PREPARING FOR AN FDA AUDIT

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PREPARING FOR AN FDA AUDIT

• ANDREA BRANCHE
• INVESTIGATOR
• USFDA
• Houston Resident Post
• Dallas District

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The Inspection Process Perspective and Approach

• Purpose is quality assurance, not quality
  control/monitoring
• Inspections must serve both a compliance
  function as well as a review function
• Individual sites serve as indicators of
  system controls
• Supplemented, as appropriate, with inspections of
  sponsor/monitor/CRO

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What Defines GCP in the United States

• FDA has GCP regulations governing the
  approval, conduct, review and reporting of
  clinical research intended for submission
• 21 CFR 312 IND regulations (rev.1987)
• 21 CFR 50 Informed consent (rev.1981)
• 21 CFR 56 IRB (rev.1981)
• 21 CFR 314 NDA regulations (rev. 1985)
• These are legally enforceable requirements

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Routine vs. Directed Inspections

• Routine
• Inspections assigned for PMAs and NDAs
• Directed (for cause)
• Problems identified during review process
• Complaints reported to DSI
• FDA, other Agencies
• Sponsors/monitors
• Institutions/IRBs
• Subjects/Public

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Directed vs. Routine
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Directed Inspection Criteria

• Suspicion of false or fraudulent data
• Data that appear unrealistic
• Evidence that a sponsor has rejected data from an
  investigator
• Evidence of delay in submitting adverse clinical
  findings
• Evidence of inadequately monitored clinical
  investigations
• Evidence of inadequate or inappropriate informed
  consent
• Evidence of delayed or inappropriate IRB approval
• Evidence that an investigator has a significant
  financial interest in the product

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Inspection Programs GCP

• Clinical Investigator
• Inspections assigned for each pending NDA/PMA
• Supplements are routinely inspected only when
  there is a significant public health impact (eg.,
  significant new indication significant new
  population) justification is required in the
  request
• May be assigned for active IDE/IND, if indicated

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How We Do It!!!!

• Clinical investigator inspections usually done by
  appointment
• Opening interview with investigator and study
  coordinator(s)
• Facilities inspection
• Record review
• Periodic discussion with investigator,
  sub-investigators, study coordinator,
  technicians, laboratory personnel
• Pharmacy records/drug accountability review
• Exit interview - conveyance of FDA 483 inspection
  findings to investigator of record (or his/her
  designee)

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And.

• Opening interview with investigator and study
  coordinator(s)
• Emphasis on understanding who did what how
  specific study taks may have been delegated
• To what extent did the investigator of record
  maintain control over the study
• How were subjects screened and allocated to
  treatment groups
• Who was responsible for determining subject
  eligibility and at what point in the study was
  this accomplished
• What degree of unblinding occurred

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More.

• How compliant were the study subjects with the
  protocol
• What notable serious or unexpected adverse
  experiences occurred
• Can the investigator identify sources of bias in
  the study
• What is the completeness of required
  documentation
• Can the investigator identify difficulties with
  the study and/or CRF design that made the
  protocol difficult to follow
• If the study were to be repeated, what would the
  investigator do differently

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More..

• Record keeping What is the completeness of
  required documentation?
• Not just paper! FDA inspectors can ask to see
  actual x-ray films, ultrasound recordings,
  pulmonary function test tracings, and other true
  source materials to substantiate data submitted
  in CRFs
• Are consent forms available for all subjects? Do
  they bear signature dates prior to the subjectss
  start of participation in the trial?
• Are investigator copies of CRFs present for all
  subjects?
• Are supporting medical records/source documents
  available for all subjects?
• What is the nature of original documentation for
  study-specific procedures, such as biopsy
  reports, special tests?

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Source Data

• Medical history information
• Medical examination results
• All lab results
• Demographic data
• DOB, sex, weight, age, race, height
• Concomitant meds

• Patient ID number
• Study number
• Drug dispensing information
• Informed consent
• IRB approval
• Visit dates
• Concurrent illness

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Source Documents

• Hospital Records
• Clinic and office charts
• Laboratory reports
• Memoranda
• Subject diaries
• Pharmacy dispensing records

• X-rays, CT scans, MRIs
• Case report forms when data is entered directly
• Magnetic media
• Photographic negatives

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And

• Additional inspectional activities/areas of
  concern
• Compare investigators version of the protocol to
  the version submitted by the sponsor to FDA
• Check the integrity of the randomization process
• Observe and note reasons for protocol violations
• Note reporting of serious adverse experiences,
  including time frames
• Observe evidence of unreported interim analyses
• Note correspondence/telecons between clinical
  investigator and the IRB, monitor, and sponsor,
  referring physicians, and consultants

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What is Generated After an Inspection

• FDA Form 483 Inspectional observations
• Left with CI at close of inspection
• Immediately available via FOI
• Establishment Inspection Report (EIR)
• Prepared by field investigator after inspection
• Includes exhibits supporting observed
  deficiencies
• Supervisory endorsement from District Office
• Brief summary statement
• Field recommendations

16
Maxine-Says
Money can't buy happiness -- but somehow its
more comfortable to cry in a Porsche than in a
Hyundai.
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QUESTIONS??????

• ANDREA BRANCHE
• abranche_at_ora.fda.gov
• [phone]
• THANK YOU

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There are worse jobs than being a QA Auditor