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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
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
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
Monitoring systems: Global policy
NO BLOOD, NO DRUG
Monitoring systems: Global Objective
Early detection of moderate leukopenia
in order to reduce or prevent the
occurrence of severe leukopenia,
agranulocytosis and death.
Risk of moderate leukopenia &
agranulocytosis over time
US Hazard Rates
50
45 Hazard rate (Moderate Leukopenia)
hazard rate (per 1000 patient-years)
40 Hazard rate (Agranulocytosis)
35
30
25
20
15
10
5
0
time (wks) 25 39 78 130 182 234 286 338 390 442
time (years) 1 2 3 4 5 6 7 8
Source: Appendix 1, Post-text Tables 3,4-4,3.2-4
Risk of agranulocytosis after first
6 months of Clozaril treatment
US Hazard Rate for agranulocytosis after the first 6 months
3.0
hazard rate (per 1000 patient-years)
2.5
2.0
1.5
1.0
0.5
0.0
time (wks) 39 78 130 182 234 286 338 390 442
time (years) 1 2 3 4 5 6 7 8
Source: Appendix 1, Post-text Tables 3,4-4,3.2-4
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
Clozaril registries (cont.)
• Centralized, “non-rechallengable”
database
• Generic manufacturers maintain
separate monitoring database
United States Registry
and Analyses
Clozaril National Registry (CNR)
History of monitoring system in US
1990 1998 2003
initial system current system
weekly monitoring weekly for the first 26 weeks
at least every two weeks thereafter
introduction of
generic clozapine
Clozaril registry actions
Action US UK Australia
Initiation of Clozaril WBC ≥3500 WBC ≥3500 WBC ≥3500
cells/mm3 and ANC >2000 and ANC >2000
Twice weekly monitoring WBC 3000-3500 WBC 3000-3500 WBC ≤3500
cells/mm3 and and/or and/or
ANC >1500 ANC 1500-2000 ANC 1500-2000
Temporary discontinuation WBC 2000-3000 N/A N/A
cells/mm3 and /or ANC
1000-1500
Permanent discontinuation WBC <2000 WBC <3000 WBC <3000
& patients enter non- and/or and/or and/or
rechallengable database ANC <1000 ANC ≤1500 ANC ≤1500
cells/mm3
Source: US, UK and Australia Clozaril prescribing information
US monitoring system:
description of initial & current systems
Total patients: 178,104
Weekly monitoring Weekly / bi-weekly
Generic clozapine introduced
Data excluded
“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
Feb 1990 Oct 1997 Apr 1998 Sept. 2001
every two weeks
Definitions for analysis
US UK Australia
Moderate WBC ≤ 3000
WBC ≤ 3000 WBC ≤ 3000
leukopenia or ANC < 2000
Severe leukopenia WBC < 2000 WBC <2000 WBC < 2000
or ANC <1000
Agranulocytosis WBC ≤ 1000 WBC ≤ 1000 WBC ≤ 1000
or or ANC <500 or
ANC ≤ 500 ANC ≤ 500
United States Results
US rates during first 6 months of
treatment (weekly monitoring under both systems)
35 Differences between
30.7 27.96
Initial System Systems (with CI’s
rate per 1000 patient-years
30 and p values)
Current system
25 Moderate leukopenia
2.74 (-0.37, 5.85)
20 (p = 0.0837)
15 Severe leukopenia
3.54 (2.36, 4.71)
10 6.93 6.76 (p < 0.0001)
3.39* 3.25 *
5 Agranulocytosis
3.51 (2.35, 4.66)
0 (p < 0.0001)
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
* significant difference
Data source: Appendix 1, Post-text Tables 3.4-1b, 3.2-1b
US rates for > 6 months of treatment
(weekly monitoring in old system and bi-weekly in new system)
10 Differences between
8.92 Initial system Systems (with CI’s
9 and p values)
8.0 Current system
rate per 1000 patient-years
8
Moderate leukopenia
7 0.92 (-0.2, 2.05)
6 (p = 0.1073)
5 Severe leukopenia
4 0.15 (-0.08, 0.38)
(p = 0.2085)
3
2 Agranulocytosis
0.48 0.33 0.4 0.37 0.03 (-0.21, 0.27)
1
(p =0.804)
0
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
Data source: Appendix 1, Post-text Tables 3.4-1b, 3.3-1b, 3.2-1b
US Rates for > 52 weeks of treatment
(weekly monitoring under initial system and bi-weekly under current system)
16 Differences between
Initial system Systems (with CI’s
14 and p values)
rate per 1000 patient-years
Current system
12
Moderate leukopenia
10 1.11 (-0.20, 2.42)
8.33 7.22 (p = 0.097)
8
Severe leukopenia
6
0.16 (-0.10, 0.43)
4 (p =0.220)
0.45 0.28
0.39
2 0.11* Agranulocytosis
0
0.27 (0.10, 0.45)
(p = 0.002)
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
*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
Time trend of agranulocytosis rate
% New Patients & Agranulocytosis Rate/1000 patient-years
100.0 12.00
Agranulocytosis rate
% new patients
10.00
% New Patients
80.0 agranulo cyto sis rate
8.00
60.0
6.00
40.0
4.00
20.0 2.00
0.0 0.00
1990
1992
1994
1996
1998
2000
Year 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
Patient Demographics: all patients
Demographic Category Initial System Current System
N (%) N (%)
Gender Male 79256 (57.1) 22287 (56.8)
Female 56430 (40.6) 16149 (41.1)
Missing 3158 ( 2.3) 824 ( 2.1)
Age at initiation < 35 50124 (36.1) 12794 (32.6)
of treatment 36-50 53225 (38.3) 14808 (37.7)
51-65 17474 (12.6) 6073 (15.5)
>65 14863 (10.7) 4761 (12.1)
Missing 3158 ( 2.3) 824 ( 2.1)
Mean 42.1 43.0
Race White 95958 (69.1) 24528 (62.5)
Black 17367 (12.5) 6058 (15.4)
Hispanic 5819 ( 4.2) 2014 ( 5.1)
Oriental 1725 ( 1.2) 460 ( 1.2)
Other 1578 ( 1.1) 724 ( 1.8) Source:
Missing 16397 (11.8) 5476 (13.9) Appendix 1, Post-text Table 3.1-1
No clinically meaningful differences between systems
Patient Demographics: agranulocytosis
Demographic Category Initial System Current System
N (%) N (%)
Gender Male 283 (54.7) 31 (55.4)
Female 234 (45.3) 25 (44.6)
Missing 0 ( 0.0) 0( 0.0)
Age at initiation < 35 109 (21.1) 13 (23.2)
of treatment 36-50 200 (38.7) 18 (32.1)
51-65 159 (30.8) 17 (30.4)
>65 49 ( 9.5) 8 (14.3)
Missing 0 ( 0.0) 0 ( 0.0)
Mean 46.8 47.7
Race White 349 (67.5) 37 (66.1)
Black 15 ( 2.9) 3 ( 5.4)
Hispanic 24 ( 4.6) 4 ( 7.1)
Oriental 3 ( 0.6) 0 ( 0.0)
Other 7 ( 1.4) 0 ( 0.0)
Source:
Missing 119 (23.0) 129 (21.4)
Appendix 1, Post-text Table 3.1-4
No clinically meaningful differences between systems
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
United Kingdom and Ireland
Registry and Analyses
Clozaril Patient Monitoring Service (CPMS)
CPMS monitoring frequency:system change
1990 1995 1999 2003
initial system current system Ireland adopts UK
(UK & Ireland) (UK)
system with at least
weeks 0-18: weekly weeks 0-18: weekly
thereafter: at least every weeks 19-52: at least every 2 weeks monthly monitoring
2 weeks > 52 weeks: at least monthly thereafter after 52 weeks
Clozaril registry actions
Action US UK Australia
Initiation of Clozaril WBC ≥3500 WBC ≥3500 WBC ≥3500
cells/mm3 and ANC >2000 and ANC >2000
Twice weekly monitoring WBC 3000-3500 WBC 3000-3500 WBC ≤3500
cells/mm3 and and/or and/or
ANC >1500 ANC 1500-2000 ANC 1500-2000
Temporary discontinuation WBC 2000-3000 N/A N/A
cells/mm3 and /or ANC
1000-1500
Permanent discontinuation WBC <2000 WBC <3000 WBC <3000
& patients enter non- and/or and/or and/or
rechallengable database ANC <1000 ANC ≤1500 ANC ≤1500
cells/mm3
Source: US, UK and Australia Clozaril prescribing information
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 included in analyses
12
months
1990 1994 1995 2002
monthly
monitoring
Definitions for analysis:
US UK Australia
Moderate WBC ≤ 3000
WBC ≤ 3000 WBC ≤ 3000
leukopenia or ANC < 2000
Severe leukopenia WBC < 2000 WBC <2000 WBC < 2000
or ANC <1000
Agranulocytosis WBC ≤ 1000 WBC ≤ 1000 WBC ≤ 1000
or or ANC <500 or
ANC ≤ 500 ANC ≤ 500
United Kingdom & Ireland
Results
UK rates during first 18 weeks of
treatment (weekly monitoring under both systems)
140 Differences between
105.1 Initial system Systems (with CI’s
120 Current system and p values)
rate per 1000 patient-years
82.5 *
100 Moderate leukopenia
22.56 (5.61, 39.51)
(p = 0.009)
80
Severe leukopenia
60
33.5 1.64 (-8.12, 11.40)
31.9 24.8 (p = 0.742)
40
20.4
Agranulocytosis
20 4.45 (-3.82, 12.73)
(p = 0.292)
0
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
* significant difference
Data source: Appendix 2, Post-text Tables 4.5, 4.11, and 4.18
UK rates for weeks 19-52 of treatment
(bi-weekly monitoring under both systems)
40 Differences between
Systems (with CI’s
Initial system
rate per 1000 patient-years
35 and p values)
30.54
Current system
30 Moderate leukopenia
20.7 * 9.85 (2.45, 17.24)
25 (p = 0.009)
20
Severe leukopenia
15 0.28 (-2.57, 3.12)
4.25 3.98 (p = 0.849)
10
1.16 1.52 Agranulocytosis
5 -0.36 (-1.91, 1.19)
(p = 0.649)
0
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
* significant difference
Data source: Appendix 2, Post-text Tables 4.5, 4.11, and 4.18
UK rates for >52 weeks of treatment
(bi-weekly monitoring under initial system and monthly under
current system)
16 Differences between
Systems (with CI’s
14 Initial system and p values)
rate per 1000 patient-years
11.77 Current system
12 Moderate leukopenia
4.34 (1.54, 7.14)
10 7.43 * (p = 0.002)
8 Severe leukopenia
0.71 (-0.62, 2.04)
6 2.6 (p = 0.295)
1.89
4 Agranulocytosis
0.31 0.59 -0.28 (-0.78, 0.22)
2
(p = 0.274)
0
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
* significant difference
Data source: Appendix 2, post-text tables 4.5, 4.11, and 4.18
Time trend of agranulocytosis rate
% New Patients & Agranulocytosis Rate/1000 patient-years
100 25.0
90
% new patients
Agranulocytosis rate
80 20.0
% New Patients
70 agranulo cyto sis rate
60 15.0
50
40 10.0
30
20 5.0
10
0 0.0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Incudes all data for all patients
Year
Fewer new patients because of availability of alternative atypical antipsychotics?
Fewer new patients = fewer high risk patients?
Source: Clozaril National registry
Patient Demographics: all patients
Demographic Category Initial system Current System
N (%) N (%)
Gender Male 4201 (65.0) 14583 (67.9)
Female 2174 (34.1) 6890 (32.1)
Age at initiation < 35 3220 (50.5) 11236 (52.3)
of treatment 36-50 2208 (34.6) 7053 (32.8)
51-65 767(12.0) 2627 (12.2)
>65 180 ( 2.8) 557 ( 2.5)
Race Caucasian 5755 (90.3) 18652 (86.7)
Afro-Carib 278 ( 4.3) 1389 ( 6.5)
Mixed 112 ( 1.7) 345 ( 1.6)
Oriental 24 ( 0.4) 90 ( 0.4)
Asian 206 ( 3.2) 997( 4.6)
Source:
Appendix 2, Post-text Table 4.22
No clinically meaningful differences between systems
Patient Demographics: agranulocytosis
Demographic Category Initial system Current System
N (%) N (%)
Gender Male 28 (58.3) 92 (61.3)
Female 20 (41.7) 58 (38.7)
Age at < 35 12 (25.0) 35 (23.3)
initiation 36-50 25 (52.1) 54 (35.0)
of treatment 51-65 11 (22.9) 52 (34.7)
>65 0 (0.00) 9 ( 6.0)
Race Caucasian 45 (93.7) 138 (92.0)
Afro-Carib 1 ( 2.1) 1 ( 0.7)
Mixed 0 ( 0.0) 2 ( 1.3)
Oriental 0 ( 0.0) 0 ( 0.0)
Asian 2 ( 4.2) 9 ( 6.0)
Source:
Appendix 2, Post-text Table 4.22
No clinically meaningful differences between systems
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.
Australian Registry
and Analyses
Clozaril Patient Monitoring Service (CPMS)
CPMS monitoring frequency and
cohort for analysis.
1992 2003
Weekly for the first 18 weeks
and monthly thereafter
Data from approximately 10,000 patients were analyzed
Clozaril registry actions
Action US UK Australia
Initiation of Clozaril WBC ≥3500 WBC ≥3500 WBC ≥3500
cells/mm3 and ANC >2000 and ANC >2000
Twice weekly monitoring WBC 3000-3500 WBC 3000-3500 WBC ≤3500
cells/mm3 and and/or and/or
ANC >1500 ANC 1500-2000 ANC 1500-2000
Temporary discontinuation WBC 2000-3000 N/A N/A
cells/mm3 and /or ANC
1000-1500
Permanent discontinuation WBC <2000 WBC <3000 WBC <3000
& patients enter non- and/or and/or and/or
rechallengable database ANC <1000 ANC ≤1500 ANC ≤1500
cells/mm3
Source: US, UK and Australia Clozaril prescribing information
Definitions for analysis
US UK Australia
Moderate WBC ≤ 3000
WBC ≤ 3000 WBC ≤ 3000
leukopenia or ANC < 2000
Severe leukopenia WBC < 2000 WBC <2000 WBC < 2000
or ANC <1000
Agranulocytosis WBC ≤ 1000 WBC ≤ 1000 WBC ≤ 1000
or or ANC <500 or
ANC ≤ 500 ANC ≤ 500
Australian Results
Australian Rates
weekly monitoring (weeks 0-18)
monthly monitoring (weeks 19-52 & 52+)
60
52.54
rate per 1000 patient-years
50 0-18 w eeks (w eekly)
19-52 w eeks (monthly)
40 52+ w eeks (monthly)
30
20 12.72
11.85
8.27
10 6.13
1.58 2.17
0.70 0.52
0
Moderate Severe Agranulocytosis
Leukopenia Leukopenia
Data source: Appendix 3, post-text tables 5.1-2, 5.2-2, and 5.3-2
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
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)
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)
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