Clozaril Monitoring Systems, Registry Data and Analyses United States, United Kingdom,

1
Clozaril Monitoring Systems, Registry Data and
Analyses (United States, United Kingdom,
Australia)

• Vinod Kumar, MD
• Executive DirectorClinical Development and
  Medical Affairs
  
• Novartis Pharmaceuticals Corporation

2
Overview of Presentation

• Historical perspective
• Registry policy and objective
• Data on rates of leukopenia and agranulocytosis
  from United States, United Kingdom, and
  Australian registries
  
• 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
Psychiatry59 Suppl 33-7, United States pack
age insert
4
Monitoring systems Global policy

• NO BLOOD, NO DRUG

5
Monitoring systems Global Objective

• 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
time (years) 1 2
3 4 5
6 7 8
Source Appendix 1, Post-text Tables 3,4-4,3.2-4
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?

• Data is collected for patient safety, not for
  research
  
• Database is a rich source for epidemiologic
  study.
  
• Collects White Blood Cell (WBC) count data from
  local labs
  
• 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 Registryand Analyses
Clozaril National Registry (CNR)
11

History of monitoring system in US

• 1990 1998 2003

initial system weekly monitoring
current system weekly for the first 26 weeks at
least every two weeks thereafter
introduction of generic clozapine
12
Clozaril registry actions
Source US, UK and Australia Clozaril prescribing
information
13
US monitoring system description of initial
current systems
Total patients 178,104
Weekly monitoring
? Weekly / bi-weekly ?
Generic clozapine introduced Data exc
luded
Initial System cohort (138,844 pt)
Enrollment period
? 8 years of data included in analyses
?
Patients continue on drug but data excluded
Current System cohort (39,260 pt)
Enrollment period
4 years of data included

• six
• months?

Sept. 2001
Feb 1990
Oct 1997
Apr 1998 every two weeks
14
Definitions for analysis
15
United States Results
16
US rates during first 6 months of treatment
(weekly monitoring under both systems)
Differences between Systems (with CIs and p v
alues) Moderate leukopenia 2.74 (-0.37, 5.85)
(p 0.0837) Severe leukopenia 3.54 (2.36, 4
.71) (p 4.66) (p

significant difference
Data source Appendix 1, Post-text Tables 3.4-1b,
3.2-1b

17
US rates for 6 months of treatment (weekly
monitoring in old system and bi-weekly in new
system)
Differences between Systems (with CIs and p v
alues) 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 (-0.2
1, 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 CIs and p v
alues) 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)

significant difference P-value and 95 CI are
based on normal approximation to Poisson
distribution
Data source Appendix 1, post-text tables 3.2-1c,
3.3-1c, and 3.4-1c
19
Time trend of agranulocytosis rate
New Patients Agranulocytosis Rate/1000
patient-years
Agranulocytosis rate
Incudes all data for all patients

• Fewer new patients because of availability of
  alternative atypical antipsychotics?
  
• Fewer new patients fewer high risk patients?

Source Clozaril Patient Monitoring Service
20
Patient Demographics all patients
Source Appendix 1, Post-text Table 3.1-1
No clinically meaningful differences between
systems
21
Patient Demographics agranulocytosis
Source Appendix 1, Post-text Table 3.1-4
No clinically meaningful differences between
systems
22
Summary of US results initial vs current system

• Moderate leukopenia
• similar during the first 6 months of treatment
• similar after the first 6 months of treatment
• Severe leukopenia and agranulocytosis
• less during the first six months in current
  system
  
• similar after the first six months
• 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
• Findings not related to demographic differences
  between monitoring systems
  
• 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 frequencysystem 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 1
9-52 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
Source US, UK and Australia Clozaril prescribing
information
26
Monitoring system description of initial
current systems
Total patients 27,848
Weekly and bi-weekly
? Monthly monitoring ?
Initial System cohort (6,375 pt)
Enrollment period
? 5 years of data included in analyses ?
Patients continue on Clozaril but data excluded
Current System cohort (21,473 pt)
Enrollment period. ? 8 years of data inclu
ded in analyses ?

• 12
• months?

2002
1990
1994
1995 monthly monitoring
27
Definitions for analysis
28
United Kingdom IrelandResults
29
UK rates during first 18 weeks of treatment
(weekly monitoring under both systems)
Differences between Systems (with CIs and p v
alues) 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 (-3.8
2, 12.73) (p 0.292)

significant difference
Data source Appendix 2, Post-text Tables 4.5,
4.11, and 4.18
30
UK rates for weeks 19-52 of treatment (bi-weekly
monitoring under both systems)
Differences between Systems (with CIs and p v
alues) 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
Data source Appendix 2, Post-text Tables 4.5,
4.11, and 4.18
31
UK rates for 52 weeks of treatment(bi-weekly
monitoring under initial system and monthly under
current system)
Differences between Systems (with CIs and p v
alues) 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 (-0.7
8, 0.22) (p 0.274)

significant difference
Data source Appendix 2, post-text tables 4.5,
4.11, and 4.18
32
Time trend of agranulocytosis rate
New Patients Agranulocytosis Rate/1000
patient-years
Agranulocytosis rate
Incudes all data for all patients

• Fewer new patients because of availability of
  alternative atypical antipsychotics?
  
• Fewer new patients fewer high risk patients?

Source Clozaril National registry
33
Patient Demographics all patients
Source Appendix 2, Post-text Table 4.22
No clinically meaningful differences between
systems
34
Patient Demographics agranulocytosis
Source Appendix 2, Post-text Table 4.22
No clinically meaningful differences between
systems
35
Summary of UK results initial vs current system

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

36
Australian Registryand 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 there
after

38
Clozaril registry actions
Source US, UK and Australia Clozaril prescribing
information
39
Definitions for analysis
40
Australian Results
41
Australian Ratesweekly 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

• The rates of moderate leukopenia, severe
  leukopenia, and agranulocytosis decreased over
  time
  
• 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, p0.274)

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, p0.002)