1. Clozaril Monitoring Systems, Registry Data and Analyses (United States, United Kingdom, & Australia) Vinod Kumar, MD Executive Director Clinical Development and Medical Affairs Novartis Pharmaceuticals Corporation

2. Overview of Presentation l Historical perspective l Registry policy and objective l Data on rates of leukopenia and agranulocytosis from United States, United Kingdom, and Australian registries l Results, summaries and conclusions

3. Historical perspective: agranulocytosis: Incidence of agranulocytosis in Europe prior to monitoring: 1 to 2% per year # Incidence of agranulocytosis during Clozaril clinical trials prior to US approval (1989): 1.3% at 1 year* Mortality among agranulocytosis cases prior to 1989: 32%* # Honigfeld, et. al.(1998). J Clin Psychiatry;59 Suppl 3:3-7, *United States package insert

4. Monitoring systems : Global policy NO BLOOD, NO DRUG

5. Monitoring systems: Global Objective l Early detection of moderate leukopenia in order to reduce or prevent the occurrence of severe leukopenia, agranulocytosis and death.

6. Risk of moderate leukopenia & agranulocytosis over time Source: Appendix 1, Post-text Tables 3,4-4,3.2-4 time (years) 1 2 3 4 5 6 7 8

7. Risk of agranulocytosis after first 6 months of Clozaril treatment time (years) 1 2 3 4 5 6 7 8 Source: Appendix 1, Post-text Tables 3,4-4,3.2-4

8. What data do the registries collect? l Data is collected for patient safety, not for research  Database is a rich source for epidemiologic study. l Collects White Blood Cell (WBC) count data from local labs l Variables collected:  initials  patient identification number  date of birth  gender  race

9. Clozaril registries (cont.) Centralized, “non-rechallengable” database Generic manufacturers maintain separate monitoring database

10. United States Registry and Analyses Clozaril National Registry (CNR)

11. 19901998 2003 History of monitoring system in US initial system weekly monitoring current system weekly for the first 26 weeks at least every two weeks thereafter introduction of generic clozapine

12. ActionUSUKAustralia Initiation of Clozaril cells/mm 3 WBC ≥3500 and ANC >2000 WBC ≥3500 and ANC >2000 Twice weekly monitoring cells/mm 3 WBC 3000-3500 and ANC >1500 WBC 3000-3500 and/or ANC 1500-2000 WBC ≤3500 and/or ANC 1500-2000 Temporary discontinuation cells/mm 3 WBC 2000-3000 and /or ANC 1000-1500 N/A Permanent discontinuation & patients enter non- rechallengable database cells/mm 3 WBC <2000 and/or ANC <1000 WBC <3000 and/or ANC ≤1500 WBC <3000 and/or ANC ≤1500 Clozaril registry actions Source: US, UK and Australia Clozaril prescribing information

13. US monitoring system: description of initial & current systems Apr 1998 every two weeks Sept. 2001 Oct 1997  six months  Feb 1990 Weekly monitoring  Weekly / bi-weekly  “Current System” cohort (39,260 pt) Enrollment period ~ 4 years of data included “Initial System” cohort (138,844 pt) Enrollment period  ~8 years of data included in analyses  Total patients: 178,104 Patients continue on drug but data excluded Generic clozapine introduced Data excluded

14. Definitions for analysis USUKAustralia Moderate leukopenia WBC ≤ 3000 or ANC < 2000 WBC ≤ 3000 Severe leukopenia WBC < 2000 or ANC <1000 WBC < 2000 Agranulocytosis WBC ≤ 1000 or ANC ≤ 500 WBC ≤ 1000 or ANC <500 WBC ≤ 1000 or ANC ≤ 500

15. United States Results

16. Data source: Appendix 1, Post-text Tables 3.4-1b, 3.2-1b US rates during first 6 months of treatment (weekly monitoring under both systems) Differences between Systems (with CI’s and p values) Moderate leukopenia 2.74 (-0.37, 5.85) (p = 0.0837) Severe leukopenia 3.54 (2.36, 4.71) (p < 0.0001) Agranulocytosis 3.51 (2.35, 4.66) (p < 0.0001) ** * significant difference

17. US rates for > 6 months of treatment (weekly monitoring in old system and bi-weekly in new system) Differences between Systems (with CI’s and p values) Moderate leukopenia 0.92 (-0.2, 2.05) (p = 0.1073) Severe leukopenia 0.15 (-0.08, 0.38) (p = 0.2085) Agranulocytosis 0.03 (-0.21, 0.27) (p =0.804) Data source: Appendix 1, Post-text Tables 3.4-1b, 3.3-1b, 3.2-1b

18. US Rates for > 52 weeks of treatment (weekly monitoring under initial system and bi-weekly under current system) Differences between Systems (with CI’s and p values) Moderate leukopenia 1.11 (-0.20, 2.42) (p = 0.097) Severe leukopenia 0.16 (-0.10, 0.43) (p =0.220) Agranulocytosis 0.27 (0.10, 0.45) (p = 0.002) Data source: Appendix 1, post-text tables 3.2-1c, 3.3-1c, and 3.4-1c * significant difference P-value and 95% CI are based on normal approximation to Poisson distribution *

19. Time trend of agranulocytosis rate Incudes all data for all patients l Fewer new patients because of availability of alternative atypical antipsychotics? l Fewer new patients = fewer high risk patients? Agranulocytosis rate % New Patients & Agranulocytosis Rate/1000 patient-years Source: Clozaril Patient Monitoring Service

20. Patient Demographics: all patients No clinically meaningful differences between systems Source: Appendix 1, Post-text Table 3.1-1

21. Patient Demographics: agranulocytosis No clinically meaningful differences between systems Source: Appendix 1, Post-text Table 3.1-4

22. Summary of US results: initial vs current system l Moderate leukopenia  similar during the first 6 months of treatment  similar after the first 6 months of treatment l Severe leukopenia and agranulocytosis  less during the first six months in current system  similar after the first six months l After more than 52 weeks of treatment, rates of moderate and severe leukopenia were similar. Rate of agranulocytosis was significantly lower in the current system l Findings not related to demographic differences between monitoring systems l Findings may be related to introduction of newer agents or generics

23. United Kingdom and Ireland Registry and Analyses Clozaril Patient Monitoring Service (CPMS)

24. CPMS monitoring frequency: system change 1990 1995 1999 2003 initial system (UK & Ireland) weeks 0-18: weekly thereafter: at least every 2 weeks current system (UK) weeks 0-18: weekly weeks 19-52: at least every 2 weeks > 52 weeks: at least monthly thereafter Ireland adopts UK system with at least monthly monitoring after 52 weeks

25. Clozaril registry actions ActionUSUKAustralia Initiation of Clozaril cells/mm 3 WBC ≥3500 and ANC >2000 WBC ≥3500 and ANC >2000 Twice weekly monitoring cells/mm 3 WBC 3000-3500 and ANC >1500 WBC 3000-3500 and/or ANC 1500-2000 WBC ≤3500 and/or ANC 1500-2000 Temporary discontinuation cells/mm 3 WBC 2000-3000 and /or ANC 1000-1500 N/A Permanent discontinuation & patients enter non- rechallengable database cells/mm 3 WBC <2000 and/or ANC <1000 WBC <3000 and/or ANC ≤1500 WBC <3000 and/or ANC ≤1500 Source: US, UK and Australia Clozaril prescribing information

26. 1995 monthly monitoring 2002 1994  12 months  1990 Weekly and bi-weekly  Monthly monitoring  “Current System” cohort (21,473 pt) Enrollment period.  ~ 8 years of data included in analyses  “Initial System” cohort (6,375 pt) Enrollment period  ~ 5 years of data included in analyses  Total patients: 27,848 Patients continue on Clozaril but data excluded Monitoring system: description of initial & current systems

27. Definitions for analysis: USUKAustralia Moderate leukopenia WBC ≤ 3000 or ANC < 2000 WBC ≤ 3000 Severe leukopenia WBC < 2000 or ANC <1000 WBC < 2000 Agranulocytosis WBC ≤ 1000 or ANC ≤ 500 WBC ≤ 1000 or ANC <500 WBC ≤ 1000 or ANC ≤ 500

28. United Kingdom & Ireland Results

29. UK rates during first 18 weeks of treatment (weekly monitoring under both systems) Data source: Appendix 2, Post-text Tables 4.5, 4.11, and 4.18 Differences between Systems (with CI’s and p values) Moderate leukopenia 22.56 (5.61, 39.51) (p = 0.009) Severe leukopenia 1.64 (-8.12, 11.40) (p = 0.742) Agranulocytosis 4.45 (-3.82, 12.73) (p = 0.292) * * significant difference

30. UK rates for weeks 19-52 of treatment (bi-weekly monitoring under both systems) Data source: Appendix 2, Post-text Tables 4.5, 4.11, and 4.18 Differences between Systems (with CI’s and p values) Moderate leukopenia 9.85 (2.45, 17.24) (p = 0.009) Severe leukopenia 0.28 (-2.57, 3.12) (p = 0.849) Agranulocytosis -0.36 (-1.91, 1.19) (p = 0.649) * * significant difference

31. UK rates for >52 weeks of treatment (bi-weekly monitoring under initial system and monthly under current system) Differences between Systems (with CI’s and p values) Moderate leukopenia 4.34 (1.54, 7.14) (p = 0.002) Severe leukopenia 0.71 (-0.62, 2.04) (p = 0.295) Agranulocytosis -0.28 (-0.78, 0.22) (p = 0.274) Data source: Appendix 2, post-text tables 4.5, 4.11, and 4.18 * * significant difference

32. Time trend of agranulocytosis rate Agranulocytosis rate Incudes all data for all patients l Fewer new patients because of availability of alternative atypical antipsychotics? l Fewer new patients = fewer high risk patients? % New Patients & Agranulocytosis Rate/1000 patient-years Source: Clozaril National registry

33. Patient Demographics: all patients No clinically meaningful differences between systems Source: Appendix 2, Post-text Table 4.22

34. Patient Demographics: agranulocytosis No clinically meaningful differences between systems DemographicCategoryInitial system N (%) Current System N (%) GenderMale Female 28 (58.3) 20 (41.7) 92 (61.3) 58 (38.7) Age at initiation of treatment < 35 36-50 51-65 >65 12 (25.0) 25 (52.1) 11 (22.9) 0 (0.00) 35 (23.3) 54 (35.0) 52 (34.7) 9 ( 6.0) RaceCaucasian Afro-Carib Mixed Oriental Asian 45 (93.7) 1 ( 2.1) 0 ( 0.0) 2 ( 4.2) 138 (92.0) 1 ( 0.7) 2 ( 1.3) 0 ( 0.0) 9 ( 6.0) Source: Appendix 2, Post-text Table 4.22

35. Summary of UK results: initial vs current system l Moderate leukopenia  significantly lower in the current system. l Severe leukopenia  similar in both systems. l Agranulocytosis  similar in both systems under weekly and bi-weekly monitoring.  increased approximately 2 fold under monthly monitoring l Demographic characteristics  no clinically meaningful differences between the two systems. l Rate of agranulocytosis for all patients  declined overtime  may be related to introduction of newer antipsychotic agents.

36. Australian Registry and Analyses Clozaril Patient Monitoring Service (CPMS)

37. CPMS monitoring frequency and cohort for analysis. 1992 2003 Data from approximately 10,000 patients were analyzed Weekly for the first 18 weeks and monthly thereafter

38. Clozaril registry actions ActionUSUKAustralia Initiation of Clozaril cells/mm 3 WBC ≥3500 and ANC >2000 WBC ≥3500 and ANC >2000 Twice weekly monitoring cells/mm 3 WBC 3000-3500 and ANC >1500 WBC 3000-3500 and/or ANC 1500-2000 WBC ≤3500 and/or ANC 1500-2000 Temporary discontinuation cells/mm 3 WBC 2000-3000 and /or ANC 1000-1500 N/A Permanent discontinuation & patients enter non- rechallengable database cells/mm 3 WBC <2000 and/or ANC <1000 WBC <3000 and/or ANC ≤1500 WBC <3000 and/or ANC ≤1500 Source: US, UK and Australia Clozaril prescribing information

39. Definitions for analysis USUKAustralia Moderate leukopenia WBC ≤ 3000 or ANC < 2000 WBC ≤ 3000 Severe leukopenia WBC < 2000 or ANC <1000 WBC < 2000 Agranulocytosis WBC ≤ 1000 or ANC ≤ 500 WBC ≤ 1000 or ANC <500 WBC ≤ 1000 or ANC ≤ 500

40. Australian Results

41. Australian Rates weekly monitoring (weeks 0-18) monthly monitoring (weeks 19-52 & 52+) Data source: Appendix 3, post-text tables 5.1-2, 5.2-2, and 5.3-2

42. Summary of Australian results l The rates of moderate leukopenia, severe leukopenia, and agranulocytosis decreased over time l The agranulocytosis rate after 52 weeks (monthly monitoring) was 0.5 per 1000 patient-years

43. Overall conclusions Registries effectively:  detect moderate leukopenia  reduce severe leukopenia, agranulocytosis and death Australia  Under monthly monitoring after 52 weeks the rate of agranulocytosis in Australia is similar to the rate observed in the United Kingdom United Kingdom  Change from bi-weekly to monthly monitoring after 52 weeks of treatment was associated with:  decreases in moderate leukopenia  increase in the incidence of agranulocytosis (0.3 vs 0.6/1000 patient-years, p=0.274)

44. Overall conclusions (cont.) United States  Reasons for observed decline in the rates of agranulocytosis during the first 6 months are unclear  Change in monitoring frequency (weekly to bi- weekly) after 6 months of treatment was not associated with an expected increase in the rate of agranulocytosis  After 52 weeks of treatment, the rate of agranulocytosis was significantly lower in the current system under bi-weekly monitoring than in the initial system under weekly monitoring (0.11 vs 0.39 per 1000 patient-years, p=0.002)