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

1. 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

2. 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

3. FDA’s 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

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

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, including • Accidental or intentional overdose • Occurring from abuse or drug withdrawal • Failure of expected pharmacological action

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. 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)

8. 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

9. 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.)

10. 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

11. 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

12. Role of the Committee:Primary Materials for Review • One-year post-exclusivity adverse event report review • Focus on pediatric AE reports during the year and SAE’s 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

13. Role of the Committee:Additional Materials for Review • Summaries of clinical, pharmacology & toxicology reviews of exclusivity studies • Drug product label • Published literature • Sponsor materials/presentations

14. 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)

15. Overview of Today’s 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

16. Overview of Today’s BPCA Safety Review Presentations (cont’d) • 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.

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