Brief Regulatory History of Antidepressants and Suicidality and Update on Current Plans for Analysis of Pediatric Suicidality Data from Controlled Trials

1
Brief Regulatory History of Antidepressants and
SuicidalityandUpdate 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
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.

3
Slater and Roths Clinical Psychiatry, by
Bailliere, Tindall and CassellLondon, 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
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 DataIs
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 FDAs 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
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
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
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
Timeline for Key Events Subsequent to Original
Paroxetine Report (continued)

• Sept-Oct, 2003 Responses to FDAs 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 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 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 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 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 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 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 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 Possibly Suicide-Related Possibly Suicide-Related Suicide Attempts Suicide Attempts Suicide Attempts
Drug/Study Number 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

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
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
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 sponsors analysis in
  response to 7-22-03 request (thus raising
  concerns about the case finding approach)

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
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
Characterization of Events Classified by Sponsors
as Possibly Suicide-Related

• N109 patients having gt 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
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
Approach to Characterization of N109 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
Summary Data for N109 Possibly
Suicide-Related Events

• Overall Hospitalization Rate 47/109 (43)
• Subgroup having suicidal ideation without
  self-harm N43 (39)
• Subgroup with some indication of self-harm N66
  (61)
• No completed suicides
• All fully recovered
• Precipitation by interpersonal conflict N20/66
  (30)

25
Types of Self-Harm (Total N66)

• Cutting 19
• Overdose 37
• Hanging 2
• Burning 1
• Slapping 1
• Nonspecific 6

26
Self Harm Cutting (N19)
Suicide Intent/Ideation Suicide Intent/Ideation
Yes No
H O S P Yes 1 3
H O S P No 2 13
27
Self Harm Overdose (N37)
Suicide Intent/Ideation Suicide Intent/Ideation
Yes No
H O S P Yes 1 15
H O S P No 2 19
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Suidical Ideation Without Self-Harm (N43)
Suicide Plan Suicide Plan
Yes No
H O S P Yes 7 19
H O S P 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