Overview of Pediatric Safety Reporting and Role of the Committee Pediatric Advisory Committee Meeting March 22, 2006

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Overview of Pediatric Safety Reporting and Role
of the Committee Pediatric Advisory Committee
Meeting March 22, 2006
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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FDAs 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 reports)
• 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 exposed patients) must be
  estimated, virtually impossible for inpatient,
  hospital outpatient clinics, and OTC drugs

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Randomized Clinical Trials (RCT)

• RCTs best for establishing causality between drug
  and adverse event
• Unbiased estimate of risk
• Comparative data from RCTs is critical to assess
  causality when event is related to both the drug
  and the underlying disease (high background rate)
• Limitations of RCTs
• May not pick up rare events due to short study
  duration and small sample size (low power)
• need to pull safety data across RCTs to improve
  precision and power
• RCT subjects more select and homogeneous than
  patient population receiving drug after marketing

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Role of the CommitteePrimary Materials for
Review

• One-year post-exclusivity adverse event report
  review
• Focus on pediatric AE reports during the year and
  SAEs including any deaths in prior years
• As appropriate, additional reviews or information
• Pediatric drug use review
• Outpatient use can be projected nationally
• Dispensed prescriptions from retail pharmacies
• Number of unique patients who received a
  dispensed prescription
• 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, pharmacology toxicology
  reviews of exclusivity studies
• Drug product label
• Published literature
• Sponsor materials/presentations

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Types of Safety ReviewPresentations

• Abbreviated
• No new safety concern
• Standard
• No unlabeled new safety concern
• Drug product has reports of labeled SAEs that are
  of interest (e.g.Cipro)
• Drug Product with safety issues of recent public
  interest (e.g.Vioxx)
• In-depth
• Possible safety concern or reported adverse
  events warranting review (e.g. Fentanyl
  transdermal system)
• Entire AC meeting or session dedicated to drug or
  class-specific safety concern (e.g. SSRIs, ADHD
  drugs)

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Overview of Todays BPCA Safety Review
Presentations

• Abbreviated
• Clofarabine (CLOLAR)
• Irbesartan (AVAPRO)
• Standard
• Sibutramine (Meridia)
• Regulatory history including summary of FDA
  review in response to a Citizen Petition
• One-year Post-exclusivity AE review with an
  additional focus on pediatric SAEs reported to
  AERS since initial drug approval

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Overview of Todays BPCA Safety Review
Presentations (contd)

• Mixed amphetamine salts (ADDERALL XR)
• In-depth presentation of the one-year
  post-exclusivity AE review as part of the
  session on safety concerns of all ADHD
  medications.

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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