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How to Prepare for an FDA Inspection

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Title: How to Prepare for an FDA Inspection


1
How to Prepare for an FDA Inspection
  • 30 March 2006
  • Presented by Christine Boes, Senior Manager,
    Clinical Quality
  • Cardiac Rhythm Disease Management

2
Topics for Today
  • How does the FDA inspector prepare to inspect?
  • How can you be prepared?
  • How should you act during the inspection?
  • How should you respond post-inspection?

3
FDA Organization
Site Inspections- BIMO
Data Submission Reviews IDE, PMA, 510(k), IND,
NDA
4
FDA Inspections of Investigators
  • Purpose
  • Determine that the rights, safety and welfare of
    subjects have properly been protected
  • Assess adherence to FDA regulations and statutory
    requirements
  • Determine quality and integrity of data submitted
    in support of products pending FDA approval

5
Permitting FDA Inspections Investigators and
Sponsors
  • Regulations require that sponsors and
    investigators grant access to authorized FDA
    employees
  • Any location where devices are manufactured,
    processed, packed, installed, used or implanted
    or where records of use/results are kept (IDE
    Regulations)
  • Regulations allow inspection and copying of all
    records relating to an investigation

6
FDA Inspections of Investigators
  • Two types of inspections
  • Routine Surveillance
  • Occur after PMA/NDA submitted
  • For Cause
  • Suspicion of wrong doing, complaints, termination
    of a site, etc.

7
Reasons for Inspecting an Investigator Could
Include
  • The investigator is doing a large volume of work
  • Gaps in IRB approvals and/or IRB suspension
  • The investigator has done work outside of his/her
    field of specialty
  • The investigator reports substantially superior
    efficacy for a device when compared to data
    generated by other investigators studying the
    same device
  • The investigator reports no severe or few adverse
    effects when other investigators report numerous
    adverse effects of a given type

8
Reasons for Inspecting an Investigator Could
Include Cont.
  • The investigator seems to have too many patients
    with a given disease for the locale or setting in
    which he/she practices
  • The investigator reports results showing a lack
    of visit-to-visit variability or which are
    inconsistent with results submitted by other
    investigators
  • Investigator participated in clinical
    investigation for which data was used to support
    a PMA/NDA.

9
CDRH BIMO InspectionsFiscal Years 2000-2004
357
350
353
214
190
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
10
Investigator Deficiencies FY 2000-2004
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
11
IRB Deficiencies FY 2000-2004
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
12
CDRH BIMO ComplaintsAllegations of Research
Misconduct
41
41
15
9
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
13
Preparing for Inspection
  • Ensure all site personnel are trained prior to
    study start
  • Discuss potential for inspection and what to
    expect
  • Notify appropriate interested parties immediately
    if contacted
  • Assess the site
  • Discuss potential issues
  • Identify work space for inspector

14
When the FDA calls for Inspection
  • Schedule the inspection as soon as possible after
    being called by the FDA investigator. Generally
    the inspection is requested/scheduled within a
    few business days to a week of the call
  • When confirming the appointment, request
    information on the reason for the inspection and
    any special areas to be emphasized during the
    inspection

15
Conduct of Inspection
  • Identify the primary contact person for
    inspection
  • Upon arrival, the FDA investigator MUST present
    credentials and issue a Notice of Inspection,
    Form FDA-482
  • The inspectors name and credentials numbers
    should be obtained and documented.
  • The Investigator and/or primary contact person
    should arrange for and attend all interviews
    conducted by the FDA investigator
  • Escort the FDA Inspector to a designated work
    area and escort throughout inspection
  • Establish a schedule for the visit

16
Conduct of Inspection cont.
  • Interview Guidelines
  • Do not engage in conversation unless asked a
    direct question
  • Restrict statements to answering those questions
    asked by the FDA Investigator
  • Do not provide excuses or shift blame (either on
    previous employees, staff members, IRB)
  • Do not guess at answers If uncertain of correct
    answer, obtain the correct information and
    provide to the FDA Investigator
  • Do not answer questions which lie outside the
    authority of the Inspector (sales data, personnel
    information relating to salaries, performance
    reviews, etc)

17
Conduct of Inspection Interview Guidelines cont.
  • Be responsive and cooperative, but do not
    volunteer information
  • Should a question be unclearclarify!!
  • Should a question or request seem unreasonable,
    state your objection
  • The FDA keeps notes on everything you state, make
    sure it is the truth
  • FDA will ask you and/or others similar questions
    multiple times to ensure similar response

18
Conduct of Inspection cont.
  • Generally, inspections follow the format
    established in FDAs Compliance Program Guidance
    Manual 7348.811.
  • Make certain that all documents are current and
    immediately accessible. Since the inspector(s)
    will want to review source documentation, notify
    your medical record departments of the scheduled
    inspection so medical records will be easily
    accessible.

19
Conduct of Inspection cont.
  • Provide requested copies of documents and stamp
    confidential (keep extra copy as a reference)
  • Maintain notes of requests/questions of the
    Investigator during the inspection
  • FDA will request a list of other study/research
    projects that the investigator is involved
  • Clarify any misunderstandings or confusion as
    soon as possible

20
Conduct of Inspection cont.
  • Areas to be addressed will include
  • Identify who is responsible for various tasks,
    examples
  • Who verified eligibility criteria
  • Who obtained informed consent
  • Who collected adverse event data
  • Determine degree authority is delegated to other
    staff members-how the investigator supervised the
    conduct of the trial

21
  • Finding from a 2003 Warning Letter to an
    investigator

Delegating work to research staff does not
relieve you of the responsibility to supervise
the clinical investigation. You are responsible
for the accuracy and completeness of the study
records and for any discrepancies found in the
records.
22
Conduct of Inspection cont.
  • What the IRB reporting/communication requirements
    are (e.g. specific adverse event and protocol
    deviation reporting)?
  • What is your process for informed consent?

23
  • Findings from a 2002 Warning Letter an
    Investigator
  • You failed to ensure that legally effective
    informed consent was obtained. For example, study
    subjects with randomization numbers X through Y
    signed a wrong version of the consent form.

24
Conduct of Inspection cont.
  • How, when, and where study data/activities is
    collected/performed
  • How investigational product is accounted for and
    controlled (whether or not devices are on the
    shelf or not)
  • Monitors communications with the clinical
    investigator
  • The monitors evaluations of the progress of the
    investigation

25
How FDA Trains BIMO Inspectors
  • Get Technical - Read x-rays, EKGs, lab results,
    dont just inventory
  • Fill in the Blanks - Question missing dates,
    times, information, offer to retrieve records
    yourself
  • Be suspicious of blame shifting - tell CI he/she
    is totally responsible for the conduct of the
    study
  • Expect Fraud - Start from the assumption the
    records are bogus and the study is a fraud, and
    work back
  • Cultivate Whistleblowers - establish rapport with
    study staff, be approachable and available,
    listen to grievances, observe working conditions

Reference Stan W. Woolen, Associate Director for
Bioresearch Monitoring, FDA Misconduct in
Research Innocent Ignorance or Malicious
Malfeasance? 2003
26
Study Documents Required for the Inspection Will
Include
  • Reports of unanticipated adverse events/serious
    adverse events reported to IRB and sponsor
  • Your IRBs SOPs for AE/Protocol Deviations
  • All IRB approvals, including all approved
    versions of informed consent
  • Progress reports to the IRB
  • Clinical Investigation Plan/protocol (all
    versions) and Case Report Forms
  • Investigator Agreement/1572 and CVs

27
Study Documents Required for the Inspection Will
include cont.
  • Training records of all site personnel involved
    in trial
  • Source documents for CRF entries, prior medical
    history, condition of the subject at the time of
    entry into study, meds, if required by study,
    laboratory reports, and any special testing per
    protocol.
  • Documentation for any correction to CRFs
  • All correspondence, records, reports
  • Investigational device/drug accountability

28
  • Finding from a 2003 Warning Letter to an
    investigator

In addition to the failure to use the device
control documents required by the investigational
plan, you failed to prepare and maintain
accurate, complete, and current device
accountability records, as required by 21 CFR
812.140(a)(2). Specifically, records of
investigational devices returned to the sponsor
contained inaccurate information regarding lot
numbers and quantities.
29
  • Finding from a 2003 Warning Letter to an
    investigator

You failed to fulfill you device control
responsibilities under the investigational plan.
You did not ensure that the investigational
devices were maintained under controlled access
storage. The devices were received by hospital
staff not part of the clinical investigationperso
nnel who were not clinical study staff had keys
to the storage area where devices were kept
30
What Happens After an Inspection?
  • FDA Investigator will conduct exit interview
  • Will discuss findings issue a written Form FDA
    483 (Inspectional Observations)
  • Clarify any questions/confusion
  • Investigator may respond verbally during exit
    interview and/or respond in writing (strongly
    recommended to respond in writing)
  • Be accountable to issues have a corrective
    action plan!
  • Direct responses to FDA District Office in upper
    left corner of 483

31
What Happens After an Inspection cont
  • Inspector prepares detailed report called
    Established Inspection Report (EIR)
  • EIR, 483 (if applicable), copies of all materials
    collected during inspection, any responses from
    Investigator are forwarded to the FDA Center
  • FDA Center evaluates information

32
Evaluation to Classify and May Prompt Letter to
Investigator
  • NAI No Action Indicated
  • A letter that generally states that the FDA
    observed no significant deviations from
    regulations. Letter may not actually be sent all
    the time
  • VAI Voluntary Action Indicated (483)
  • An informational or untitled letter identifies
    deviations from statutes and regulations for
    which voluntary corrective action is sufficient
    (unless otherwise specified)

33
Evaluation to Classify and May Prompt Letter to
Investigator cont.
  • OAI Official Action Indicated (Warning letter)
  • A Warning Letter identifies serious deviations
    from statutes and regulations. A Warning Letter
    generally requests prompt corrective action by
    the clinical investigator and formal written
    response to the agency (FDA).

34
Investigator Non-Compliance
  • FDA may disclose to Sponsors and IRBs records
    indicating violation or potential violation by
    investigator that is conducting or has conducted
    studies
  • Besides issuing letters, FDA may take other
    administrative action against investigator
  • May initiate process of disqualifying an
    investigator from receiving investigational
    product or research if he/she has
  • Repeatedly or deliberately violated FDA
    regulations
  • Submitted false information to the Sponsor or FDA

35
In Conclusion.
  • The best preparation for an FDA inspection is
    close adherence to the Clinical Investigational
    Plan/protocol and FDA regulations
  • Particular attention should be paid to
    documentation of
  • medical histories
  • adverse events/deviations
  • receipt and disposition of investigational
    product
  • documentation of informed consent process
  • training
  • The importance of orderly, accurate records can
    not be underestimated!!

36
  • 483 Finding from a 1999 Investigator Inspection
  • Consent form contained unapproved whiteout
    where subjects signature appears.
  • 483 Finding from a 1995 Investigator Inspection
  • Several instances of data being scratched out
    (obliterated) rather than lined out were noted.
    One instance of liquid paper being used to
    correct data was noted

37
FDA Information
  • FDA Home Web Page
  • http//www.fda.gov
  • FDA Compliance Web Page
  • http//www.fda.gov/ora/compliance_ref/default.htm
  • Compliance Program Guidance Manuals
  • Disqualified List
  • Debarment List
  • Warning Letters
  • Recalls

38
Questions?
39
Thank You!!
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