Conducting Clinical Trials

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Conducting Clinical Trials

• University of Virginia
• SOM Clinical Trials Office

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Lessons learned from federal inspections

• Objectives of investigative site inspections
• Determine the facts surrounding a study
• Determine adherence to regulations
• Verify subject safety
• Verify validity of data
• Compare practices/procedures to research
  commitments/applications
• Unwritten objective - education

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Most common inspection findings

• Informed consent form inadequacies
• Protocol non-adherence
• Inadequate/inaccurate records
• Inadequate investigational article accountability
• Inaccurate case histories

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Most common inspection findings

• IRB not informed of protocol changes
• Unapproved concomitant therapy
• Records not available
• Subinvestigators/study personnel not listed
• Inappropriate follow-up of adverse events

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Most common inspection findings

• Failure to report adverse events
• Subjects enrolled into simultaneous
  investigations
• Submission of false information
• Inappropriate delegation

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Topics for discussion

• Study Conduct
• Regulatory / Administrative
• Data Collection / Documentation
• Safety Monitoring

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Study Conduct

• Investigator Agreement (and/or Form FDA 1572)
  summarize the responsibilities of the
  investigator for the conduct of the trial.
• Conduct trials according to Standard Operating
  Procedures (SOPs) which are consistent with the
  regulations governing clinical trials

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Study Conduct

• Informed consent form inadequacies
• Protocol non-adherence
• Inadequate investigational article accountability
  I
• RB not informed of protocol changes
• Unapproved concomitant therapy
• Subjects enrolled into simultaneous
  investigations
• Inappropriate delegation

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Regulatory / Administrative

• Investigator is responsible to maintain all
  regulatory documents for each study
• Protocol
• Protocol amendments
• Case Report Forms (CRFs)
• Investigator Agreement (and/or Form FDA 1572)
• Current CV and medical license of PI and
  sub-investigator

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Regulatory / Administrative

• All correspondence with the IRB (HIC)
• IRB (HIC) approval
• IRB (HIC) approved informed consent (all approved
  versions)
• All safety reports sent to IRB and/or federal
  regulators
• Normal values for laboratory tests (if
  applicable)
• All materials used in recruiting subjects

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Regulatory / Administrative

• Drug / device accountability records (if
  applicable)
• Screening log / subject log
• Correspondence
• Original signed consents
• All correspondence with federal regulators
• Financial records

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Regulatory / Administrative

• Record retention
• FDA regulated trial - retain all records for 2
  years following the NDA approval (or final
  decision not to approve)
• Non-FDA regulated trial - 3 years following the
  completion of the research
• HIPAA - 6 years following the completion of the
  research

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Regulatory / Administrative

• Informed consent form inadequacies
• Inadequate/inaccurate records
• Records not available
• Subinvestigators/study personnel not listed

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Safety Monitoring / Reporting

• Safety monitoring is required in all clinical
  research studies
• HIC requires a data safety monitoring plan be
  incorporated in the protocol
• Plan should be consistent with the degree of risk
  involved with the study

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Safety Monitoring / Reporting

• Adverse event
• any untoward or undesirable sign, symptom or
  medical condition (including an abnormal
  laboratory finding) occurring after administering
  the investigational agent even if the event is
  not considered to be related to the
  investigational agent.
• Non-drug study - same definition, replace
  investigational agent

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Safety Monitoring / Reporting

• Unexpected / unanticipated adverse event
• any adverse event, the specificity or severity
  of which is not consistent with the current
  investigator brochure (or package insert).

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Safety Monitoring / Reporting

• Serious adverse event
• any adverse event that
• results in death
• is life threatening
• requires hospitalization (or prolongation of
  hospitalization)
• results in persistent or significant disability /
  incapacity
• results in a congenital anomaly / birth defect
• is deemed serious based on medical judgement

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Safety Monitoring / Reporting

• Severity grading
• Usually reported as mild, moderate, or severe
  (except in oncology trials)
• Severity is a measurement of intensity not of
  seriousness
• A serious adverse event is not necessarily severe
• A severe adverse event is not necessarily serious

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Safety Monitoring / Reporting

• Expedited safety reporting
• Notify the HIC of any study-related adverse
  events that are unexpected, serious, probably and
  possibly associated with the investigational
  agent/device
• Notification must be made within 24 hours of the
  event

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Safety Monitoring / Reporting

• Expedited safety reporting (drugs/biologics)
• Sponsor must notify the federal regulators by
  telephone or by fax
• details of any unexpected fatal or
  life-threatening experience associated with the
  use of the drug
• Notification must be made no later than 7
  calendar days after the initial receipt of the
  information

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Safety Monitoring / Reporting

• Sponsor must notify the federal regulators and
  all participating investigators in writing
• details of any AE associated with the use of the
  investigational drug that is both serious and
  unexpected
• any finding from laboratory tests that suggests a
  significant risk for human subjects
• Notification must be made no later than 15
  calendar days after initial receipt of info

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Safety Monitoring / Reporting

• Expedited safety reporting (medical device)
• Sponsor must immediately conduct and evaluation
  of any unanticipated adverse device effect.
• If effect presents an unreasonable risk to the
  subjects, all studies with this device must
  terminated (within 5 working days of making
  decision and within 15 working days of learning
  of the event)
• Federal regulators and the HIC must be informed
  of unanticipated adverse device effects. If
  study was terminated, cannot be resumed without
  approval of both

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Safety Monitoring / Reporting

• Inappropriate follow-up of adverse events
• Failure to report adverse events

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Data Collection / Documentation

• Investigators are required to prepare and
  maintain adequate and accurate records of all
  observations and other data pertinent to the
  study for each subject.
• Investigators must maintain primary source
  documents supporting significant data for each
  subject in the case history records.
• Source documentation is where the information is
  first recorded.

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Data Collection / Documentation

• Source documentation should include (as
  appropriate)
• documentation that informed consent was obtained
  prior to any study procedures
• demographics
• evidence supporting diagnosis/condition
• information demonstrating that the subject meets
  the inclusion criteria (e.g., medical history and
  physical exam)

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Data Collection / Documentation

• documentation of each study visit
• information regarding the subjects exposure to
  test or control article (or any investigational
  procedures)
• documentation of adverse events (with evidence of
  appropriate follow-up as appropriate)
• diagnostic test results, x-ray and laboratory
  test results (for study-related tests)
• Subject diaries
• ...

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Data Collection / Documentation

• Case Report Forms
• content of the case report form must capture data
  as required by the protocol
• the investigator ensures the accuracy of the data
  recorded on the case report form
• record data in pen, maintain audit trail (never
  use white-out)

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Data Collection / Documentation

• Inaccurate case histories
• Submission of false information

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Who do you need to know?

• GCRC
• Human Investigation Committee (HIC)
• Grants and Contracts
• Ancillary service providers
• Pharmacy
• Laboratory
• Radiology
• Patient Financial Services
• Medical Records
• etc.

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Clinical Trials Office

• Contact the SOM Clinical Trials Office with
  clinical research questions.
• 924-8530