Overview of Pediatric Safety Reporting and Role of the Committee Pediatric Advisory Committee Meetin

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Overview of Pediatric Safety Reporting and Role
of the Committee Pediatric Advisory Committee
Meeting November 18, 2005
Solomon Iyasu, M.D., M.P.H.Acting Deputy
Director Division of Pediatric Drug
DevelopmentCenter for Drug Evaluation and
Research Food and Drug Administration
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Best Pharmaceuticals for Children Act
Legislative Mandate

• Section 17 of the BPCA mandates the Office of
  Pediatric Therapeutics (OPT) to
• Review post-marketing adverse event reports
  during the one-year period after a drug receives
  market exclusivity
• Refer such reports to the Pediatric Advisory
  Committee for review and obtaining any
  recommendations for action

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FDA Adverse Event Reporting System (AERS)

• Database of all AERS and manufacturer reports
• Origin 1969 (SRS until 1997)
• 2 million reports
• Contains drug and "therapeutic" biologic reports
• Exception vaccines
  VAERS
  1-800-822-7967

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Source of Reports

• Voluntary/spontaneous reporting
• Health care professionals, consumers/ patients,
  or others
• Manufacturers Required for post-marketing
  reporting (gt90)
• All adverse drug experience information obtained
  or otherwise received from any source, foreign or
  domestic

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FDA post-marketing Definitions (21 CFR 314.80 )

• Adverse Drug Experience (ADE) any adverse event
  associated with the use of a drug, whether or not
  considered drug related, including
• Accidental or intentional overdose
• Occurring from abuse or drug withdrawal
• Failure of expected pharmacological action

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FDA post-marketing Definitions (21 CFR 314.80)

• Unexpected ADE any event not listed in the
  current labeling for the drug product including
  events that may be symptomatically and
  pathophysiologically related to a labeled event,
  but differ because of greater severity or
  specificity (e.g. hepatic necrosis vs hepatitis)

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FDA post-marketing Definitions (21 CFR 314.80)

• Serious Adverse Event (SAE) any event occurring
  at any dose that results in any of the following
  outcomes
• Death
• Life-threatening ADE (immediate risk)
• Hospitalization or prolongation of
  hospitalization
• Persistent/significant disability/incapacity
• Congenital anomaly/birth defect
• Other/requiring intervention (e.g. bronchospasm)

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Causality Assessment of AE reports

• Temporal relationship
• De-challenge - ADR subsides when drug is
  discontinued
• Re-challenge - ADR returns when drug is
  re-administered
• Dose-response
• Biologic plausibility (knowledge of PK and PD)
• Animal preclinical studies
• Laboratory evidence
• Known class effect
• Underlying disease
• Concomitant drugs

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AERS Strengths

• Includes all U.S. marketed drugs
• Simple, inexpensive reporting system
• Provides for early detection of safety signals
• Especially good for rare Adverse Drug Reactions
  (anaphylaxis, liver failure, aplastic anemia,
  serious skin reactions etc.)

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AERS Limitations

• Underreporting varies from drug to drug and over
  time
• Quality and completeness of reports variable,
  often poor
• Can estimate rates of events only grossly
• Numerator uncertain (event counts)
• Denominator (number of patient exposed) must be
  estimated, virtually impossible for inpatient,
  hospital outpatient clinics, and OTC drugs

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Role of the CommitteePrimary Materials for
Review

• One-year post-exclusivity adverse event reports
• Focus on pediatric AE reports
• Pediatric drug use data (denominator)
• Outpatient use can be projected nationally
• Dispensed prescriptions from retail pharmacies
• Drug mentions in office based practice
• Inpatient use cannot be projected nationally

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Role of the CommitteeAdditional Materials for
Review

• Summaries of clinical, and pharmacology
  toxicology reviews of exclusivity studies
• Drug product label
• Published literature
• Sponsor materials/presentations

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Types of Safety ReviewPresentations

• Abbreviated
• No safety signal of concern
• Standard
• No unlabeled safety signal
• Drug product has reports of labeled SAEs that are
  of interest (Cipro)
• Drug Product with safety concern of recent public
  interest (Vioxx)
• In-depth
• New possible safety concern
• Entire AC meeting or session dedicated to drug or
  class-specific safety concern ( SSRIs, ADHD
  drugs)

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Overview of Todays Presentations

• Abbreviated Presentations
• Sumatriptan (IMITREX)
• Irinotecan (CAMPTOSAR)
• Carboplatin (PARAPLATIN)
• Rofecoxib (VIOXX)
• Anagrelide (AGRYLIN)
• Sodium Ferric Gluconate (FERRLECIT)

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Overview of Todays Presentations (contd)

• Standard Presentation
• Fluconazole (DIFLUCAN)
• In-depth Presentation
• Oseltamivir (TAMIFLU)
• Presentations include
• One-year post-exclusivity AEs, drug use review
  and summary of materials from the Japanese
  Regulatory Authorities
• Literature and pediatric clinical trial review
• Influenza surveillance in the US
• Sponsor presentation
• Committee Discussion of Questions

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Acknowledgments

• Division of Pediatric Drug Development, OCTAP
• Office of Drug Safety (DDRE, DSRCS)
• Office of New Drugs
• Office of Pediatric Therapeutics