# Presentation: 546030

## 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

- Objectives
- Analysis plan
- Populations
- Endpoints
- Methods
- Results
- Primary and secondary
- Sensitivity
- Subgroup
- Summary

## 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

## Analysis Plan

## Study Indication Groups

- Major depressive disorder (MDD)
- Other depressive disorders
- Other psychiatric disorders
- Behavioral disorders
- Other disorders

- Non-MDD Indications

## 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

*Suicidal Behavior and Ideation*
- Completed suicide
- Suicide attempt
- Preparatory acts
- Suicidal ideation

## Secondary Endpoints

*Suicidal Behavior*
- Completed suicide
- Suicide attempt
- Preparatory acts
*Suicidal Ideation Only*
- Suicidal ideation

## 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

- 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)

- 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

- 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

## 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

## Location of TrialsPsychiatric Indications

| Characteristic | Category | n/N | % |
| --- | --- | --- | --- |
|     Location  | North America | 219/295  | 74.2 |
|  | Non-North America | 73/295  | 24.7 |
|  | Both | 3/295  | 1.0 |

## Trial Duration Psychiatric Indications

| Characteristic | Statistic/
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) |  |

## 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

|  | Treatment Group |  |  |  |
| --- | --- | --- | --- | --- |
| Event | Placebo
N=27164 | Test Drug
N=39729 | Active
Control
N=10489 | Total
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 |

## Suicidal Behavior and Ideation Unadjusted Rates

|   | Treatment Groups |  |
| --- | --- | --- |
| Indication | Placebo (%) | 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 |

## 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

## Slide 22

## Slide 23

## Slide 24

## Results: Sensitivity Analysis

## *

- * Per 1000 subjects

## Slide 27

## Results: Subgroups

## 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 |

## *

- * Reanalysis of FDA/Hammad 2004 data

## *

- †

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

## 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) |

## Slide 33

## 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

- 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