Antidepressants and Suicidality in Adults: Statistical Evaluation

Mark Levenson, Ph.D.* and Chris Holland, M.S.Statistical Safety Reviewers

Quantitative Safety and Pharmacoepidemiology Assessment Team

Division of Biometrics 6/CDER/FDA

Psychopharmacologic Drugs Advisory CommitteeDecember 13, 2006

* Presenter

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Outline• Objectives• Analysis plan

– Populations– Endpoints– Methods

• Results– Primary and secondary– Sensitivity– Subgroup

• Summary

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Objectives

Primary ObjectiveTo estimate the effect of antidepressant drugs versus placebo on suicidality in adults in double-blind, randomized, placebo-controlled clinical trials

Secondary ObjectiveTo explore the effect for various subgroups defined by subject-level and trial-level characteristics

Analysis Plan

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Study Indication Groups

1. Major depressive disorder (MDD)

2. Other depressive disorders

3. Other psychiatric disorders

4. Behavioral disorders

5. Other disorders

Non-MDD Indications

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Analysis Populations

Primary: “Psychiatric Indications”Major depressive disorder

Other depressive disorders

Other psychiatric disorders

SecondaryThe indication groups considered individually

(major depressive disorder, other depressive disorders, other psychiatric disorders, behavioral disorders, other disorders)

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Primary Endpoint

Suicidal Behavior and Ideation

– Completed suicide

– Suicide attempt

– Preparatory acts

– Suicidal ideation

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Secondary Endpoints

Suicidal Behavior– Completed suicide– Suicide attempt– Preparatory acts

Suicidal Ideation Only– Suicidal ideation

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Primary Analysis Method

“Exact method” for common odds ratio– Stratified method– Handles low event counts and small trial sizes– Assumes a common odds ratio across trials– Does not make use of trials with no events

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Sensitivity Analysis

Traditional and model-based methods– Mantel-Haenszel odds ratio

• With and without continuity correction

– Logistic regression• Unconditional and conditional estimates

Methods that allow “trial-to-trial” treatment variation “Random effects methods”– Generalized linear mixed model (GLMM)– DerSimonian-Laird

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Sensitivity Analysis(Continued)

Method that makes use of trials with no events– Mantel-Haenszel risk difference

Bayesian methods– Encompass fixed- and random-effect models

and hierarchical models– Make use of trials with no events– Kaizar et al. (2006) models

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Subgroup Analysis

Performed on subject- and trial-level characteristics– Age group– Gender– Race– Drug type: SSRI vs. non-SSRI– Location: North America vs. other– Setting: in-patient/out-patient vs. out-patient

only

Results: Trial and Subject Summaries

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Trial Indication Groups

Indication

Trials

n Subtotal

Major Depressive Disorder 162 162

Other Depressive Disorders 25 187

Other Psychiatric Disorders 108 295

Behavioral Disorders 43 338

Other Disorders 34 372

Psychiatric Indications

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Location of TrialsPsychiatric Indications

Characteristic Category n/N %

Location North America

219/295 74.2

Non-North America

73/295 24.7

Both 3/295 1.0

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Trial Duration Psychiatric Indications

CharacteristicStatistic/Category n/N %

Duration Category 1-4 Weeks 16/295 5.4

5-8 Weeks 153/295 51.9

9-12 Weeks 105/295 35.6

13-18 Weeks 14/295 4.7

>18 Weeks 7/295 2.4

Duration (weeks) Mean ± SD 10.3 ± 9.73

Median (Range) 8.0 (4 - 84)

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Subject Characteristics:Psychiatric Indications

• No notable differences between test drug subjects and placebo subjects for: – Age– Gender– Race– Baseline history of suicide attempts– Baseline history of suicide ideation– Treatment exposure

• Subject (not subject-years) is unit of analysis

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Events Psychiatric Indications

Treatment Group

EventPlaceboN=27164

Test DrugN=39729

ActiveControl

N=10489Total

N=77382

Completed suicide 2 5 1 8

Suicide attempt 44 71 18 133

Preparatory acts 3 3 4 10

Suicidal ideation 147 169 42 358

Total Events 196 248 65 509

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Suicidal Behavior and Ideation Unadjusted Rates

  Treatment Groups

IndicationPlacebo

(%)Test Drug

(%)

Major Depressive Disorder 0.84 0.73

Other Depressive Disorders 0.48 0.34

Other Psychiatric Disorders 0.61 0.51

Behavioral Disorders 0.06 0.07

Other Disorders 0.11 0.12

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Suicidal Behavior and Ideation Psychiatric Indications

Placebo: 0.72% of subjects with event

Test Drug: 0.62% of subjects with event

174/295 = 59% trials had reported events

Results: Primary and Secondary Analyses

22Odds Ratio

0.1 0.3 1 3.2 10

OVERALL

venlafaxinesertraline

paroxetinenefazodonemirtazapinefluvoxamine

fluoxetineescitalopram

duloxetinecitaloprambupropion

0.84 (0.69, 1.02)

0.68 (0.40, 1.16)0.63 (0.32, 1.21)0.96 (0.59, 1.58)0.61 (0.27, 1.35)1.04 (0.34, 3.35)1.37 (0.69, 2.84)0.65 (0.44, 0.96)1.57 (0.38, 7.88)0.81 (0.43, 1.56)2.21 (0.79, 7.63)1.41 (0.40, 5.58)

Trials OR (95% CI)

Suicidal Behavior and Ideation Psychiatric Indications

Odds Ratio

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Odds Ratio

0.1 0.3 1 3.2 10

All Indications

Other Disorders

Behavioral Disorders

Other Psychiatric Disorders

Other Depressive Disorders

Major Depressive Disorder

0.86 (0.71, 1.04)

1.51 (0.41, 6.12)

1.43 (0.34, 7.17)

0.79 (0.56, 1.12)

0.78 (0.29, 2.11)

0.86 (0.67, 1.10)

Indication Class OR (95% CI)

Suicidal Behavior and Ideation Odds Ratio

24Odds Ratio

0.1 0.3 1 3.2 10

Suicidal Behavior and Ideation

Suicidal Ideation Only

Suicidal Behavior

0.84 (0.69, 1.02)

0.75 (0.59, 0.94)

1.11 (0.77, 1.61)

Endpoint OR (95% CI)

Psychiatric Indications Odds Ratio

Results: Sensitivity Analysis

26Risk Difference per 1000 Subjects

-20 -10 0 10 20

OVERALL

venlafaxinesertraline

paroxetinenefazodonemirtazapinefluvoxamine

fluoxetineescitalopram

duloxetinecitaloprambupropion

-1.17 (-2.45, 0.11)

-2.46 (-6.02, 1.10)-1.88 (-4.46, 0.70)-0.19 (-2.56, 2.18)-2.97 (-7.85, 1.91)0.37 (-8.58, 9.31)2.65 (-3.03, 8.34)-6.43 (-12.16, -0.70)0.81 (-1.85, 3.46)-2.23 (-9.31, 4.85)6.38 (-1.49, 14.25)0.88 (-2.38, 4.14)

Trials RD (95% CI)

Suicidal Behavior and Ideation Psychiatric Indications

Risk Difference*

* Per 1000 subjects

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Odds Ratio

0.6 1 1.6

Exact Method

Bayesian Hierarchical Model

Bayesian Random Effects

Bayesian Fixed Effects

Generalized Linear Mixed Model

Cond. Logistic Model

Logistic Model

DerSimonian-Laird

Mantel-Haenszel w/Cont. Corr.

Mantel-Haenszel

0.84 (0.69, 1.02)

0.79 (0.61, 0.98)

0.83 (0.68, 1.00)

0.84 (0.69, 1.02)

0.84 (0.68, 1.02)

0.84 (0.69, 1.02)

0.84 (0.69, 1.02)

0.83 (0.68, 1.01)

0.81 (0.68, 0.97)

0.84 (0.69, 1.02)

Trials OR (95% CI)

Suicidal Behavior and Ideation Psychiatric Indications

Odds Ratio

Results: Subgroups

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Suicidal Behavior and Ideation Unadjusted Rates

Psychiatric Indications

  Treatment Groups

Age Group (Years)Placebo

(%)Test Drug

(%)

18 – 24 0.81 1.23

25 – 30 0.72 0.74

31 – 64 0.68 0.54

≥ 65 1.00 0.37

30Odds Ratio

0.1 0.3 1 3.2 10

Adult Overall

65 and Up

31 to 64

25 to 30

18 to 24

Pediatric Data

0.84 (0.69, 1.02)

0.39 (0.18, 0.78)

0.77 (0.60, 1.00)

1.00 (0.60, 1.69)

1.55 (0.91, 2.70)

2.22 (1.40, 3.60)

Age Class OR (95% CI)

Suicidal Behavior and Ideation Psychiatric Indications

Odds Ratio

*

* Reanalysis of FDA/Hammad 2004 data

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Risk Difference per 1000 Subjects

-20 -10 0 10 20

Adult Overall

65 and Up

31 to 64

25 to 30

18 to 24

Pediatric Data

-1.17 (-2.45, 0.11)

-6.17 (-10.64, -1.69)

-1.50 (-3.00, 0.00)

0.03 (-3.34, 3.39)

4.35 (-0.52, 9.21)

14.33 (6.31, 22.35)

Age Class RD (95% CI)

Suicidal Behavior and Ideation Psychiatric Indications

Risk Difference*

†

* Per 1000 Subjects. † Reanalysis of FDA/Hammad 2004 data.

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Additional Subjects with Suicidal Behavior and Ideation

(Per 1000 Subjects)

Age Class Estimate 95% Interval

Pediatric Data 14 (6, 22)

18 – 24 4 (-1, 9)

25 – 30 0 (-3, 3)

31 – 64 -2 (-3, 0)

65 and up -6 (-11, -2)

Adult Overall -1 (-2, 0)

33Odds Ratio

0.1 0.3 1 3.2 10

Suicidal Behavior and Ideation

Suicidal Ideation Only

Suicidal Behavior

1.55 (0.91, 2.70)

1.11 (0.55, 2.32)

2.31 (1.02, 5.64)

Endpoint OR (95% CI)

Suicidal Behavior and Ideation Psychiatric Indications, Age Group 18 to 24

Odds Ratio

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Other Subgroups

No notable differences in other subgroups– Gender– Race– Location of trial– Setting of care (in-patient vs. out-patient)– SSRI vs. non-SSRI drug class

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Summary

• Primary analysis population and endpoint OR = 0.84 (95% CI: 0.69, 1.02)

• Clear pattern in the estimates with increasing age

• Other subgroups (gender, race, location, setting, drug class) do not have notable effect

• Results are not sensitive to method