1. 1 Characteristics of Pediatric Antidepressant Trials Gregory M. Dubitsky, MD Division of Neuropharmacological Drug Products FDA

2. 2 Objective Descriptive only. Will not address effect of study characteristics on suicidality risk: See Dr. Hammad’s Presentation

3. 3 Study Pool 23 placebo-controlled studies conducted between 1984 and 2001. 9 drugs. 5 indications (major depression, OCD, GAD, SAD, ADD).

4. 4 Common Design Features Randomized. Double-blind. Placebo-controlled. Parallel group. Flexible-dose.

5. 5 Basic Study Design See Handout: Table 1 Drug, study, indication. Age range. Number of patients in analysis by TX. Duration of double-blind TX. Protocol-specified dose range.

6. 6 Screening and Key Exclusionary Criteria See Handout: Table 2 Extensive diagnostic screening. Placebo lead-in preceding DB TX (and exclusion of placebo responders). Exclusionary criteria: H/O treatment resistance, current suicide risk, H/O suicide attempt, bipolar disorder, family H/O bipolar disorder.

7. 7 Other Study Features (see Appendix to my review) study dates/location/number of centers. stratified randomization by age group. exclusionary criteria: -homicidal risk. -psychotic symptoms. -alcohol/drug abuse. -borderline personality disorder. -eating disorder.

8. 8 Notable Study Differences Prozac HCCJ (MDD): small & terminated early. One active-control study: - Paxil 329 (MDD) (imipramine). Two studies included inpatients: - Celexa 94404 (MDD) & Wellbutrin 75 (ADD). Three studies used extensive DX screening: -Prozac X065 & HCJE; Paxil 329 (all MDD).

9. 9 Post-DB Phase TX Options Variable across trials: Taper of acute TX (8 trials). Abrupt D/C (7 trials). Open-label TX (5 trials). Continued DB TX (3 trials). Also variable within trials: e.g., Paxil 329 (MDD) - responders continued DB TX, non-responders tapered. Variable follow-up hindered W/D effect analysis.

10. 10 No study was specifically designed to assess suicidality. suicide attempts and ideation detected only by routine safety monitoring: -treatment-emergent adverse events. -suicide-related items on depression scales (CDRS-R, K-SADS, HAM-D, and MADRS). AE description often incomplete or vague.

11. 11 Conclusions Potential influence of study design characteristics on suicide risk: See Dr. Hammad’s analysis.