# Presentation: 799779

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

- Vinod Kumar, MD
-  Executive DirectorClinical 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

- Source: Appendix 1, Post-text Tables 3,4-4,3.2-4

**time (years)             1             2                3                4                5               6               7               8**

## Risk of agranulocytosis after first 6 months of Clozaril treatment

- 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

## 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)**

## 				    	

	1990					1998		    2003											

- 	**1990****	****	****	****	****	****1998****	****	****    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**

## Clozaril registry actions 

| Action | US | UK | Australia |
| --- | --- | --- | --- |
| Initiation of Clozaril
cells/mm3 | WBC ≥3500 | WBC ≥3500
and ANC >2000 | WBC ≥3500
and ANC >2000 |
| Twice weekly monitoring
cells/mm3 | WBC 3000-3500
 and 
ANC >1500 | WBC 3000-3500
 and/or 
ANC 1500-2000 | WBC ≤3500
and/or 
ANC 1500-2000 |
| Temporary discontinuation
cells/mm3 | WBC 2000-3000
and /or ANC 1000-1500 | N/A | N/A
 |
| Permanent discontinuation
& patients enter non-rechallengable database
cells/mm3 | 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

## US monitoring system: description of initial & current systems

- 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**

## Definitions for analysis

|  | US | UK | Australia |
| --- | --- | --- | --- |
| 
Moderate leukopenia | 
WBC ≤ 3000 | 

WBC ≤ 3000
or ANC < 2000
 | 
WBC ≤ 3000 |
| 
Severe leukopenia | 
WBC < 2000 | 
WBC <2000 
or ANC <1000
 | 
WBC < 2000 |
| 
Agranulocytosis | 
WBC ≤ 1000 
or
ANC ≤ 500 | 
WBC ≤ 1000
or ANC <500
 | 
WBC ≤ 1000 
or
ANC ≤ 500 |

## United States Results

## US rates during first 6 months of treatment (weekly monitoring under both systems)

- 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

## 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

## 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

- *

## Time trend of 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?**

**Agranulocytosis rate**

**% New Patients & Agranulocytosis Rate/1000 patient-years**

- Source: Clozaril Patient Monitoring Service

## Patient Demographics: all patients

**No clinically meaningful differences between systems**

- Source:
- Appendix 1, Post-text Table 3.1-1

## Patient Demographics: agranulocytosis

**No clinically meaningful differences between systems**

- Source:
- Appendix 1, Post-text Table 3.1-4

## 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)

- 			**	****    ****	**
- 	      **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**

## Clozaril registry actions 

| Action | US | UK | Australia |
| --- | --- | --- | --- |
| Initiation of Clozaril
cells/mm3 | WBC ≥3500 | WBC ≥3500
and ANC >2000 | WBC ≥3500
and ANC >2000 |
| Twice weekly monitoring
cells/mm3 | WBC 3000-3500
 and 
ANC >1500 | WBC 3000-3500
 and/or 
ANC 1500-2000 | WBC ≤3500
and/or 
ANC 1500-2000 |
| Temporary discontinuation
cells/mm3 | WBC 2000-3000
and /or ANC 1000-1500 | N/A | N/A
 |
| Permanent discontinuation
& patients enter non-rechallengable database
cells/mm3 | 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

## Monitoring system: description of initial & current systems 

**  ****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

## Definitions for analysis:

|  | US | UK | Australia |
| --- | --- | --- | --- |
| 
Moderate leukopenia | 
WBC ≤ 3000 | 

WBC ≤ 3000
or ANC < 2000
 | 
WBC ≤ 3000 |
| 
Severe leukopenia | 
WBC < 2000 | 
WBC <2000 
or ANC <1000
 | 
WBC < 2000 |
| 
Agranulocytosis | 
WBC ≤ 1000 
or
ANC ≤ 500 | 
WBC ≤ 1000
or ANC <500
 | 
WBC ≤ 1000 
or
ANC ≤ 500 |

## United Kingdom & IrelandResults

## 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

## 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

## 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

## Time trend of agranulocytosis rate

**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?**

**% New Patients & Agranulocytosis Rate/1000 patient-years**

- Source: Clozaril National registry

## Patient Demographics: all patients

**No clinically meaningful differences between systems**

- Source:
- Appendix 2, Post-text Table 4.22

## Patient Demographics: agranulocytosis

**No clinically meaningful differences between systems**

| Demographic | Category | Initial system
N (%) | Current System
N (%) |
| --- | --- | --- | --- |
| Gender | Male
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) |
| Race | Caucasian
Afro-Carib
Mixed
Oriental
Asian | 45 (93.7)
1 (  2.1)
0 (  0.0)
  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

## 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****	****	****	****	****	**
**	****	****      ****	****	**
**	**
**	****	**
-       Data from approximately 10,000 patients were analyzed

**Weekly for the first 18 weeks and monthly thereafter**

## Clozaril registry actions 

| Action | US | UK | Australia |
| --- | --- | --- | --- |
| Initiation of Clozaril
cells/mm3 | WBC ≥3500 | WBC ≥3500
and ANC >2000 | WBC ≥3500
and ANC >2000 |
| Twice weekly monitoring
cells/mm3 | WBC 3000-3500
 and 
ANC >1500 | WBC 3000-3500
 and/or 
ANC 1500-2000 | WBC ≤3500
and/or 
ANC 1500-2000 |
| Temporary discontinuation
cells/mm3 | WBC 2000-3000
and /or ANC 1000-1500 | N/A | N/A
 |
| Permanent discontinuation
& patients enter non-rechallengable database
cells/mm3 | 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

## Definitions for analysis

|  | US | UK | Australia |
| --- | --- | --- | --- |
| 
Moderate leukopenia | 
WBC ≤ 3000 | 

WBC ≤ 3000
or ANC < 2000
 | 
WBC ≤ 3000 |
| 
Severe leukopenia | 
WBC < 2000 | 
WBC <2000 
or ANC <1000
 | 
WBC < 2000 |
| 
Agranulocytosis | 
WBC ≤ 1000 
or
ANC ≤ 500 | 
WBC ≤ 1000
or ANC <500
 | 
WBC ≤ 1000 
or
ANC ≤ 500 |

## Australian Results

## 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

## 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)