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Brief Regulatory History of Antidepressants and Suicidality

andUpdate on Current Plans for

Analysis of Pediatric Suicidality Data from Controlled Trials

Thomas Laughren, M.D.Team Leader, Psychiatric Drug

Products GroupDivision of Neuropharmacological Drug

Products, FDA

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Standard Language inAntidepressant 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.”

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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.”

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Listing of Various Mechanisms Proposed to Explain Emergence of Suicidality Early in Antidepressant TreatmentSeptember, 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

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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.

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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

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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

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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

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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

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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

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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.

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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

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Appendix 2aRisk [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”

Drug Placebo Risk Ratio

Drug Placebo Risk Ratio

Paroxetine/329 6/93(6.5%) 1/88(1.1%) 5.9 5/93(5.4%) 0/88(0) --

Paroxetine/377 7/181(3.9%) 4/95(4.2%) 0.9 7/181(3.9%) 4/95(4.2%) 0.9

Paroxetine/701 1/104(1.0%) 1/102(1.0%) 1.0 1/104(1.0%) 1/102(1.0%) 1.0

Fluoxetine/HCCJ 0/21(0) 1/19(5.3%) -- 0/21(0) 1/19(5.3%) --

Fluoxetine/HCJE 3/109(2.8%) 4/110(3.6%) 0.8 0/109(0) 2/110(1.8%) --

Fluoxetine/X065 2/48(4.2%) 2/48(4.2%) 1.0 2/48(4.2%) 0/48(0) --

Sertraline/A050-1001 4/97(4.1%) 0/91(0) -- 1/97(1.0%) 0/91(0) --

Sertraline/A050-1017 2/92(2.2%) 2/93(2.2%) 1.0 2/92(2.2%) 2/93(2.2%) 1.0

Venlafaxine/382 5/80(6.25%) 1/85(1.18%) 5.3 2/80(2.50%) 1/85(1.18%) 2.1

Venlafaxine/394 8/102(7.84%) 0/94(0) -- 2/102(1.96%) 0/94(0) --

Citalopram/CIT-MD-18 1/89(1%) 2/85(2%) 0.5 1/89(1%) 1/85(1%) 1.0

Citalopram/94404 16/121(13%) 9/112(8%) 1.6 16/121(13%) 9/112(8%) 1.6

Nefazodone/CN104-141 1/95(1.1%) 0/95(0) -- 1/95(1.1%) 0/95(0) --

Nefazodone/CN104-187 1/184(0.5%) 0/94(0) -- 1/184(0.5%) 0/94(0) --

Mirtazapine/003-045 1/170(0.59%) 1/88(1.14%) 0.5 0/170(0) 1/88(1.14) --

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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

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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

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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

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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

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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)

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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)

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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

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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)

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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

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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

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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%)

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Types of Self-Harm (Total N=66)

• Cutting: 19

• Overdose: 37

• Hanging: 2

• Burning: 1

• Slapping: 1

• Nonspecific: 6

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Self Harm: Cutting (N=19)

Suicide Intent/Ideation

Yes No

HOSP

Yes 1 3

No 2 13

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Self Harm: Overdose (N=37)

Suicide Intent/Ideation

Yes No

HOSP

Yes 1 15

No 2 19

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Suidical Ideation Without Self-Harm (N=43)

Suicide Plan

Yes No

HOSP

Yes 7 19

No 0 17

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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

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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

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Issues for Which FDA Requests Feedbackfrom 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

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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