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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 Committee

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Antidepressants and suicidality in adults statistical evaluation

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 Committee

December 13, 2006

* Presenter


Outline
Outline

  • Objectives

  • Analysis plan

    • Populations

    • Endpoints

    • Methods

  • Results

    • Primary and secondary

    • Sensitivity

    • Subgroup

  • Summary


Objectives
Objectives

Primary Objective

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

Secondary Objective

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



Study indication groups
Study Indication Groups

  • Major depressive disorder (MDD)

  • Other depressive disorders

  • Other psychiatric disorders

  • Behavioral disorders

  • Other disorders

Non-MDD Indications


Analysis populations
Analysis Populations

Primary: “Psychiatric Indications”

Major depressive disorder

Other depressive disorders

Other psychiatric disorders

Secondary

The indication groups considered individually (major depressive disorder, other depressive disorders, other psychiatric disorders, behavioral disorders, other disorders)


Primary endpoint
Primary Endpoint

Suicidal Behavior and Ideation

  • Completed suicide

  • Suicide attempt

  • Preparatory acts

  • Suicidal ideation


Secondary endpoints
Secondary Endpoints

Suicidal Behavior

  • Completed suicide

  • Suicide attempt

  • Preparatory acts

    Suicidal Ideation Only

  • Suicidal ideation


Primary analysis method
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


Sensitivity analysis
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


Sensitivity analysis continued
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


Subgroup analysis
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

Results: Trial and Subject Summaries


Trial indication groups
Trial Indication Groups

Psychiatric

Indications


Location of trials psychiatric indications
Location of TrialsPsychiatric Indications


Trial duration psychiatric indications
Trial Duration Psychiatric Indications


Subject characteristics psychiatric indications
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


Events psychiatric indications
Events Psychiatric Indications



Suicidal behavior and ideation psychiatric indications
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

Results: Primary and Secondary Analyses



Antidepressants and suicidality in adults statistical evaluation

*

* Per 1000 subjects



Suicidal behavior and ideation unadjusted rates psychiatric indications
Suicidal Behavior and Ideation Unadjusted RatesPsychiatric Indications


Antidepressants and suicidality in adults statistical evaluation

*

* Reanalysisof FDA/Hammad 2004 data


Antidepressants and suicidality in adults statistical evaluation

*

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


Additional subjects with suicidal behavior and ideation per 1000 subjects
Additional Subjects with Suicidal Behavior and Ideation (Per 1000 Subjects)


Other subgroups
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


Summary
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