# Presentation: 310090

## SUICIDALITY CLASSIFICATION PROJECT

**Kelly Posner, Ph.D.**
**Maria Oquendo, M.D.**
**Barbara Stanley, Ph.D.**
**Madelyn Gould, Ph.D, M.P.H **
**Statistical Consultant: Mark Davies, M.P.H.**

## Rationale for Reclassification 

- The Problem:
- Field challenged by lack of conceptual clarity about suicidal behavior  and corresponding lack of well-defined terminology
- Lack of systematic or standardized language used to define suicidal behavior in the 25 industry antidepressant trials
- Difficulty in interpreting the meaning of reported adverse events that occurred in these trials

## The Problem...

- AEs that should have been called suicidal may have been missed
- AEs may have been inappropriately classified as suicidal

## Examples of Difficulties in Adverse Event Labeling

| Original Label | Narratives |
| --- | --- |
| Personality Disorder | Age 10: The patient exhibited symptoms of personality disorder, assessed as moderate in severity, and was discontinued from the study due to this event.  One day later (date), the patient attempted to hang himself with a rope after a dispute with his father.  The investigator did not consider this event to be a suicide attempt, but rather to be part of the personality disorder, which was still ongoing.   |
| Suicide Event | this patient is reported to have engaged in an episode of ‘automutilation’ where she slapped herself in the face.   |
| Medication Error
 | Age 14:  The patient took 11 tablets impulsively and then went to school...the patient denied that it was a suicide attempt.   |
| Hostility | Age 10:  Before his mother’s call to the site and again after arguing with his stepfather, he wrapped a cord from the miniblinds around his neck, threatening to kill himself.   |

## How to Address this Problem? 

- a common set of guidelines needed to be applied
- Data needed to be examined consistently across trials
- Used research-supported definitions/concepts with reliability and validity

## Broaden Range of Adverse Events: 

- To avoid bias in ratings (would not want raters to only have what sponsors had identified as possibly suicidal)
- To identify suicidal events that may have been missed

## What Was Included to Broaden Range:

- Events originally identified by sponsors as possibly suicide related
- Accidental Injuries (including accidental overdoses)
- Serious Adverse Events (this includes life-threatening events and all hospitalizations)

## Why Were Experts in Suicide Needed?

- Limited information provided in narratives, particularly frequent lack of stated suicidal intent
- Allowed for inference based on details of behaviors and related clinical information

## Expert Rater Panel

**Annette Beautrais**, Ph.D
**David Brent**, M.D.
**Greg Brown, **Ph.D.
**Kees van Heeringen**, M.D., Ph.D.
**Cheryl King, **Ph.D., ABPP
**Peter Marzuk**, M.D.
**Patrick O'Carroll**, M.D., M.P.H
**David Rudd**, Ph.D., ABPP
**Anthony Spirito**, Ph.D., ABPP
- Alternate:  **Alec Miller**, PsyD.

## Columbia Suicidality Classification Rating Scale

| Behavior Towards 
Self Injury  | Suicidal Thoughts: Intent or Wish to Die  | Event category  | Rating
 |
| --- | --- | --- | --- |
| 
++ | 
+ | Suicide Attempt
__ Check if intent is inferred
___ Check if “Suicide Attempt” is only information provided  |  |
| + | + | Preparatory Actions Towards Imminent Suicidal Behavior  |  |
| ++ | ? | Self-Injurious Behavior, Intent Unknown  |  |
| ++ | _ | Self-Injurious Behavior, No Suicidal Intent,  (To Affect Internal State /Circumstance)  |  |
| _ | + | Suicidal Ideation
__ passive   __ active__   active w/ plan   __type unknown |  |
| _ | _ | Other: No indication of deliberate self-injury or suicidal behavior or ideation 
Accident________    Medical*________  Psychiatric*________ |  |
| ? | ? | Not Enough Information
 |  |

***Please specify**

*** ******Comments:***

## Definitions for the Columbia Suicidality Classification Scale 

| Suicide Attempt | Self- injurious behavior associated with some intent to die.  Intent can be stated or inferred by rater.  No injury needed. |
| --- | --- |
| Preparatory Acts Towards Imminent Suicidal Behavior  | Person takes steps to injure self but is stopped by self or other.  Intent to die is either stated or inferred. |
| Self-Injurious 
Behavior, Intent Unknown  | Self- injurious behavior where associated intent to die is unknown and cannot be inferred.  |
| Self-Injurious 
Behavior, No Intent, Primarily to Affect Circumstance  | Self- injurious behavior associated with no intent to die – behavior is intended to effect change in others or the environment.  |
| Self-Injurious Behavior, No Intent, Primarily to Affect Internal State | Self- injurious behavior associated with no intent to die intended to relieve distress.  Typical examples are superficial cuts or scratches, hitting/banging, or burns.  |
| Suicidal Ideation
 | Passive thoughts about wanting to be dead or active thoughts about killing oneself, not accompanied by preparatory behavior.  |
| Other: Accident
 | Passive thoughts about wanting to be dead or active thoughts about killing oneself, not accompanied by preparatory behavior.  |
| Other: Psychiatric*_____________ | Psychiatric symptoms only (when no evidence of any type of suicidality)  |
| Other:  Medical*______________  | Medical symptoms or procedure only  |
| Not Enough Information  | Insufficient information to classify the event  |

***** Infer intent if the behavior is clinically impressive or there is more than one piece of evidence suggesting suicidal intent**

## What is the Classification Scheme?

- Suicidal

- Non Suicidal

- Suicide
-  Attempt
- Code= 1
- N= 36

- Suicidal Ideation
- Code=6
- N=62

- Self-Injurious
- Behavior
- Without Suicidal
- Intent
- Codes=4,5,,11
- N=17

- Other:
- -Accidental
- -Psychiatric
- -Medical
- Codes=7,8,9,12
- N= 260

- Indeterminate

- Non-
- Consensus
- N = 0

- Not Enough Information:
- Unable to Classify Whether
- Deliberate Self-Injury or “other”
- Code = 10
- N = 9

- Preparatory Actions Towards Imminent Suicidal Behavior
- Code =2
- N = 8

- Self-Injurious
- Behavior
- With Unknown
- Intent
- Code=3
- N=35

- ?
-  Suicidal

## What Was Done?: Classification Methodology

- Chose expert panel
- Expertise in adolescent suicide and suicide assessment
- Based on reputation and publications
- No involvement in industry youth depression trials in question
- No expert rater was employee of Columbia University
- Training teleconference to review classification parameters
- Training reliability exercises (to ensure appropriate application of classification)

## Design continued......

- All case narratives blinded to any potentially biasing information
- Random distribution of 427 events to 9 experts
- PI blind to randomization procedures
- Each case independently rated by 3 raters
- Each rater received approx.  125 events to rate
- Any group of 3 raters shared only 5 cases
- Review of all ratings for QA and identification of non-agreement cases
- Consensus teleconferences for any disagreement cases
- Double data entry for quality assurance

## Consensus Process

- If ratings did not have unanimous agreement, consensus discussion held
- Each case discussed by 3 raters involved
- Discussion of each case led by an expert *other*  than those originally assigned the case
- Goal of discussion was to reach 100% agreement
- If 100% agreement could not be reached, case became indeterminant
- Original majority opinion did not always end up as the final consensed classification

## What Was Rated? Blinding of Event Narratives to Avoid Bias

- Received from FDA blind to all potential drug identifying information:
- Drug name
- Company/sponsor name
- Patient identification numbers
- Active or placebo arm
*Any and all*  medication names and types (e.g. tx with other meds may be associated with a particular antidepressant side effect profile and thus could potentially bias)
- Primary Diagnosis
- Additional Blinding of potentially biasing information:
- Original label of event given by investigator or sponsor
- “serious” or “non-serious” labels

## Rating Guidelines: How Was Classification Scheme Applied?

- Applied concepts using their clinical expertise and judgment
- Used experience to integrate clinical information and infer when appropriate
- “Reasonable” certainty in order to commit to a rating
- Rating based on what was probable or likely, not what was “possible”

## Guidelines for Intent Inference

- Infer if “clinically impressive” or
- Using 2 smaller pieces of clinical information
- Clinical information that could inform inference of intent included:
- Clinical circumstances (method used, number of pills)
- Past history of suicide attempt
- Past history of self-injurious behavior/self-mutilation
- Family history of suicide/suicide attempts

## Case Example of Inferred Intent: “Clinically Impressive” Circumstances

- Clinical impressiveness overrules stated intent

- 	“The subject attempted suicide by immolation.  Her siblings doused the flames immediately.  She was left with minor burns on her abdomen and one on her left shoulder that were treated.  The subject admitted that she was angry with her parents for going away and leaving her alone at home, because she was fearful.  The subject admitted that she had acted impulsively and had not intended to kill herself.”

## Another Examples of Clinically Impressive Circumstance: Suicide Attempt

- CASE 1: The patient, age 16, claimed to have ingested 100 tablets of the taper study medication after a fight with her mother.
- The patient informed her mother, who then brought the patient to an emergency room.  The patient reportedly felt “shaky”
- The emergency room physician stated that the patient “looked okay,” but was “slightly tachycardic” with a pulse of 100
- Tox screen negative
- The patient remained in the emergency room for several hours until she was completely asymptomatic
- The patient was later admitted to psych unit

## Examples of Suicide Attempt, cont. 

- CASE 2: After a conflict with her father, the patient, age 17, took an overdose of 20 (several) tablets. In her father’s opinion, the overdose was 5 tablets.  The patient did not have any symptoms of an overdose, “not even nausea”.

## Examples of Suicide Attempt, cont.

- CASE 3: Following a disagreement with her mother, the patient, age 15, intentionally overdosed.  She consumed 12 tablets of study meds, 23 __, 12 __, 23 ___, 29 ___, 4 ___ and 10 __ tablets.  Consumed 113 tablets.
- CASE 4: The patient, age 15, impulsively slit her wrists following an altercation with her mother.  The wounds were superficial and were not stitched.
- CASE 5: Age 17, she attempted suicide by taking 8 tablets of ____ after a fight with her father, whom she considered harsh and rejecting.

## Examples of Self-Injurious Behavior, Intent Unknown

- CASE 1: The patient, age 10, had superficial scratches, left arm, scratched self with scissors
- CASE 2: The patient, age 14, ingested or simulated ingestion of 2-3 cigarettes.  The patient was reported as feeling tired and playing a theatrical role
- CASE 3: Subject, age 9, reported he had ingested four of his brother’s tablets “on a dare”
- CASE 4: The patient, age 10, swallowed a small amount of aftershave lotion while angry

## Examples of Preparatory Actions

- CASE 1: Age 16: on day 63, she tried to hang herself and was prevented from doing so by her family.
- CASE 2: The voice commanded the patient, age 18, to jump from the roof.  Although the patient went to the roof, he did not jump.
- CASE 3: The patient, age 10, experienced suicidal ideation with plan.  Reportedly, the subject held a kitchen knife to her neck while alone but did not cut herself and the event was not witnessed.  At her next scheduled visit, the subject reported the suicidal ideation described above.
- CASE 4: The patient, age 18,  was noted to be hostile, hopeless, and helpless and had written suicide notes.

## Examples of Self-Injurious Behavior, No Intent

- CASE 1: The patient stated that there is increased family tension over the past six days and that she made superficial cuts on her wrist with an Exacto Knife.  The patient and mother reported that the cuts weren’t deep and that they looked like a “cat scratched her.”  The patient adamantly denied any suicidal gestures or intent.   The patient stated that she only wanted “a release” and that cutting and hitting her legs offers a “release.”
- CASE 2: Denies suicidal thoughts.  The first time she cut herself was at age 16 and stated that she did it for attention.  Today her cutting was more spontaneous.  She reported that cutting gives her “a good weird feeling.”

## Results: Number of Events and Cases

- 427 Events

- FDA
- Severity
- Hierarchy

- 378 Cases

- Suicide Attempt
- Preparatory Actions
- Suicidal Ideation
- SIB, intent unknown
- Not enough Information

## Results: Expert Rater Consensus 

- Only 2/427 cases had no agreement among the 3 raters
- 59 cases had agreement among 2 of 3 raters, had to go to teleconference
- No cases in which consensus not able to be reached during teleconference

## Discordant Cases Between Sponsor and Columbia Classifications

- 40/427 cases in which sponsor and Columbia classification differed
- 26 new cases identified that had not been identified by sponsors as possibly suicide-related
- 2 new cases of self-injurious behavior without suicidal intent that had been labeled something other than deliberate self-harm
- -12 cases originally called possibly suicidal changed to something other than possibly suicidal

## Discordant Cases: Newly Identified

- 26 new possibly suicide-related cases identified among expanded body of events
- 26 possibly suicide-related
- 1 Suicide Attempt
- 1 Preparatory Act
- 13 Suicide Ideation Events
- 4 Self-Injurious Behavior Intent Unknown
- 7 Not Enough Information to say whether deliberate self-harm

## Example of Newly Identified Suicidal Event: Preparatory Act

- The patient, age 11, held a knife to his wrist and threatened to harm himself.  The patient was hospitalized with an acute exacerbation of major depressive disorder.  The patient was treated with __ and discharged in stable condition.
- Original Adverse Event Label: Exacerbation of Major Depressive Disorder

## Discordant Cases: Events Changed from Suicidal to Something “Other” 

- 12 Events
- 2 changed to psychiatric
- 1 changed to accident
- 9 changed to self-injurious behavior no suicidal intent
- Example Event:
- 	“this patient is reported to have engaged in an episode of ‘automutilation’ where she slapped herself in the face.  The event resolved the same day without any intervention.”

## Results: Agreement with Sponsor (I): Possibly Suicidal (1,2,6,3,10)

| 237 | 26 |
| --- | --- |
| 12 | 102 |

- Columbia Classification-
- Possibly Suicide Related:

- Yes

- No

- No

- Yes

**263**

**114**

**128**

**249**

- Sponsor Classification-
- Possibly Suicide Related:

- Kappa=.77

## Results: Agreement with Sponsor (II) Definitely Suicidal (1,2,6)

| 248 | 15 |
| --- | --- |
| 32 | 82 |

- Columbia Classification-
- Definitely Suicide Related:

- Yes

- No

- No

- Yes

**263**

**114**

**97**

**280**

- Sponsor Classification-
- Definitely Suicide Related:

- Kappa=.69

## Results: Reliability of Columbia University Classification

*Primary Outcome*:			ICC
- 			Suicide Attempt		.81
- 			Preparatory Actions		.89
- 			Suicidal Ideation		.97
*Sensitivity Outcome*:
- 			SIB, Intent Unknown	.67
- 			Not Enough Info		.47
- 			*Median ICC*	.86

## Future Directions

- Improve adverse event reporting for suicide-related events by:
- Developing a consistent terminology
- Developing guidelines for classification of suicidality (so adequate info provided by clinician)
- Utilization of research assessment tools (what questions to ask, how to ask, and what measures aid this)
- Improved, More Valid Identification and
- Documentation Of Suicidality

- Also describes 12