Review
and Evaluation of Clinical Data
Briefing Document for Psychopharmacological Drugs Advisory
Committee Meeting
NDA: 19-758
Sponsor: Novartis
Drug: Clozaril (clozapine)
Subject: Agranulocytosis
rates in the Clozaril
National Registry (CNR)
Reviewers: Tarek A. Hammad, M.D., Ph.D., M.Sc., M.S.
Judith
A. Racoosin, MD, MPH
Submission date:
Date Completed:
This document summarizes and evaluates the sponsor’s
analyses of the effect of white blood cell (WBC) count monitoring frequency on
the rate of clozapine-associated agranulocytosis using data from Clozaril
National Registry (CNR). In addition, the document summarizes the Office of
Drug Safety consult on those reports.
Table of contents
1. Background..................................................................................................................... 3
2. The
sponsor’s stated objectives of the analyses............................................................. 4
3. Methods.......................................................................................................................... 4
3.1. Restrictions
on CNR Data for Analysis.............................................................. 4
3.2. Patient
cohorts for analysis................................................................................. 4
3.3. Actual
rates of agranulocytosis, severe leukopenia, and moderate leukopenia... 6
3.4. Additional
data requested by FDA..................................................................... 7
3.4.1....... Demographics.................................................................................... 7
3.4.2....... WBC
at discontinuation...................................................................... 7
3.5. Projected
rates of agranulocytosis and severe leukopenia.................................. 7
3.5.1....... Reviewer’s
comment.......................................................................... 9
4. Results............................................................................................................................ 9
4.1. Actual
rates of agranulocytosis and severe leukopenia....................................... 9
4.1.1....... Reviewer’s
comments...................................................................... 11
4.2. Breakdown
of agranulocytosis rates after six months....................................... 12
4.2.1....... Reviewer’s
comments...................................................................... 13
4.3. Demographics
of patients in Cohorts 1 and 2 (combined) and Cohort 3........... 13
4.3.1....... Reviewer’s comment....................................................................... 14
4.4. White
blood cell count at time of discontinuation............................................. 14
4.4.1....... Reviewer’s
comment........................................................................ 18
4.5. Projected
rates of agranulocytosis and severe leukopenia................................ 18
4.5.1....... Prodrome
and slope......................................................................... 18
4.5.2....... Projected
Rates................................................................................ 20
4.5.3....... Reviewer’s
comment........................................................................ 21
4.6. Projected
number of fatal outcomes related to agranulocytosis........................ 22
5. Sponsor’s comments..................................................................................................... 22
5.1. Reviewer’s
comments...................................................................................... 24
6. Foreign
data (UK and Australia).................................................................................. 24
6.1. Reviewer’s
comments...................................................................................... 26
7. Office of
Drug Safety consult........................................................................................ 26
7.1. Reviewer’s
comments...................................................................................... 27
8. Appendix 1
1997 DNDP Briefing package................................................................... 28
9. Appendix 2
Sponsor’s method for estimating rates....................................................... 44
10. Appendix
3 Projected numbers of agranulocytosis
and severe leukopenia cases........ 49
11. Appendix
4 Agranulocytosis rates in various
monitoring schedules............................ 51
12. Appendix
5 ODS consult............................................... Error! Bookmark not defined.
1. Background
Clozaril® (clozapine) was approved on
Patients who develop agranulocytosis (ANC £ 500/mm3 or WBC £ 1000/mm3) or severe leukopenia (WBC < 2000/mm3) during treatment are discontinued from therapy and deemed “non-rechallengable”. The CNR maintains a list of all non-rechallengable patients, and new patients are crosschecked against this list prior to treatment initiation.
Previous analyses of
CNR data for the Psychopharmacologic Drugs Advisory Committee (PDAC) on
“Patients
who are being treated with Clozaril (clozapine) must have a baseline white
blood cell (WBC) and differential count before initiation of treatment,
and a WBC count every week for the first six months. Thereafter, if acceptable WBC counts (WBC
greater than or equal to 3,000/mm3, ANC>1500/mm3)
have been maintained during the first six months of continuous therapy, WBC
counts can be monitored every other week.
WBC counts must be monitored weekly for at least 4 weeks after the
discontinuation of Clozaril (clozapine).”
On
This document summarizes
the results of the analysis plan as submitted by the sponsor in its reports
dated
2. The sponsor’s stated objectives of the analyses
· To compare the effect of biweekly monitoring of WBC after six months of treatment with clozapine (started in April 1998) on the incidence rate of agranulocytosis and severe leukopenia with that of weekly monitoring of WBC (prevailed before April 1998).
· To estimate the additional risk of agranulocytosis and severe leukopenia if the WBC monitoring is further reduced to monthly monitoring or no monitoring after six months, one year or two years of treatment with clozapine.
3. Methods
3.1. Restrictions on CNR Data for Analysis
Since the introduction of generic clozapine in the
1. Exclude all data for patients who were enrolled in CNR but never started treatment with clozapine or had only one record of WBC in the database (Approximately 22,000 patients were excluded).
2. Exclude all data for patients who started treatment with generic clozapine before any treatment with brand Clozaril® (Approximately 4,000 patients were excluded).
3. For patients started on brand Clozaril but switched to generic clozapine at some point in time -- exclude all data after the first treatment with generic clozapine (Approximately 19,000 patients were affected by this criterion).
3.2. Patient cohorts for analysis
To estimate the rates and ratios relevant to the objective of this analysis, the sponsor defined the following cohorts of patient population (graphically presented in sponsor’s figure 1):
Cohort 1:
Cohort 1 includes data from approximately 97,000 patients.
This cohort represents the group of patients who were included in the last briefing book submitted (
a) Patients
discontinued brand clozapine treatment before
b) Patients
continued brand clozapine beyond
c) Patients
continued clozapine beyond
d) Patients
continued clozapine beyond
e) Patients
continuing treatment with brand clozapine on
Cohort 2:
Cohort 2 includes data from approximately 41,000 patients.
This cohort represents all patients who initiated Clozaril therapy after the
a) Patients
discontinued brand clozapine treatment before
b) Patients
continued on brand clozapine beyond
c) Patients
continuing treatment with brand clozapine on
Cohort 3:
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 brand clozapine after
a) Patients
discontinued brand clozapine treatment before
b) Patients
discontinued brand clozapine treatment after
c) Patients
continuing treatment with brand clozapine on
Sponsor’s figure 1: Population Cohorts
It is worthy to note that cohorts 1 and 2 include patients that were
treated with Clozaril during both the weekly monitoring period (prior to
3.3. Actual rates of agranulocytosis, severe leukopenia, and moderate leukopenia
Using the cohorts defined as above, the sponsor calculated the incidence rates per 1000 patient-years for agranulocytosis (WBC <1000/mm3 or ANC < 500/mm3), severe leukopenia (WBC <2000/mm3), and moderate leukopenia (WBC <3000/mm3 or ANC < 1500/mm3). These rates were calculated separately for the first six months of therapy and for the period subsequent to that because the rates have been observed to decrease markedly after the first six months of clozapine therapy.
The sponsor did not break
out the agranulocytosis rate after six months into any smaller intervals.
Previous analyses (see briefing package for 7/97 PDAC meeting, Appendix 1)
suggest that the agranulocytosis rate continues to fall over the subsequent
months and years before stabilizing. We wanted to determine if the same pattern
occurred in the current set of cohorts being analyzed. For the agranulocytosis
rates in the first six months, we divided the number of agranulocytosis cases
occurring in that period by the exact amount of patient time accrued (as
provided in post-text table 1.1-2a,
3.4. Additional data requested by FDA
The agranulocytosis and severe leukopenia rates calculated in the section above showed a secular downward trend between cohorts 1-2 and cohort 3 for the initial six-month period, despite no change in monitoring during those first six months. In an effort to explain this secular trend, DNDP requested that the sponsor provide the following additional information in order to evaluate the potential impact of these factors on the observed incidence rates:
· Demographic information for patients in each cohort
· Median white blood cells count at the time of discontinuation for all patients in the Clozaril National Registry
3.4.1. Demographics
Summary statistics of the demographics (i.e., age, sex, and race) for all three cohorts as described above were provided.
3.4.2. WBC at discontinuation
· The WBC at the time of discontinuation for each patient was determined as follows:
“If a patient had a gap between WBC counts greater than 15 days during the first six months of therapy or a gap between WBC counts greater than 30 days after 6 months of therapy then the last WBC count prior to the date of discontinuation was used. For patients who discontinued on multiple occurrences then only the first point of discontinuation was utilized.”
· Patients who discontinued (as defined above) with a WBC value between 3,000 to 6,000 were identified and median WBC values were compared for patients in Cohorts 1 and 2 (combined) and Cohort 3.
3.5. Projected rates of agranulocytosis and severe leukopenia
As part of the preparation for the July 1997 PDAC discussion of the clozapine WBC monitoring schedule, the sponsor modeled predictions for what might happen to the rates of agranulocytosis, severe, and moderate leukopenia should the monitoring schedule be made less frequent. The sponsor applied very similar modeling methodology to the Cohort 3 data to predict what might happen to the rates of agranulocytosis and severe and moderate leukopenia should the monitoring schedule be made less frequent again.
In order to determine the projected rates of agranulocytosis and severe leukopenia, the sponsor calculated the duration of the prodrome (period leading up to moderate leukopenia) and an estimate of the slope of WBC decline during the prodrome for each patient. Briefly, the onset of the prodrome was determined by examining data for WBC counts and determining the date from which the count showed a continual decline until moderate leukopenia (WBC £3000/mm3) 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 method of estimation of rates of agranulocytosis and severe leukopenia if the current bi-weekly monitoring of WBC counts after six months of treatment with clozapine is changed to a monthly schedule, or discontinued altogether is similar to the method of estimation of these rates for less frequent monitoring described at the 1997 PDAC meeting (Appendix 2).
Briefly,
the projection of rates of agranulocytosis
and severe leukopenia 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 the
moderate leukopenia stage (2000/mm3 <WBC£3000/mm3).
2. P2 = Probability that a patient will develop
agranulocytosis given that the patient was detected (“caught”) at the moderate
leukopenia stage (2000/mm3 <WBC£3000/mm3).
3. P3 = Probability that a patient will develop
agranulocytosis given that the patient was not detected (“missed”) at the
moderate stage (i.e. became severely leukopenic, 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 (i.e., missed at the moderate and severe stage).
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 ten. Therefore, these four quantities were
estimated using data from Cohorts 1 and 2 during their weekly monitoring of
WBC.
Sponsor’s table B illustrates the computation of the number of severe leukopenia and agranulocytosis cases that would be projected under a monitoring frequency program that was weekly for six months followed by monthly monitoring.
Sponsor’s
table B: Estimation of the number of severe leukopenia and agranulocytosis
cases for patients in Cohort 3 after weekly monitoring for six months and
monthly thereafter
(source: submission dated 2/12/2003)
|
|
Number of Patients with >6 months of treatment |
Agranulocytosis rate |
Estimated number of agranulocytosis cases |
Estimated number of
severe leukopenia cases |
|
Moderate under the bi-weekly 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
The estimated number of agranulocytosis and severe leukopenia were computed if the monitoring was changed to monthly after one year and two years of treatment. The results are presented in sponsor’s post-text table 4 (appendix 3) with the corresponding projected rates of agranulocytosis and severe leukopenia that would have been observed should the monitoring frequency be reduced to once monthly or no monitoring at all.
In order to compare the effect of a change in the monitoring system at different points in time (six months, one year, and two years), the estimated cumulative number of cases of agranulocytosis and corresponding rates per 1000 person-years after six months are presented in sponsor’s post-text table 5 (appendix 3).
3.5.1. Reviewer’s comment
· I note that the actual calculations of P1, P2, and P3 are based on persons and the calculation of P4 is based on person-years. This approach seems reasonable because those patients used to generate P4 are followed for a variable amount of time.
4. Results
4.1. Actual rates of agranulocytosis and severe leukopenia
At the time of data cut-off, 178,104 enrolled patients treated with table Clozaril were included in the primary analyses. Among these patients, 22 (0.012%) of them died due to agranulocytosis, 593 (0.33 %) of them experienced agranulocytosis, and 658 (0.37%) of them developed severe leukopenia.
I summarized the findings reported by the sponsor in the
following (source: sponsor’s post-text Table 1.1-2a, submission dated
|
|
Cohort number* |
# of cases/ patient year 0-6 months |
Rate /1000 patient year 0-6 months |
# of cases/ patient year >6 months |
Rate /1000 patient year >6 months |
|
Agranulocytosis (WBC 1000/mm3 or ANC < 500/mm3) |
Cohort 1 |
315/41649 |
7.56 |
117/278324 |
0.42 |
|
Cohort 2 |
78/16513 |
4.72 |
7/31305 |
0.22 |
|
|
Cohort 3 |
46/14152 |
3.25 |
10/27020 |
0.37 |
|
|
Death from agranulocytosis& |
Cohorts 1 & 2 |
18/58162 |
0.31 |
1/309629 |
0.003 |
|
Cohort 3 |
2 /14152 |
0.14 |
1/27020 |
0.037 |
|
|
Severe leukopenia (WBC <2000/mm3) |
Cohort 1 |
321/41644 |
7.71 |
137/278265 |
0.49 |
|
Cohort 2 |
82/16512 |
4.97 |
12/31304 |
0.38 |
|
|
Cohort 3 |
48/14149 |
3.39 |
9/27017 |
0.33 |
|
|
Moderate leukopenia# (WBC <3000/mm3 or ANC < 1500/mm3) |
Cohort 1 |
1286/41473 |
31.00 |
2387/272491 |
8.76 |
|
Cohort 2 |
492/16444 |
29.92 |
319/30939 |
10.31 |
|
|
Cohort 3 |
394/14093 |
27.96 |
214/26765 |
8.00 |
* Cohorts 1 and 2 had weekly
monitoring after six months; Cohort 3 had biweekly monitoring after six months.
# Source: post-text table 2, submission dated
& These rates were
not provided by the sponsor, but the death counts were provided in their submission dated
4.1.1. Reviewer’s comments
· Note that the incidence rate of agranulocytosis during the first six months for Cohorts 1, 2, and 3 were unexpectedly different given that all three cohorts were subjected to the same weekly monitoring during this period.
· The incidence rate of agranulocytosis after the first six months of treatment for Cohorts 1, 2 and 3 were also unexpected because it did not show that the risk was increasing with the bi-weekly monitoring as was projected.
· The rate of severe leukopenia showed a similar decline as observed with agranulocytosis during and after the first six months.
· The difference in incidence of agranulocytosis and severe leukopenia between cohorts 1 and 3 in the first six months, might speculatively be explained by the fact that as physician awareness of clozapine-associated agranulocytosis increased over the early-mid 1990’s they tended to stop treatment or to temporary interrupt it if they noticed a downward trend in a patient’s WBC count.
· Note that the rates of agranulocytosis per 1000 patient-years after six months went down from cohort 1 (0.42) to cohort 2 (0.22) then came up in cohort 3 (0.37). This might be a result of random variation or a trend that supports a slight increase in the rate after changing the monitoring frequency to bi-weekly. We should keep in mind that the comparison of the rates of agranulocytosis after six months in cohorts 1 (0.42) and 3 (0.37) is difficult to interpret because of the downward trend of the incidence rates in the first six months of treatment between cohorts 1 and 3.
· After the substantial decrease in agranulocytosis incidence after six months, the rate of agranulocytosis associated with clozapine use in cohort 3remains higher than the background rate of 3-7 cases/million person years[4],[5].
· The death rate before six months in cohort 3 is about half that of the combined cohorts 1 and 2. In contrast, the death rate in cohort 3 after six months is about 10 times higher than the earlier cohorts. However, the cohort 3 death rate is based on one case and thus is unstable.
4.2. Breakdown of agranulocytosis rates after six months
The figure below shows the agranulocytosis rates for the first six months
and for the subsequent periods (0.5- 1 year, 1-2 years, etc.) for each cohort.
Because the rates after the first six months
drop substantially, a second figure with an expanded y-axis shows the rates
beginning at the second six months of therapy.
4.2.1. Reviewer’s comments
· After six months, the agranulocytosis rates trended down in all three cohorts, although cohort 1 had a brief increase at year 5-6.
· The agranulocytosis rates going to zero in all three cohorts (at year 8-9 for cohort 1 and year 2-3 for cohorts 2 and 3) was associated with a substantial decrease in the size of the cohort (presumably related to switching to generic formulations). We will evaluate the WBC data from the generic companies to see if similar patterns of agranulocytosis rate decrease are observed after six months.
4.3. Demographics of patients in Cohorts 1 and 2 (combined) and Cohort 3
Sponsor’s table 1 (submission
dated 2/12/2003) below shows that the demographics of the patients within
Cohorts 1 and 2 combined and Cohort 3 are similar with respect to sex, age, and
race. The percentage of missing
information was also similar between these groups.
Sponsor’s table 1: Demographics of patients in Cohorts 1 and 2 (combined) and Cohort 3
|
Demographic |
Category |
Cohort 1 and 2 N (%) |
Cohort 3 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 |
<=
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) |
4.3.1. Reviewer’s comment
· Patients participating in the three cohorts are not different regarding their known attributes. Thus differences in the demographic make-up of the cohorts to the extent described above does not explain the discrepancy between those cohorts in the observed rates of agranulocytosis and severe leukopenia.
4.4. White blood cell count at time of discontinuation
In an effort to understand the secular decrease in the agranulocytosis rate over the three cohorts, despite the exact same monitoring schedule for the first six months in each cohort, we requested data on the WBC count at the time of patient discontinuation. We aimed to determine whether patients who appeared to have dropping WBC counts were discontinued at a higher WBC count in later years of the CNR (cohort 3) as compared to earlier years (cohorts 1 and 2). One factor hindering this analysis was the fact that the reason for a patient’s discontinuation from the CNR is not recorded in the database. Thus there is no way to distinguish patients who discontinue for lack of efficacy or non-compliance from those who discontinue for a dropping WBC count (unless the patient develops severe leukopenia or agranulocytosis). As such, we have to consider the WBC count prior to discontinuation for all patients, and not just the ones we are interested in (those discontinuing due to a concern that their WBC count was falling).
There were 110,663 patients defined as patients who discontinued therapy. Of these patients, there were 56,986 who discontinued during the first six months of therapy and 53,677 who discontinued sometime after six months of therapy.
The median white blood cell count at the time of discontinuation for patients in Cohort 1 and 2 combined and Cohort 3 were 7700 and 7400, respectively, for patients on therapy for less than or equal to six months, and 7900 and 7500, respectively, for patients on therapy for more than six months (Sponsor’s post-text Table 8, submission 2/12/2003). 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.
Sponsors’ figure 1 shows that more than 50% of the patients
in Cohort 3 discontinued therapy within 6 months after initiating therapy. In comparison, less than 35% of the patients
in Cohorts 1 and 2 (combined) discontinued therapy within 6 months after
initiating therapy.
The WBC values for patients who were discontinued with a WBC value between 3000 and 6000 were also evaluated. The sponsor justified its choice of the value of 3000 as this is the lower level of normal for WBC and presumably a value at which a Healthcare practitioner would discontinue a patient due to developing leukopenia. The sponsor choose the upper limit of 6000 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).
The median and mean WBC at the time of discontinuation for patients in Cohort 1 and 2 combined and Cohort 3 were similar for patients on therapy for less than or equal to 6 months and greater than 6 months (sponsor’s table 2, submission dated 2/12/2003).
Sponsor’s table 2: White Blood Cell Count (WBC) at time of discontinuation by duration for patients with WBC value between 3000 and 6000 at time of discontinuation (Cohort 1 and 2 combined and Cohort 3)
|
|
<6
months |
>6 months |
Total duration of therapy |
|||
|
Cohort 1
& 2 |
Cohort 3 |
Cohort 1
& 2 |
Cohort 3 |
Cohort 1
& 2 |
Cohort 3 |
|
|
N |
8325 |
4113 |
8833 |
1109 |
17158 |
5222 |
|
Median WBC |
5300 |
5300 |
5300 |
5300 |
5300 |
5300 |
|
Mean WBC |
5186 |
5154 |
5222 |
5180 |
5205 |
5160 |
Source:
Post-text Table 9, submission dated
The proportions of patients
who discontinued with values between 3000 and 6000 and within each stratum were
similar between the groups. Over 60% of
the patients in both groups were discontinued with a WBC value >5000-6000
regardless of duration of therapy (sponsor’s table 3, submission dated
Sponsor’s table 3: Stratified White Blood Cell Count (WBC) at time of discontinuation by duration for patients with WBC value at time of discontinuation (Cohort 1 and 2 combined and Cohort 3)
|
|
Median WBC N (%) |
|||||
|
<6
months |
>6 months |
Total duration of therapy |
||||
|
Cohort 1
& 2 |
Cohort 3 |
Cohort 1
& 2 |
Cohort 3 |
Cohort 1
& 2 |
Cohort 3 |
|
|
>3000-4000 |
3800 531 (7%) |
3800 299 (7%) |
3800 477 (5%) |
3800 56 (5%) |
3800 1008 (6%) |
3800 355 (7%) |
|
>4000-5000 |
4700 2520 (30%) |
4700 1260 (30%) |
4700 2494 (28%) |
4600 349 (31%) |
4700 5014 (29%) |
4700 1609 (31%) |
|
>5000-6000 |
5600 5274 (63%) |
5600 2554 (62%) |
5600 5862 (66%) |
5600 704 (63%) |
5600 11136 (65%) |
5600 3258 (62%) |
Source: Post-text Table 10, submission dated
4.4.1. Reviewer’s comment
· One hypothesis that might explain the secular decreasing trend in agranulocytosis rates from Cohort 1 to Cohort 3 would be increased physician awareness of clozapine-associated agranulocytosis by the late 90’s (in comparison to the early 90’s), if this awareness led to patients being discontinued at the first sign of declining WBC counts. Based on the data shown above, the distribution of WBC count at time of discontinuation does not suggest that patients were discontinued for reasons related to abnormal WBC values.
· Description of the demographics (age, gender, and race) of patients that discontinued in the first six months is missing. This might give an idea about potential differential pattern of discontinuation between various cohorts in a way that might explain the discrepancy between the rates of agranulocytosis and severe leukopenia in those cohorts.
· This analysis is may be flawed by the definition used for selecting the last WBC count prior to discontinuation.
“If a patient had a gap between
WBC counts greater than 15 days during the first six months of therapy or a
gap between WBC counts greater than 30 days after 6 months of therapy then the
last WBC count prior to the date of discontinuation was used. For patients who discontinued on multiple
occurrences then only the first point of discontinuation was utilized.”
Exploration of the data by one of the generic clozapine manufacturers identified that a substantial proportion of their patients had gaps in WBC count data the size of those used in the definition above. These gaps are due in many cases to non-compliance with the WBC monitoring as a result of the underlying schizophrenia (i.e., patient goes a few weeks without medication because they are non-compliant with their blood draw), but are not related to a true discontinuation of therapy. Because the definition used by the sponsor censors any WBC count data following the first 15 or 30 day (depending on the duration of their clozapine therapy) gap in data, this analysis approach could miss subsequent low WBC counts that truly led to discontinuation.
4.5. Projected rates of agranulocytosis and severe leukopenia
4.5.1. Prodrome and slope
As mentioned earlier, in order to determine the projected rates of agranulocytosis and severe leukopenia, the sponsor calculated the duration of the prodrome (period leading up to moderate leukopenia) and an estimate of the slope of WBC decline during the prodrome for each patient. Briefly, the onset of the prodrome was determined by examining data for WBC counts and determining the date from which the count showed a continual decline until moderate leukopenia (WBC £3000/mm3) 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 median duration of prodrome ranged from 21-25 days and 26-29 days for patients in Cohorts 1 and 2 (combined) and Cohort 3, respectively (post-text Table 3.1, submission dated 2/12/2003) who were treated with Clozaril from >6 months to >2 years of therapy.
Sponsor’s table 4 (submission
This
difference in the slope for the patients that developed agranulocytosis between
these cohorts during the first six months of therapy may have contributed to
the different incidence rates of severe leukopenia and agranulocytosis among
these cohorts that we previously observed, because a steeper slope would
decrease the likelihood that a patient would be identified as at risk (“caught”)
before they developed severe leukopenia or agranulocytosis.
Sponsor’s table 4: Median slope for patients who developed moderate leukopenia and did or did not develop agranulocytosis
|
Duration of Therapy |
Cohort 1 and 2 (combined) Median Slope (n) |
Cohort 3 Median Slope (n) |
||
|
Did not Develop Agranulocytosis* |
Developed Agranulocytosis ** |
Did not Develop Agranulocytosis * |
Developed Agranulocytosis ** |
|
|
<6 mos. |
150
(1444) |
241 (334) |
144
(366) |
161 (28) |
|
6
mos. – 1 year |
135
(563) |
244
(19) |
126
(87) |
71
(1) |
|
1-2
years |
161
(743) |
150
(32) |
121
(77) |
None |
|
>2
years |
142
(2175) |
156
(48) |
167
(49) |
- |
Slope = decrease in WBC/day; *Source:
sponsor’s post-text table 3.3,
451...1. Reviewer’s comment
· The observation that patients that developed agranulocytosis in cohorts 1 and 2 combined had a steeper slope of WBC fall (241) than those in the third cohort (161) provides some support for the possibility that physicians practicing in the late 1990’s (during cohort 3) discontinued or temporarily stopped patients who had a rapidly declining WBC counts prior to them getting into the range of moderate/severe leukopenia and agranulocytosis.
4.5.2. Projected Rates
The
report that was submitted on
Sponsor’s table 5: 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, monthly, or no monitoring (Cohort 3 patients)
|
|
Change to bi-week monitoring after weekly monitoring for: |
Actual Cases Observed |
Projected Additional Cases with Monthly Monitoring |
Projected Additional Cases with No monitoring |
|
Severe
Leukopenia |
Six months |
9 |
91 |
221 |
|
One year |
5* |
56 |
123 |
|
|
Two years |
4* |
16 |
46 |
|
|
|
|
|
|
|
|
Agranulocytosis |
Six months |
7 |
38 |
150 |
|
One year |
2* |
26 |
86 |
|
|
Two years |
0* |
9 |
34 |
*Assumes that
bi-weekly monitoring still occurs (i.e., no change from current monitoring
system)
Source: Post-text Tables 4 and 6,
As seen in sponsor’s table 5, if the current monitoring was changed to
“monthly monitoring” after six months
then we would observe 91 additional cases (as compared to the number
observed with biweekly monitoring) of
severe leukopenia and 38 additional cases of agranulocytosis, and 221 and 150
additional cases of severe leukopenia and agranulocytosis, respectively, if “no
monitoring” was in place.
-
After six
months of therapy, bi-weekly monitoring is currently required and the actual
observed rate[6]
of agranulocytosis is 0.26/1000
person-years. Based on the projections
in sponsor’s table 5, the rate of agranulocytosis would increase to 1.68/1000 person-years if the
monitoring frequency was decreased to monthly intervals and increased to 5.81/1000 person-year if monitoring was
discontinued (source: post-text table 5, submission dated
If the current monitoring was changed to “monthly monitoring” after one year then we would observe 56
additional cases of severe leukopenia and 26 additional cases of
agranulocytosis, and 123 and 86 additional cases of severe leukopenia and
agranulocytosis, respectively, if “no monitoring” was in place.
-
Based on the
projections in sponsor’s table 5, the rate of agranulocytosis would increase to
1.21/1000 person-year if the
monitoring frequency was decreased to monthly intervals and increase to 3.43/1000 person-year if monitoring was
discontinued (source: post-text table 5, submission dated
If the current monitoring was changed to “monthly
monitoring” after two years then we
would have observed 16 additional cases of severe leukopenia and 9 additional
cases of agranulocytosis, and 46 and 34 additional cases of severe leukopenia
and agranulocytosis, respectively, if “no monitoring” was in place.
-
Based on the
projections in sponsor’s table 5, the rate of agranulocytosis would increase to
0.6/1000 person-year if the
monitoring frequency was decreased to monthly intervals and increased to 1.52/1000 person-year if monitoring was
discontinued (source: post-text table 5, submission dated
4.5.3. Reviewer’s comment
· When the projection methodology was applied at the July 1997 PDAC meeting to predict what might happen if the WBC monitoring schedule was stretched out further, the prediction was that changing from weekly to biweekly after six months would result in an agran rate of 0.9/1000 patient years (as compared to what had been the observed rate of 0.54/1000 patient years after six months on weekly monitoring). In contrast, what has been observed in cohort 3, is an actual decrease over time to 0.37/1000
· Based on the above data, the sponsor concluded that the predictions of the additional risk due to further reduction of monitoring based on their projection methodology were “unreliable and misleading”. As such, they did not initially submit any projections of number and risk of agranulocytosis or severe leukopenia cases for a monthly or no monitoring scenario. Subsequently, the Division requested that they adjust their projection methodology to take into consideration what had actually happened with the agranulocytosis rate. Because it was difficult to identify with any certainty the factors which led to the decrease in the agranulocytosis rate (when an increase had been expected), the sponsor submitted the current projections using a very similar methodology as that used in the 1997 analysis.
· For logistical reasons, the sponsor’s analysis is limited to patients who started and remained on brand clozapine; if patients started on brand clozapine and then switched to generic, only their time on brand clozapine is counted in the analysis. Because we don’t know what selection factors may determine which patients are more likely to stay on brand clozapine or switch to a potentially less expensive generic version, the sponsor’s projections may not be generalizable to the total population of clozapine users. We have requested agranulocytosis rate data and demographic data from the two main generic manufacturers of clozapine in order to assess the comparability of the populations of generic and brand users. .
4.6. Projected number of fatal outcomes related to agranulocytosis
As of
September 2001, there were 22 fatalities of patients who developed
agranulocytosis as recorded in the CNR. Among them, 20 patients developed
agranulocytosis within the first six months of Clozaril therapy. Only 3 of the 22 fatalities occurred in
patients from Cohort 3 and 2 of these 3 occurred during the first six months of
treatment.
The estimated additional
number of deaths for patients in Cohort 3 is presented in sponsor’s post-text
table 7 (submission dated
5. Sponsor’s comments
· The rates of moderate leukopenia that are provided with the current analysis are similar between the two groups and demonstrate that the current monitoring system (bi-weekly monitoring after six months) provides a level of patient safety that is equal to the previous monitoring system.
· Careful monitoring of patients in the first six months with the current system continues to be warranted.
· There have been 22 fatalities since the
introduction of monitoring in US. Of
these fatalities, four took place since the implementation of the current
bi-weekly monitoring schedule. This fact alone emphasizes the need for
vigilance in monitoring to minimize the risk to patients.
· Since
the monitoring procedure was the same (i.e., weekly) for the first six months
for all three cohorts, the rates of agranulocytosis and severe leukopenia
should have been similar. However, the agranulocytosis and severe leukopenia
rates for Cohort 3 were less than one-half that for Cohort 1. The sponsor
hypothesized a number of possible explanations for this lack of comparability
for the rates within the first six months. These include:
1. Increased
awareness of agranulocytosis by the providers.
2. The decreased
percent of new patients, since a significant portion of the agranulocytosis
cases are seen during the first six months of treatment.
3. It is possible
that for patients who started on generic clozapine and subsequently switched to
Clozaril, the data during the first six months of generic clozapine therapy
would not have been available for the analysis.
This would result in the exclusion of data during the highest risk
period (first six months of therapy) of agranulocytosis and a reduction in the
risk of agranulocytosis for this cohort.
4. The steady
decline in the agranulocytosis incidence rate per 1000 patient-years by
calendar year since 1990.
5. Given
the similar rates of moderate leukopenia between the two groups (cohort 1and 2
combined and cohort 3), the lower rate of agranulocytosis between the groups
that we previously observed may be due to other factors (e.g., discontinuation
of patients, medical advancements in the treatment of leukopenia, alternative
therapies for the treatment of schizophrenia) that can not be considered when
utilizing models to estimate the number of additional agranulocytosis cases
under alternative monitoring frequency systems.
However, the sponsor has not been able to determine with the current data in the CNR whether any of the possible explanations are responsible for the inconsistent first six months results.
· The projections in sponsor’s table 5 demonstrate that there will be substantial increases in the number of agranulocytosis cases with changes in the current monitoring system; however, the validity of these projections should be taken in context with the projections provided in 1997. The projected rate for cohort 3 (111/67661, 0.00164) based on the 1997 analysis was 5.29 times than that actually observed for cohort 3 (7/22209, 0.00031). Clearly there are variables (e.g., medical advancements in the treatment of leukopenia, alternative therapies for the treatment of schizophrenia) influencing the development of agranulocytosis that can not be considered in the projection model.
5.1. Reviewer’s comments
· The sponsor provided a number of possible explanations for the observed decrease in agranulocytosis rate between cohorts 1 and 2 combined and cohort 3 despite identical monitoring frequencies within the first six months. The sponsor’s points 2 and 4 refer to “decreased percent of new patients” and “steady decline in the agranulocytosis incidence…by calendar year”. This reasoning explains the decline in agranulocytosis incidence by calendar year because the pool of the patients most susceptible to agranulocytosis (i.e., new users) was shrinking each subsequent calendar year. However, the agranulocytosis rate in the first six months of use includes only new users, so it is not affected by the declining proportion of new users/total users.
· In point 3 above, the explanation that patients “who started on generic clozapine and subsequently switched to Clozaril” might be responsible for the apparent reductions is not applicable because those patients were actively excluded from the studied cohorts.
· I agree with the sponsor about the difficulty on relying on the calculated rate projections.
6. Foreign
data (UK Australia
The sponsor submitted a brief
report describing the rates of agranulocytosis, severe leukopenia and moderate
leukopenia in the
|
|
Weeks 0-18 |
Weeks 19-52 |
Weeks 52+ |
|
|
Weekly |
Monthly |
Monthly |
|
|
Weekly |
Biweekly |
Biweekly pre-1995 Monthly post-1995 |
|
US |
Weeks 0-26 Weekly |
Weeks 26+ Weekly
pre-1998; biweekly post-1998 |
|
The report recalculated the
|
|
Weeks 0-18 |
Weeks 19-52 |
Weeks >52 |
|
Australian Data |
|||
|
Severe Leukopenia {per 1,000 pt. Yrs.
(N)} |
12.7 (40) weekly |
1.6 (8) monthly |
0.7 (19) monthly |
|
Agranulocytosis {per 1,000 pt. Yrs.
(N)} |
8.3 (26) weekly |
2.2 (11) monthly |
0.5 (14) monthly |
|
|
|||
|
Severe Leukopenia {per 1,000 pt. Yrs. (N)} |
|
|
|
|
Pre-1995 (monitoring frequency) |
33.5 (58) weekly |
4.3 (11) bi-weekly |
2.6 (17) bi-weekly |
|
Post-1995 (monitoring frequency) |
31.9 (186) weekly |
4.0 (34) bi-weekly |
1.9 (58) monthly |
|
Agranulocytosis {per 1,000 pt. Yrs. (N)} |
|
|
|
|
Pre-1995 (monitoring frequency) |
24.8 (43) weekly |
1.2 (3) bi-weekly |
0.3 (2) bi-weekly |
|
Post-1995 (monitoring frequency) |
20.4 (119) weekly |
1.5 (13) bi-weekly |
0.6 (18) monthly |
|
|
|||
|
Severe Leukopenia {per 1,000 pt. Yrs. (N)} |
|
|
|
|
Pre-1998 (monitoring frequency) |
8.8 (369) weekly |
1.0 (66) weekly |
0.4 (117) weekly |
|
Post-1998 (monitoring frequency) |
4.1 (43) weekly |
0.7 (9) weekly/bi-weekly |
0.3 (5) bi-weekly |
|
Agranulocytosis {per 1,000 pt. Yrs. (N)} |
|
|
|
|
Pre-1998 | |||