1. Sertraline Use in Pediatric Population: A Risk Benefit Discussion Steven J. Romano, MD September 13, 2004 Steven J. Romano, MD September 13, 2004 Joint Meeting of the CDER Psychopharmacology Drugs Advisory Committee and the FDA Pediatric Advisory Committee

2. Points to Consider in Assessment of Risk Benefit uMDD is a serious illness that affects many children and adolescents in the US and is associated with suicidal behavior uPhysicians have limited approved treatment options for pediatric patients with MDD uThe risk/benefit of antidepressant use in pediatric depression should be assessed on an individual product basis Antidepressants differ with regard to chemical structure, pharmacological profile, pharmacokinetics, adverse events and discontinuation symptom profile Results of the studies reviewed in FDA analysis vary uApproaching this issue as a class effect might jeopardize beneficial treatments for children and adolescents with MDD uMDD is a serious illness that affects many children and adolescents in the US and is associated with suicidal behavior uPhysicians have limited approved treatment options for pediatric patients with MDD uThe risk/benefit of antidepressant use in pediatric depression should be assessed on an individual product basis Antidepressants differ with regard to chemical structure, pharmacological profile, pharmacokinetics, adverse events and discontinuation symptom profile Results of the studies reviewed in FDA analysis vary uApproaching this issue as a class effect might jeopardize beneficial treatments for children and adolescents with MDD

3. Suicide-Related Behavior and MDD in the Pediatric Population uSuicide is the third leading cause of death in adolescents 15-19 years old 1 uAnnual prevalence of MDD 2 Children (8-12): 2-3% Adolescents (11/12-18): Up to 8% uDiagnostic criteria (DSM IV-R) includes recurrent thoughts of death, suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide uSuicidality in depressed children and adolescents at time of study entry 3 Suicide attempts: 9% Suicidal ideation: 66% uSuicide is the third leading cause of death in adolescents 15-19 years old 1 uAnnual prevalence of MDD 2 Children (8-12): 2-3% Adolescents (11/12-18): Up to 8% uDiagnostic criteria (DSM IV-R) includes recurrent thoughts of death, suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide uSuicidality in depressed children and adolescents at time of study entry 3 Suicide attempts: 9% Suicidal ideation: 66% 1 Anderson RN. Deaths: leading causes for 2000. Natl Vital Stat Rep. 2002; 50:1-85 2 American Academy of Child and Adolescent Psychiatry (1998), Practice Parameters for the Assessment and Treatment of Children and Adolescents with Depressive Disorders. J Amer Acad Child Adolesc Psychiatry 37 (10 suppl); 3 Kovacs et al. Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation. J Amer Acad Child Adolesc Psychiatry 1993; 32 (1): 8-20

4. Pfizer Sponsored Placebo-Controlled* Pediatric Studies with Sertraline Ongoing, Blinded 92 97 92 Sertraline A0501033*** OCD Ongoing, Blinded 38 Weeks 6-17 6-17 10 Weeks PTSDA0501061** 6-17 93MDD A0501017 2 6-17 10 Weeks 91MDD A0501001 2 6-17 12 Weeks 95OCD 90-CE21-0498 1 Placebo Age Range (Yrs) Treatment Duration Number of Subjects Indication Study Number *Pfizer performed 6 additional uncontrolled studies with sertraline in pediatric population which are published or being submitted for publication **A total of 75 patients have been enrolled to date ***A total of 24 patients have been enrolled to date 1 March JS et al., JAMA 1998; 280 (20): 1752-1756 2 Wagner KD et al., JAMA 2003; 290 (8): 1033-1041 (pooled analysis of 2 studies)

5. Placebo-Controlled Pediatric OCD Study with Sertraline – Primary Efficacy Results CY-BOCS Change Score *p= < 0.05 March JS et al., JAMA 1998; 280 (20): 1752-1756 * * * * * * * * * * * * CY-BOCS: Children’s Yale-Brown Obsessive Compulsive Scale Baseline score = 23

6. Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Results SertralinePlaceboP-Value Study A0501001 N=9388 CDRS-R: Baseline  Endpoint 64.2  38.1 63.8  41.9 0.08 CDRS-R: Responders, % 62.4%56.8%0.46 Study A0501017 N=9291 CDRS-R: Baseline  Endpoint 64.4  36.1 65.4  39.3 0.17 CDRS-R: Responders, % 75.0%60.4%0.03 Pooled Study Data (A0501001+A0501017) 1 N=185179 CDRS-R: Baseline  Endpoint 64.3  37.1 64.6  40.6 0.03 CDRS-R: Responders, % 68.7%58.7%0.05 Primary analysis: Change from baseline in CDRS-R total score at endpoint (LOCF) CDRS-R Responders: ≥ 40% decrease on CDRS total score from baseline ANCOVA for CDRS-R change from baseline to LOCF endpoint; CMH test for responder rate 1 Wagner KD et al., JAMA 2003; 290 (8): 1033-1041 (pooled analysis of 2 studies) CDRS-R: Children’s Depression Rating Scale – Revised

7. Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Response Rates in Children vs Adolescents *p<0.05 Response rate defined as a ≥40% decrease on CDRS total score from baseline CDRS-R response rates (%) * * 84 87 101 92

8. Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Item 13 (“Suicidal Ideation”) Suicidal Ideation Mean score from Baseline to Endpoint (LOCF) Suicidal Ideation Mean score from Baseline to Endpoint (LOCF) CDRS-R Total Score

9. Placebo-Controlled Pediatric Studies with Sertraline SertralinePlacebo Diagnosisn/N Incidence % [95% CI] n/N Incidence % [95% CI] MDD2/1891.1 [0.1-3.8] 2/1841.1 [0.1-3.9] OCD0/920 [0-3.21] 0/950 [0-3.10] Combined2/2810.7 [0.1-2.6] 2/2790.7 Suicide Attempts FDA analysis is consistent with Pfizer analysis; no new cases of suicide-related behavior identified by Columbia University FDA review compared to Pfizer’s submissions

10. Placebo-Controlled Pediatric Studies with Sertraline SertralinePlacebo Diagnosis/ Study n/N Incidence % [95% CI] n/N Incidence % [95% CI] MDD3/1891.6 [0.33-4.57] 0/1840[0-1.61] OCD0/920 [0-3.21] 1/951.1 [0.03-5.73] Combined3/2811.1 [0.22-3.09] 1/2790.4 [0.01-1.98] Suicidal Ideation FDA analysis is consistent with Pfizer analysis; no new cases of suicide-related behavior identified by Columbia University / FDA review compared to Pfizer’s submissions

11. Placebo-Controlled Pediatric Studies with Sertraline – Timing of Events Patient IDAge, SexSA/SIDay of event Sertraline 200612, MSI49 108910, FSI35 102211, MSI21 402216, FSA50 30956, MSA34 Placebo 432917, FSA9 432115, FSA x 263, 66 19 (OCD)6, FSI12 uNo specific pattern in time of event uNo association between time of event and dose increases uMost events associated with immediate psychosocial precipitant

12. Placebo-Controlled Pediatric Studies with Sertraline – Summary uSertraline is effective and safe in the treatment of pediatric OCD uThe a-priori pooled analysis of the sertraline clinical studies in pediatric MDD demonstrated a statistically significant effect on CDRS-R Benefit relative to placebo was modest due to a high placebo response, primarily in children uThere were no suicides in any pediatric study with sertraline uNo statistically significant difference between sertraline and placebo in placebo-controlled studies of MDD or OCD with respect to: Suicide attempts (2 patients/2 attempts in sertraline and 2 patients/3 attempts in placebo group) Suicidal ideation (3 patients in sertraline, 1 in placebo) uNo temporal association between onset of double-blind treatment or dose increases and suicide-related events uSertraline is effective and safe in the treatment of pediatric OCD uThe a-priori pooled analysis of the sertraline clinical studies in pediatric MDD demonstrated a statistically significant effect on CDRS-R Benefit relative to placebo was modest due to a high placebo response, primarily in children uThere were no suicides in any pediatric study with sertraline uNo statistically significant difference between sertraline and placebo in placebo-controlled studies of MDD or OCD with respect to: Suicide attempts (2 patients/2 attempts in sertraline and 2 patients/3 attempts in placebo group) Suicidal ideation (3 patients in sertraline, 1 in placebo) uNo temporal association between onset of double-blind treatment or dose increases and suicide-related events

13. Points to Consider in Assessment of Risk Benefit uMDD is a serious illness that affects many children and adolescents in the US and is associated with suicidal behavior uPhysicians have limited approved treatment options for pediatric patients with MDD uThe risk/benefit of antidepressant use in pediatric depression should be assessed on an individual product basis Antidepressants differ with regard to chemical structure, pharmacological profile, pharmacokinetics, adverse events and discontinuation symptom profile Results of the studies reviewed in FDA analysis vary uApproaching this issue as a class effect might jeopardize beneficial treatments for children and adolescents with MDD uMDD is a serious illness that affects many children and adolescents in the US and is associated with suicidal behavior uPhysicians have limited approved treatment options for pediatric patients with MDD uThe risk/benefit of antidepressant use in pediatric depression should be assessed on an individual product basis Antidepressants differ with regard to chemical structure, pharmacological profile, pharmacokinetics, adverse events and discontinuation symptom profile Results of the studies reviewed in FDA analysis vary uApproaching this issue as a class effect might jeopardize beneficial treatments for children and adolescents with MDD

14. Pfizer’s Position uCurrent class labeling for monitoring during treatment with antidepressants accurately reflects the risk of suicidality in adult and pediatric patients Such labeling should be applied to all medications indicated for the treatment of depression and not just SSRIs/SNRIs uIf the FDA considers a label change is necessary, product specific labeling would be most beneficial to prescribers and patients Inclusion of specific event rates of suicide-related behavior for the placebo-controlled clinical trials in the Adverse Event section of the Label uCurrent class labeling for monitoring during treatment with antidepressants accurately reflects the risk of suicidality in adult and pediatric patients Such labeling should be applied to all medications indicated for the treatment of depression and not just SSRIs/SNRIs uIf the FDA considers a label change is necessary, product specific labeling would be most beneficial to prescribers and patients Inclusion of specific event rates of suicide-related behavior for the placebo-controlled clinical trials in the Adverse Event section of the Label