The FDA Inspector Cometh

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The FDA Inspector Cometh

• Inspection Process for Clinical Trials

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ACCME Requirement CMEs

• The University of Michigan Medical School is
  accredited by the Accreditation Council for
  Continuing Medical Education (ACCME) to provide
  continuing medical education for physicians. The
  University of Michigan Medical School takes
  responsibility for the content, quality, and
  scientific integrity of this CME activity
• The University of Michigan Medical School
  designates this educational activity for a
  maximum of 1.0 category 1 credits
  towards the AMA Physicians Recognition Award.
  Each physician should claim only those credits
  that he/she actually spent in the activity.

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FDA Good Clinical Practice Inspections

• What has happened at UMHS?
• Who conducts the inspections?
• Who and what are inspected?
• What is the inspection process?
• How can the process go better?

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What has happened at UMHS?

• Some Metrics

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FDA Inspection History at UMHS

• gt24 investigators and/or drug trials since 1981
• http//www.fda.gov/cder/regulatory/investigators/d
  efault.htm

• Hematology/Oncology
• Endocrinology/Metabolism
• Neurosurgery
• Rheumatology
• Human Genetics
• Gastroenterology
• Dermatology

• Opthamology
• Pharmacology
• Urology
• Cardiology
• Radiology
• Anaesthesiology
• Pulmonary

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FDA Inspection History at UMHS

• FDA has inspected IRBs since 1980
• Per IRBMED
• Inspections occur about every 5 years
• Known inspections
• 1992
• 1997
• Latest in Oct, 2001

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Who conducts inspections?

• Hint
• Motto Compliance, Science, Protection

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Office of Regulatory Affairs (ORA)http//www.fda.
gov/ora/
Headquarters Rockville, MD
Regional Office Philadelphia, PA
District Office Detroit, MI
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FDA Field Investigators

• Conduct inspections to enforce the Food, Drug and
  Cosmetic Act
• Train themselves in evidence collection
• If its not documented, it didnt happen.

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Who and What are Inspected?

• Todays Focus
• GCP-Related People and Places

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Who?

• Investigators (Doctors) and Study Coordinators
• IRB (IRBMED)
• Sponsor, if applicable (Industry)
• Contract Research Organization, if involved
• Laboratories (e.g., Mlabs)
• Pharmacy (e.g., Investigational Drug Services)
• Devices (e.g., Biomedical Engineering)

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What studies?

• Usual Emphasis Phase 3
• Adequate and well controlled
• Blinded
• Safety and Efficacy
• Multi-site
• High patient enrolling sites
• Recent marketing application (e.g. New Drug
  Application) filed to an Investigational New Drug
  (IND)

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What is the inspection process?

• 10 Steps
• for
• Investigators

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1. FDA selects Site(s)

• FDA selects site for inspection
• Usually within 6 months of marketing application
  NDA (Data Audit)
• Selects 3 sites (average) per study, if
  multi-site
• May concurrently inspect the associated IRB
• If no previous inspection or
• Last inspection gt5 years
• OR
• May conduct a For Cause Audit

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Reasons For Cause Inspections

• Study of singular importance in product
  approval
• Study has major impact on medical practice
• Sponsor reports concerns about investigator
• Patient complaint

• Investigator conducts too many studies
• Investigator works outside of specialty area
• Safety or efficacy findings are inconsistent with
  other investigators
• Lab results are outside range of biological
  expectations

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2. FDA Investigator contacts Site

• FDA investigator from local District Office
  contacts responsible person at site
• Gives short advance notice or no notice of visit
• Becomes suspicious on attempts to delay visit
  (e.g., gt10 days without valid reason)
• Previews internally following subject related
  data
• Number of total subjects, dropouts and evaluable
  subjects
• List of AEs and deaths (with description and
  cause)

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3. FDA and Site agree on Visit Date

• FDA investigator and site person agree on
  appointment for site visit
• Averages 3-5 days for appointment
• Targets typically one study, but may review other
  studies performed by same investigator

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Preparation Tips for Site

• Notify all staff involved in AND/OR knowledgeable
  about the study
• Key staff, information providers are on standby
• Office of General Counsel
• Industry sponsor, if any
• Review UMHS procedures
• http//www.med.umich.edu/i/policies/umh/01-01-020.
  html for unannounced inspections
• http//www.med.umich.edu/irbmed/ae/oriotwoc.htmau
  dit for IRBMED notification

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Preparation Tips for Site

• Assign a site escort/facilitator
• Assemble all study documents in 1 place
• Include list of staff responsibilities and
  training
• Request all patient charts
• Prepare a list of investigators studies
• Reserve adequate work space for field
  investigator for entire inspection
• Assure accessible photocopier

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4. FDA presents Notice of Inspection

• Upon arrival FDA displays credentials (eg., photo
  ID) and FDA Form 482, Notice of Inspection
• Conducts inspection during routine business hours
• May meet and greet 1-3 FDA investigators

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FDA Form 482
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5. FDA requests data and documents

• FDA investigator requests related trial data and
  documents during site visit
• May need copies of documents
• Make 2 copies
• Give 1 copy to FDA
• Keep 1 copy at site to facilitate future
  communications

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Tips on Document Requests

• Do not provide or copy these information for FDA
• Financial data (salary information, budgets)
• (except financial disclosure of clinical
  investigators)
• Personnel data (performance appraisals)
• (except qualifications job descriptions and
  training records)

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6. FDA interviews Site Staff

• FDA investigator interviews site staff directly
  involved in trial activities and processes
• May question any staff member during inspection
• May use Compliance Program Guidance Manual as
  interview guide

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Tips for Anticipating FDA Questions

• Compliance Program Guidance Manuals (CPGMs)
• http//www.fda.gov/ora/cpgm/default.htm

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Tips for Handling FDA Questions

• Answer
• Politely, cooperatively, understanding them (ask
  for clarification), factually, briefly, within
  ones expertise (seek expert), directly (remain
  within scope), without speculation or guesswork
• Avoid
• Unsolicited questions, hypothetical questions,
  long delays to requests, affidavits

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7. FDA conducts Exit Interview

• Review findings with FDA investigator at end of
  each inspection day
• At site visit completion, FDA investigator
  conducts exit interview with responsible site
  personnel to
• Review findings
• Clarify misunderstandings
• Describe any deviations from current regulations
• Suggest corrective action, if appropriate

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8. FDA presents Notice of Observations

• If deviations, FDA investigator leaves a FDA Form
  483, Notice of Observations
• Submits findings to local District Office for any
  additional needed actions

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FDA Form 483
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Most Common Observations (for Investigators)

• Protocol non-adherence
• Inadequate and inaccurate records
• Failure to report adverse events
• Failure to report concomitant therapy
• Inadequate drug accountability
• IRB/IEC problems
• Informed consent issues

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9. FDA writes Inspection Report

• Upon return to local District Office, FDA
  investigator
• Writes an Establishment Inspection Report (EIR)
  and
• Forwards to headquarters for evaluation

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10. FDA classifies Inspection

• When evaluation is completed, FDA classifies
  inspection and sends a letter to site

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FDA Inspection Process
FDA Office
Site Location