1. Quantitative Analysis of Data from Clozaril National Registry Lawrence Hauptman, PhD Director Drug Regulatory Affairs Novartis Pharmaceuticals Corporation

2. Goal of Presentation l Examine factors that may have contributed to the lower than expected rate of agranulocytosis when the monitoring frequency changed from weekly to every two weeks

3. Rates of Agranulocytosis After First 6 Months (weekly monitoring in initial system and every two weeks in current system) Source: Appendix 1, Post-text table 3.2-1b Difference between Systems (with 95% CI and p value) Agranulocytosis 0.03 (-0.21, 0.27) (p = 0.80)

4. Overview of Presentation Evaluate the initial (weekly) monitoring results relative to the current (every two weeks) monitoring results, after 6 months of Clozaril ® treatment, with respect to the:  rate of moderate leukopenia  factors that may have affected the rate of agranulocytosis

5. Factors that Could Have Affected the Agranulocytosis Rate Factors covered by Dr. Kumar: l Patients switching to alternative therapies (generics or newer agents) l Differences in demographic profiles Additional factors: l Overall rate of Moderate Leukopenia l Percentage of Moderate Leukopenia Cases found with WBC < 2000 l Rate of Moderate Leukopenia by Calendar Year l WBC count at treatment discontinuation l Overall discontinuation rate

6. Lower Rate of Moderate Leukopenia After First 6 Months in Current Monitoring System? Source: Appendix 1, Post-text table 3.4-1b Result: Moderate Leukopenia Rates After 6 Months are Similar Difference between Systems (with 95% CI and p value) Moderate leukopenia 0.92 (-0.20, 2.05) (p = 0.11)

7. Probability of Progression after 6 months 37.5/2.16 = 17 Risk of progressing to agranulocytosis is 17 times greater if Moderate Leukopenia is found at WBC <2000

8. Lower Percentage of High Risk (WBC<2000) Moderate Leukopenia in Current System after 6 Months? Source: Data on file Result: Percentages found with “ Higher Risk ” Moderate Leukopenia (WBC < 2000) are similar between the 2 systems

9. Lower Rate of Moderate Leukopenia by Calendar Year After 6 Months in Current System? Result: Consistent Moderate Leukopenia Rates per Year Source: Appendix 1, Post-text Table 3.4-6

10. l WBC count at treatment discontinuation l Overall discontinuation rate

11. Patients Discontinued at a Higher WBC Count in Current System After 6 Months? Result: Patients Discontinued at Similar WBC Count Source: Appendix 1, Post-text Table 3.5-1

12. Higher Discontinuation Rate in Current System Within 6 months? Source: Appendix 1, Post-text Table 3.5-4 36.4% Result: Discontinuation Rate Within 6 Months is Higher in Current System 57.6%

13. Summary: Factors that Do Not Explain the Lower Rate of Agranulocytosis These analyses showed similar: demographic profiles rates of moderate leukopenia percentages of moderate leukopenias found with WBC < 2000 rate of moderate leukopenia by calendar year WBC counts at discontinuation Therefore, these factors do not explain the lower than expected agranulocytosis rate with biweekly monitoring

14. Summary: Factors that May Explain the Lower Rate of Agranulocytosis Patients switching to alternative therapies (generics or newer agents) Higher discontinuation rate within the first 6 months

15. Overall Conclusion We were not able to find any convincing explanations for why the agranulocytosis rate did not increase when the monitoring frequency decreased to every two weeks. This unexpected result, which we have not been able to explain to our satisfaction, may just reflect a limitation of the Clozaril National Registry, which was set up to protect individual patients, and not for use as a research tool.