1. 1 Suicidality Issues in Clinical Trials: Columbia Suicidal Adverse Event Identification in FDA Safety Analyses Kelly Posner, Ph.D. Principal Investigator: FDA/Columbia Classification Study Columbia University Division of Metabolism and Endocrinology Products Advisory Committee Meeting Advisory Committee Meeting June 13 2007

2. 2 Co-Investigators FDA Classification Work: Kelly Posner, Ph.D.; Maria Oquendo, M.D.; Madelyn Gould, M.P.H, Ph.D.;Barbara Stanley, Ph.D.; Mark Davies, M.P.H. C-SSRS Authors : C-SSRS Authors : Posner,K.; Brent,D.; Lucas,C.; Gould, M; Stanley, B; Brown,G.; Zelazny,J.; Fisher,P.; Burke, A; Oquendo,M.; Mann,J.

3. 3 The Problem… Field of medicine challenged by lack of conceptual clarity about suicidal behavior and corresponding lack of well-defined terminology Field of medicine challenged by lack of conceptual clarity about suicidal behavior and corresponding lack of well-defined terminology -in both research and clinical descriptions of suicidal acts Lack of systematic or standardized language used to define suicidal ideation and behavior across clinical trials Lack of systematic or standardized language used to define suicidal ideation and behavior across clinical trials Variability of terms referring to same behaviors, e.g. threat, gesture. Often pejorative and based on incorrect notions about seriousness and lethality in methods Variability of terms referring to same behaviors, e.g. threat, gesture. Often pejorative and based on incorrect notions about seriousness and lethality in methods

4. 4 Consequences… Difficulty in interpreting the meaning of reported adverse events that occurred in these trials Difficulty in interpreting the meaning of reported adverse events that occurred in these trials –Adverse Events that should have been called suicidal may have been missed –Adverse Events may have been inappropriately classified as suicidal

5. 5 Examples of Difficulties in Adverse Event Labeling Original Label Narratives Personality Disorder 10 y.o. male exhibited sxs of PD of moderate severity and was discontinued, one day later pt. attempted to hang himself w/ a rope after dispute w/ his father. Investigator did not consider this an SAE but rather part of the PD Accidental Overdose AND Neurosis The overdose of 6 capsules of study medication was in fact intentional and in response to an argument with the subject’s mother. 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.

6. 6 More Examples of Difficulties in Adverse Event Labeling Original Label Narratives Emotional Lab./ Suicide Attempt Age 14: The patient is reported to have engaged in an episode of “ automutilation ” where she slapped herself in the face. Suicide Attempt Pt. had thoughts of killing self but had no intention of acting on them Trauma “…The patient made an attempt to stab himself in the abdomen on day 49 which resulted in minor injury only. This was not considered a true suicide attempt by the investigator and no action was taken…Hence it was not considered to be clinically significant.” **Note severity goes both ways- labels more severe than they should be as well as less severe than warranted

7. 7 How to Address this Problem? Columbia commissioned by FDA Columbia commissioned by FDA A common set of guidelines needed to be applied A common set of guidelines needed to be applied Data needed to be examined consistently Data needed to be examined consistently Developed the research supported Columbia- Classification Algorithm for Suicide Assessment (C- CASA 1 ) Developed the research supported Columbia- Classification Algorithm for Suicide Assessment (C- CASA 1 ) –Mandated to be used in all antidepressant and anticonvulsant trials as well as other CNS agents, nonpsychotropic drug classes, including cannabinoid 1 receptor (CB1R) inverse agonists. 1 Posner et al. American Journal of Psychiatry. 2007;167:1035-1043

8. 8 How were Suicidal Adverse Events Classified? Electronic text string search of database for these events –Search of preferred terms for the following 2 text strings: “suic” or “overdos” “attempt; cut; gas; hang; hung; jump; mutilat; overdos; self damag; self harm; self inflict; self injur; shoot; slash; suic” –Permitted exclusions for events that represented obvious false positives (e.g., “gas” in “gastrointestinal”) –All accidental injuries, serious adverse events and deaths Companies constructed narratives of events according to FDA/C-CASA guidelines and sent them to the Columbia group. Companies constructed narratives of events according to FDA/C-CASA guidelines and sent them to the Columbia group.

9. 9 Blinding of Event Narratives to Avoid Bias Received from Company blind to all potential drug identifying information: Received from Company 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/Indication of study Additional Blinding of potentially biasing information: Additional Blinding of potentially biasing information: –Original label of event given by investigator or sponsor –“serious” or “non-serious” labels

10. 10 SuicidalNon SuicidalIndeterminate 2. Suicide Attempt 3. Preparatory Actions Towards Imminent Suicidal Behavior (Including: Interrupted Attempt or Aborted Attempt) 4. Suicidal Ideation 8. Other: - Accidental - Psychiatric - Medical 7. Self- Injurious Behavior Without Suicidal Intent 6/9 Not Enough Information: (? Suicidal or “Other”) 6: death 9 non death 5. Self-Injurious Behavior with Unknown Intent: (? Suicidal or Non - Suicidal Self-Injurious Behavior) 1. Completed Suicide What is the Classification Scheme (C-CASA)?

11. 11 Columbia- Classification Algorithm for Suicide Assessment: Codes 1. Completed Suicide 2. Suicide Attempt 3. Preparatory Actions Towards Imminent Suicidal Behavior Suicidal Behavior 4. Suicidal Ideation 5. Self-injurious Behavior Intent Unknown 6. Not Enough Information: Death 9. Not Enough Information: Non-Death 7. Self-Injurious Behavior Without Suicidal Intent 8. Other (Accident; Psychiatric; Medical) Suicidal Non Suicidal Indeterminate

12. 12 Suicide Attempt Definition A self-injurious act committed with at least some intent to die, as a result of the act. A self-injurious act committed with at least some intent to die, as a result of the act. Any non-zero intent to die- does not have to be 100%. Any non-zero intent to die- does not have to be 100%. There does not have to be any injury or harm, just the potential for injury or harm. There does not have to be any injury or harm, just the potential for injury or harm. Intent does not have to be explicit, it can be inferred, from circumstances for example. Intent does not have to be explicit, it can be inferred, from circumstances for example. For Example For Example –Patient puts gun in mouth and pulls trigger but gun fails to fire –Patient wants to die. Ingests some pills as a way to kill self.

13. 13 Suicidal Ideation Definition Thoughts of wanting to die or ending one’s life. Thoughts of wanting to die or ending one’s life. For example: For example: –Following a fight with her boyfriend, patient thought about taking an overdose to end her life –Patient was feeling depressed and thought his bad luck would never change and wished he were dead

14. 14 C:CASA Key Findings From Previous FDA Safety Analyses (Pediatric Antidepressants) From Previous FDA Safety Analyses (Pediatric Antidepressants) –More suicidal events overall, but fewer events were labeled suicidal attempts (50% reduction in attempts) –Excellent reliability (median ICC=.86) –FDA Audit C-CASA “robust and reproducible” excellent transportability. –This FDA safety analysis using C-CASA comprised 1/3 different events than earlier analysis relying on pharmaceutical labels (substantial turnover)

15. 15 Misclassification can lead to over estimation of risk Safety analysis using C-CASA (Hammad et al. 2006) had more precise estimate of risk (tighter confidence interval) compared to a prior analysis relying on an sponsor ratings (Mosholder, 2004). Safety analysis using C-CASA (Hammad et al. 2006) had more precise estimate of risk (tighter confidence interval) compared to a prior analysis relying on an sponsor ratings (Mosholder, 2004). This is consistent with previous findings that misclassification leads to overestimation of true risk (Jurek et al. 2005). This is consistent with previous findings that misclassification leads to overestimation of true risk (Jurek et al. 2005).

16. 16 Limitations of the Data: Lessons Learned Studies not designed to assess suicidality Studies not designed to assess suicidality Association does not mean causality Association does not mean causality Alternative Explanation to Causal Link - Ascertainment Bias Alternative Explanation to Causal Link - Ascertainment Bias –Spontaneously generated not systematically elicited –Med subjects potentially have more contact with provider consequent to the more common occurrence of physical side effects. (more face-to-face time to hear about suicidal incidents) -Possibly accounts for differential rates among subjects receiving drug versus placebo in any safety analysis

17. 17 Systematic vs. Spontaneous Data: Different Results In earlier safety analysis (pediatric antidepressant) a systematically collected data (suicide item from a depression rating scales) did not confirm the risk shown by the adverse event data. In earlier safety analysis (pediatric antidepressant) a systematically collected data (suicide item from a depression rating scales) did not confirm the risk shown by the adverse event data. Thus may be false or misleading results Thus may be false or misleading results

18. 18 How to Fix the Problem… Columbia - Suicide Severity Rating Scale Systematic administration of a tool designed to track suicidal adverse events across a treatment trial Systematic administration of a tool designed to track suicidal adverse events across a treatment trial Prospective version of the system we developed for the FDA Prospective version of the system we developed for the FDA Way to get better safety monitoring and avoid inconclusive results Way to get better safety monitoring and avoid inconclusive results This is why FDA is often recommending C- SSRS in ongoing or future studies. This is why FDA is often recommending C- SSRS in ongoing or future studies.

19. 19 Columbia-Suicide Severity Rating Scale (C-SSRS) Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann. Columbia-Suicide Severity Rating Scale (C-SSRS) Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann. Developed by leading experts/evidence-based Developed by leading experts/evidence-based Feasible, low- burden (typical admin time 5 minutes) Feasible, low- burden (typical admin time 5 minutes) Assesses both behavior and ideation, Assesses both behavior and ideation, Appropriately assesses and tracks suicidal all events Appropriately assesses and tracks suicidal all events Uniquely address the need for a summary measure of suicidality Uniquely address the need for a summary measure of suicidality For all C-SSRS inquiries contact: posnerk@childpsych.columbia.edu

20. 20 SUICIDAL BEHAVIOR (Check all that apply, so long as these are separate events; must ask about all types) Lifetime For Baseli ne or Since Last Assess ment LastWeek Actual Attempt: A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an attempt. Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. Have you tried to harm yourself in order to end your life or because you wanted to die/kill yourself? Did you______ as a way to end your life? Did you want to die (even a little) when you_____? Were you trying to end your life when you _____? Or Did you think it was possible you could have died from…? Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) Indicate if subject has engaged in Non-Suicidal Self-Injurious Behavior : Yes No Yes No □ □ Total # of attempts ____ ____□ Yes No Yes No □ □ Total # of attem pts ____□ Interrupted Attempt: When the person is interrupted (by an outside circumstance) from starting the potentially self- injurious act (if not for that, actual attempt would have occurred). Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. Has there been a time when you started to do something to end your life but someone or something stopped you before you actually did anything? Yes No Yes No □ □ Total # of interrup ted ____ Yes No Yes No □ □ Total # of interr upted ____

21. 21 Aborted Attempt: When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did anything? Yes No Yes No □ □ □ □ Total # of aborted____ Yes No Yes No □ □ Total # of aborted ____ Preparatory Acts or Behavior: Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a suicide note). Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, giving valuables away or writing a suicide note)? Yes No Yes No □ □ □ □ Yes No Yes No □ □ Absence of Suicidal Behavior: No Suicidal behavior present during the assessment period. Yes No Yes No □ □ □ □ Yes No Yes No □ □

22. 22 SUICIDAL IDEATION Ask about all 5 types of ideation, starting with least severe (wish to be dead) through most severe. Since Last Assessment or For Baseline Time He/She Felt Most Suicidal Last Week Non-suicidal Suicidal ideation present during the assessment period. Yes No □ □ Yes No □ □ 1. Wish to be Dead Subject endorses thoughts about their own death, including any of the following: a wish to be dead/better off dead, wish he/she were never born, thoughts that life is not worth living or the world would be better off without him/her, wish to fall asleep and not wake up, Have you wished you were dead or wished you could go to sleep and not wake up? Do you think that it might be better if you weren’t alive any more? Frequency of Ideation: ______ Yes No □ □ Yes No □ □ 2. Non-Specific Active Suicidal Thoughts General non-specific thoughts of wanting to end one’s life/commit suicide “I’ve thought about killing myself” without general thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. Have you actually had any thoughts of killing yourself? Frequency of Ideation: ______ Yes No □ □ Yes No □ □ 3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act to Act Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, place or method details worked out (e.g. thought of method to kill self but not a specific plan). Includes person who would say, “I thought about taking an overdose but I never made a specific plan as to when where or how I would actually do it…..and I would never go through with it”. Have you been thinking about how you might do this? Frequency of Ideation: ______ Yes No □ □ Yes No □ □

23. 23 SUICIDAL IDEATION 4. Active Suicidal Ideation with Some Intent to Act, Without Specific Plan Plan Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I definitely will not do anything about them”. Have you had these thoughts and had some intention of acting on them? Frequency of Ideation: ______ Yes No □ □ Yes No □ □ 5. Active Suicidal Ideation with Specific Plan and Intent Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? Frequency of Ideation: ______ Frequency of Ideation: ______ Yes No □ □ Yes No □ □

24. 24 Additional Features Assessed Lethality of Attempts Lethality of Attempts Other Features of Ideation Other Features of Ideation –Frequency –Duration –Controllability –Reasons for Ideation –Deterrents All these items significantly predictive of completed suicide *Minimum amount of information needed for tracking and severity. *Minimum amount of information needed for tracking and severity.

25. 25 Various Uses of C-SSRS Within a Study Treatment benefit outcomes Treatment benefit outcomes Safety outcomes Safety outcomes Clinical safety monitoring Clinical safety monitoring Coordinated efficiently with other measures Coordinated efficiently with other measures Easily coupled with inclusion/exclusion Easily coupled with inclusion/exclusion –In past exclusion arbitrary e.g. “serious risk”?? (criteria can be operationalized and assessed by C-SSRS (criteria can be operationalized and assessed by C-SSRS e.g. past attempt ever -early phases; recent attempt-later phase; current ideation (intent or plan)) e.g. past attempt ever -early phases; recent attempt-later phase; current ideation (intent or plan))

26. 26 C-SSRS Current Uses 4 years of use in clinical trials 4 years of use in clinical trials Large multi-site industry trials nationally and internationally Large multi-site industry trials nationally and internationally Range of therapeutic areas, disorders/indications non-psychotropics, and CNS agents; Range of therapeutic areas, disorders/indications non-psychotropics, and CNS agents;-Psychiatry-Neurology-Urology-Endocrinology Over 20 languages Over 20 languages NIMH Trials NIMH Trials Surveillance Efforts Surveillance Efforts Community clinics and practice Community clinics and practice

27. 27 Conclusions Intervention trials using prospective and systematic measurement of suicidality would more clearly delineate the relationship between suicidal adverse events and medication treatment. Intervention trials using prospective and systematic measurement of suicidality would more clearly delineate the relationship between suicidal adverse events and medication treatment. Consistent and systematic assessment (e.g. C- SSRS) can provide more meaningful data within a study, as well as across studies, improving pooled analyses Consistent and systematic assessment (e.g. C- SSRS) can provide more meaningful data within a study, as well as across studies, improving pooled analyses Improved assessment of suicidal events is necessary to better inform risk benefit analyses. Improved assessment of suicidal events is necessary to better inform risk benefit analyses.

28. 28 Some Perspective on Suicidal Ideation Suicidal ideation is a symptom of depressive disorder Suicidal ideation is a symptom of depressive disorder Lifetime prevalence of depressive disorders is 29% (Kessler et al. 2005) Lifetime prevalence of depressive disorders is 29% (Kessler et al. 2005) Estimated 10.5 million people nationally experienced suicidal ideation (1994 CDC Data; Crosby et al. 1999) Estimated 10.5 million people nationally experienced suicidal ideation (1994 CDC Data; Crosby et al. 1999) 30,575 Completed Suicides (1994 CDC Data) 30,575 Completed Suicides (1994 CDC Data)