Quantitative Analysis of Data from Clozaril National Registry

1
Quantitative Analysis of Data from Clozaril
National Registry

• Lawrence Hauptman, PhD
• Director
• Drug Regulatory Affairs
• Novartis Pharmaceuticals Corporation

2
Goal of Presentation

• 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

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

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Factors that Could Have Affected the
Agranulocytosis Rate

• Factors covered by Dr. Kumar
• Patients switching to alternative therapies
  (generics or newer agents)
• Differences in demographic profiles
• Additional factors
• Overall rate of Moderate Leukopenia
• Percentage of Moderate Leukopenia Cases found
  with WBC lt 2000
• Rate of Moderate Leukopenia by Calendar Year
• WBC count at treatment discontinuation
• Overall discontinuation rate

6
Lower Rate of Moderate Leukopenia After First 6
Months in Current Monitoring System?
Difference between Systems (with 95 CI and p
value) Moderate leukopenia 0.92 (-0.20, 2.05) (p
0.11)
Result Moderate Leukopenia Rates After 6 Months
are Similar
Source Appendix 1, Post-text table 3.4-1b
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 lt2000
8
Lower Percentage of High Risk (WBClt2000) Moderate
Leukopenia in Current System after 6 Months?

• Result Percentages found with Higher Risk
  Moderate Leukopenia
• (WBC lt 2000) are similar between the 2 systems

Source Data on file
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

• WBC count at treatment discontinuation
• Overall discontinuation rate

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

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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

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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.