1. 1 Brief Regulatory History of Antidepressants and Suicidality and Update on Current Plans for Analysis of Pediatric Suicidality Data from Controlled Trials Thomas Laughren, M.D. Team Leader, Psychiatric Drug Products Group Division of Neuropharmacological Drug Products, FDA

2. 2 Standard Language in Antidepressant Labeling “Suicide: The possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for Drug X should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.”

3. 3 Slater and Roth’s Clinical Psychiatry, by Bailliere, Tindall and Cassell London, 1960, p. 231 “With beginning convalescence (following initiation of treatment with tricyclic antidepressants), the risk of suicide once more becomes serious as retardation fades.”

4. 4 Listing of Various Mechanisms Proposed to Explain Emergence of Suicidality Early in Antidepressant Treatment September, 1991 PDAC Meeting on Prozac and Suicidality (from comments by Dr. Martin Teicher) Roll back phenomenon Paradoxical worsening of depression Akathisia Induction of anxiety and panic attacks Stage shifts (from depression into mixed states in bipolar depressed patients) Insomnia

5. 5 Key Question for Pediatric Suicidality Data: Is there a causal link between antidepressant drug use and suicidality in pediatric patients with major depressive disorder or other psychiatric disorders? Critically important question to answer Also important to answer in a careful, thoughtful manner Erring in either direction would have adverse consequences: –Missing a signal of increased risk of suicidality would result in greater comfort than is warranted in the safety of these drugs in treating pediatric depression. –A premature decision on the strength of the signal could result in the overly conservative use of these drugs, or their lack of availability entirely for the pediatric population.

6. 6 Scope of FDA’s Review of Pediatric Suicidality Data Nine drugs included in review: –Prozac (fluoxetine) –Zoloft (sertraline) –Paxil (paroxetine) –Luvox (fluvoxamine) –Celexa (citalopram) –Wellbutrin (bupropion) –Effexor (venlafaxine) –Serzone (nefazodone) –Remeron (mirtazapine) -25 studies: –16 in major depressive disorder –4 in obsessive compulsive disorder –2 in generalized anxiety disorder –1 in social anxiety disorder –2 in ADHD Over 4000 patients

7. 7 Origins of Present Concern About Emergence of Suicidality in Association with Antidepressant Use in Pediatric Patients FDA had reviewed safety and efficacy data from 8 pediatric programs for antidepressants over roughly 3 year period Adverse events, including those suggestive of possible suicidality, coded by sponsors using approaches unique to each program Suicidality did not emerge as a matter for concern based on these reviews Paxil review did raise a question of data management, in that events suggestive of possible suicidality were subsumed, along with other events, under preferred term “emotional lability” Finding led to request to GSK to separate out verbatim terms suggestive of suicidality

8. 8 Original Report on Emergence of Suicidality in Association with Paxil Use in Pediatric Patients Request for clarification of events coded under “emotional lability” was basis for additional work done by GSK Resulted in submission of report on paroxetine and pediatric suicidality, first to the MHRA, and shortly thereafter, to FDA, on May 22, 2003 Report suggested increased risk of suicidality associated with paroxetine use, especially in 1 of 3 studies in pediatric major depressive disorder

9. 9 Timeline for Key Events Subsequent to Original Paroxetine Report June, 2003: Regulatory responses to paroxetine signal by MHRA (UK) and FDA July, 2003: FDA request to sponsors of 8 other antidepressant products for pediatric suicidality summary data (modeled after GSK approach) Aug, 2003: Re-evaluation of suicidality data from 8 pediatric supplements Aug, 2003: Wyeth labeling change and Dear Health Care Professional letter for Effexor, and regulatory responses (MHRA) Sept, 2003: FDA internal regulatory briefing

10. 10 Timeline for Key Events Subsequent to Original Paroxetine Report (continued) Sept-Oct, 2003: Responses to FDA’s 7-22-03 requests for summary data for other antidepressants Oct, 2003: Updated FDA Public Health Advisory and Talk Paper Oct, 2003: FDA request to sponsors of all 9 antidepressant products for patient level pediatric study data sets Oct, 2003: Decision to seek outside review and reclassification of clinical events Nov-Dec, 2003: Second request for identification of events of potential interest with regard to suicidality Dec, 2003: Most recent action by MHRA regarding antidepressant use in pediatric MDD

11. 11 Summary Data vs Patient Level Data Summary Data: Data tables provided by sponsors that include only numbers of patients with events as numerators and either total patients exposed or total accumulated person-time as denominators Patient Level Data: Data sets provided by sponsors in response to detailed requests made by FDA for electronic data sets structured to include one row per patient participating in each study, with multiple variables for each patient. –Patient level data sets permit adjustments for potentially important covariates, while summary data do not.

12. 12 Categories for Suicidality Possibly Suicide-Related: Any events including thoughts or behaviors the sponsor considered to represent possible suicidality Suicide Attempt: Subset of “Possibly Suicide-Related” events that included behaviors the sponsor considered to represent self-harm

13. 13 Appendix 2a Risk [n/N(%)] and Risk Ratio for Patients with Events Classified as “Possibly Suicide-Related” and “Suicide Attempts” in Pediatric Studies of Major Depressive Disorder [All subjects; On-Therapy Data] Drug/Study Number“Possibly Suicide-Related”“Suicide Attempts” DrugPlaceboRisk Ratio DrugPlaceboRisk Ratio Paroxetine/3296/93(6.5%)1/88(1.1%)5.95/93(5.4%)0/88(0)-- Paroxetine/3777/181(3.9%)4/95(4.2%)0.97/181(3.9%)4/95(4.2%)0.9 Paroxetine/7011/104(1.0%)1/102(1.0%)1.01/104(1.0%)1/102(1.0%)1.0 Fluoxetine/HCCJ0/21(0)1/19(5.3%)--0/21(0)1/19(5.3%)-- Fluoxetine/HCJE3/109(2.8%)4/110(3.6%)0.80/109(0)2/110(1.8%)-- Fluoxetine/X0652/48(4.2%) 1.02/48(4.2%)0/48(0)-- Sertraline/A050-10014/97(4.1%)0/91(0)--1/97(1.0%)0/91(0)-- Sertraline/A050-10172/92(2.2%)2/93(2.2%)1.02/92(2.2%)2/93(2.2%)1.0 Venlafaxine/3825/80(6.25%)1/85(1.18%)5.32/80(2.50%)1/85(1.18%)2.1 Venlafaxine/3948/102(7.84%)0/94(0)--2/102(1.96%)0/94(0)-- Citalopram/CIT-MD-181/89(1%)2/85(2%)0.51/89(1%)1/85(1%)1.0 Citalopram/9440416/121(13%)9/112(8%)1.616/121(13%)9/112(8%)1.6 Nefazodone/CN104-1411/95(1.1%)0/95(0)--1/95(1.1%)0/95(0)-- Nefazodone/CN104-1871/184(0.5%)0/94(0)--1/184(0.5%)0/94(0)-- Mirtazapine/003-0451/170(0.59%)1/88(1.14%)0.50/170(0)1/88(1.14)--

14. 14 Major Concerns in Interpreting Available Data Approaches to finding clinical events possibly suggestive of suicidality Approaches to classifying events with regard to suicidality Inconsistency in signal across individual studies within programs

15. 15 Key Elements of Original Search Strategy for Finding Events Possibly Related to Suicidality (FDA 7-22-03 Summary Data Request) Electronic text string search of database for “possibly suicide- related” events (and blinded selection of events of interest) –Search of preferred terms for the following 2 text strings: “suic” or “overdos” Asked for separate listing of events coded as accidental overdoses –Search of verbatim (i.e., investigator) terms for following 15 text strings: “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”) Blinded review of narratives for any deaths and serious adverse events (regulatory definition) Blinded selection from among “suicide-related events” a subset of events that could be considered “suicide attempts” (self harm) Sponsors asked to provide narrative for each patient identified as having one or more potential events

16. 16 Problems in Implementation of Search Strategy for Potential Cases Based on 7-22-03 Request Failure to account for exclusions from events identified by searches –Narratives often provided only for patients judged by sponsor to have events that represented suicidality –Little or no explanation provided for exclusion of events and patients –Specific criteria used in excluding cases not provided

17. 17 Problems in Implementation of Search Strategy for Potential Cases Based on 7-22-03 Request (continued) Failure to provide listing of accidental injuries –Cases coded as accidental overdose provided, but we had failed to inquire about cases coded as accidental injury –Many sponsors excluded all cases coded as accidental injury, without further review –Example: One case provided only after inquiry was a child excluded as accidental injury with an event characterized as “patient stabbed himself in the neck with a pencil while taking a test.” –Such cases raised a concern that cases possibly needing further review had been excluded

18. 18 Problems in Implementation of Search Strategy for Potential Cases Based on 7-22-03 Request (continued) Unblinded searches –One sponsor acknowledged conducting some of searching and selection of cases with knowledge of treatment assignment Exclusion of “non-treatment emergent” events –Some sponsors excluded cases for not being “treatment emergent,” but without sufficient details to evaluate the cases Discrepancies in signals of suicidality –For one program, discrepancy seen in strength of signal emerging from re-examination of pediatric supplement (strong signal) compared to only the weak signal based on the sponsor’s analysis in response to 7-22-03 request (thus raising concerns about the case finding approach)

19. 19 Second Request for Identification of Events of Potential Interest with Regard to Suicidality Clarification of what electronic searches had actually been conducted Complete accounting of the winnowing down of potential events/patients identified by electronic searches to arrive at events to be blindly reclassified by outside experts –Events occurring pre-randomization or post-30 days, and false positives Requested summary narratives for all remaining patients with potential events, including patients classified as having accidental injury or accidental overdose Requested narratives for all patients having one or more serious adverse events (SAE, based on regulatory definition) during on-therapy or +30 days period (and not already included in narratives)

20. 20 Concerns About the Classification of Events As “Possibly Suicide-Related” and “Suicide Attempt” A wide variability in types of events included within these categories Variable approaches to “suicide attempts” –Substantial differences across different programs in the selection of cases representing suicide attempts, with some sponsors deciding to include essentially all captured events as suicide attempts, even though there was clearly not enough information in the cases to justify such a classification, and others using a far more conservative approach

21. 21 Characterization of Events Classified by Sponsors as “Possibly Suicide-Related” N=109 patients having > 1 “Possibly Suicide- Related” events were included in numerators for sponsors’ summary data (for 25 trials in review) No completed suicides Very wide variability in types of verbal expressions and behaviors considered by sponsors to be representative of suicidality Majority of cases not well-described Goal: Provide committees a sense of the range of events to consider (not a formal approach to classification)

22. 22 Key Questions Question: Is it meaningful to subsume such diverse events under the “Possibly Suicide- Related” category? Question: Is it meaningful to subsume the subset of “Possibly Suicide-Related” events having any mention of self-harm under the “Suicide Attempt” category? Note: Not an attempt to trivialize any of these events; rather, trying to establish what classification approach is most useful and clinically meaningful for analysis and regulatory decision-making

23. 23 Approach to Characterization of N=109 Events Focus on first event (most patients had only one) Selected subset with some indication of self-harm For patients having “self-harm” –Hospitalization (yes/no): if hospitalized for event –Suicidal Intent (yes/no): if active expression of intent or any concurrent suicidal ideation For remaining patients having suicidal ideation without “self-harm” –Hospitalization (yes/no): if hospitalized for event –Suicidal Plan (yes/no): if active expression of suicide plan

24. 24 Summary Data for N=109 “Possibly Suicide-Related” Events Overall Hospitalization Rate: 47/109 (43%) Subgroup having suicidal ideation without “self-harm”: N=43 (39%) Subgroup with some indication of self- harm: N=66 (61%) –No completed suicides –All fully recovered –Precipitation by interpersonal conflict: N=20/66 (30%)

25. 25 Types of Self-Harm (Total N=66) Cutting: 19 Overdose:37 Hanging: 2 Burning: 1 Slapping: 1 Nonspecific: 6

26. 26 Self Harm: Cutting (N=19) Suicide Intent/Ideation YesNo HOSPHOSP Yes13 No213

27. 27 Self Harm: Overdose (N=37) Suicide Intent/Ideation YesNo HOSPHOSP Yes115 No219

28. 28 Suidical Ideation Without Self-Harm (N=43) Suicide Plan YesNo HOSPHOSP Yes719 No017

29. 29 Columbia University Suicidality Research Group Over 20 years of experience in suicide research ~ 40 federally and non-federally funded grants over past 5 years Development of measures, manuals, and methodology for evaluation of suicidality Center for training on suicide assessment and research, including reliability and validity Currently involved in blinded suicide determinations for NIMH study of adolescent suicide attempters ~ 600 suicide-related publications

30. 30 Key Steps to Definitive Advisory Committee Meeting on Pediatric Suicidality Reclassification of “Possibly Suicide- Related Events” –Columbia University Contract –Kelly Posner Designing an Appropriate Patient Level Data Analysis –Safety Group (DNDP) –Tarek Hammad

31. 31 Issues for Which FDA Requests Feedback from Committees Present Concerns: –Optimal approaches for searching this database for events suggestive of suicidality –Optimal approaches for rationally classifying possibly suicide-related events into categories for analysis –Optimal approaches for planned patient level data analysis Future Concerns: –Optimal approaches for ascertainment of suicidality –Comments on largely negative efficacy results in short-term pediatric MDD trials, and possible value of randomized withdrawal design

32. 32 Serious Adverse Event (FDA Definition) Death Life-threatening Hospitalization (or prolongation of hospitalization) Persistent or significant disability/incapacity Congenital anomaly/birth defect Other important medical events requiring interventions to prevent above outcomes