General

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WHAT TO EXPECT AND HOW TO HANDLE AN FDA
INSPECTION!!! Joseph X. Kaufman Director of
Quality Assurance 4460 Red Bank
Expressway Cincinnati, Ohio 45227 Phone
513-721-3868
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Learning Objectives!!!!

• Developing your strategy
• What happens during an FDA Inspection?
• Dos Donts with the FDA Investigator!
• What records will the FDA review?
• Training Files Yours and its contents
• Common inspection deficiencies
• The inspection is overNow what happens!

November 11, 2009
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The FDAs Bioresearch Monitoring Program

• A comprehensive, Agency-wide program of on-site
  inspections and data audits designed to monitor
  all aspects of the conduct and reporting of
  FDA-regulated research.
• Includes IRBs/CROs/Clinical Sites/
• Academia/Sponsors/Hospitals

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The FDA Motto

• In God we Trust all others must show their
  data!!!

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The Purpose of an FDA Inspection

• The purpose of the FDA Inspection is two fold
• Protect the rights, safety, and welfare of human
  research subjects
• Declaration of Helsinki/Belmont Report and
  Nuremberg Code Ethics Training
• Assure the quality and integrity of data
  collected.

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FDA INSPECTION

• INITIAL CONTACT BY FDA INVESTIGATOR
• Routine Inspection Surveillance
• Inspection Notice 7-10 days by phone.
• Do not delay the inspection, accommodate a
  convenient time/date.
• For Cause Inspection Just show up!!!
• A particular event or circumstance triggered
  
• the inspection. Consumer complaint.
• Data results are too good to be true.

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Inspection References

• Compliance Program 7348.811.
• Clinical Investigators - see link
• http//www.fda.gov/ora/ftparea/compliance/48_811.p
  df
• These are the test questions!!!

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Documentation

• Compliance Program 7348.811, states
• See Part III Page 5 Describes the
  Investigators Source Documents in terms of their
  legibility, organization, completeness.
• One item FDA-483, Data cannot be evaluated in
  its current condition.

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FDA Arrival

• FDA-482 - Notice of Inspection to most
  responsible individual. Principal
  Investigator/Sub-Investigator or Coordinator.
  Photo Identification, Credentials, Badge will be
  presented.
• Hand copy name, badge number/business card
• You are not permitted to photocopy credentials
• Typical inspection lasts 2-5 days.

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FDA Investigators backgroundWho are you dealing
with?

• Majority have at least a Bachelors in a
  scientific fieldbiology, chemistry,
  biochemistry, or closely related field.
• Training in FDA Law Food, Drug and Cosmetic Act
• Training in Investigative Interviewing Techniques
• Training in a variety of subject fields- IRBs
  Clinical Studies, Contract Research
  Organizations, Phase I etc..

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Audit Procedures

• FDA Investigator is going to provide a reason for
  the inspection.
• Place them in a friendly work environment.
• This is the time where you want to discuss your
  schedule/meetings/availability of the PI.
• Ongoing discussion of inspection proceedings and
  findings no surprises at conclusion. Ask the
  investigator for a time frame, schedule end of
  the day wrap up meetings.
• Collect records to substantiate
  observations/facts
• May collect sworn affidavits FDA-463(a)

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Previous work in hand!

• The FDA investigator has in her/his possession
  the following prior to visiting your site
• The previous inspection report if applicable.
• List of adverse events/serious adverse events.
• Copy of protocol
• Example copy of Case Report Form or maybe, a
  subject case report form.if so, they are looking
  for something particular.

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Your Game Plan!

• Develop an SOP (Standard Operating Procedure) on
  how to handle FDA Inspections.
• Keep everyone under control.
• Who are the contact people?
• Those who cannot keep quiet or talk way too much
  Quarantine these folks.

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The Dos

• Do provide good directions and a meeting place
• Do offer a cup of coffee or beverage
• (No dinners/No breakfasts/No lunches/No gifts)
• Provide photocopying for the FDA Investigator!
• Make duplicates Copy for the FDA and your
  site.
• Why? Helpful/Control/Theyre not walking
  around
• Do dress in a professional manner.

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The Donts with the FDA

• Do not be left alone with the FDA Investigator,
  be in pairs at all times.
• Do not feel a need to fill silence, be aware!
• Do not disappear for hours at a time. Check in
  every 40-45 minutesyou do not want them to
  assume if something is missing, you do not have
  it.

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The Donts with the FDA-cont.

• Do not comment on other sites or competitors, Do
  not talk disrespectfully of co-workers or your
  superiors. No unnecessary talking by other
  employees.
• Do not make jokes about the FDA, or other
  government agencies. No politics.
• If you do not know an answer to a question, say
  so!

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Records Reviewed

• Records subject to review
• IRB correspondence
• Protocol
• Subject Case Report Forms
• Informed Consents
• Test Article Accountability Records (Drugs)
• Monitoring Visits
• Protocol Amendments
• Adverse Events/Serious Adverse Events

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Records Reviewed

• Protocol
• Investigational Plan
• Is it the same one provided by the sponsor and
  
• approved by the IRB?
• Have all protocol amendments and addendums
• been approved by the IRB?
• Is the most recent version being used?
• Is the protocol being followed?
• The FDA will ask for a copy of the latest
  revision.

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Subjects Reviewed

• Do not ask which subjects are going to be
  evaluated ahead of time! The FDA will not tell
  you.
• Typically, the normal inspection entails a review
  of the square root 1 of subjects enrolled in
  the clinical study. 25 6
• The FDA Investigator is looking to find a pattern
  of deficiencies.

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Case Report Forms

• Case Report Forms will be cross-checked with the
  source documents to confirm captured data,
  medical records, test results, physician progress
  notes, medical history and source documents
  contain the same data.
• Post it Notes

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Reporting

• Do not use white-out.
• When crossing out data, put initials/date and
  correct information.
• Note-To-File for obvious protocol violations or
  deviations, send to IRB and Sponsor.not just the
  sponsor.
• Notes-to-File do not absolve you from your error
  or mistakes.

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Informed Consent

• Approved by the IRB? All revisions?
• Contained all required elements of informed
  consent, see 21 CFR 50.25
• Have the subjects signed informed consent prior
  to any study treatment or medical procedures?
  EKGs versus time on consents!

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Informed Consent

• Add a statement to your source documents in this
  sort of fashion
• Informed Consent was obtained prior to
  initiation of any screening procedures or study
  related activities.
• Explain the Informed Consent Does subject truly
  realize the time, medication, schedules, needle
  sticks,EKGs, Single/Double Blind/Placebo?

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COMMON DEFICIENCIES

• Informed Consents
• Failure to have subjects sign informed consent.
• Informed Consent fails to meet the required
  elements of informed consent per 21 CFR 50.25.
• Failure to maintain original copy.
• FDA will check every subjects informed consent.
  
• Informed Consent Dates

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COMMON DEFICIENCIES

• FDA-1572s
• Sub-Investigators must be identified on the
  FDA-1572 prior to seeing subjects in the clinical
  study.
• FDA-1572s are the Principal Investigators
  documentthey are the ones who sign the form.
• This document should be signed by PI and
  dated by PI. No pre-printed dates. Handwritten
  dates.
• Co-Investigators and Sub-Investigators are not
  the same term.

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Co-Investigators/Sub-Investigators

• Co-Investigator is used when a study is conducted
  by more than one investigator, each of whom
  assumes equal responsibility for the conduct of
  the study and adherence to the regulations.
  Co-PIs are often used in drug studies when an
  investigator has multiple sites where a different
  investigator is responsible for each location.
• Sub-Investigator is any individual member of the
  clinical trial team designated and supervised by
  the Principal Investigator to perform trial
  related procedures.

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Pregnancy

• Pregnancy is not considered a serious adverse
  event.
• Subject may be taken off study (IRB/Sponsor/PI).
• Multiple subject pregnancies Does the informed
  consent explain acceptable means of birth
  control?
• Subject must be followed until birth of
  baby.status and health of child at birth must be
  reported to Sponsor/IRB.

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Test Article Accountability Records

• Records of receiptUPS, FED-EX
• If subject loses a pill or forgets medication,
  record in source documents/progress notes.
• When monitor packages drug for return shipment,
  be present to verify count.
• Pharmacy FDA will visit the pharmacy if drug
  dispensing occurs by Pharmacist.

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SUBJECTS LOST TO FOLLOW-UP

• Document in subjects progress notes attempts to
  contact subject via phone or e-mail. Record
  date/time message left or sent
• Send registered letter, keep copy of letter or
  postal receipt.most favored.
• Three attempts is due diligence.

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TRAINING FILES

• Contents
• Job Description
• Resume/Curriculum Vitae updated once a year.
• Licenses/Certifications
• Standard Operating Procedure Training
• Continuing Education (GCP Training).
• Ethics Belmont Report/Declaration of
  Helsinki/Nuremberg Code

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SIGNATURES

• There is never an instance or situation during an
  inspection of a clinical investigator in which
  anyone at the site would be required to sign any
  FDA Document.
• You do not sign the FDA-482, FDA-483 or FDA-463(a)

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AFFIDAVITS

• Affidavits, Form 463a
• 
  
• If the FDA Investigator presents an
  affidavit, you do not read, listen to or sign the
  affidavit. If the FDA attempts to read this
  document to you, excuse yourself from the room.
• This is not a refusal. No matter what.
• you do not sign this document!

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CLOSE-OUT DISCUSSION

• FDA Investigator will have a close-out meeting
• FDA-483 Inspectional Observations
• Responding to FDA-483 Items
• Explain any special circumstances regarding
  observations
• Describe specific actions taken or planned that
  will correct and prevent future deviations
• If issued, respond verbally during the final
  discussion (FDA investigator will include
  response in EIR)
• Send a written response to District Office and
  Center contact
• You may opt to do both (most do)

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FDA INSPECTORS REPORT

• Establishment Inspection Report (EIR)
• Prepared by the FDA investigator performing the
  inspection following every inspection
• Details inspection and findings
• Includes exhibits to document findings
• EIRs for BIMO inspections sent to CDER (Center
  for Drug Evaluation and Research) for review and
  final classification
• Assigning Center issues post-inspection
  correspondence and initiates follow-up actions
• Available through Freedom of Info Act

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FOI Freedom of Information

• FDA's Electronic Freedom of InformationWarning
  Letters and Responses
• http//www.fda.gov/foi/warning.htm

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Inspection Classification

• EIR Inspection Classifications
• No Action Indicated (NAI)
• No objectionable conditions or practices
• Voluntary Action Indicated (VAI)
• Objectionable conditions or practices
• But not at threshold to take or recommend
  administrative or regulatory action
• Official Action Indicated (OAI)
• Serious objectionable conditions found
• Regulatory action recommended

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References

• Division of Bioresearch Monitoring
• www.fda.gov/cdrh/comp/bimo.html
• Application Integrity Policy List
• www.fda.gov/ora/compliance_ref/aiplist.html
• Disqualification List
• www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.
  htm

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Disclaimer

• The contents of this presentation are my own, and
  do not necessarily reflect the views and/or
  policies of the Food and Drug Administration or
  its staff. The Food and Drug Administration will
  not be bound by any of the comments or
  information contained in this presentation.