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					PREPARING FOR
 AN FDA AUDIT

  ANDREA BRANCHE
    INVESTIGATOR
        USFDA
 Houston Resident Post
     Dallas District
 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
           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   50: Informed consent
   21   CFR   56: IRB
   21   CFR   312/314: IND/NDA Drugs
   21   CFR   812/814: IDE/PMA Medical Devices

    These are legally enforceable requirements
         Routine vs. Directed
            Inspections
Routine
   Inspections assigned for PMA’s and NDA’s


Directed (“for cause”)
   Problems identified during review process
   Complaints reported to DSI
      FDA, other Agencies
      Sponsors/monitors

      Institutions/IRB’s

      Subjects/Public
Directed vs. Routine
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
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
              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)
                  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
                  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
                           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 subjects’s 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?
               Source Data
   Medical history            Patient ID number
    information                Study number
   Medical examination        Drug dispensing
    results                     information
   All lab results            Informed consent
   Demographic data           IRB approval
       DOB, sex, weight,      Visit dates
        age, race, height
                               Concurrent illness
   Concomitant meds
      Source Documents
   Hospital Records         X-rays, CT scans,
   Clinic and office         MRIs
    charts                   Case report forms
   Laboratory reports        when data is entered
   Memoranda                 directly
   Subject diaries          Magnetic media
   Pharmacy dispensing      Photographic
    records                   negatives
                           And……
Additional inspectional activities/areas of concern:
      Compare investigator’s 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
         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
               Maxine-Says
Money can't buy happiness -- but somehow it’s more
comfortable to cry in a Porsche than in a Hyundai.
      QUESTIONS??????

ANDREA BRANCHE
abranche@ora.fda.gov
(713) 802-7521

        THANK YOU
There are worse jobs than being a QA Auditor

				
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posted:10/28/2011
language:English
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