1. 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. 2 Summary of Issues Brief overview of events leading up to today’s meeting Key elements in DNDP’s 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. 3 FDA Staff Contributing to Evaluation of Pediatric Suicidality and Antidepressant Use Several Different Sections of FDA Have Participated in this Effort Division of Neuropharmacological Drug Products Cara Alfaro Paul David Greg Dubitsky Tarek Hammad Alice Hughes Russell Katz Thomas Laughren Robert Levin Judith Racoosin Office of Drug Safety/ Office of Biometrics Mark Avigan Michael Evans Andrew Mosholder Parivash Nourjah Gianna Rigoni Paul Seligman Judy Staffa Anne Trontell Yi Tsong Mary Willy Diane Wysowski Office of Counter-Terrorism and Pediatrics Rosemary Addy ShaAvhree Buckman Susan Cummins Dianne Murphy Shirley Murphy Soloman Iyasu Kristin Phucas Hari Sachs

4. 4 Source of Pediatric Safety Data for 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. 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. 6 Overview of Events Leading up to Today’s 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 FDA’s 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. 7 Overview of Events Leading up to Today’s 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. 8 Key Elements in DNDP’s Exploration and Analysis of Pediatric Suicidality Data Ensuring completeness of case finding Rational classification of suicidality events (Columbia University) Patient level data analysis

9. 9 FDA’s March 22, 2004 Public Health Advisory (PHA) Advice from Feb 2 nd AC was to strengthen labeling with regard to monitoring for suicidality, while completing analysis March 22 nd 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. 10 Key Elements in Labeling Changes (Advice for Clinicians Using Antidepressants for 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 patient’s 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. 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. 12 Brief Overview of Efficacy Data for Antidepressants in Pediatric Major 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. 13 Appendix 1 Summary of Efficacy Results (Primary Outcomes) for Short-Term Placebo-Controlled Pediatric Studies in Major Depressive Disorder Drug Program/Study NumberAge Range Outcome 1 (Drug vs Placebo) Paroxetine/32912-18 Negative 2 Paroxetine/37713-18Negative Paroxetine/7017-17Negative Fluoxetine/HCJE8-17Positive Fluoxetine/X0658-17Positive Sertraline/A050-10016-17Trend Sertraline/A050-10176-17 Negative 3 Venlafaxine/3827-17Negative Venlafaxine/3947-17Negative Citalopram/CIT-MD-187-17Positive Citalopram/9440413-18Negative Nefazodone/CN104-14112-18Trend Nefazodone/CN104-1877-17Negative Mirtazapine/003-004/Study 17-17Negative Mirtazapine/003-004/Study 27-17Negative 1.Positive (p 0.10); Trend (0.05<p<0.10) 2.Keller, et al, 2001; positive on most secondary endpoints 3.Wagner, et al, 2003; positive on pooling of 2 studies

14. 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. 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. 16 Summary Comments on Pediatric MDD 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 FDA’s 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. 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. 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. 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. 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. 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.