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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 Development
Center for Drug Evaluation and Research
Food and Drug Administration
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

FDA Adverse Event Reporting
System (AERS)
• Database of all AERS and manufacturer
• Origin 1969 (SRS until 1997)
• ~ 2 million reports
• Contains drug and "therapeutic" biologic
• Exception = vaccines
VAERS 1-800-822-
7967 3
Source of Reports
• Voluntary/spontaneous reporting
• Health care professionals, consumers/
patients, or others
• Manufacturers: Required for post-
marketing reporting (>90%)
– All adverse drug experience information
obtained or otherwise received from any
source, foreign or domestic

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

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)

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) 7
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
AERS: Strengths
• Includes all U.S. marketed drugs
• Simple, inexpensive reporting system
• Provides for early detection of safety
– Especially good for rare Adverse Drug
Reactions (anaphylaxis, liver failure, aplastic
anemia, serious skin reactions etc.)

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

Role of the Committee:
Primary Materials for Review
• One-year post-exclusivity adverse event
– 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

Role of the Committee:
Additional Materials for Review

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

Types of Safety Review
• 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 ( SSRI’s, ADHD drugs)
Overview of Today’s Presentations

• Abbreviated Presentations:

– Sumatriptan (IMITREX®)
– Irinotecan (CAMPTOSAR®)
– Carboplatin (PARAPLATIN®)
– Rofecoxib (VIOXX®)
– Anagrelide (AGRYLIN®)
– Sodium Ferric Gluconate (FERRLECIT®)

Overview of Today’s Presentations
• 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

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