APPROVAL PROCESS

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APPROVAL PROCESS

• MYTHS and MYSTERIES
• Presenters Nasim Mirkiani and Barrie Pitts

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Clinical Research Whats the Big Deal???

• Nuremberg
• Tuskegee
• The Belmont Report
• Recent issues
• U Penn Gene Therapy
• Johns Hopkins

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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

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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

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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

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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!

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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

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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

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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

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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.

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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?)

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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

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Agenda Continued

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

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The Path

• SCIENTIFIC COMMITTEE APPROVAL
• IRB APPROVAL
• CONTRACT APPROVAL

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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

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Scientific Review Committees

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

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Starting April 1, 2008

• The Deans Scientific Review Committees
• duties have been assumed
• by the ICTS

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Documents for IRB Submission

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

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Master Protocol

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

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Protocol Narrative

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

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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

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Consent Form

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

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Consent Form Continued

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

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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

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IRB Application

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

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IRB Application Continued

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

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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

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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

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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

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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)

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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

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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

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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

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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.

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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.

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Sponsor Documents

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

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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

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Renewals

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

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Modifications

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

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Adverse Events

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

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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

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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

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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

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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

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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.

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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

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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

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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

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Questions and Answers