Regulatory Background on Antidepressants and Suicidality in Pediatric Patients

1
Regulatory Background on Antidepressants and
Suicidality in Pediatric Patients

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

2
Summary of Issues

• Brief overview of events leading up to todays
  meeting
• Key elements in DNDPs exploration and analysis
  of pediatric suicidality data
• March 22, 2004 Public Health Advisory and
  subsequent labeling changes
• Brief overview of effectiveness data for
  antidepressants in pediatric major depressive
  disorder
• Questions/issues for which FDA seeks feedback

3
FDA Staff Contributing to Evaluation of Pediatric
Suicidality and Antidepressant Use
4
Source of Pediatric Safety Datafor
Antidepressants

• FDAMA/BPCA additional market exclusivity for
  pediatric studies done according to terms of
  written request
• FDA has reviewed safety and efficacy data from 8
  pediatric programs for antidepressants
• We have included a ninth antidepressant drug for
  which studies were done outside the context of
  pediatric exclusivity
• TADS data added to FDA analysis

5
Origins of Present Concern About Emergence of
Suicidality in Association with Antidepressant
Use in Pediatric Patients

• Review of pediatric supplement for Paxil led to
  finding that events suggestive of possible
  suicidality were subsumed, along with other
  events, under preferred term emotional lability
• FDA issued request to GSK to separate out
  verbatim terms suggestive of suicidality
• 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

6
Overview of EventsLeading up to Todays Meeting

• June, 2003 Public Health Advisory
• July, 2003 FDA request to sponsors of 8 other
  antidepressant products for pediatric suicidality
  summary data (modeled after GSK approach)
• Sept, 2003 FDA internal regulatory briefing
• Sept-Oct, 2003 Responses to FDAs 7-22-03
  requests for summary data for other
  antidepressants
• 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
  classification of suicidality events
• Oct, 2003 Public Health Advisory
• Nov-Dec, 2003 Second request for identification
  of events of potential interest with regard to
  suicidality

7
Overview of Events Leading upto Todays Meeting
(continued)

• Feb, 2004 Advisory Committee meeting
• Mar, 2004 Public Health Advisory and request for
  label changes
• June, 2004 Columbia classifications completed
• Aug, 2004 DNDP analysis of pediatric suicidality
  completed

8
Key Elements in DNDPs Exploration and Analysis
ofPediatric Suicidality Data

• Ensuring completeness of case finding
• Rational classification of suicidality events
  (Columbia University)
• Patient level data analysis

9
FDAs March 22, 2004Public Health Advisory (PHA)

• Advice from Feb 2nd AC was to strengthen labeling
  with regard to monitoring for suicidality, while
  completing analysis
• March 22nd PHA announced FDA request for new
  Warning statements regarding suicidality
• Labeling for all 10 drugs has now been
  implemented
• Plan to add language to all antidepressants

10
Key Elements in Labeling Changes(Advice for
Clinicians Using Antidepressantsfor Treating any
Condition, Adult or Pediatric)

• Observe closely patients being treated with
  antidepressants, for clinical worsening and
  suicidality, especially at beginning of therapy,
  or at times of dose changes
• Consider changing therapeutic regimen in patients
  whose depression is persistently worse or whose
  emergent suicidality is severe, abrupt in onset,
  or was not part of patients presenting symptoms
• Observe for emergence of other symptoms as well,
  including anxiety, agitation, panic attacks,
  insomnia, irritability, hostility
  (aggressiveness), impulsivity, akathisia
  (psychomotor restlessness), hypomania and mania

11
Key Elements in Labeling Changes(Advice for
Families and Caregivers of Others Being Treated
with Antidepressants)

• Be alert to emergence of these same symptoms
• Report such symptoms to the health care providers

12
Brief Overview of Efficacy Data for
Antidepressants in PediatricMajor Depressive
Disorder (MDD)(Limited to data reviewed by FDA)

• Summary of efficacy results on primary outcomes
  for 15 short-term trials
• Discussion of difficulties in interpreting
  negative results in this setting
• Note TADS efficacy data

13

• Positive (plt0.05) Negative (pgt0.10) Trend
  (0.05ltplt0.10)
• Keller, et al, 2001 positive on most secondary
  endpoints
• Wagner, et al, 2003 positive on pooling of 2
  studies

14
Expected Efficacy Results in Pediatric MDD
Studies(2 study programs) Based on Overall
Success Rate in Adult MDD Studies

• Finding in Adult MDD Studies 50 failure rate in
  studies that on face are adequate in every
  respect for drugs that have been shown to be
  effective
• Assuming failure rate is similar for pediatric
  MDD, 3 out of 4 two-study programs would be
  expected to fail
• Nevertheless, the overall success rate of 20
  (3/15) is clearly a concern

15
Other Factors That May Have Compromised These
Pediatric MDD Programs

• Overall negative history of short-term trials
  with tricyclic antidepressants in pediatric MDD
  may suggest even greater heterogeneity in
  pediatric patients meeting MDD criteria than is
  true in adults meeting these criteria
• Unusual regulatory context for pediatric MDD
  studies no requirement to have positive results
  to gain additional market exclusivity
• Lack of phase 2 dose finding that is routinely
  required in Written Requests now being issued

16
Summary Comments on PediatricMDD Efficacy Data

• Several plausible explanations for failure to
  find efficacy in these trials (other than
  possibility that these drugs have no benefits in
  pediatric MDD)
• Failure to meet FDAs standard for approval in
  most of these programs does not prove lack of
  benefit in pediatric MDD
• Nevertheless, failure to show benefit in MDD does
  heighten concern about possibility of certain
  risks, in particular, induction of suicidality
• Burden is clearly upon those who believe these
  drugs do have benefits in pediatric MDD to design
  and conduct studies capable of demonstrating such
  benefits, both short-term and long-term

17
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.

18
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?

19
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.

20
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?

21
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.