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

1. Summary Comments onAntidepressants and Suicidality in Pediatric Patients&Questions/Topics for Comment Thomas Laughren, M.D. Team Leader Psychiatric Drug Products Group Division of Neuropharmacological Drug Products FDA

3. Key Elements in DNDP’sExploration and Analysis ofPediatric Suicidality Data • Ensuring completeness of case finding • Rational classification of suicidality events • Patient level data analysis

4. 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

5. 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

6. 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

10. 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

11. Summary Comments on Findings(continued) • Suicide Item Data • Signal not confirmed • Not explained by dropouts

12. 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

13. 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

14. 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

15. 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

16. 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.

17. 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?

18. 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.

19. 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.

20. Proposed Question 4 Revised 2 • Does the Committee support a “black box” warning for all antidepressants for pediatric use?

21. 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?

22. 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.