,
`
`r
`Effects of the Clozapine National
`Registry System on Incidence of
`Deaths Related to Agranulocytosis
`
`• Gilbert Honigfdd, Ph.D.
`
`Okiective; Clozapine is the only medication distributed in the U.S. through a
`national patient registry system that provides the medication only if results of
`patients' weekly blood tests show no evidence of significant white blood cell
`suppression, an effect that can be fatal if it progresses to advanced agranulo(cid:173)
`cytosis. This study assessed morbidity and mortality related to agranulocyto(cid:173)
`sis during the first five years of the national registry system. MethocUi Data
`from the national registry database maintained by the U.S. manufacturer of
`c10zapine was used to determine the level of treating systems' adherence to
`the mandated program of weekly white blood cell counts, number of in·
`stances in which c10zapine treatment was denied because of prior determi(cid:173)
`nation of white blood cell suppression, and number of cases of agranulocyto(cid:173)
`sis and deaths related- to agranulocytosis among treated patients from Febru(cid:173)
`ary 1999-'1 when c10zapine was commercially introduced in the U.S., through
`Dectimber 1994. The actual numbers of cases of agranulocytosis and related
`deaths were compared with expected outcomes based on clinical research
`done before the drug became available commercially.~ Approximate(cid:173)
`ly 97 percent of treating systems had a high overall level of adherence to the
`registry protocol. In 28 instances, the pretreatment authorization require(cid:173)
`ment resulted in denial of c1ozapine; after additional data were considered,
`15 of the patients were cleared for treatment. The actual incidences of 382
`cases of agranulocytosis and 12 related deaths were lower than the expected
`995 cases and 149 deaths. ConclusjQ1Hi The c10zapine national registry system
`fostered early detection of white blood cell suppression, prevented retreat(cid:173)
`ment with c10zapine of patients who had previously developed white blood
`cell suppression, and brought about lower than expected rates of agranulocy(cid:173)
`tosis and associated deaths. (PaychWtric Service. 47:52-56, 1996)
`
`Or. H01ligfeld is associate profess(ff in the
`the Robert
`department of psychiatry at
`Wood Johnson Medical School of the Urn(cid:173)
`c-ersity of Medicine and Dentistry of New
`JITsey, 675 Hoes Lane, Piscataway, New
`}('rsey 08854. He served as consultant ta
`S<lfUJO= PhamuJcl'uticau Corporation at
`1M lillie of the study.
`
`I n 1990, approximately 5 million
`
`persons in the United States suf(cid:173)
`fered from severe mental disor(cid:173)
`ders. Of those, more than half, about
`2.5 million had schizophrenia (1).
`Among persons with schizophrenia,
`between 10 and 30 percent do not re(cid:173)
`spond adequately to standard anti(cid:173)
`psychotic agents. because the agents
`have suboptimal efficacy or intolera(cid:173)
`ble adverse effects (2). Thus between
`250,000 and 750.000 treatment-resis(cid:173)
`tant persons with schizophrenia re-
`
`side in the United States. They rl'pre(cid:173)
`sent potential candidates for
`treat(cid:173)
`ment with c1ozapine, an atypical an(cid:173)
`tipsychotic medication indicated for
`the treatment-resistant patient As of
`December 31, 1994, a total of 99,502
`patients in the U_S_ had heen exposed
`to c1ozapine, and more than half of
`them remained on the medication at
`that time.
`Increased public interest in c1oza(cid:173)
`pine and enhanced familiarity of
`physicians with the medication make
`it likely that therapeutic use of dOI.a(cid:173)
`pine will become more common in
`the coming years. However, c1ow(cid:173)
`pine use is associated with risk of
`agranulocytosis, a potelltially fatal
`blood disorder
`that
`is lIsuallv re(cid:173)
`versible if detected early enough_
`Limitations in social and medical SlIp(cid:173)
`port networks for persons with severe
`mental
`illness underscore the need
`for procedures to help safeguard this
`vulnerable patient group from sllch
`adverse side effects.
`In keeping with gencml principles
`developed by the Food and Drug Ad(cid:173)
`ministration, current procedures for
`distribution of c10zapine stipu!ak
`that the medication is avallahle ill till"
`U.S. only through treatment s\ste,n,
`registered with the national reglst,,,
`developed and maintained hv Ihl'
`U,S. manufacturer of clozapine. The
`purpose of the registry is to enhance
`patient safety by facilitating early de(cid:173)
`tection of potentially dangerous white
`blood cell suppression, dispensing
`the medication only to patients with
`current blood tests. delineating rc-
`
`52
`
`PSYOIIATRIC SERVICES • January 1996 Vol. 47 N<) I
`
`Page 1 of 5
`
`CELGENE EXHIBIT 2014
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01102
`
`

`
`/
`
`'Sl~~siPilitjes for patient monitoring,
`•andehminating as candidates fol'
`. tb~rapy anyone with a history of
`.c1ozapine-related white blood cell
`s\lppression.
`,
`All potential candidates for
`the
`medication must be cleared through
`the national registry to identify per(cid:173)
`sons who have had significant c1oza(cid:173)
`pine-related white blood cell sup(cid:173)
`pression in the past and who should
`not receive the medication again be(cid:173)
`cause of markedly increased risk of
`agranulocytosis. White blood cell
`counts are nonnally 5,000 per cubic
`millimeter or greater. A white blood
`cell count below 3,500 per cubic mil(cid:173)
`limeter indicates leukopenia, a condi(cid:173)
`tion of mild white blood cell suppres(cid:173)
`sion that is generally reversible upon
`interruption of c10zapine therapy.
`:\granulocytosis, a potentially fatal
`complication, is indicated by a white
`blood cell count below 2,000 and de(cid:173)
`fined by an absolute neutrophil count
`below 500 per cubic millimeter. Dis(cid:173)
`continuation of c10zapine is mandato(cid:173)
`ry for patients with agranulocytosis
`bt>callse they are at high risk of death
`secondary to a wide range of oppor(cid:173)
`tunistic infections.
`The registry system requires all pa(cid:173)
`tients to have a baseline white blood
`cell count and weekly white blood
`throughout
`treatment
`cell counts
`with c10zapine and for four weeks af(cid:173)
`IeI' treatment ends. The medication is
`dispensed weekly only to patients for
`whom data on current white blood
`cell counts are available. The registry
`system also outlines the responSibili(cid:173)
`ties of physicians, pharmacies, pa(cid:173)
`tients. and the medication's manufac(cid:173)
`tllfer and wholesale Jistrihutors in
`ellsuring proper use of the medica(cid:173)
`I ion. ,Oismbuhon of the medication is'
`to registered pharmacies,
`li.lll~ted
`whidl
`agree
`to follow fhe ~no
`hlood:..no drug': guidehnes.'
`Treatment systems that fail to fulfill
`their ohligations to report results of
`weekly monitoring of patients' white
`hlood cell counts are contacted by na(cid:173)
`tional registry stafT, who explain the
`risks of c10zapine therapy and the re(cid:173)
`quirements for weekly monitoring.
`Suhsequently, nalional registry staff
`I<lllow lip with the physicians and
`pharmacists involved to verify that
`the problems have been corrected.
`
`This paper discusses clinical prac(cid:173)
`tice related to the dozapine national
`registry system, reports on the inci(cid:173)
`dence of agranulocytosis and agranu(cid:173)
`locytosis-related deaths from Febru(cid:173)
`ary 1990, when clozapine was first
`distributed commercially in the U.S.,
`to December 1994, and compares this
`clinical experience with expectations
`based on premarket clinical research
`projections.
`This study does not address direct(cid:173)
`ly the issue of optimizing the fre(cid:173)
`quency and pattern of white blood
`cell
`testing, although the study's
`prospective analyses of rates of agran(cid:173)
`ulocytosis and related deaths may
`have some bearing on this issue. The
`issue of whether fonnal alterations in
`the current
`requirement of weekly
`blood tests will result in an "accept(cid:173)
`able" increase in risk is the focus of
`separate epidemiologic studies and
`will not be considered here. This
`study specifically addressed current
`quality assurance
`functions
`and
`to answer
`the question of
`sought
`whether the use of a single, national
`registry of all c10zapine users in the
`United States has enhanced patient
`safety and contributed to the saving of
`lives.
`
`Methods
`Tbe national registry
`All data coming totheclozapine na(cid:173)
`tionaJregistryare eoter~ into an in(cid:173)
`tegr~ed. . computerized
`database
`maintained by the manufacturer. Pa(cid:173)
`tients' computer records are estab(cid:173)
`lished during the initial phone calls
`made by physicians who are seeking
`clearance to start a specific patient on
`dozapine. The records include the
`patient's identifying code numher
`and initials, the physician's identifka(cid:173)
`tion,
`the phannacy's identification,
`daily dosage of clozapine in mil(cid:173)
`ligrams, and while blood cell
`test
`dates and results.
`These data are retained penna(cid:173)
`nently, and additional data are added
`each week. As more than 60,000 pa(cid:173)
`tients currently receive c1ozapine,
`more than 500,000 separate fields of
`data are sent to the manufacturer's
`national registry each week. In addi(cid:173)
`tion, separate databases are main(cid:173)
`tained to track all reported adverse
`reactions. All data analyzed in this re-
`
`PSYOflATRlC SERVICES. JWlW/' 1996 Vol.47 No I
`
`port were drawn from those sources
`and were provided by the manufac(cid:173)
`turer.
`We used these data to examine two
`process variables related to functions
`of the national registry system over
`the first five years of commercial dis(cid:173)
`tribution of the medication: level of
`adherence to the registry protocol
`and denial of clinically inappropri'lte
`retreatment. We also examined two
`outcome variables-rate of agranulo(cid:173)
`cytosis and rate of deaths related to
`agranulocytOSis-and compared those
`rates with the rates that were predict(cid:173)
`ed in analyses conducted before the
`medication was commercially distrib(cid:173)
`uted in the U.S.
`
`Results and discussion
`Adherence to registry protocol
`The manufacturer's educational and
`servicing activities, plus the potential
`threat of disciplinary action such a~
`deregistration as a clozapine treat(cid:173)
`ment system, appear to have resulted
`in generally high levels of adherence
`to weekly monitoring. Over the first
`five years of commercial distribution
`of dozapine, more than 97 percent of
`treating physicians and pham1acists
`managed their patients on clozapine
`at high overall levels of adherence to
`the requirements of the product
`la(cid:173)
`beling. The remaining 3 percent have
`been characterized by varying levels
`of protocol compliance. National reg(cid:173)
`istry data show that a small percent(cid:173)
`age of treatment systems periodically
`relax adherence to monitoring guide(cid:173)
`lines.
`Of the more than 10,000 physicians
`and phannacists currently involved in
`dispensing dozapine, ahout 70() are
`contacted annually because of poor
`compliance in reporting data to the
`national
`registry. National
`registry
`stafT institute corrective actions,
`in(cid:173)
`cluding education, clinical manage(cid:173)
`ment training, and intensified review.
`As new treatment systems are added,
`and older ones may become large or
`complacent,
`this
`iterative process
`continues.
`Between 199(} and 1992, analyses
`were perfornled to detennine if cor(cid:173)
`rective actions by national
`registry
`staff were associated ....ith improved
`reporting of white blood cell counts.
`In March 1992 registry staff idenli-
`
`5J
`
`Page 2 of 5
`
`

`
`Figure 1
`Cumulative number of actual and predicted cases of agranulocytosis among pa(cid:173)
`tients receiving c1ozapine, 1990-19941
`
`""f'D
`!.
`z
`
`1.000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`Predicted
`Actual
`
`......
`
`.'
`
`.'
`
`.'
`
`.......•...
`
`.....
`
`.....
`
`.•...
`
`,.
`
`0-
`
`1990
`
`1991
`
`1992
`
`1993
`
`1994
`
`I Cumulative numbers of patients receiving c10zapine were 9.807 In 1900,24.112 In 1991. 47.246 in 1992.
`H.:WS In 1993, and 99.502 In 1994. Prl!dicted number of cases was calculated using a conservative esti(cid:173)
`mate of a 1 percent rate of agranulocytosis. based on premarlcet clinical re$e8l'Ch.
`
`fled physicians who had more than six
`patients for whom more than 10 per(cid:173)
`cent of the required reports of white
`blood cell counts in the latest three
`months were missing. From this list,
`the 100 physicians with the highest
`percentage of patients
`for whom
`
`more than 10 percent of the reports
`were missing were identified. At that
`time,
`these 100 physicians were re(cid:173)
`sponsible for 2,343 patients.
`Before the Intervention by national
`registry staff, 58 percent of those pa(cid:173)
`tients were missing more than 10 per-
`
`Pigure 2
`
`Cumulative number of actual and predicted deaths related to complications of
`agranulocytosis among patients receiving c1ozaplne, 1990-19941
`
`""~
`'"
`'D
`!.
`Z
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`-- - - Predicted
`- - Actual
`
`.'./'.
`
`/
`
`/ /
`
`,,/
`
`/
`
`//
`
`/ /
`
`./
`
`//
`
`~/..A'
`
`1990
`
`1991
`
`1992
`
`1993
`
`1994
`
`I Cumulative numben of patients recoelving d<naplne we", 9.807 in 1900. Z4.1 12 in 1991. 47.246 In 1992.
`74.3465 in 1900. and 99.502 in 1994. PredIcted number of deaths wu caIcu1aled uJinl COfUefVadve esti(cid:173)
`males of a I percent rate of agranulocytosis and • 15 percent rale of usociated mortality. based on pre(cid:173)
`market clinical research.
`
`cent of the required records of white
`in
`blood cell counts. One year later,
`April 1993, despite the addition of
`more than 400 patients to the case(cid:173)
`loads of these 100 physicians. for a to(cid:173)
`tal of2,767 patients, the percentage of
`acceptable reports of white blood cell
`counts by these physicians had im(cid:173)
`proved to 61 percent.
`
`Denial of retreatment
`Patients who have discontinued use
`of c10zapine due to agranulocytosis
`are at increased risk of developing the
`in
`reaction again, generally earlier
`therapy and in a more aggressive
`form, if c10zapine is reinstituted (3).
`The national registry clears each po(cid:173)
`tential candidate for c10zapine thera(cid:173)
`py to reduce the chances of reexpo(cid:173)
`sure to the medication by persons at
`increased risk of developing agranu(cid:173)
`locytosis.
`Between February 1990 and De(cid:173)
`cember 1994, there were 28 instances
`in which potential candidates for the
`medication were denied retreahnent.
`Nine instances involved eight pa(cid:173)
`tients who had confirmed histories of
`white blood cell counts below 2,000
`or absolute neutrophil counts below
`1,000. The nine instances included
`two attempts to obtain retreatment
`clearance for one patient. In four oth(cid:173)
`er instances the registry was tested by
`the manufacturer using identification
`numbers of non-retreatable patients
`to assure that the system functioned
`In the other 15 in(cid:173)
`appropriately.
`stances, retreatment was denied until
`closer inspection revealed errors in
`data; these patients were subsequent(cid:173)
`ly cleared for retreatment.
`
`Ratl! of agranulocytosis
`Between February 1990 and Decem(cid:173)
`ber 1994, a total of 99.502 patients
`were exposed to doupine in the l:.S.
`and had records of more than one
`while blood cell count. During the
`first calendar year in the study period
`(February through December I 990).
`9,807 patients were exposed to doz.a(cid:173)
`pine. The cumulative total had in(cid:173)
`creased to 24,112 patients by the "nel
`of calendar year 1991. to 47,246 at the
`the cnd of
`end of 1992, to 74,345 at
`1993, and to 99,502 by the end of
`1994.
`Among the total of 99,502 patients
`
`54
`
`PSYCHIAl'RlC S£RVICES • January 19'.>6 VoU 7 No. I
`
`Page 3 of 5
`
`

`
`Table 1
`E!Tects of actual and hypothetical rates of compliance in reporting of white blood
`cell counts on incidence of agranulocytosis and related deaths among patients re(cid:173)
`L'eiving c10zapine
`
`Agranulocytosis
`---------
`Rate (%)1
`Rate of compliance (%)
`111 cases
`_._.
`_.._-------- -- - --" - - - -
`Actual
`90 to t()(tl
`30 to -I5s
`Hypothetical
`75 to 90
`60 to 75
`-15 to 60
`
`.60
`80
`100
`
`-_..-
`
`.38
`na
`
`382
`16
`
`Death
`-----_..
`N cases
`Rate (%)2
`
`N pre-
`ventable
`deathsJ
`
`3.t
`50.0
`
`t2
`8
`
`18
`68
`137
`
`30
`597
`50
`10.0
`796
`80
`t5.0
`995
`t49
`.. _------- ------
`:-; ""'~, ","on~ 99.SO-2 pati..nt,. th.. tumul.ti\·~ number of pali~nt' included in thE' national rE'gislTy from
`Fehn,.,,· 1990 thmtl~ Deet'mher 199.J
`.\1 d('ath'i amooR 'J (;'<ises of .. ~nulo('~1osis
`'!
`'J Compar~d with '.J deaths at 90 to 100 pertent compliance in reporting
`• Rat,· ..mong 99.502 cas~, included in the national rE'g;stry from Fehnlary 1990 through December 199-1
`, Rat" .,"10"~ patients treated whe" dozapint' was first distributed eommerdally in Finland in 1975
`
`I
`
`during the study period, there were
`2,931 cases of leukopenia (crude inci(cid:173)
`dence rate of2,95 percent), 382 cases
`of agranulocytosis (.38 percent), and
`12 deaths associated with a~anulocy­
`tosis
`(.012 percent). The rate of
`leukopenia conforms quite closely to
`predictions based on premarket clini(cid:173)
`cal research of approximately 2.5 to 3
`percent of all persons exposed to
`c1ozapine,
`However, the crude rate of agranu(cid:173)
`locytosis during the study period (.38
`percent) was less than half that antic(cid:173)
`irated from prcmarkct research (l to
`2 percent). Figure I shows the annual
`number of expected and actual cases
`of ,lgranuloc)'tosis over the study pe(cid:173)
`riod. The expected number of cases
`
`was calculated conservatively, using
`the lower percentage estimate of 1
`percent based on the premarket clin(cid:173)
`ical
`research. Because the rate of
`leukopenia was consistent in the pre(cid:173)
`and postmarket data, the more favor(cid:173)
`able postmarket findings on agranulo(cid:173)
`cytosis appear to be the result of sys(cid:173)
`tematic monitoring, early detection of
`abnormalities in white blood cell
`counts, prompt
`reporting of those
`counts to the national registry, and
`prompt discontinuation of c10zapine
`among patients who were at risk for
`agranulocytosis.
`
`Death rate
`Despite intense monitoring, 12 per(cid:173)
`sons died as a result of agranulocyto-
`
`Table 1
`Prospcctive analysis of effects of rates of compliance in reporting of white blood
`cell counts on incidence of agranulocytosis and related deaths among 20,000 new
`patients receiving clozapine over a one-year period
`
`Optimistic scenario'
`
`Realistic scenario'
`
`Aff.lnulocytosis
`
`Rate 1%)
`
`"
`
`N
`deaths
`
`N pre-
`ventable
`deathsJ
`
`2
`6
`16
`30
`
`0
`4
`14
`28
`
`Rate of
`,-ampli-
`.tnt't' ,'lI-}
`
`~JO to lOG
`7S to 90
`
`tj() 10 7"
`
`·IS 10 fiO
`
`N pre-
`"i
`Rate of
`ventable
`deaths')
`death (%)
`deaths
`- ------_.~----_.
`0
`76
`2
`J8
`3.1
`2
`5.0
`60
`120
`~
`10.0
`160
`3
`5
`SO
`200
`100
`15.0
`6
`~
`- - - - - - _ . - - -
`I .\"un"" 1 3.1 IX'"",nl ratE' or dt'alh among case, of awanulocytosis. reprdJe,J of the number of~ a'
`\ anc)u~ I",,'ds of Ct,mphalK't"
`I .\»uolle, rate of J",.dh iUlWn!t case. of ."......ul"'''10.is incr.....,. &> number of cases increases wj!h de(cid:173)
`"rcast-tl I~vds of rompliant'e
`; Corllpar"d wilh two death, at 90 10 100 percent romplianCt' in ",porting
`
`~"YCHlAJ1UCSERVl<P.l • January 1996 vol.47 No 1
`
`sis-related complications between
`February 1990 and December 1994.
`figure 2 shows the cumulative ex(cid:173)
`pected and actual numbers of deaths
`related to agranulocytosis each calen(cid:173)
`dar year during the study period. The
`expected death rate assumes a I per(cid:173)
`cent rate ofagranulocytosis and an as(cid:173)
`sociated mortality rate of 15 percent.
`This rate is consistent with conserva(cid:173)
`tive estimates based on experience
`abroad with c10zapine and on pub(cid:173)
`lished research on mianserin, an anti(cid:173)
`depressant that has leukopenia as a
`potential adverse effect (4,5).
`The difference between the pre(cid:173)
`dicted and actual cumulative death
`rates-149 predicted deaths com(cid:173)
`pared with 12 actual deaths-sug(cid:173)
`gests the benefits of rigorous patient
`monitoring. These data show that cur(cid:173)
`rent medical practice and monitoring
`procedures have contributed sub(cid:173)
`stantiaUy toward saving the lives of
`many patients who require clozapine
`therapy.
`Table 1 shows how patient survival
`might have been affected over the
`study period if monitoring had been
`less rigorous. Actual clinical experi(cid:173)
`ence in the U.S. from Fehmury 1990
`through December 1994 showed 90
`to 100 percent compliance with re(cid:173)
`porting of white blood cell counts. In
`that context, patients with agranulo(cid:173)
`cytosis had an overall
`risk of fatal
`complications of 3.1 percent
`(12
`deaths among 382 cases of agranulo(cid:173)
`cytosis).
`At the other extreme are the initial
`findings on this topic from Finland in
`1975-1976, where a 50 percent rate
`of mortality emerged among patients
`who developed agranulocytosis (eight
`deaths among 16 cases of agranulocy(cid:173)
`tosis). Rates of white blood cell moni(cid:173)
`toring were estimated to be 30 to 45
`percent. The outdated medical and
`monitoring conditions existing at that
`time clearly no longer apply, given
`the heightened awareness of c107..ap(cid:173)
`ioe and its therapeutic and adverse
`effects. However, between the cur(cid:173)
`rent U.S. experience,
`representing
`the highest level of monitoring, and
`the early Finnish experience, one can
`interpolate intermediate scenarios of
`adequate, fair. or poor levels of moni(cid:173)
`toring and the associated risks of fatal
`complications of agranulocytosis.
`
`Page 4 of 5
`
`

`
`...
`
`For example. a rate of compliance
`with white blood cell monitoring of
`75 to 90 percent would be associated
`with a risk of fatal complications of an
`estimated 5 percent among patients
`who developed agranulocytosis, a
`monitoring rate of 60 to 75 percent
`with an estimated 10 percent rate of
`fatal complications, and a monitoring
`rate of 45 to 60 percent with an esti(cid:173)
`mated 15 percent rate of fatal compli(cid:173)
`the level
`recently reported
`cations.
`for deaths related to agranulocytosis
`associated with mianserin (4). Thus if
`monitoring standards in the u.s. had
`been less stringent between 1990 and
`1994. between 30 and 149 deaths
`might have occurred,
`instead of the
`12 deaths that actually occurred.
`
`Prospective analyses
`Based on conservative projections of
`current rates of access to c1ozapine, at
`least 20.000 Americans per year are
`likely to be newly exposed to c1oza(cid:173)
`pine in the coming years. If these pa(cid:173)
`tients are treated under current mon(cid:173)
`itoring conditions, about 76 patients
`(,38 percent) are likely to develop
`agranulocytosis. and two patients are
`likely to die of complications of agran(cid:173)
`ulocytosis (3.1 percent among agranu(cid:173)
`locytosis cases) in each annual cohort.
`Given these rates, what would hap(cid:173)
`pen if standards for monitoring were
`lowercd~ Two principal scenarios,
`whose rates are shown in Table 2, can
`
`be considered. An optimistic scenario
`presumes that medical practice has ad(cid:173)
`vanced enough that most cases of
`agranulocytosis.
`including sympto(cid:173)
`matic cases, can be arrested without
`fatal complications. Thus if one as(cid:173)
`sumes that adequacy of monitoring has
`no bearing on fatal outcomes,
`two
`deaths could be anticipated among the
`next 20,000 new c10zapine patients if
`monitoring compliance remains at
`current levels. If the mte of compli(cid:173)
`ance drops, one will likely see an in(cid:173)
`crease in the rate of agranulocytosis
`and an additional two to four deaths.
`The second, more realistic scenario
`assumes that early detection and con(cid:173)
`tinued vigilance exert a favorable im(cid:173)
`pact on the rate of agranulocytosis
`and the rate of fatalities. In this sce(cid:173)
`nario, a wider range of outcomes can
`be projected, and substantially poorer
`outcomes are likely. For example, the
`estimated risk of agranulocytosis
`would range from .38 to 1 percent and
`the rate of fatalities from 5 to 15 per(cid:173)
`cent. The projections shown in Table
`2 suggest that if monitoring deterio(cid:173)
`rates from current
`levels, between
`four and 28 additional deaths may oc(cid:173)
`cur among each annual cohort of new
`patients,
`
`Conclusions
`In the first five years of commercial
`distribution of c10zapine in the U.S..
`the national c10zapine registry system
`
`appears to have contrihlltt'd to reduc(cid:173)
`ing mortality rt>lated to complications
`of agnmulocytosis sub,tantiallv below
`projected rates derived from prernar(cid:173)
`ket data. The rigorous :;afeguards in
`place to maximize the opportunities
`for early detection of white blood cell
`suppression have been associated
`with favorable outcomes in mtes of
`both agranulocytosis and fatal compli·
`cations. Decreased vigilance would
`likely be associated with an increast'
`in otherwise preventable deaths.•
`
`Acknowledgments
`The author thanks FelIX Arellano, \I lJ.
`and Sheila Waiter, \1.0, of the dr\lg 'eg(cid:173)
`istration and reglliator\'
`.tlTairs dr'p,lrl'
`ment and Anthol1\' Bianchini of
`I h"
`Clozaril national registrv at Sandnz Phar(cid:173)
`maceuticals CorporatiOl;.
`
`I.
`
`References
`lIt"i.llth care r~fonll ff)r AIlH'rican\ wI! h ... f'·
`vere Illenuol ill"""t". report of th" \ ,1!Jonal
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`Joum,u"of Psydlialr, 1.50: [·1-17-116.5. J!)lJ:3
`2. Kan~ J\I, Ilonigfeld r.. Sing"r ). (·t ,Ii Ch
`zapine for tht> tn'atllH.'nt-n''iislant
`\c!lll.o.
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`-15,7119-796. Will>
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`3, Pisciotta A\': Agranuloc\tom induced h,
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`certain phcnothialiup dpr!\ aIIlL'S
`208:l862-1116ii.lflii8
`
`-I. Adams PC: \Iiaoserin-indlle(·d ,,~rallul()t"
`tosis. British \le(htal Journal 2-".) 20S-21;),
`1982
`
`IR:
`5. Coulter D\1. Ed"anl,
`\I,a",prin and
`af..,rranllincytosis in \' ('\\' Zealand.
`l..tl1C(·'
`336:71>5-71>7.19YO
`
`Peer Reviewers Sought by Journal
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`
`.O\ltcoIflc research. partk'uhu1y in the area of pliychopharrnacologkal treatlll<'rd
`(if mental disorders
`• H.ltiH~ sl~al...s [(Ir symptoms, oult'ome, and other aspe<.'ts of treatment
`• Dutil dlagllo,i, (meutal illness and drug ahuse and mental illness a.llllllll'lltal n"
`Lirt/atlOn)
`
`• Rlllal psvchmtJic servlees
`• Patient ,mel cuusumer perspectives and attitudes.
`Reviewers should he fiuniliar \\"itb the liternture in their afe'dS of expl'rtist,.
`should have published in peeHevieWwjoUmafs, and shOuld be familiar with the
`content and tOcusofPsychwtric Serobr.t; ,.,
`,
`Prospcetive fe\iewersshouId send a cuOiculum \itae. spedfying art.'aS of in(cid:173)
`ll'fest, to John.-\. Talbott, M.D~ Editor, &ychwtrlc SeroW8, APA, 1400 K Strt·e!.
`\. W. Washington. D.C. 2()()()5.
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`S6
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`!'SYQfIATR)CSERVICf5 • Januan 1')<)6 Vol4~ ~"I
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