Adverse Event Tracking as mandated by the Best Pharmaceuticals for Children Act

1. Adverse Event Trackingas mandated by theBest Pharmaceuticals for Children Act March 3, 2003 Dr. Solomon IyasuMedical Team Leader Division of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration

2. Outline • Adverse event reporting requirements mandated by BPCA • FDA’s adverse event review plan • Proposed review template • Example of a preliminary AE review

3. Best Pharmaceuticals for Children Act(1/4/02) • Section 17: Adverse Event (AE) Reporting • review AE reports for a period of one-year after a drug is granted pediatric exclusivity • report to the Pediatric Advisory Sub-Committee for review

4. Adverse Event ReportReview Plan OPT Responsibilities • will coordinate and facilitate all FDA activities that affect the pediatric population or the practice of pediatrics • receives post-pediatric exclusivity AE reports and provides report to the Pediatric Advisory Subcommittee for their review and recommendations

5. Adverse Event ReportReview Plan OCTAP Responsibilities • notifies Office of Drug Safety (ODS) of drugs granted/or denied exclusivity • serves as clinical contact point for the Office of Pediatric Therapeutics (OPT)

6. Adverse Event ReportReview Plan ODS Responsibilities • review adverse event reports for the one year after the date of exclusivity • complete review within 90 days of the one-year post exclusivity date • discuss serious unexpected events including deaths with the Office of Pediatric Therapeutics immediately • share results of AE review with Office of New Drugs

7. Proposed Adverse Event Report Review Template • Executive Summary • Usage information for adults and pediatric patients. • 2 years prior and 1 year post exclusivity

8. Proposed Adverse Event ReportReview Template(cont’d) • Adverse Events Reporting System (AERS) Search • Counts of AE reports from drug approval date and one-year post exclusivity • Adult (>16 yo) • Pediatric Ages ( 0-16 yo) • most frequently reported adverse events • frequency of unexpected adverse events

9. Proposed Adverse Event ReportReview Template(cont’d) • Detailed Review of Pediatric AEs • demographics, serious outcomes, indications and doses • unexpected or unique pediatric adverse events • increased frequency of known pediatric adverse events • summary of pediatric death reports • summary adverse event profile (including use data)

10. Example of an Adverse Event Report • Example: Sertraline • 10-month data • Preliminary data/Incomplete analysis • No final conclusions drawn • More detailed analysis in future

11. Preliminary Review ofAdverse Event Report • Moiety: Sertraline (ZOLOFT) • Sponsor: Pfizer • Indication: • Adults: major depressive disorder, obsessive compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, social anxiety disorder • Children: Obsessive compulsive disorder (6 years and older) • One-year post exclusivity date: 3/1/03 *Preliminary data/Incomplete analysis

12. Number of Adverse Event Reports by Age(2/1/02 to 12/5/02) AgeAll reports (US)Serious (US)Death (US) All Ages 892 (577) 724 (464) 133 (88) Adults (>16) 610 (372) 528 (322) 98 (64) Peds (0-16) 41 (32) 30 (22) 4 (4) *Total for all ages includes reports with unknown age Numbers may include duplicates

13. Adults Dizziness Nausea drug withdrawal syndrome agitation confusion headache feeling abnormal suicidal ideation tremor vomiting *AE not in label Pediatric age maternal drug affecting fetus* dyspnea aggression insomnia abnormal behavior c- section complication of maternal exp* convulsions crying memory impairment* Most Frequently Reported Adult & Pediatric Adverse Events

14. Pediatric Adverse Events by Age and Gender(N=40 unduplicated) • Age • 0-<1 mo 7 • 1 mo- <2 yrs 4 • 2-5 yrs 2 • 6-11 yrs 9 • 12-16 yrs 18 • Gender • Female (23), Male (16), unknown (1)

15. Serious Outcomes in Pediatric Patients* • 3 Deaths • 15 Hospitalization • 21 Others (life threatening or required interventions or medically important events) *events are not mutually exclusive

16. Clinical Conditions for Which Sertraline was Used • Depression = 16 • Obsessive compulsive disorders= 4 • ADHD = 3 • Vocal cord disorder = 1 • Stress emotional problems = 1 • Adjustment disorder= 1 • Unknown or accidental use = 14

17. Review of Pediatric Deaths • Case 1: • 7 yo male prescribed sertraline for depression • also using amitriptyline, clonidine • dose and duration unknown • “drug levels 2-3 times higher in the liver than the prescribed amount” • possible conclusion: death due to chronic multiple drug toxicity

18. Review of Pediatric Deaths • Case 2: • premature male child born to an HIV positive mother • mother using sertraline for depression (100 mg/day) also using multiple other medications during last three months of pregnancy • baby died 15 days after birth from pneumothorax and septic shock • possible conclusion: death unrelated to sertraline

19. Review of Pediatric Deaths • Case 3: • 13 yo male, committed suicide following one-week of trial of 50 mg /day of Sertraline therapy for Depression • patient remained significantly depressed during therapy • parents did not notice any agitation or mood changes • exact event date unknown but initial report in 1997 • suicide ideation is labeled but rare • possible conclusion: unclear relationship to sertraline??

20. Summary • Developed a plan and process for tracking adverse events as mandated in the BPCA • Defined the roles and responsibilities of ODS, OCTAP and OPT • Discussed a proposed AE review template • Presented an example of an adverse event review using preliminary data for sertraline

21. Role of the Pediatric Advisory Subcommittee • provide feedback on the review template and plan • review the summary adverse event reports • recommend further investigations and/or any regulatory action to FDA

22. Thank You