Thomas Laughren, M.D. Team Leader, Psychiatric Drug Products Group DNDP (HFD-120)

1. Psychopharmacological Drugs Advisory CommitteeNovember 4, 2002 MeetingClozaril (Clozapine) and Suicidality in Schizophrenia or Schizoaffective Disorder Thomas Laughren, M.D. Team Leader, Psychiatric Drug Products Group DNDP (HFD-120)

2. Background to InterSePT Study • Estimated 10% lifetime prevalence of suicide in patients with schizophrenia or schizoaffective disorder • Meta-analyses of clinical trials of atypical antipsychotic drugs suggesting that these drugs are neutral regarding suicidality • ERI Study: • Retrospective cohort mortality study based on Clozaril registry • Rate ratio favoring clozapine over other treatment: 0.17 • FDA agreement that one adequate and well-controlled trial showing benefit for Clozaril in suicidality would be sufficient to support new claim • Agreement on design of 2-year comparision of clozapine and olanzapine on suicidality outcome

3. Supplemental NDA 19-758/S-047 • Submitted February 28, 2002 • Original Claim Sought: “use in the treatment of suicidality in patients with schizophrenia or schizoaffective disorder” • Approvable letter issued August 30, 2002

4. Issues For Which We Would Like Feedback • Potential bias in referral of events to SMB • Claim focusing on suicidality in schizophrenia or schizoaffective disorder • Expansion of Clozaril claim beyond treatment resistant schizophrenia • Interpretation of the InterSePT study with regard to olanzapine • Adequacy of single randomized controlled trial to support suicidality claim • Adequacy of “suicidality” outcome in InterSePT study

5. Potential Bias in Referral of Events to SMB • Type 1 events critical component of primary outcome for InterSePT study • Confirmation of Type 1 events by blinded Suicide Monitoring Board (SMB) • Referral of events to SMB was unblinded • Rate of confirmation of events as Type 1 events was high and virtually identical for clozapine (83%) and olanzapine (84%) events • Thus, there was a strong relationship between the number of events referred and the number confirmed

6. Evaluation of Potential Bias in Referral of Events to SMB • Sponsor will report on it’s assessment of this potential problem • FDA will give update on DSI audit focusing on possibility of non-referred events • Does the committee feel that this concern has been adequately addressed?

7. Claim Focusing on Suicidality in Schizophrenia or Schizoaffective Disorder • No precedent for claim focusing on suicidality behavior • Is “suicidality” an appropriate target for a claim • Is this a pseudospecific claim? • Ordinarily claims don’t focus on specific symptom of recognized syndrome • Justification (seriousness of suicidality and lack of effective treatments for this aspect of these illnesses) • -What should the claim be? • FDA Proposal: “reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk for emergent suicidal behavior, based on history and recent clinical state...”

8. Expansion of Clozaril Claim Beyond Refractory Schizophrenia • Current labeling limits clozapine to patients with treatment resistant schizophrenia • Only 1/4 of patients in InterSePT study could be considered treatment resistant • Do these data support expansion of claim into non-treatment resistant schizophrenia and schizoaffective disorder?

9. Interpretation of the InterSePT Study With Regard to Olanzapine • Possible interpretations regarding claim of reduced risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder • Clozapine is superior to olanzapine with regard to suicidality • Clozapine is superior to atypical antipsychotics with regard to suicidality • Clozapine is effective for this clinical target, based on comparison with standard drug • Which language is most appropriate for labeling?

10. Adequacy of Single Randomized Controlled Trial to Support Suicidality Claim • Ordinarily, effectiveness claims supported by two adequate and well-controlled trials • Alternative standard: a single adequate and well-controlled trial, along with “confirmatory evidence” • Usual circumstances for alternative standard: • Outcome in single trial is on mortality or irreversible morbidity, making replication difficult • Single trial is strongly positive (e.g., small p-value, individual centers are positive) • Is this alternative standard appropriate for this claim?

11. Adequacy of “Suicidality” Outcome in InterSePT Study • Primary outcome in InterSePT Study depended predominantly on Type 1 events: • Suicide • Suicide attempt • Hospitalization for suicidality • Need for increased surveillance due to suicidality for inpatients • While clozapine was superior to olanzapine on this outcome, no effect was demonstrated on completed suicides • Is the primary outcome in InterSePT Study adequate to support this claim?

12. General Question for Which Vote is Needed • Do the data provide sufficient basis for new claim involving suicidality in schizophrenia and schizoaffective disorder • Articulation of precise question is part of challenge to Committee