The FDA

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The FDAs Postmarketing Adverse Drug Experience
Inspectional Program

• Surveillance Programs Team
• Office of Compliance
• Center for Drug Evaluation and Research
• U.S. Food and Drug Administration

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AGENDA

• Postmarketing adverse drug experience reporting
  regulations
• Role of headquarters and field
• Inspectional strategies

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Purpose of ADE Regulations

• To obtain additional information on adverse
  events that may not have been detected prior to
  marketing
• To improve the labeling of drug products

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Brief Overview of Reporting Regulations

• 21 CFR Sections
• 310.305 - RX drugs not subject to approved
  applications
• 314.80 - RX drugs subject to NDAs/ANDAs and OTCs
  associated with approved applications
• 314.98- RX drugs subject to AADAs

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What is an Adverse Drug Experience?

• Any adverse event associated with the use of drug
  in humans whether or not it is considered drug
  related.

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Serious Adverse Drug Experience

• Death
• Life threatening (per initial reporter)
• Permanently or significantly disabling
• Hospitalization
• Congenital anomaly/birth defect
• Important medical events

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Unexpected Adverse Drug Experience

• Not listed in current labeling
• Listed in labeling but greater specificity or
  severity
• e.g. renal impairment listed, patient experiences
  renal failure

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Reporting Requirements

• Within 15 calendar days if Serious and Unexpected
  (domestic and foreign)
• Follow-up information
• Non-applicant notifies applicant within five
  calendar days

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Periodic Report

• Quarterly and Annual Reports
• Serious Expected ADEs
• All Non-serious

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When does the Regulatory Clock Start?

• First day a firm or any affiliate receives event
  data containing all four elements
• An identifiable patient
• An identifiable reporter
• A suspect drug
• An adverse event or fatal outcome

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Forms

• 3500A (Medwatch Form)
• Council for International Organization of Medical
  Science (CIOMS I Foreign) or other form if
  approved in advance

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The Headquarter/Field Adverse Event Team

• The headquarters scientists use adverse event
  reports to evaluate the safety of marketed drugs
• OC/ADE Team coordinates between regulatory and
  scientific staff.
• The field investigators assure industry
  compliance with reporting regulations

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Role of the Field Investigator

• To verify through on-site visits that firms are
  submitting all required reports of adverse events
  to FDA and the reports are complete, accurate and
  timely.

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Role of the Field Investigator

• When reports of adverse events are not
• submitted, or are incomplete, inaccurate
• or late, then document to support
• appropriate regulatory action.

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Role of the Field Investigator

• Look for adverse events not cited on the product
  labeling.
• Do not make medical evaluation of adverse
  events.
• Do not evaluate labeling or make labeling change
  recommendations

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Selection of the Firms Risk Management Approach

• Firms with ADE reporting problems
• Firms with prior violative history
• Recalls
• AIP list
• NDA field alerts
• High-risk drugs

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References Used Prior, During and After
Inspection

• CP 7353.001, Enforcement of the Postmarketing
  Adverse Drug Experience Reporting Regulations.
• Regulations
• Guidance documents
• Inspectional package

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SOPs

• Procedure to specify the minimum qualifications
  of persons involved in investigating and
  evaluating ADEs
• Make sure that current reporting requirements are
  cited in SOPs
• SOPs should specify control activities to ensure
  that ADEs are investigated, followed-up,
  evaluated and sent to FDA.

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Source Documents

• Complaint logs - numerical for completeness
• Medical Department Logs
• Distribution records
• Annual product reviews

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We are looking for...

• Outcomes to identify problem areas for
  inspectional coverage.
• What system failure(s) caused the firm not to
  comply with the regulations.

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Look for Discrepancies such as...

• Omissions
• Minimizing results
• Lack of follow-up
• Inadequate follow-up

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Significance of Deviations

• Most serious - not submitting 15-day reports
• Serious - report accuracy
• Moderately serious - timeliness

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If reports are found that have not been filed...

• Determine the nature of the event and the cause
  for failure to report.
• Determine what changes have been made to prevent
  reoccurrence.

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When Discrepancies are Found

• Review raw data
• Ask questions and understand how the event and
  investigation was handled
• Look for patterns or trends
• Document

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Type of Violations Uncovered

• Serious and unlabeled events not submitted in a
  timely manner (range 30 days up to ten years
• Lack of assurance that all ADEs were submitted
• Foreign serious and unlabeled events not
  submitted from foreign affiliates

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Cont. Violations Uncovered

• Failure to conduct prompt and adequate follow-up
  investigations of ADEs
• Serious and unlabeled events not assessed
  properly
• No periodic reports submitted

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Cont. Violations Uncovered

• Computer system used to process and generate ADR
  reports is not validated
• Coding errors in Medwatch forms
• No approved SOPs

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Remember

• Scientific evaluation of adverse events depends
  upon the field investigator assuring that
  industry submits reports that are complete,
  accurate, and timely.

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For Additional Information...Contact the
Surveillance Program Team

• Jay Schmid 301-827-8929
• Schmid_at_cder.fda.gov
• Carol Krueger 301-827-8989
• Kruegerc_at_cder.fda.gov
• Juliaette Johnson 301-827-8928
• Johnsonju_at_cder.fda.gov
• Denis Mackey 301-827-8926
• Mackey_at_cder.fda.gov

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Internet Sites for ADR Information

• http//www.fda.gov/cder/aers/index.htm
• http//www.fda.gov/cder/regguide.htm
• http//www.fda.gov/medwatch

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