# Presentation: 371858

## Suicidality and Anti-epileptic Drugs: Status of Clinical Trial Data Analysis

- Evelyn Mentari, MD, MS
- Division of Neurology Products

## Background

- The Division of Neurology Products is analyzing the potential association between anti-epileptic drugs (AEDs) and suicidal thinking and behavior in placebo-controlled trials
- The division’s analysis is independent of the post-pediatric exclusivity post-marketing adverse event review just presented
- Post-marketing cases of suicidal thinking and behavior are difficult to interpret
- Known limitations of post-marketing data
- Patients with epilepsy (and other illnesses for which AEDs are being prescribed) have increased risk of suicide

**Notes:**
So a control group provides critical information...

Note in presentation that our analysis was planned before the pediatric exclusivity adverse event review was conducted...NOT triggered by worry about any particular post-marketing cases

## Background

- An AED sponsor approached the Division with concern of a suicidality signal in their controlled clinical trial database
- In response, the Division initiated an analysis of suicidality events in controlled clinical trial databases of all AEDS
- Sponsors were asked (in March, 2005) to provide data from their placebo-controlled trial experience
- Division will conduct meta-analysis of all data

## Background

- Standardized approach is based on previous FDA analysis of suicidality in children and adolescents treated with antidepressants
- In this analysis, pediatric patients treated with antidepressants were found to have an increased risk of suicidality compared to those treated with placebo

## Suicidality Analysis

- Analysis includes parallel-arm, placebo- controlled trials with at least 20 subjects in each treatment arm
- A search for events related to suicidal behavior or possibly related to suicidal behavior was performed by the sponsors, using search terms specified by FDA

## Suicidality Events:  Search Terms

- Preferred terms with text strings “suic” or “overdos,” including all events coded as “accidental overdose”
- Verbatim terms with the text strings: “attempt”, “cut”, “gas”, “hang”, “hung”, “jump”, “mutilat-”, “overdos-”, “self damag-”, “self harm”, “self inflict”, “self injur-”, “shoot”, “slash”, “suic-”, “poison”, “asphyxiation”, “suffocation”, “firearm”; events were screened for false positives
- All deaths and other serious adverse events (SAEs)
- All adverse events coded as “accidental injury”

## Suicidality Analysis

- After events were found using this search strategy, structured narratives were prepared
- Based on these narratives, events were classified into 7 categories
- Classification was done by raters blinded to treatment

## Suicidality Event Classification

- Completed suicide
- Suicide attempt
- Preparatory acts toward imminent suicidal behavior
- Suicidal ideation
- Self-injurious behavior, intent unknown
- Not enough information, fatal
- Not enough information, non-fatal

**Notes:**
Sponsors were asked to use the adverse event classification developed by Dr. Posner at Columbia (that was used for the peds/antidepressant suicidality analysis)

## Drugs To Be Evaluated

- Pregabalin (Lyrica)
- Valproic acid (Depakote)
- Gabapentin (Neurontin)
- Lamotrigine (Lamictal)
- Tiagabine (Gabitril)
- Zonisamide (Zonegran)
- Oxcarbazepine (Trileptal)
- Levetiracetam (Keppra)
- Carbamazepine (Carbatrol)
- Topiramate (Topamax)
- Felbamate (Felbatol)

## Status of Submissions

- Nine sponsors have submitted data
- Data received includes 36,290 subjects from 170 trials
- Oxcarbazepine (Trileptal) data has been submitted

## Nine Submissions Received:  Subject Age Distribution

- 36,290 subjects
- 170 trials

| Age | # Subjects (%) |
| --- | --- |
| <5 y | 135        (0.3%) |
| 5-11 y | 1,173     (3.2%) |
| 12-17 y | 771        (2.1%) |
| 18-24 y | 3,212     (8.8%) |
| 25-64 y | 26,021 (71.7%) |
| >64 y | 4990    (13.7%) |

## Nine Submissions Received: Trial Indication Distribution

- Epilepsy 29.4%
- Psychiatric Diagnoses 34.6% (e.g., Bipolar Disorder, Anxiety Disorders)
- Other 34.6% (e.g., Neuropathic Pain, Chronic Pain)

## Oxcarbazepine (Trileptal) Submission

- 12 trials
- Total of 2370 subjects
- 1470 subjects treated with Trileptal

| Age | # Subjects (%) |
| --- | --- |
| <5 y | 18          (0.7%) |
| 5-11 y | 193        (8.1%) |
| 12-17 y | 227        (9.6%) |
| 18-24 y | 189        (8.0%) |
| 25-64 y | 1470    (62.0%) |
| >64 y | 273      (11.5%) |

## Oxcarbazepine (Trileptal): Trial Indication Distribution

- Epilepsy 55.3%
- Psychiatric Diagnoses 4.9% (e.g., Bipolar Disorder)
- Other 39.8% (e.g., Neuropathic Pain, Chronic Pain)

## Future Plans

- Meta-analysis will proceed once all sponsor submissions are received
- Depending on results of analysis, data may be presented at an advisory committee meeting and/or regulatory action may be indicated