • New Findings
  • Other Considerations
  • Use of Specimens
  • Investigator Financial Conflict of Interest
  • Questions
  • Voluntary Participation

24
Additional Forms
  • Subjects Bill of Rights
  • to be attached at the end of the Consent Form
  • HIPAA (Health Insurance Portability and
    Accountability Act) form
  • Given to subjects with Consent Form for release
    of personal health information

25
IRB Application
  • Title
  • Level of Review (Exempt, Expedited, or Full)
  • Department or Research Unit
  • HIPAA Determination
  • Study Team Members
  • Funding
  • Performance Sites

26
IRB Application Continued
  • Subject Population
  • Research Procedures
  • Data Safety Monitoring Plan
  • Hazardous Materials
  • Other Committee Reviews
  • Applicable Appendices

27
IRB Appendix B
  • Studies involving
  • Pregnant Women
  • Fetuses
  • Neonates
  • Must justify the need to include this vulnerable
    population, describe the risks and anticipated
    benefits, and explain why risks involved are
    least possible to the pregnant woman and fetus
    for achieving objectives of the research

28
IRB Appendix D
  • Studies involving
  • use of children as subjects
  • Select whether proposed research poses no
    greater than minimal risk to children or greater
    than minimal risk
  • Select whether parental permission will be
    obtained or if parental permission can be waived
  • Select whether assent from children will be
    obtained or waived

29
IRB Appendix E
  • Studies involving
  • cognitively impaired/medically incapacitated
    subjects
  • require use of surrogate consent
  • Must provide compelling and scientifically sound
    rationale for inclusion of this subject
    population
  • Describe in detail plan for assessing
    decision-making capacity and specify who will be
    performing the decision-making capacity
    evaluation
  • Explain how assent from cognitively impaired
    individuals will be solicited

30
IRB Appendix J
  • Use of FDA-Approved Drugs and Investigational
    Drugs or Biological Products in Clinical
    Investigations
  • Elements
  • Product Description
  • Clinical Pharmacology
  • Indications and Usage
  • Dosage and Guidelines for Administration
  • Toxicity and Known Side Effects
  • Precautions and Contraindications
  • IND Information (IND and filing date)

31
IRB Appendix K
  • Device Study
  • Device Product Name
  • Manufacturer
  • FDA Approval Status
  • IDE Number (not needed if there is a 510(k))
  • Risk Classification
  • Description of Device

32
IRB Appendix L
  • Use of Placebo, placebo Washout or Sham
    Procedures
  • Provide compelling and scientifically sound
    methodological reasons for use of placebo or sham
    procedure
  • Explain if subjects disease/condition will have
    potential to progress to higher risk condition if
    treated with placebo
  • Clarify if subjects in placebo group would be
    exposed to increased risk
  • Explain how study design will minimize risks to
    subjects

33
IRB Appendix O
  • Waiver or Alteration of Informed Consent
  • Level of Review if marked Exempt for this
    appendix, no other questions need to be filled
    out
  • If study qualifies for Expedited or Full review,
    rationale for why research qualifies as minimal
    risk and why waiver will not adversely affect the
    rights and welfare of subjects must be provided

34
IRB Appendix S
  • Description of Data Safety Monitoring Plan (DSMP)
  • If study involves greater than minimal risks
    (Phase I, II, and III studies) and no DSMP is
    provided by sponsor
  • Elements of appendix
  • 1. List who will conduct the safety review
    (including the name, title and experience of the
    individual(s)).
  • 2. Indicate how frequently the monitor will
    review and evaluate the accumulated study data
    for participant safety, study conduct and
    progress, and, when appropriate, efficacy.
  • 3. Explain the process by which the monitor will
    make recommendations concerning the continuation,
    modification, or termination of the trial.
  • 4. Describe the event(s) that would trigger an
    unscheduled review. Also include stopping
    guidelines and un-blinding rules, if applicable.

35
Appendix S Continued
  • 5. List who will be monitoring and collecting
    information on adverse events and/or
    unanticipated problems (e.g., Lead Researcher,
    Research Coordinator, etc.). Include the name,
    title and experience of the individual(s).
  • 6. Describe procedures to assure compliance with
    reporting of adverse events and/or unanticipated
    problems involving risk to participants or
    others.
  • 7. Explain the process for detecting and
    reporting adverse events and/or unanticipated
    problems involving risk to participants or others
    and specify of who will be notified of such
    events (e.g., IRB, NIH, FDA).
  • 8. Describe the plan for annual reporting of the
    participants safety, and the studys conduct,
    progress, and efficacy, when appropriate.
  • 9. Explain the plan to assure data accuracy and
    protocol compliance.

36
Sponsor Documents
  • Investigators Brochure or Package Insert
  • Sponsors Data Safety Monitoring Plan
  • FDA Letter(s)
  • Recruitment Materials
  • Data Collection Worksheets

37
1572 Form
  • Sign by the PI accepting responsibility
  • Must include all co-investigators
  • Must be updated whenever changes occur
  • Make sure you use current version

38
Renewals
  • Once a year
  • Progress on the protocol
  • Accrual information

39
Modifications
  • When changes occur on the protocol
  • Personnel
  • Dosing Schedule
  • Risks and Benefits
  • Costing information

40
Adverse Events
  • Internal or External
  • Must Be
  • Unexpected
  • Related or Possibly Related
  • Greater Risk of Harm
  • Reported within 10 Days of Knowledge

41
Internal Serious Adverse Event (SAE)
  • Must Be
  • Unexpected
  • Related or Possibly Related to the Procedures or
    Drugs in the Study
  • Reported within 5 Days of Knowledge

42
External Adverse Event (AE)
  • Must Be
  • Change Risk/Benefit Profile
  • Necessitates Submission of an E-Mod to Revise
    Consent
  • Reported within 10 Days of Knowledge

43
Other Reporting
  • Any Permanent or Temporary Study Hold
  • Early Termination
  • Any Changes in Safety Labeling
  • Any Event that Affects Safety and Welfare of
    Participants
  • Protocol Violations Such as
  • Any Change to Protocol without IRB Approval to
    Eliminate a Hazard
  • Any Breach in Confidentiality
  • Any Complaint by Participants that Indicates A
    High Risk and Cannot be Resolved by PI
  • All Should be Reported within 10 Days

44
Clinicaltrials.gov
  • When approved studies must be placed on
    ClinicalTrials.gov before the first patient is
    accrued
  • Each department has a contact person for this

45
Site Qualification Visit
  • Sponsor sees if we have the resources to do the
    trial
  • Often request a tour
  • Where we see patients
  • The pharmacy, where drug stored
  • Any special equipment radiology, PET, etc.

46
Site Initiation Meeting
  • When IRB and contract is
  • approved
  • All personnel involved in
  • the study
  • Go over the details
  • Prepare for the first subject accrual

47
Trouble Spots
  • Investigator is responsible for conduct of the
    trial
  • Inaccurate study records
  • 1572 not up to date
  • Adverse events not properly reported
  • Regulatory documents are not kept up to date

48
Useful Links
  • Tutorials Website http//tutorials.rgs.uci.edu/
  • IRB Website (IRB application, modification
    application, protocol narrative template, consent
    form template, SAE submission forms, and other
    forms) http//www.rgs.uci.edu/ora/forms/irb.htm
  • On this website, you can look up the IRB staff
    directory, IRB Calendar deadlines, and other
    information
  • Full Committee Results Link http//www.rgs.uci.ed
    u/ora/fullcommitteeresults.htmIRB
  • You can check the status of your protocol (A
    approved, M minor modifications needed, T
    tabled) at this website after 3pm on the Full
    Committee Review date
  • Protocol Query Link http//www.rgs.uci.edu/hpsear
    ch/index.cfm?actionstartCFID2315529CFTOKEN535
    28233
  • You can check on the approved studies (approval
    status, expiration date) you are currently
    working on at this link
  • GCRC Website http//www.gcrc.uci.edu/application/
    howto.cfm
  • GCRC application is now electronic. You will be
    able to complete and submit the entire
    application online without submitting any
    hardcopy documents
  • Clinical Trials.gov Website http//clinicaltrials
    .gov/
  • Clinical studies that are investigator-initiated
    will need to be registered with
    clinicaltrials.gov, a federal regulation
    requirement

49
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