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Sertraline Use in Pediatric Population: A Risk Benefit Discussion

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

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Sertraline Use in Pediatric Population: A Risk Benefit Discussion

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  1. Sertraline Use in Pediatric Population:A Risk Benefit Discussion 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 Assessmentof Risk Benefit • MDD is a serious illness that affects many children and adolescents in the US and is associated with suicidal behavior • Physicians have limited approved treatment options for pediatric patients with MDD • The 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 • Approaching 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 • Suicide is the third leading cause of death in adolescents 15-19 years old1 • Annual prevalence of MDD2 • Children (8-12): 2-3% • Adolescents (11/12-18): Up to 8% • Diagnostic 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 • Suicidality in depressed children and adolescents at time of study entry3 • Suicide attempts: 9% • Suicidal ideation: 66% 1Anderson RN. Deaths: leading causes for 2000. Natl Vital Stat Rep. 2002; 50:1-85 2American 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); 3Kovacs 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 Study Number Indication Number of Subjects Treatment Duration Age Range (Yrs) Sertraline Placebo 90-CE21-04981 OCD 92 95 12 Weeks 6-17 A05010012 MDD 97 91 10 Weeks 6-17 A05010172 MDD 92 93 10 Weeks 6-17 A0501061** PTSD Ongoing, Blinded 10 Weeks 6-17 A0501033*** OCD Ongoing, Blinded 38 Weeks 6-17 *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 1March JS et al., JAMA 1998; 280 (20): 1752-1756 2Wagner 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: Children’s Yale-Brown Obsessive Compulsive Scale Baseline score = 23 * CY-BOCS Change Score * * * * * *p= < 0.05 March JS et al., JAMA 1998; 280 (20): 1752-1756

  6. Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Results CDRS-R: Children’s Depression Rating Scale – Revised 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 1Wagner KD et al., JAMA 2003; 290 (8): 1033-1041 (pooled analysis of 2 studies)

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

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

  9. Placebo-Controlled Pediatric Studies with Sertraline 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 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 • No specific pattern in time of event • No association between time of event and dose increases • Most events associated with immediate psychosocial precipitant

  12. Placebo-Controlled Pediatric Studies with Sertraline – Summary • Sertraline is effective and safe in the treatment of pediatric OCD • The 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 • There were no suicides in any pediatric study with sertraline • No 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 and2 patients/3 attempts in placebo group) • Suicidal ideation (3 patients in sertraline, 1 in placebo) • No temporal association between onset of double-blind treatment or dose increases and suicide-related events

  13. Points to Consider in Assessmentof Risk Benefit • MDD is a serious illness that affects many children and adolescents in the US and is associated with suicidal behavior • Physicians have limited approved treatment options for pediatric patients with MDD • The 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 • Approaching this issue as a class effect might jeopardize beneficial treatments for children and adolescents with MDD

  14. Pfizer’s Position • Current 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 • If 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

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