Table of contents
1.... Introduction................................................................................................................. 5
2.... Monitoring Systems.................................................................................................... 7
2.1 Policy and Objectives..................................................................................... 7
2.2 Limitations...................................................................................................... 7
2.3 Differences..................................................................................................... 7
2.3.1 Historical background.................................................................... 7
2.3.2 Definitions of Leukopenia and Agranulocytosis used in
analysis... 9
2.4 Criteria for Action.......................................................................................... 9
3.... United States............................................................................................................. 10
3.1 Methods for Analysis.................................................................................... 10
3.1.1 Patient population......................................................................... 10
3.1.2 Demographics............................................................................... 14
3.1.3 Incidence rates and life table analyses of severe
leukopenia and agranulocytosis............................................................................. 14
3.1.4 WBC at Time of Discontinuation.................................................. 15
3.1.5 Projected rates of severe leukopenia and
agranulocytosis............ 15
3.2 Results from United States............................................................................ 18
3.2.1 Demographics of patients in the initial monitoring
system and the current monitoring system............................................................. 18
3.2.2 Incidence of leukopenia and agranulocytosis................................ 21
3.2.3 Risk of moderate leukopenia and agranulocytosis over
time........ 23
3.2.4 White Blood Cell Count at Time of Discontinuation.................... 24
3.2.5 Fatal Outcomes Related to Agranulocytosis................................. 26
3.2.6 Analysis of Prodrome Period....................................................... 27
3.2.7 Projected Rates............................................................................ 27
3.3 Discussion and Conclusion (United States).................................................. 29
4.... United Kingdom........................................................................................................ 30
4.1 Methods for Analysis.................................................................................... 30
4.1.1 Patient Population......................................................................... 30
4.1.2 Cohorts......................................................................................... 30
4.1.3 Statistics....................................................................................... 30
4.2 Results from United Kingdom....................................................................... 31
4.2.1 Demographics............................................................................... 31
4.2.2 Incidence of leukopenia and agranulocytosis................................ 32
4.3 Discussion and Conclusion (United Kingdom)............................................. 34
5.... Australia................................................................................................................... 35
5.1 Methods for Analysis.................................................................................... 35
5.2 Results from Australia.................................................................................. 36
5.3 Discussion and Conclusion (Australian)....................................................... 36
6.... Overall Discussion................................................................................................... 37
7.... Overall Conclusion................................................................................................... 40
List of In-text tables
Table 1....... Definitions of leukopenia and agranulocytosis used in analysis by
monitoring system............................................................................................................ 9
Table 2....... Registry Criteria
for Action......................................................................... 10
Table 3: .... Description of patients treated with Clozaril since
introduction of generic clozapine...................................................................................................... 11
Table 4: ..... Patient
disposition....................................................................................... 14
Table 5: .... Estimation of the number of severe leukopenia and
agranulocytosis cases for patients in Cohort 3 after weekly monitoring for six
months and monthly thereafter...................................................................................................... 18
Table 6: .... Demographics of
all patients in Initial system and Current system............. 19
Table 7:...... Demographics of
patients in Initial system and Current system who developed agranulocytosis........................................................................... 20
Table 8: .... White Blood Cell Count (WBC) at time of
discontinuation by duration for patients with WBC value between 3000 and 6000
at time of discontinuation by system cohort.......................................................................................... 26
Table 9: ..... Stratified White
Blood Cell Count (WBC) at time of discontinuation by duration for patients with
WBC value at time of discontinuation by system cohort........................................................................................................... 26
Table 10: ... Median Slope for
Patients Who Developed Moderate Leukopenia and Did or Did Not Develop
Agranulocytosis............................................................... 27
Table 11: ... Actual and projected
number of cases of severe leukopenia and agranulocytosis after weekly
monitoring during the first six months of therapy followed by bi-weekly
monitoring (Current system cohort)........................ 28
Table 12: .. Demographics of all patients in Initial system and
Current system.............. 31
Table 13: .. Demographics of all patients with agranulocytosis in
Initial system and Current system............................................................................................. 32
Table 14..... Summary of Results..................................................................................... 34
Table 15:.... Summary of Results..................................................................................... 36
Table 16: ... Incidence of
agranulocytosis in US, UK and Australia................................ 40
List of figures
Figure 1: .................. US
changes in CNR monitoring frequency..................................... 8
Figure 2:.................... UK
and Ireland, changes in CPMS monitoring frequency............... 8
Figure 3: ................... Australian
CPMS monitoring frequency......................................... 8
Figure 4: ................... Overview
of Cohorts.................................................................... 12
Figure 5:.................... Algorithm
for Probabilities.......................................................... 17
Figure 6: ................... Trend
of Agranulocytosis Rate..................................................... 21
Figure 7:.................... Incidence
of moderate leukopenia, severe leukopenia and agranulocytosis during the first
6 months of treatment by monitoring system cohort................................................................................ 22
Figure 8:.................... Incidence
of moderate leukopenia, severe leukopenia and agranulocytosis after the first 6
months of treatment by monitoring system cohort................................................................................ 23
Figure 9: ................... Hazard
rate for moderate leukopenia and agranulocytosis over 8.5 years............................................................................................. 24
Figure 10: ................. Time
to first discontinuation......................................................... 25
Figure 11: ................. Trend
of Agranulocytosis Rate..................................................... 33
List of Appendices
Appendix 1: Post-text
Tables regarding data from the
Appendix 2: Post-text
Tables regarding data from the
Appendix 3: Post-text
Tables regarding data from
Appendix 4: Method for Estimating the Rates of Agranulocytosis and Severe Leukopenia if the Current Bi-weekly Monitoring Option of WBC Counts After Six Months of Treatment with Clozaril is Changed to a Less Frequent Monitoring Option
Appendix 5: Narratives of fatal outcomes associated with Clozaril use and the development of agranulocytosis
Appendix 6:Algorithm for criteria for changes in monitoring
frequency in the
1 Introduction
Clozaril® (clozapine) is an antipsychotic drug that
was approved in the
As previously mentioned, the initial indication for Clozaril was for the treatment of patients with treatment-resistant schizophrenia. This restricted indication was primarily based on the risk/benefit profile considered at the time of approval. The efficacy of Clozaril in the treatment of patients with schizophrenia was well established; however, the risk of developing agranulocytosis that was associated with its use during clinical trials and foreign marketing experience was also well established. Agranulocytosis is clinically defined as the absence of granulocytes, which may lead to serious infections and fatal outcomes. The potential risk to Clozaril-treated patients of developing such a serious complication (i.e., agranulocytosis) was considered high enough compared not only to other antipsychotic drugs but to other drugs on the market at the time to warrant a restricted indication.
The lack of known predictors for patients who will develop agranulocytosis and the overall morbidity and mortality associated with agranulocytosis were the leading reasons why the Food and Drug Administration (FDA) and Novartis Pharmaceuticals Corporation (Novartis) mutually agreed to implement a hematological monitoring system to reduce the risk of agranulocytosis and its serious sequale. The rationale for the frequency of monitoring was based on the premise that a relationship existed between the frequency of monitoring and the probability of early detection of leukopenia. Early detection is considered important because the development of agranulocytosis could be minimized if patients were identified at a point prior to agranulocytosis (e.g., moderate leukopenia; WBC between 2000 and 3000 cells/mm3). Monitoring on a daily basis was thought to be impractical, but a schedule of weekly monitoring seemed practical and safe. Thus, Novartis developed the Clozaril National Registry (CNR) to ensure weekly monitoring of White Blood Cell (WBC) counts for Clorzaril-treated patients throughout their duration of therapy.
In
1997, following nearly eight years of safe and effective use of Clozaril in the
1. The risk of agranulocytosis was greatest during the first six months of therapy and gradually declines thereafter, but never reaches zero.
2. The number of fatal outcomes was lower than expected.
Given these observations, the possibility of reducing the frequency of monitoring was considered at the 48th meeting (July 14, 1997) of the Psychopharmacological Drugs Advisory Committee (PDAC). Specifically, the following questions were posed to the PDAC:
1. Should the frequency of monitoring be reduced at some time point after initiation of therapy? If so, when and to what frequency?
2. Should monitoring be discontinued at some time point? If so, when?
3. Should monitoring become voluntary?
The PDAC provided the following recommendations to the questions
posed at the meeting:
·
Monitoring frequency should be reduced after six
months to every two weeks.
·
Mandatory monitoring should be continued.
·
After implementation of the current monitoring
system, an evaluation of the impact this frequency of monitoring had on the
rate of agranulocytosis should be conducted.
In 1998, Novartis implemented the current monitoring system that was recommended by the PDAC members (i.e., weekly for the first 26 weeks of treatment and every two weeks thereafter). Also, shortly thereafter the first generic version of Clozaril became available in US (note: brand clozapine is referred to as “Clozaril” and generic as “generic clozapine” throughout this document) and patients treated with generic clozapine became subject to the current monitoring system. Manufacturers of generic clozapine are responsible for ensuring adherence to the current monitoring frequency schedule by maintaining a registry database with functionality identical to the CNR. Novartis, however, is responsible for maintaining a database of patients who should not be rechallenged with clozapine (“Non-rechallengable database”) and generic manufacturers are responsible for:
1. contacting Novartis prior to initiating patients to cross-check them against the “Non-rechallengable database” and
2. informing Novartis of patients who should be added to this
database.
In 2001, the FDA contacted Novartis to follow up on the 1997 PDAC
recommendation to evaluate the impact of the current monitoring system on the
rate of agranulocytosis and whether further reductions were warranted based on
the new data from the CNR.
There were a series of meetings that occurred with the FDA over
the next several months regarding the methods of analyses that were eventually
agreed upon between the FDA and Novartis and the data from those analyses were
summarized and submitted to the FDA in 2002 and 2003. One important milestone that also occurred in
late 2002 was the approval of Clozaril for the treatment of recurrent suicidal
behavior. Consequently, the number of
patients who will be exposed to Clozaril is expected to increase since this new
indication allows for the use of Clozaril in patients who are not
treatment-resistant, which is a considerably broader group of patients who were
not previously exposed to Clozaril.
Following their review of the updated registry data, the FDA informed Novartis that these data should be reviewed by the PDAC, where once again the question of whether to reduce the frequency of monitoring would be discussed.
The data summarized herein were prepared as background
information for review and discussion at the PDAC meeting scheduled for
2 Monitoring
Systems
2.1 Policy and Objectives
The Novartis policy of “No Blood No Drug” is applied globally to
all Clozaril-treated patients through national centralized monitoring services,
or institutional/physician oversight. Monitoring
systems vary somewhat from country to country, however the
These 3 registries are identified as follows:
The objective of
all monitoring systems is the early detection of moderate leukopenia in order to reduce or prevent the occurrence
of severe leukopenia, agranulocytosis and death.
2.2 Limitations
The registry databases were designed for monitoring and not for explanatory
assessment. The data for analyses are
based on single data entry and are not validated.
Section 2.3 describes important differences between the three
monitoring systems under discussion. These
differences limit the ability to compare the results of data analyses between
the systems.
2.3 Differences
2.3.1 Historical
background
Mandatory hematological monitoring accompanied
commercial introduction of Clozaril in the
Figure 1: US changes in CNR monitoring frequency.
In the
Figure 2:
In the
Figure 3: Australian CPMS monitoring frequency
In
2.3.2 Definitions of Leukopenia and Agranulocytosis used in analysis
The terms moderate leukopenia, severe leukopenia and
agranulocytosis have been used in the analysis of data from all 3 monitoring
systems. Table 1 below shows the
definitions of these terms by monitoring system.
Table 1 Definitions of leukopenia and agranulocytosis used in analysis by monitoring system
|
|
US (CNR) |
|
|
|
Moderate leukopenia cells/mm3 |
WBC ≤ 3000 |
WBC ≤ 3000 or ANC < 2000 |
WBC ≤ 3000 |
|
Severe leukopenia cells/mm3 |
WBC < 2000 |
WBC <2000 or ANC <1000 |
WBC < 2000 |
|
Agranulocytosis cells/mm3 |
WBC ≤ 1000 or ANC ≤ 500 |
WBC ≤ 1000 or ANC <500 |
WBC ≤ 1000 or ANC ≤ 500 |
The US CNR collects only WBC counts systematically. However, agranulocytosis was defined by absolute
neutrophil count (ANC) in 80% of the cases included in the analysis of US
data. These cases were identified
through Medwatch and other reports received by Novartis Clinical Safety and Epidemiology
and eventually entered in to the CNR. The
2.4 Criteria
for Action
The three monitoring systems also differ in the action taken at
different values for WBC and ANC (Table 2). Most of these differences are subtle but there
is one major difference: in the
Across all three countries, patients must meet certain criteria
before moving to the next phase of monitoring frequency (e.g., from weekly to
bi-weekly monitoring in the
Table 2 Registry Criteria for Action
|
Action |
US (CNR) |
|
|
|
Initiation of treatment 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 ANC1500-2000 |
WBC ≤3500 and/or ANC1500-2000 |
|
Temporary discontinuation cells/mm3 |
WBC 2000-3000 and/or ANC
1000-1500 |
N/A |
N/A |
|
Permanent
discontinuation. cells/mm3 |
WBC <2000 and/or ANC
<1000 |
WBC <3000 and/or ANC
≤1500 |
WBC <3000 and/or ANC
≤1500 |
Source: US,
3 United States
3.1 Methods for Analysis
3.1.1 Patient population
As of
In these analyses all patients were classified into nine classes based on their treatment with Clozaril or generic clozapine as described in the following Table 3:
Table 3: Description
of patients treated with Clozaril since introduction of generic clozapine.
|
Patient Type |
Treatment initiated with |
Treatment continued with |
Treatment ended with |
Comments |
|
1 |
Clozaril |
Clozaril |
Clozaril |
CNR has complete record of their WBC. |
|
2 |
Clozaril |
Generic clozapine |
Generic clozapine |
CNR does not have records of WBC
since their switch to Generic clozapine.
Total exposure of these patients can not be computed using CNR data. |
|
3 |
Clozaril |
Both Generic clozapine and Clozaril |
Clozaril |
CNR does not have complete records of
WBC since their switch to Generic clozapine. |
|
4 |
Clozaril |
Both Generic clozapine and Clozaril |
Generic clozapine |
CNR does not have complete records of
WBC since their switch to Generic clozapine.
Total exposure of these patients cannot be computed using CNR data. |
|
5 |
Generic clozapine |
Generic clozapine |
Generic clozapine |
CNR does not have records of WBC for
these patients. Total exposure of
these patients cannot be computed using CNR data. |
|
6 |
Generic clozapine |
Clozaril |
Clozaril |
CNR does not have complete records of
WBC since they started with Generic clozapine. Total exposure of these patients cannot be
computed using CNR data. |
|
7 |
Generic clozapine |
Both Generic clozapine and Clozaril |
Generic clozapine |
CNR does not have complete records of
WBC. Total exposure of these patients
cannot be computed using CNR data. |
|
8 |
Generic clozapine |
Both Generic clozapine and Clozaril |
Clozaril |
CNR does not have complete records of
WBC. Total exposure of these patients
cannot be computed using CNR data. |
|
9 |
_____ |
_____ |
_____ |
Patients enrolled in CNR, but never
treated with Clozaril or had only one WBC entry. Total exposure of these patients cannot be
computed using CNR data. |
3.1.1.1 Inclusion Criteria
The sole source of data for the
data from the
3.1.1.2 Exclusion Criteria
The exclusion
criteria for the
1.
Patients who were enrolled in the CNR, but never
started treatment with Clozaril or had only one WBC entry in the database
(Table 3: Patient type 9). Approximately 22,000 patients were excluded based on
this criterion.
2. Patients who were believed to have started treatment with generic clozapine before any treatment with Clozaril (Table 3: Patient types 5, 6, 7 and 8). Approximately 4,000 patients were excluded based on this criterion.
3.
Patients who started Clozaril treatment bit switched to
generic clozapine at some point in time(Table 3:
Patient types 5, 6, 7 and 8). Data for these patients after treatment with
generic clozapine were excluded. Some data from approximately 19,000 patients
were excluded based on this criterion.
3.1.1.3 Cohort Definitions
As shown in Figure 4 below, the patients in the CNR were divided into 3 cohorts and are described as follows:
Cohort 1 (Initial system):
Cohort 1 includes data from
approximately 97,000 patients. This cohort represents the group of patients who
were included in the briefing book submitted to FDA
on
Cohort 2 (Initial system):
Cohort 2 includes data from
approximately 41,000 patients. This cohort represents all patients who
initiated Clozaril therapy after the
Cohort 3 (Current system):
Cohort 3 includes data from
approximately 39,000 patients. This cohort represents patients who have been
monitored according to the current monitoring system. It includes all patients who started Clozaril
(global change) after
For purposes of comparing the initial system with the current
system patients were dichotomized into Cohorts 1 and 2 (combined). All relevant data, subject to exclusion
criteria 1, 2 and 3 and collected by April 1, 1998 (introduction of bi-weekly
monitoring) were used to compute relevant rates and ratios for Cohorts 1 and 2
(combined); all relevant data, subject to exclusion criteria 1, 2 and 3 and
collected between April 1, 1998 and September 1, 2001 were used to compute
relevant rates and ratios for Cohort 3. Therefore, combined data from Cohorts 1
and 2, also referred to as the “initial monitoring system” cohort, contain
information on patients who were subject to weekly monitoring of WBC under the
previous monitoring system effective until
Estimation of rates under monthly and
no-monitoring options were performed for patients in
Cohort 3 only.
Table 4 summarizes the disposition of
patients described above with the application of the exclusion criteria
explained in Section 3.1.1.2
Table 4: Patient disposition
|
|
Number
of Patients |
|
Enrolled in CNR¶
|
203,818 |
|
|
Excluded from analysis due to: |
|
|
|
Exclusion Criterion 1 |
21,743 |
|
|
Exclusion Criterion 2 |
3,971 |
|
|
|
|
Number
of patients for whom part of data were excluded due to Exclusion
Criterion 3 |
|
|
|
|
|
Included in Analysis: |
|
|
|
All Cohorts |
178,104 |
19,318 |
|
Cohort 1 |
97,485 |
10,791 |
|
Cohort 2 |
41,359 |
4,175 |
|
Cohort 3 |
39,260 |
4,352 |
Exclusion Citerion 1: Exclude patients who
were enrolled in CNR, but never started treatment with clozapine or had only
one record of WBC in the database
Exclusion
Citerion 2: Exclude
patient who started treatment with generic clozapine before any treatment with
Clozaril (Patient types 5, 6, 7 and 8)
Exclusion
Citerion 3:
Patients started on Clozaril, but switched to generic clozapine at some point
of time (Patient types 2, 3, and 4) after
3.1.2 Demographics
Summary statistics of the demographics variables (i.e., age, sex,
and race) are provided by cohort and for patients with agranulocytosis,
moderate leukopenia and severe leukopenia.
3.1.3 Incidence rates and life table analyses of severe leukopenia
and agranulocytosis
Number of cases, total exposure and incidence rates of moderate
leukopenia, severe leukopenia and agranulocytosis by cohort, and by treatment duration
with Clozaril are provided.
In order to study the trend of agranulocytosis, severe leukopenia
and moderate leukopenia over the years, the percent of new patients by calendar
year were tabulated along with the corresponding incidence rates of
agranulocytosis, severe leukopenia and moderate leukopenia.
Life table analysis method was used for estimating cumulative
probability of event incidence rates and hazard rates of agranulocytosis, severe
leukopenia and moderate leukopenia by cohort.
Yearly conditional risks were tabulated separately for the initial
monitoring system (Cohorts 1 and 2) and the current monitoring system (Cohort
3) for the incidence of agranulocytosis and severe leukopenia.
3.1.4 WBC at Time of Discontinuation
The WBC at the time of
discontinuation (or interruption of treatment) for each patient was determined
as follows:
For patients in Cohorts 1 and 2, if the
time elapsed (gap) between two consecutive WBC counts was greater than 15 days during the entire study period then the
patient was considered discontinued (interrupted) Clozaril treatment.
For patients in Cohort 3, if the time
elapsed (gap) between two consecutive WBC counts was greater than 15 days during the first six months of therapy or
if the gap between WBC counts was greater than 30 days after 6 months of
therapy then the patient in Cohort 3 was considered discontinued (interrupted)
Clozaril treatment.
The WBC count on the date of first discontinuation was summarized
and the time to first discontinuation from baseline was used in computing
Kaplan-Meier estimates of probability of discontinuation and presented in a
graph.
In addition, patients who discontinued (as defined above) with a
WBC value between 3,000 to 6,000 cells/mm3 were identified and
median WBC values were compared for patients in Cohorts 1 and 2 (combined) and
Cohort 3.
3.1.5 Projected rates of severe leukopenia and agranulocytosis
Estimation of rates under monthly and no-monitoring options was
performed for patients in Cohort 3 only.
These rates reflect the estimated of risk for patients in Cohort 3 if
they were monitored on a monthly basis or not monitored after their first six
months, one year, or two years of treatment with Clozaril. These rates are also referred as projected
rates under a less frequent monitoring option in this document.
The method of estimation of these rates of severe leukopenia and
agranulocytosis after 6 months (one year and two years) of treatment with
Clozaril was similar to the method of estimation of these rates for less frequent monitoring used in
the 1997 briefing book submitted to FDA (Appendix 4: Attachment 3).
The duration of prodrome and the rate of decrease in WBC counts
(slope) during prodrome were calculated for each patient. The onset of prodrome to moderate leukopenia
(WBC £3000/mm3)
was determined by examining data for WBC counts and determining the date from
which the count showed a continual decline until moderate leukopenia developed,
allowing for one possible increase in the count during that interval but only
to a level that did not exceed the baseline count. The duration of the prodrome was defined as
the time from onset to the date of moderate leukopenia (the first day with WBC £
3000/mm3). This definition of the onset of
prodrome was adapted from Alvir, et. al. and was used in the briefing document submitted to FDA
for the 1997 PDAC meeting regarding Clozaril.
The number of patients that would be “caught” or “missed” to detect at
moderate leukopenia under less frequent monitoring were estimated by
calculating the number of days it would have taken the patient to reach severe
leukopenia from the date of the last WBC count and the rate of decrease (slope)
of WBC during prodrome.
The projection of rates of severe leukopenia and
agranulocytosis under less frequent monitoring depends on the following four
quantities estimated from data collected after six months of treatment:
1. P1 = Probability that a patient will develop
severe leukopenia given that the patient was detected (“caught”) at moderate
leukopenia (2000/mm3 <WBC£3000/mm3).
2. P2 = Probability that a patient will develop
agranulocytosis given that the patient was detected (“caught”) at moderate leukopenia (2000/mm3
<WBC£3000/mm3).
3. P3 = Probability that a patient will develop
agranulocytosis given that the patient was not detected (“missed”) at moderate
leukopenia (i.e. severe leukopenia, WBC < 2000/mm3 by the time of
detection).
4. P4 = Incidence rate (per person-year) of
agranulocytosis among patients who did not have a WBC £ 3000/mm3 before developing
agranulocytosis. These are the patients
who developed agranulocytosis before they met the criteria for moderately
leukopenic.
The estimates of these four quantities based on
data from Cohort 3 were deemed unreliable since the number of occurrences of
agranulocytosis or severe leukopenia in Cohort 3 after six months of treatment
was less than 10. These four quantities
were estimated using data from Cohorts 1 and 2 during their weekly monitoring
of WBC. Estimation of these quantities
is demonstrated in Figure 5.
Figure 5: Algorithm for Probabilities
In Cohort 3, the total number of cases of
agranulocytosis occurred after six months from start of Clozaril treatment was
10. Three of these cases occurred with
less than six months of Clozaril treatment (e.g., a patient was treated for five
months with Clozaril and developed agranulocytosis at month 7). These three cases were excluded from the
analysis. The total number of severe leukopenia cases observed after six months
of treatment under the current monitoring was 9. Finally, the estimation of the rates of
agranulocytosis and severe leukopenia utilizing P1-P4 is illustrated in Table 5.
Table 5: Estimation
of the number of severe leukopenia and agranulocytosis cases for patients in
Cohort 3 after weekly monitoring for six months and monthly thereafter
|
|
Number of Patients with >6 months of treatment in Cohort
3 |
Agranulocytosis rate |
Estimated number of agranulocytosis cases |
Estimated
number of
severe leukopenia cases |
|
Moderate under the current monitoring |
230 |
|
|
|
|
“Caught”
at moderate under monthly monitoring |
134 |
P2=0.021 |
134*P2=2.83 |
134*P1=3.5 |
|
“Missed”
at moderate under monthly monitoring |
96 |
P3=0.413 |
96*P3=39.68 |
96 |
|
Never moderate under the current monitoring |
21974# |
P4=0.000104 |
26696*P4=2.78 |
|
|
Total |
22204 |
|
45.29 |
99.5 |
#These patients were treated for 26696 person-years
As seen in Table 5, there were 230 patients within Cohort 3 who
developed moderate leukopenia under the current monitoring system. If there were no monitoring of WBC after six
months of treatment then all those 230 patients would have continued taking
Clozaril even after developing moderate leukopenia. It is expected these patients’ WBC counts
would continue to decrease at a median rate of 126/mm3 per day (see Post-text
Table 3.6-3). Ultimately, all these patients
would have developed severe leukopenia.
These patients would have considerably higher probability of developing
agranulocytosis due to late detection in the absence of monitoring. As mentioned in the 1997 briefing book, 67%
of these patients would develop agranulocytosis. Hence under no monitoring option of WBC, the
total number of agranulocytosis cases is estimated as 230*.67 + 26696*P4 = 154.1 + 2.8 =
156.9.
3.2 Results from United
States
3.2.1 Demographics of patients in the initial monitoring system and
the current monitoring system
Within the initial and
current monitoring systems, the demographics of all patients, patients with
moderate leukopenia, severe leukopenia or agranulocytosis are comparable with
respect to sex, age, and race. The
percentage of patients with missing information was also similar between these
groups. The demographic data for all patients and patients with agranulocytosis
are shown in Tables 6 and 7 below. Demographics
for patients with moderate or severe leukopenia are presented in Appendix
1 Post-text Tables 3.1-2 and 3.1-3
Table 6: Demographics of all patients in Initial system and Current system
|
Demographic |
Category |
Initial system N (%) |
Current system N (%) |
|
Sex |
Male |
79256 (57.1) |
22287 (56.8) |
|
Female |
56430 (40.6) |
16149 (41.1) |
|
|
Missing |
3158 ( 2.3) |
824 ( 2.1) |
|
|
Total |
138844 (100) |
39260 (100) |
|
|
|
|
|
|
|
Age (years) |
<= 35
|
50124 (36.1) |
12794 (32.6) |
|
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) |
|
|
Total
|
138844 (100) |
39260 (100) |
|
|
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) |
|
|
Missing |
16397 (11.8) |
5476 (13.9) |
|
|
Total |
138844 (100) |
39260 (100) |
Source: Appendix 1, Post-text Table 3.1-1
Table 7: Demographics of patients in Initial
system and Current system who developed agranulocytosis
|
Demographic |
Category |
Initial system N (%) |
Current system N (%) |
|
Sex |
Male |
283 ( 54.7%) |
31 ( 55.4%) |
|
Female |
234 ( 45.3%) |
25 ( 44.6%) |
|
|
Total |
|
|
|
|
|
|
|
|
|
Age |
<= 35
|
109 ( 21.1%) |
13 ( 23.2%) |
|
36 - 50 |
200 ( 38.7%) |
18 ( 32.1%) |
|
|
51 - 65 |
159 ( 30.8%) |
17 ( 30.4%) |
|
|
> 65 |
49 ( 9.5%) |
8 ( 14.3%) |
|
|
Total |
517 (100.0%) |
56 (100.0%) |
|
|
Mean
|
46.8 |
47.7 |
|
|
SD |
13.4 |
15.4 |
|
|
|
|
|
|
|
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%) |
|
|
Missing |
119 ( 23.0%) |
12 ( 21.4%) |
|
|
|
|
|
Source: Appendix 1, Post-text Table 3.1-4
3.2.2 Incidence of leukopenia and agranulocytosis
Figure 6 below shows that the overall rate of agranulocytosis decreased consistently by calendar year. This decrease may be explained to some extent by the similarly consistent decrease in the proportion of new patients entering the registry overtime.
Figure 6: Trend of Agranulocytosis Rate
Source: Clozaril
National Registry Note:
All data from all patient included
During the first six months the monitoring frequency was weekly for both the initial and current monitoring systems. The rates of moderate leukopenia was similar for both systems; however, severe leukopenia and agranulocytosis were less under the current monitoring system compared to the initial monitoring system (Figure 7).
After the first 6 months of treatment, the frequency of
monitoring remained weekly under the initial system and changed to bi-weekly
under the current system. The rates of moderate leukopenia severe leukopenia
and agranulocytosis were less compared to the first six months but similar
between the systems (Figure 8).
3.2.3 Risk of moderate leukopenia and agranulocytosis over time
The hazard rate for developing moderate leukopenia or agranulocytosis is greatest during the first 6 months of Clozaril treatment (up to approximately 45/1000 patient-years and 15/1000 patient-years respectively) after which the risk diminishes significantly. The hazard rate begins to stabilize after about 18 months of treatment at approximately 9 per thousand patient-years for moderate leukopenia and approximately 0.3 per thousand patient-years for agranulocytosis (Figure 9).
Figure 9: Hazard
rate for moderate leukopenia and agranulocytosis over 8.5 years
Source: Appendix
1, Post-text Tables
3.4-4,3.2-4
3.2.4 White Blood Cell Count at Time of Discontinuation
There were 110,659 patients defined as patients who discontinued
therapy (see Section 3.1.4 for definition).
Of these patients, there were 67,883 who discontinued during the first 6
months of therapy and 42,776 who discontinued after 6 months of therapy.
The median white blood cell count at the time of discontinuation
for patients in the initial system and current system were 7800 and 7400
cells/mm3,
respectively for patients on therapy for less than or equal to 6 months and
7900 and 7600 cells/mm3,
respectively for patients on therapy for more than 6 months (Appendix 1, Post-text
Table 3.5-1). Additionally, there is no
clinically meaningful difference between the groups with regard to the
distribution (i.e., 5th, 25th, 75th, 95th
percentiles) of WBC values at the time of discontinuation. These WBC counts may
be high because patients may have been discontinued for any reason (e.g., lost
to follow-up) and not for reasons related to abnormal lab values.
Figure 10 shows
that 58% of the patients within the current system discontinued therapy within
6 months after initiating therapy. In
comparison, 40% of the patients within the initial system discontinued therapy
within 6 months after initiating therapy.
Figure 10: Time to first discontinuation
Duration (year)
The WBC values for patients who were discontinued with a WBC
value between 3000 and 6000 cells/mm3
were also evaluated. The value of 3000
cells/mm3 was chosen
because this is the level of WBC counts where patients discontinue from
Clozaril treatment and are considered to have developed moderate
leukopenia. The upper limit of 6000
cells/mm3 was chosen
because patients who were discontinued with a value above this level would be
less likely to have been discontinued for a reason related to an abnormal WBC
value and more likely for other reasons (e.g., availability of alternative
treatment).
As seen in Table 8 below, the median and mean WBC at the time of discontinuation for patients with a WBC value between 3000 and 6000 in the initial system and the current system were similar for patients on therapy for less than or equal to 6 months and greater than 6 months.
Table
8: White
Blood Cell Count (WBC) at time of discontinuation by duration for patients with
WBC value between 3000 and 6000 at time of discontinuation by system cohort
|
WBC (cells/mm3) |
<6
months |
>6 months |
Total duration of therapy |
|||
|
Initial |
Current |
Initial |
Current |
Initial |
Current |
|
|
N |
9837 |
4396 |
7084 |
712 |
16921 |
5108 |
|
Median WBC |
5300 |
5300 |
5400 |
5300 |
5300 |
5300 |
|
Mean WBC |
5183 |
5165 |
5236 |
5185 |
5205 |
5168 |
Source: Appendix 1, Post-text
Table 3.5-2
The proportion of patients who discontinued with values between
3000 and 6000 cells/mm3
and within each stratum was similar between the groups (Table 9). Over 60% of the patients in both groups discontinued
with a WBC value >5000-6000 cells/mm3 regardless of duration of therapy.
Table 9:
Stratified White Blood Cell Count
(WBC) at time of discontinuation by duration for patients with WBC value at
time of discontinuation by system cohort
|
WBC (cells/mm3) |
Median WBC N (%) |
|||||
|
<6
months |
>6 months |
Total duration of therapy |
||||
|
Initial |
Current |
Initial |
Current |
Initial |
Current |
|
|
>3000-4000 |
3800 649 (7%) |
3800 284(6%) |
3800 376 (5%) |
3800 50 (7%) |
3800 1025 (6%) |
3800 334 (7%) |
|
>4000-5000 |
4700 2955 (30%) |
4700 1387(32%) |
4700 1935 (27%) |
4700 216 (30%) |
4700 4890 (29%) |
4700 1603(31%) |
|
>5000-6000 |
5600 6233 (63%) |
5600 2725 (62%) |
5600 4773 (68%) |
5600 446 (63%) |
5600 11006 (65%) |
5600 3171 (62%) |
Source: Appendix 1, Post-text Table
3.5-3a, 3.5-3b, 3.5-3c
3.2.5 Fatal Outcomes Related to Agranulocytosis
Overall, there were 22 (4%) fatalities among the
620 patients who developed agranulocytosis. Of these 22 fatalities, 20 (91%)
occurred within the first six months of treatment. Two (9%) of the 22 fatalities occurred in
patients in the current system cohort and 1 of the 2 occurred during the first
6 months of treatment (see Appendix 5 for narratives regarding these fatal
outcomes).
3.2.6 Analysis of Prodrome Period
The rate of decline in WBC from normal to moderate leukopenia was analyzed in patients who subsequently did or
did not develop agranulocytosis.
In Appendix 1, Post-text Tables 3.6-1 to 3.6-3
provide summary statistics on the duration of prodrome and the rate of decrease
(i.e., slope) of WBC counts during prodrome.
The median duration of prodrome for all patients who developed moderate
leukopenia in the initial system and the current system appears to be
independent of the duration of Clozaril therapy. The median duration of prodrome ranged from
21-25 days and 26-29 days for patients in the initial system cohort and current
system cohort, respectively (Appendix 1, Post-text Table 3.6-1) who were
treated with Clozaril from >6 months to >2 years of therapy.
Table 10 provides the median slope for patients
with moderate leukopenia who did or did not develop agranulocytosis. Patients who developed agranulocytosis during
the first 6 months declined faster across both groups than those who did not
develop agranulocytosis. Also, patients
who did develop agranulocytosis during the first 6 months of therapy in the
initial system had a much steeper slope in WBC counts than those in the current
system.
Table 10:
Median Slope for Patients Who
Developed Moderate Leukopenia and Did or Did Not Develop Agranulocytosis
|
Duration
of Therapy |
Initial
system Median
Slope {WBC cells/mm3 (n)} |
Current
system Median
Slope {WBC cells/mm3 (n)} |
||
|
Did not
Develop Agranulocytosis* |
Developed
Agranulocytosis ** |
Did not
Develop Agranulocytosis * |
Developed
Agranulocytosis ** |
|