1. 1 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

2. 2 Best Pharmaceuticals for Children Act: Legislative Mandate Section 17 of the BPCA mandates the Office of Pediatric Therapeutics (OPT) to: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

3. 3 FDA Adverse Event Reporting System (AERS) Database of all AERS and manufacturer reportsDatabase of all AERS and manufacturer reports Origin 1969 (SRS until 1997)Origin 1969 (SRS until 1997) ~ 2 million reports~ 2 million reports Contains drug and "therapeutic" biologic reportsContains drug and "therapeutic" biologic reports Exception = vaccines VAERS 1-800-822-7967Exception = vaccines VAERS 1-800-822-7967

4. 4 Source of Reports Source of Reports Voluntary/spontaneous reportingVoluntary/spontaneous reporting Health care professionals, consumers/ patients, or othersHealth care professionals, consumers/ patients, or others Manufacturers: Required for post- marketing reporting (>90%)Manufacturers: Required for post- marketing reporting (>90%) –All adverse drug experience information obtained or otherwise received from any source, foreign or domestic

5. 5 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, includingAdverse 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

6. 6 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)

7. 7 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:Serious Adverse Event (SAE): any event occurring at any dose that results in any of the following outcomes: DeathDeath Life-threatening ADE (immediate risk)Life-threatening ADE (immediate risk) Hospitalization or prolongation of hospitalizationHospitalization or prolongation of hospitalization Persistent/significant disability/incapacityPersistent/significant disability/incapacity Congenital anomaly/birth defectCongenital anomaly/birth defect Other/requiring intervention (e.g. bronchospasm)Other/requiring intervention (e.g. bronchospasm)

8. 8 Causality Assessment of AE reports Temporal relationshipTemporal relationship De-challenge - ADR subsides when drug is discontinuedDe-challenge - ADR subsides when drug is discontinued Re-challenge - ADR returns when drug is re-administeredRe-challenge - ADR returns when drug is re-administered Dose-responseDose-response Biologic plausibility (knowledge of PK and PD)Biologic plausibility (knowledge of PK and PD) Animal preclinical studiesAnimal preclinical studies Laboratory evidenceLaboratory evidence Known class effectKnown class effect Underlying diseaseUnderlying disease Concomitant drugsConcomitant drugs

9. 9 AERS: Strengths Includes all U.S. marketed drugsIncludes all U.S. marketed drugs Simple, inexpensive reporting systemSimple, inexpensive reporting system Provides for early detection of safety signalsProvides for early detection of safety signals –Especially good for rare Adverse Drug Reactions (anaphylaxis, liver failure, aplastic anemia, serious skin reactions etc.)

10. 10 AERS: Limitations Underreporting: varies from drug to drug and over timeUnderreporting: varies from drug to drug and over time Quality and completeness of reports: variable, often poorQuality and completeness of reports: variable, often poor Can estimate rates of events only grossly: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

11. 11 Role of the Committee: Primary Materials for Review One-year post-exclusivity adverse event reportsOne-year post-exclusivity adverse event reports –Focus on pediatric AE reports Pediatric drug use data (denominator)Pediatric drug use data (denominator) –Outpatient use can be projected nationally Dispensed prescriptions from retail pharmaciesDispensed prescriptions from retail pharmacies Drug mentions in office based practiceDrug mentions in office based practice –Inpatient use cannot be projected nationally

12. 12 Role of the Committee: Additional Materials for Review Summaries of clinical, and pharmacology & toxicology reviews of exclusivity studiesSummaries of clinical, and pharmacology & toxicology reviews of exclusivity studies Drug product labelDrug product label Published literaturePublished literature Sponsor materials/presentationsSponsor materials/presentations

13. 13 Types of Safety Review Presentations Abbreviated:Abbreviated: – No safety signal of concern StandardStandard –No unlabeled safety signal Drug product has reports of labeled SAEs that are of interest (Cipro)Drug product has reports of labeled SAEs that are of interest (Cipro) Drug Product with safety concern of recent public interest (Vioxx)Drug Product with safety concern of recent public interest (Vioxx) In-depthIn-depth –New possible safety concern Entire AC meeting or session dedicated to drug or class- specific safety concern ( SSRI’s, ADHD drugs)Entire AC meeting or session dedicated to drug or class- specific safety concern ( SSRI’s, ADHD drugs)

14. 14 Overview of Today’s Presentations Abbreviated Presentations:Abbreviated Presentations: –Sumatriptan (IMITREX ® ) –Irinotecan (CAMPTOSAR ® ) –Carboplatin (PARAPLATIN ® ) –Rofecoxib (VIOXX ® ) –Anagrelide (AGRYLIN ® ) –Sodium Ferric Gluconate (FERRLECIT ® )

15. 15 Overview of Today’s Presentations (cont’d) Standard Presentation:Standard Presentation: –Fluconazole (DIFLUCAN ® ) In-depth Presentation:In-depth Presentation: –Oseltamivir (TAMIFLU ® ) –Presentations include: One-year post-exclusivity AEs, drug use review and summary of materials from the Japanese Regulatory AuthoritiesOne-year post-exclusivity AEs, drug use review and summary of materials from the Japanese Regulatory Authorities Literature and pediatric clinical trial reviewLiterature and pediatric clinical trial review Influenza surveillance in the USInfluenza surveillance in the US Sponsor presentationSponsor presentation –Committee Discussion of Questions

16. 16 Acknowledgments Division of Pediatric Drug Development, OCTAPDivision of Pediatric Drug Development, OCTAP Office of Drug Safety (DDRE, DSRCS)Office of Drug Safety (DDRE, DSRCS) Office of New DrugsOffice of New Drugs Office of Pediatric TherapeuticsOffice of Pediatric Therapeutics