Summary Comments on Antidepressants and Suicidality in Pediatric Patients

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Summary Comments onAntidepressants and
Suicidality in Pediatric PatientsQuestions/Topi
cs for Comment

• Thomas Laughren, M.D.
• Team Leader
• Psychiatric Drug Products Group
• Division of Neuropharmacological Drug Products
• FDA

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Key Elements in DNDPsExploration and Analysis
ofPediatric Suicidality Data

• Ensuring completeness of case finding
• Rational classification of suicidality events
• Patient level data analysis

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Outcomes in DNDP Analyses

• Suicidality Event Data
• Primary Suicidal behavior or ideation (1,2,6)
• Secondary Outcomes
• Suicidal behavior (1,2)
• Suicidal ideation (6)
• Possible suicidal behavior or ideation
  (1,2,3,6,10)
• Suicide Item Data
• Worsening of suicidality
• Emergence of suicidality

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Overall DNDP Analytical Plan

• Risk Ratio Analyses
• Suicidality event data (for both primary and
  secondary outcomes)
• Individual trial analyses
• Pooled analyses (by drug, SSRIs/MDD, all other
  indications combined, and over all trials)
• Suicide item data (for both worsening and
  emergence of suicidality)
• Individual trial analyses
• Pooled analyses over all trials

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DNDP Evaluations forConfounding, Effect
Modification,and Inter-trial Variability

• Approaches to explore for confounding within
  trials
• Univariate approach
• Multivariate approach
• Conclusion No evidence for important confounding
• Stratified analyses to explore for effect
  modification
• 3 strata age gender and history of suicide
  attempt or ideation
• Conclusion No evidence for effect modification
• Meta-regression approach to explore for
  trial-level covariates as a source of variation
  between trials
• Conclusion Could not explain variability
• Caution Limited power

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Summary Comments on Findings

• Event Data
• Risk ratios for pooled analyses range from 1.7 to
  2.2 (all significant)
• Signals seen predominantly in MDD patients
• Remain inconsistencies in risk
• Across trials within programs
• Across programs
• Nevertheless, a reasonably consistent signal
• Evidence for suicidality risk in 7 of 9 programs
• No events in Wellbutrin and Serzone programs
• Risk difference overall about 2 to 3
• No completed suicides in any of 24 trials

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Summary Comments on Findings(continued)

• Suicide Item Data
• Signal not confirmed
• Not explained by dropouts

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How Should These Findings Be Interpreted?

• May be increased risk for suicidality during
  short-term treatment with all drugs in the
  antidepressant class
• Signal most compelling in MDD population, but may
  not be limited to this population
• Many possible explanations for variation in
  signal within and across programs

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Regulatory Options

• Labeling Changes
• Modify existing Warning statement for all drugs
  in class to suggest causality for pediatric
  suicidality
• E.g, causality suggested for pediatric
  suicidality risk for drugs in antidepressant
  class, plus
• Provide drug specific suicidality findings
• Provide drug specific efficacy findings
• Other possible modifications to Warning
  statement bolded language black box

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Regulatory Options(Continued)

• Labeling Changes
• Contraindication in pediatric depression for some
  drugs in class
• Note Consequence is that drug is NEVER an option
  in treating depressed children or adolescents
• Note Contraindication has different meaning
  across different regulatory agencies

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Additional FDA Actions

• Medguide to inform patients and their families
  about the potential for increased risk of
  suicidality early in antidepressant treatment
• Public Health Advisory to announce whatever
  changes are to be implemented
• Communicate new information to FDA partners

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Questions/Issue for Committee Feedback

• Please comment on our approach to classification
  of the possible cases of suicidality (suicidal
  thinking and/or behaviors) and our analyses of
  the resulting data from the 23 1 pediatric
  trials involving 9 antidepressant drugs.

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Questions/Issue for Committee Feedback(Continued)

• Do the suicidality data from these trials support
  the conclusion that any or all of these drugs
  increase the risk of suicidality in pediatric
  patients?

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Questions/Issue for Committee Feedback(Continued)

• If the answer to the previous question is yes, to
  which of these 9 drugs does this increased risk
  of suicidality apply?
• Please discuss, for example, whether the
  increased risk applies to all antidepressants,
  only certain classes of antidepressants, or only
  certain antidepressants.

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Revised Question 3

• 3. The data in aggregate indicate an increased
  risk of suicidality, as previously defined, in
  pediatric patients. Although there is variability
  in the results, we are unable to conclude that
  any single antidepressant agent is free of risk
  at this time.

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Proposed Question 4 Revised 2

• Does the Committee support a black box warning
  for all antidepressants for pediatric use?

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Questions/Issue for Committee Feedback(Continued)

• If there is a class suicidality risk, or a
  suicidality risk that is limited to certain drugs
  in this class, how should this information be
  reflected in the labeling of each of the
  products?
• What, if any, additional regulatory actions
  should the Agency take?

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Questions/Issue for Committee Feedback(Continued)

• Please discuss what additional research is needed
  to further delineate the risks and benefits of
  these drugs in pediatric patients with
  psychiatric illness.