How to Prepare for an FDA Inspection

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How to Prepare for an FDA Inspection

• 30 March 2006
• Presented by Christine Boes, Senior Manager,
  Clinical Quality
• Cardiac Rhythm Disease Management

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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?

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FDA Organization
Site Inspections- BIMO
Data Submission Reviews IDE, PMA, 510(k), IND,
NDA
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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

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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

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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.

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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

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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.

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CDRH BIMO InspectionsFiscal Years 2000-2004
357
350
353
214
190
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
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Investigator Deficiencies FY 2000-2004
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
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IRB Deficiencies FY 2000-2004
Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
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CDRH BIMO ComplaintsAllegations of Research
Misconduct
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41
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Reference Building Quality into Device Clinical
Trials, Medical Alley, April 20, 2005
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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

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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

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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

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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)

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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

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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.

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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

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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

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• 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.
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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?

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• 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.

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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

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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
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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

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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

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• 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.
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• 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
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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

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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

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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)

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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).

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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

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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!!

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• 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

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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

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Questions?
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Thank You!!