Sertraline Use in Pediatric Population: A Risk Benefit Discussion Steven J. Romano, MD September 13, 2004 Steven J. Romano, MD September 13, 2004 Joint

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

Steven J. Romano, MD

September 13, 2004

Joint Meeting of the CDER Psychopharmacology Drugs Advisory Committee and the FDA

Pediatric Advisory Committee

Joint Meeting of the CDER Psychopharmacology Drugs Advisory Committee and the FDA

Pediatric Advisory Committee

Points to Consider in Assessmentof Risk BenefitPoints 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







Suicide-Related Behavior and MDD in the Pediatric PopulationSuicide-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%

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; 50:1-852American 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

Pfizer Sponsored Placebo-Controlled* Pediatric Studies with SertralinePfizer Sponsored Placebo-Controlled* Pediatric Studies with Sertraline

Ongoing, Blinded Ongoing, Blinded

9292

9797

9292

SertralineSertraline

A0501033*** A0501033*** OCD Ongoing, Blinded 38 Weeks 6-17OCD Ongoing, Blinded 38 Weeks 6-17

6-176-1710 Weeks10 WeeksPTSDPTSDA0501061**A0501061**

6-176-1710 Weeks10 Weeks9393MDDMDDA0501017A050101722

6-176-1710 Weeks10 Weeks9191MDDMDDA0501001A050100122

6-176-1712 Weeks12 Weeks9595OCDOCD90-CE21-049890-CE21-049811

PlaceboPlacebo

Age Range (Yrs)Age Range (Yrs)Treatment Treatment DurationDurationNumber of SubjectsNumber of SubjectsIndicationIndicationStudy NumberStudy 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

1March JS et al., JAMA 1998; 280 (20): 1752-17562Wagner KD et al., JAMA 2003; 290 (8): 1033-1041 (pooled analysis of 2 studies)

Placebo-Controlled Pediatric OCD Study with Sertraline – Primary Efficacy Results Placebo-Controlled Pediatric OCD Study with Sertraline – Primary Efficacy Results

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Baseline Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 End

Sertraline (N=92) Placebo (N=95)

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Baseline Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 End


CY

-BO

CS

Ch

an

ge

Sco

reC

Y-B

OC

S C

ha

ng

e S

core

*p= < 0.05March JS et al., JAMA 1998; 280 (20): 1752-1756

**

**

**

****

**

CY-BOCS: Children’s Yale-Brown Obsessive Compulsive Scale Baseline score = 23CY-BOCS: Children’s Yale-Brown Obsessive Compulsive Scale Baseline score = 23

Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R ResultsPlacebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Results

SertralineSertraline PlaceboPlacebo P-ValueP-Value

Study A0501001Study A0501001 N=N= 9393 8888

CDRS-R: Baseline CDRS-R: Baseline Endpoint Endpoint 64.2 64.2 38.1 38.1 63.8 63.8 41.9 41.9 0.080.08

CDRS-R: Responders, %CDRS-R: Responders, % 62.4%62.4% 56.8%56.8% 0.460.46

Study A0501017Study A0501017 N=N= 9292 9191



Pooled Study Data (A0501001+A0501017)Pooled Study Data (A0501001+A0501017)11 N=N= 185185 179179



Primary analysis: Change from baseline in CDRS-R total score at endpoint (LOCF)CDRS-R Responders: ≥ 40% decrease on CDRS total score from baselineANCOVA 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)

CDRS-R: Children’s Depression Rating Scale – RevisedCDRS-R: Children’s Depression Rating Scale – Revised

72.6

65.366.7

51.1

0

10

20

30

40

50

60

70

80

Children (age 6-11) n = 171 Adolescents (age 12-17) n=193

Sertraline Placebo

72.6

65.366.7

51.1

0

10

20

30

40

50

60

70

80

Children (age 6-11) n = 171 Adolescents (age 12-17) n=193

Sertraline Placebo

Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Response Rates in Children vs AdolescentsPlacebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Response Rates in Children vs Adolescents

*p<0.05Response rate defined as a ≥40% decrease on CDRS total score from baseline

CDRS-R response rates (%)CDRS-R response rates (%)

**

84 87 101 92

Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Item 13 (“Suicidal Ideation”) Placebo-Controlled Pediatric MDD Studies with Sertraline – CDRS-R Item 13 (“Suicidal Ideation”)

1.0

1.2

1.4

1.6

1.8

2.0

Baseline Week 1 Week 2 Week 3 Week 4 Week 6 Week 8 Week 10


1.0

1.2

1.4

1.6

1.8

2.0

Baseline Week 1 Week 2 Week 3 Week 4 Week 6 Week 8 Week 10


Suicidal Ideation Mean score from Baseline to Endpoint(LOCF)

Suicidal Ideation Mean score from Baseline to Endpoint(LOCF)

CD

RS

-R T

ota

l Sc

ore

CD

RS

-R T

ota

l Sc

ore

Placebo-Controlled Pediatric Studies with SertralinePlacebo-Controlled Pediatric Studies with Sertraline

SertralineSertraline PlaceboPlacebo

DiagnosisDiagnosis n/Nn/N Incidence % Incidence % [95% CI][95% CI] n/Nn/N Incidence % Incidence %

[95% CI][95% CI]

MDDMDD 2/1892/189 1.1 1.1 [[0.1-3.80.1-3.8]]

2/1842/184 1.1 1.1 [[0.1-3.90.1-3.9]]

OCDOCD 0/920/92 0 0 [[0-3.210-3.21]]

0/950/95 0 0 [[0-3.100-3.10]]

CombinedCombined 2/2812/281 0.7 0.7 [[0.1-2.60.1-2.6]]

2/2792/279 0.7 0.7 [[0.1-2.60.1-2.6]]

Suicide AttemptsSuicide 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

Placebo-Controlled Pediatric Studies with Sertraline Placebo-Controlled Pediatric Studies with Sertraline

SertralineSertraline PlaceboPlacebo

Diagnosis/Diagnosis/StudyStudy n/Nn/N Incidence % Incidence %

[[95% CI95% CI]]n/Nn/N Incidence % Incidence %

[[95% CI95% CI]]

MDDMDD 3/1893/189 1.6 1.6 [[0.33-4.570.33-4.57]]

0/1840/184 00[0-1.61][0-1.61]

OCDOCD 0/920/92 0 0 [[0-3.210-3.21]]

1/951/95 1.1 1.1 [[0.03-5.730.03-5.73]]

CombinedCombined 3/2813/281 1.1 1.1 [[0.22-3.090.22-3.09]]

1/2791/279 0.4 0.4 [[0.01-1.980.01-1.98]]

Suicidal IdeationSuicidal 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

Placebo-Controlled Pediatric Studies with Sertraline – Timing of EventsPlacebo-Controlled Pediatric Studies with Sertraline – Timing of Events

Patient ID Age, Sex SA/SI Day of event

Sertraline

2006 12, M SI 49

1089 10, F SI 35

1022 11, M SI 21

4022 16, F SA 50

3095 6, M SA 34

Placebo

4329 17, F SA 9

4321 15, F SA x 2 63, 66

19 (OCD) 6, F SI 12

No specific pattern in time of event

No association between time of event and dose increases

Most events associated with immediate psychosocial precipitant

No specific pattern in time of event

No association between time of event and dose increases

Most events associated with immediate psychosocial precipitant

Placebo-Controlled Pediatric Studies with Sertraline – SummaryPlacebo-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 and

2 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

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 and

2 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

Points to Consider in Assessmentof Risk BenefitPoints to Consider in Assessmentof Risk Benefit













Pfizer’s PositionPfizer’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

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

Documents

Sertraline Use in Pediatric Population: A Risk Benefit Discussion Steven J. Romano, MD September 13, 2004 Steven J. Romano, MD September 13, 2004 Joint