CLIACategorizationOnly
PreviouslyClearedDevice
HemoCueWBCSystem
(K071652)
OfficialCorrespondent:
AllanWhite
QualitySystemsManager
HemoCue,Inc.
40EmpireDrive
LakeForest,CA926302244
(800)8811611x110
(949)8593066FAX
allan@hemocue.com
HemoCue WBC System
Onbehalfof:
HemoCueAB
Kuvettgatan1
S26271Angelholm,
SWEDEN
Page 1 of 38
TableofContents
Introduction...................................................................................................................................... 3
DescriptionoftheHemoCueWBCSystem ...................................................................................... 4
2.1
IndicationsForUse................................................................................................................... 4
2.2
TheMeasuringPrinciple........................................................................................................... 4
2.3
Physicaldescriptionofthesystem........................................................................................... 4
2.3.1
TheHemoCueWBCAnalyzer ........................................................................................... 4
2.3.2
TheHemoCueWBCMicrocuvette ................................................................................... 5
2.4
AccessoriesandSpareParts..................................................................................................... 6
2.5
DescriptionofanAnalysis ........................................................................................................ 7
2.5.1
TestProcedure ................................................................................................................. 7
2.5.2
Results .............................................................................................................................. 9
DemonstratingthatHemoCueWBCSystemisSimpletoUse ....................................................... 10
DemonstratinginsignificantRiskofanErroneousResultFailureAlertandFailSafeMechanisms
11
4.1
4.2
4.3
RiskAnalysis ........................................................................................................................... 11
FailureAlertandFailSafeMechanisms................................................................................. 11
Conclusion .............................................................................................................................. 14
DemonstratinginsignificantRiskofanErroneousResultAccuracy............................................ 15
5.1
ObjectivewithFieldStudy...................................................................................................... 15
5.2
SummaryofFieldStudy ......................................................................................................... 15
5.3
DesignofFieldStudy .............................................................................................................. 15
5.4
PerformanceofFieldStudy.................................................................................................... 16
5.4.1
IntendedUseSettingsandIntendedUsers.................................................................... 16
5.4.2
Procedure ....................................................................................................................... 17
5.4.3
SampleMaterial ............................................................................................................. 17
5.4.4
FinancialDisclosure ........................................................................................................ 17
5.4.5
SelectionofComparativeMethod(CM) ........................................................................ 17
5.4.6
Specimencollectionandsampleanalysis ...................................................................... 19
5.4.7
StatisticalAnalysis(foreachsiteandcombined)........................................................... 19
5.4.8
TotalAnalyticalError...................................................................................................... 26
5.4.9
AllowableTotalError(ATE) ............................................................................................ 29
5.4.10 ResultfromQuestionnaire............................................................................................. 32
5.5
ConclusionoftheFieldStudy................................................................................................. 32
ProposedLabelling ......................................................................................................................... 33
Attachments ................................................................................................................................... 38
Page 2 of 38
Introduction
Apointofcaretestfortotalwhitebloodcellcount(WBC)hasbeendevelopedbyHemoCueAB.Thetestis
simpleandcanbeperformedinanydoctorsoffice.Thetestisperformedusingasmallamountofcapillaryor
venouswholebloodandtheanswerisavailablewithinminutes.TheHemoCueWBCsystemisusedfora
quantitativedeterminationofthewhitebloodcellcount.
ThepurposeofthissubmissionistodemonstratethatHemoCueWBCSystemissimpletouseandaccuratein
thehandsoftheintendedoperatorsandthatthereisaninsignificantrisktoobtainanerroneousresult.
Page 3 of 38
DescriptionoftheHemoCueWBCSystem
2.1
IndicationsForUse
TheHemoCueWBCSystemisindicatedforuseforquantitativedeterminationofwhitebloodcell(WBC)count
incapillaryorvenouswholeblood.TheHemoCueWBCSystemisforInVitroDiagnosticuseonly.The
HemoCueWBCAnalyzerisonlytobeusedwithHemoCueWBCMicrocuvettes.TheHemoCueWBCsystemis
indicatedforuseinclinicallaboratoriesandforpointofcaresettings.
2.2
TheMeasuringPrinciple
ThesystemconsistsoftheHemoCueWBCAnalyzertogetherwithspeciallydesignedmicrocuvettes,the
HemoCueWBCMicrocuvettes.Themicrocuvetteservesbothasasamplecontainerandareactionchamber.
Themicrocuvetteisforsingleuseonly.Abloodsampleofapproximately10Lisdrawnintothecavityby
capillaryaction.Ahemolysingagentlysestheredbloodcellsinthemicrocuvetteandastainingagentcolors
thewhitebloodcells.Animageistakenofthestainedwhitebloodcellsandthenumberofcellsiscountedby
imageanalysis.Theresultispresentedwithin3minutesontheanalyzersdisplay.
2.3
Physicaldescriptionofthesystem
2.3.1 TheHemoCueWBCAnalyzer
TheHemoCueWBCAnalyzer(Figure2.1)isaportabledevice.Themainpartsarethecuvetteholder(inwhich
themicrocuvetteisplaced),thecuvettemovingarm(bringsthemicrocuvetteintocorrectmeasuringposition),
amagnifyingopticunit,acamera,imageprocessingsoftware,adisplayandapoweradapter.
Figure2.1.TheHemoCueWBCAnalyzer
Page 4 of 38
TechnicalSpecifications
Optionaloutput
RS232forprinterconnection
Power
Batteries:6batteriestypeAA
Poweradapter:CEmarked,ULapproved
Input:100240VAC/5060Hz/200mA
OnlyuseadaptersrecommendedbyHemoCue,aslisted
underApprovedAdaptersintheOperatingManual
Dimensions:185x133x120mm(7.28x5.24x4.72inches)
Weight:600g(1.32pounds)(withbatteriesinstalled)
1535C(5995F),<90%noncondensinghumidity.
Allowtheanalyzertoreachambienttemperaturebeforeuse.
Physicalcharacteristics
Operatingenvironment
Storageenvironment
050C(32122F),<90%noncondensinghumidity
2.3.2 TheHemoCueWBCMicrocuvette
TheHemoCueWBCMicrocuvette(Figure2.2)ismadeofpolystyreneplasticandcontainssaponinthat
hemolyzestheredbloodcells,methylenebluethatstainsthewhitebloodcellsandnonactivereagents.A
bloodsampleofapproximately10Lisdrawnintothecavitybycapillaryaction.Themicrocuvetteservesas
samplecontainerandareactionchamber.Nodilutionofthesampleisrequired.
Figure2.2.TheHemoCueWBCMicrocuvette
TechnicalSpecifications
Composition
Themicrocuvetteismadeofpolystyreneplasticandcontainsthe
followingreagent:<20g/gmicrocuvettemethyleneblue,<500
g/gmicrocuvettesaponin,<400g/gmicrocuvette
Surfynol465,<400g/gmicrocuvetteTritonX100.
Physicalcharacteristics
Vialswith40microcuvettesineachvial
Page 5 of 38
Storageconditions
1535C(5995F),<90%noncondensinghumidity.
Anunopenedvialofmicrocuvettescanbestoredforashorter
periodoftime(upto4weeks)outsidespecifiedstorageconditions
(downto0C(32F)andupto50C(122F)
2.4
AccessoriesandSpareParts
Thefollowingaccessoriesandsparepartsareavailable:
Spareparts
Poweradapter
CuvetteHolder
Accessories
HemoCueCleanerWBC
Optionalaccessoriesbutnotsupplied
Lancets
Page 6 of 38
2.5
DescriptionofanAnalysis
2.5.1 TestProcedure
Pleasenotethatthecompletetestprocedureshouldbereadbeforeperformingthetest.
1. Pullthecuvettemovingarmouttotheloadingposition.Pressandhold
thebuttonuntilthedisplayisactivated.Thethreeflashingdashesandthe
HemoCuesymbolindicatesthattheanalyzerisreadyforuse.
2. TakeaHemoCueWBCMicrocuvettefromthevial.Keepunusedcuvettes
intheoriginalpackage.Donotremeasureoldcuvettes.
3. Makesurethepatientshandiswarmandrelaxed.Useonly
themiddleorringfingerforsampling.Avoidfingerswith
ringson.Cleanfingertipwithdisinfectantandallowtodry
completelyorwipeoffwithadry,lintfreewipe.
Usingyourthumb,lightlypressthefingerfromthetopofthe
knuckletowardsthetip.
4. Whileapplyinglightpressuretowardsthefingertip,puncture
thefingerusingalancet.
Wipeawaythefirsttwoorthreedropsofblood.
5. Whentheblooddropislargeenough,fillthemicrocuvetteinone
continuousprocess.DoNOTrefillthecuvette!NOTE:Makesurethat
themicrocuvetteisfilledfromthetip,placedatabouta45degreeangle
towardstheblooddrop.Lookforairbubblesinthefilledmicrocuvette.
Ifpresent,discardthemicrocuvetteandfillanewmicrocuvettefroma
newdropofblood.Smallbubblesaroundtheedgecanbeignored.
6. Wipeoffexcessbloodfromtheoutsideofthemicrocuvettewithaclean,
lintfreewipe.Donottouchtheopenendofthemicrocuvette.
Page 7 of 38
Page 8 of 38
7. Placethefilledmicrocuvetteinthecuvetteholderwithin40seconds
afterfilling.Gentlypushthecuvettemovingarmtowardsthemeasuring
position.Itwillautomaticallyslidetothemeasuringpositionandthemeasurement
starts.
8. Afterapproximately3minutes,theWBCvalueisdisplayedasthe
numberofWBC/Linthespecimen.Theresultwillremainonthe
displayaslongasthecuvettemovingarmisinthemeasuringposition.
Donotremeasurethefilledmicrocuvette.
Note!Alwayshandlebloodspecimenswithcare,astheymightbe
infectious.Alwayswearprotectivegloveswhenhandlingblood
specimens.Consultlocalenvironmentalauthoritiesforproperdisposal.
9. Toturntheanalyzeroff,pressandholdthebuttonuntilthedisplayreads
OFFandthengoesblank.
2.5.2 Results
Thedisplayshowsanumericalvaluewhichisthenumberofwhitebloodcellsinthespecimen
withinthemeasuringrange0.330.0x109/L.
HHH
Measurementsabove30.0x109/LaredisplayedasHHH.
LLL
Measurementsbelow0.3x109/LaredisplayedasLLL.
ErrXX
ErrXXmeansthatanerrorhasoccurred.SeetheTroubleshootingGuideinthe
operatingmanualforadditionalinformation.
Page 9 of 38
DemonstratingthatHemoCueWBCSystemisSimpletoUse
HemoCueWBCsystemisafullyautomatedinstrumentnotrequiringanyinterventionbytheoperatorduring
theanalysis.Thesystemusesdirectunprocessedspecimennotrequiringanymanipulationofthespecimenor
ofthereagentbytheuser.
TheoperationofHemoCueWBCsystemdoesnotrequireanyspecialtrainingoftheoperator.TheHemoCue
WBCAnalyzeronlyhasonebutton,theon/offbutton,whichmakestheinstrument/userinterfaceverysimple.
Theoperatingmanualincludesathoroughtroubleshootingguidewithinterpretationoftheerrorcodeswith
explanationandactionsthatshouldbetakenbytheuser.AQuickReferenceGuideaswellasatrainingvideo
onCDROMareprovidedtotheusersatdeliveryofthedevice.Performancestudieshavebeenconductedto
demonstratethattheresultsobtainedbytheintendeduserarecomparablewithresultsobtainedbya
professionaluserandareferencemethod.
Thesystemdoesnotrequireanyelectronicormechanicalmaintenance.Ifanerrorcodeisshown,the
troubleshootingguideintheoperatingmanualclearlyindicatesiftheanalyzerneedstobesenttoHemoCue
fortechnicalsupport.
TheHemoCueWBCsystemperformsasystemintegritytestforeverysinglemeasurement.Asetofchecksare
performedatstartupandinbetweenthemeasurements.Whenpassingtheselftest,thedisplaywillshowthe
HemoCuesymbolandthreeflashingdashes,indicatingthattheanalyzerisreadytoperformameasurement.
Anerrorcodewillbedisplayediftheselftestfails.
Ablankingtestisperformedpriortothefirstmeasurementafterstartupoftheanalyzerandwhenthe
cuvettemovingarmismovedtoitsouterpositionduringnormaloperation.
Asystemsuitabilitytestisperformedforeachmeasurementbyutilizingthefocalqualityofthestainedcells.If
thecellscannotbefocusedproperly,anerrorcodewillappearandthemeasurementisinterrupted.
Severalinternalchecksensurethatonlyareaswithsuitablecelldistributionareusedforimageanalysis.No
additionalqualitycontrolsarerequiredforverificationofthesystemfunctionality.
Criticalerrorcodeslockstheordinaryprogramflowuntiltheanalyzeristurnedoff.Whenanoncriticalerror
occurs,theanalyzerisresetafterblanking.
Definition:Noncriticalerrorsareerrorsthatarecorrectedbyrejectingthemeasurement.
HemoCuehasnotidentifiedanyfailuremodeswhereuseofaqualitycontrolmaterialwouldprovide
additionalassuranceofthesystemsperformancethanthebuiltinselftestcontainedintheHemoCueWBC
Analyzer.
WhenananalysishasbeenperformedwiththeHemoCueWBCsystem,theresultsgivenareshownin
numericalfigures,notrequiringtheusertofurtherinterpretorconductsubsequentcalculations.
Basedontheaboveinformation,HemoCueABconsiderstheHemoCueWBCsystemsimpletouse.
Page 10 of 38
DemonstratingInsignificantRiskofanErroneousResultFailureAlertandFail
SafeMechanisms
4.1 RiskAnalysis
AriskanalysisfortheHemoCueWBCsystemforrisksassociatedwithhazardsandhazardoussituationsdueto
userskills,humanfactorsandforeseeablemisusehasbeenperformed.
TheriskmanagementhasbeenperformedaccordingtoISO14971andHemoCuesinternalprocedureforrisk
management(QI018).SeeAttachment1fortheriskanalysis.
4.2 FailureAlertandFailSafeMechanisms
Basedontheresultsoftheriskanalysis,flexstudieshavebeenconducted.Theflexstudieshavebeen
designedtochallengethesystemunderconditionsofstresstoidentifypotentialuserrelatedfailuresand
determinetherobustnessofthesysteminthehandsoftheuser.Studiesregardingfailsafeandfailure
mechanismshavebeenconductedunderconditionsthatstressthedeviceinordertodemonstratehowfail
safeandfailurealertmechanismrespondtosuchconditions.
Table4.1.
Potentialsourceof
erroridentified
(RiskanalysisID#
Attachment1)
Angleoffilling.
Deviationfromthe
definedprocedure
(fillingangle45anda
fillingplaceatthe
edgeofthe
microcuvette)
RiskNo.19
Timeoflatency.
Deviationfromthe
definedprocedure
(<40s)
RiskNo.32and33
Trytorunananalysis
withoutfillingthe
microcuvettewith
sample
(anunfilled
HemoCue WBC System
Flexstudyconsistoffilling
anglesandfillingplaces:
Fillingangle0
Fillingangle90
Fillingangle90
FillingplaceNo1
FillingplaceNo2
Meanofbias
(%)with95% Acceptance
criteria
confidence
levelorerror
codes
15to+15
orerror
0.4to1.7
code
0.8to1.0
0.8to3.0
0.7to1.6
0.2to2.5
Flexstudyconsistofdifferent
timeoflatency:
1minute
3minutes
5minutes
10minutes
0.7to1.8
0.1to2.3
0.1to3.2
1.3to2.0
15to+15
orerror
code
Alltimeof
latencyare
approved
Studytoshowthatempty
cuvettewillgiveanerrorcode
Errorcode
Errorcode
Approved
Typeofstudy
Commentson
results
Allfillingangles
asfillingplaces
areapproved
Page 11 of 38
Potentialsourceof
erroridentified
(RiskanalysisID#
Attachment1)
microcuvetteplaced
inmeasuringposition)
RiskNo.25
Partlyfilled
microcuvette
(themicrocuvette
shouldbecompletely
filled(10L)inone
step)
RiskNo.15,16and24
Sampledilution.
(undilutedsample
shouldbeused)
Notidentifiedasa
foreseeablerisk.
However,flexstudy
hasbeendone.
Storageofsample
outsidedefined
temperature
conditions.
(Definedconditions
arestorageinroom
temperature(r.t.)
Upto48hours
stabilityinr.t.)
RiskNo30,31and38
Operating
temperatureoutside
definedconditions.
(Definedconditionsis
roomtemperature
(r.t.)forbothcuvette
andsample)
RiskNo.1and2
HemoCue WBC System
Typeofstudy
Meanofbias
(%)with95%
confidence
levelorerror
codes
Acceptance
criteria
Commentson
results
Flexstudyconsistofdifferent
leveloffilledcuvette:
filledwith5Lsample
filledwith2Lsample
Emptycuvette
1.9to+0.2
Errorcode
Errorcode
15to+15
orerror
code
Approvedresults
Flexstudyconsistofdifferent
dilutions:
Dilutionfactor1:5
Dilutionfactor1:10
Dilutionfactor1:20
8.5to+8.9
3.7to+7.6
8.8to+10.5
15to+15
Alldilution
factorsapproved
Studyconsistoftwo
temperatures:
48hoursinrefrigerator
48hoursinroomtemperature
+1.9to+11.6
3.3to+1.2
15to+15
Alltested
temperatures
approved
Flexstudyconsistofdifferent
cuvetteandsample
temperature:
r.t./+7C
r.t./+37C
+7C/+r.t.
+7C./+37C
3.8to1.4
1.2to+1.0
0.6to+1.3
1.4to+0.1
15to+15
orerror
code
Alltested
temperatures
forsampleand
cuvette
approved
Page 12 of 38
Potentialsourceof
erroridentified
(RiskanalysisID#
Attachment1)
Themicrocuvetteis
filledintwosteps.
(themicrocuvette
shouldbefilledin
onestep)
RiskNo.20
Wrongtypeof
sample.
(capillaryorvenous
samplecanbe
analyzed)
RiskNo.13and14
WrongHemoCue
productused,another
typeofmicrocuvette
toanotherHemoCue
system
(theWBC
microcuvetteshould
beused)
RiskNo.37
Themicrocuvetteis
contaminated
(e.g)/notclean
RiskNo.21and22
Coagulation.
RiskNo.28
93%Humidity.
(definedstorageand
HemoCue WBC System
Typeofstudy
Flexstudyconsistoffillingin
twosteps:
5+10L
2+13L
Meanofbias
(%)with95% Acceptance
confidence
criteria
levelorerror
codes
15to+15
orerror
11.8to8.2
code
0.2to2.7
Commentson
results
Both
combinations
approved
!Noteinpackage
insert
Flexstudyconsistofdifferent
typeofsamples
Humanurine
Humanurinewithblood
Plasma
Allsamples
not
containing
WBCbelow
the
measuring
range(LLL)
LLL
orerror
code
Alltypesof
samples
approved
Flexstudyconsistofdifferent
kindofmicrocuvettesfrom
HemoCuesystems
MicrocuvettsfromAlbumin
201,Monitor,Glucose201RT,
BGlucose,Glucose201,BHb,
Hb201+,Hb301,PlasmaLow
Hb,DonorHbChecker
Itwasnot
possibleto
positionany
typeof
cuvette
Notpossible
touseany
other
cuvettes
Alltested
variants
approved
Flexstudyconsistofdifferent
kindofdamagedcuvettes:
Scratchedcuvettesonboth
sides
Cuvettewithpowder
Cuvettewithfingerprints
Flexstudyconsistofpartly
coagulatedbloodsamples
3.4to1.1
1.1to+1.1
1.8to0.1
Notpossible
tofill
cuvetteswith
partly
coagulated
blood
samples
4.71to0.1
15to+15
orerror
code
Allkindof
damaged
cuvettesgave
approvedresults
15to+15
orerror
code
Approvedresults
15to+15
orerror
code
Approvedresults
Verificationstudy
Page 13 of 38
Potentialsourceof
erroridentified
(RiskanalysisID#
Attachment1)
operatingconditions
<90%humidity)
RiskNo.3
Operating
temperature
(definedoperating
temperature15to
35C)
RiskNo.1and2
Themicrocuvetteis
contaminatedwith
bloodontheouter
walls(theoutside)
duetopoorsampling
technique
RiskNo.17and23
HighlevelsofWBC.
(Themeasuringrange
isdefinedto0.3to30
x109/L)
RiskNo.5
Typeofstudy
Meanofbias
(%)with95%
confidence
levelorerror
codes
Acceptance
criteria
Commentson
results
Flexstudyconsistofdifferent
temperatures:
+12C
+15C
+40C
+0.2to+6.1
2.4to1.9
12.2to3.8
15to+15
orerror
code
Alltemperatures
resultedin
approvedresults
Verificationstudy
errorcode
E001
Errorcode
Approvedresults
Flexstudyconsistofsamples
withleukocytes>30x109/L
100HHH
>100error
codeorHHH
Errorcode
orHHH
Approvedresults
4.3 Conclusion
Allresultsfromconductedtestsmeetthepredefinedacceptancecriteria.Thereisnosignificantriskof
obtaininganerroneousresultwiththeHemoCueWBCsystemwhenusedbytheintendeduser.
Page 14 of 38
DemonstratingInsignificantRiskofanErroneousResultAccuracy
5.1 ObjectivewithFieldStudy
Thefieldstudywilldemonstrate,ascloseaspossible,howtheHemoCueWBCSystemperformsonactual
clinicalspecimensbyintendedoperatorsundertheconditionsofintendeduse.
5.2 SummaryofFieldStudy
AcomparisonoftheHemoCueWBCsystemusedbyanuntrainedintendeduser(WM)withtheSysmexXS
1000iusedbyaprofessionaluser(CM)wasconducted.Thestudyshowthat96.6%ofallresultsarewithinthe
ATEzone.
NosamplesatthecomparisonswerefoundoutsidetheLimitsofErroneousResults(LER),seebelow.
30
ATE
25
ATE
20
LER
15
10
LER
-------- X = Y
0
0
10
15
20
25
9
30
Figure5.1.ScatterplotinErrorgrid,HemoCueWBCvsSysmexXS1000i,x109/L
TheresultsinthisstudyfulfiltheacceptancecriteriaandherebyshowthattheHemoCueWBCSystemis
appropriateforuseinaCLIAwaivedlaboratoryaccordingtotherequirementsintheCLIADraftGuidanceof
2005.
5.3 DesignofFieldStudy
ThefieldstudywasdesignedinordertocomplywithTheDraftGuidanceforIndustryandFDAStaff:
RecommendationsforClinicalLaboratoryImprovementAmendmentsof1988(CLIA)WaiverApplications;
DraftGuidanceissuedSeptember7,2005.
Page 15 of 38
5.4
PerformanceofFieldStudy
5.4.1 IntendedUseSettingsandIntendedUsers
Fiveintendedusesettingsandatotalof11intendedusersparticipatedinthefieldstudyfortheHemoCue
WBCSystem.
Table5.1.Summaryofsites
Site
Numberof
Numberof
Totalnumber
capillary
Venous
ofsamples
samples
samples
DelfinenPrimaryCare
56(2*)
70
126(2*)
MunkaPrimaryCare
74(2*)
80
154(2*)
SjcronaPrimaryCare
70
70
PTCatngelholmHospital
60
60
NrlundaPrimaryCare
5
5
Total
135(4*)
280
415(4*)
*Numberofsamplesexcludedfromcalculationsduetoinsufficientsamplevolume.orresultoutsidedefined
measuringrange,seesection5.4.7.2.
Delfinen,Munka,SjcronaandNrlundaPrimaryCareCentersaredistricthealthcentersinprimarycare.They
areequivalenttoCLIAwaivedlaboratoriesintheUSA.ThefourthsiteisaPatientServiceCenteratngelholm
hospitalwherepatientscomeforbloodandurinesampling.Thesampleswerethenfurthertransportedto
laboratoriesforanalysis.ThestaffatthePatientServiceCenterhasthesamekindofassignmentsasthestaff
attheprimarycarecenters.
Theintendedusers(operators)inthisevaluationareassistantnurseswithalevelofhighschooleducation,and
nolaboratorytraining.ThisisequivalentwiththeexpectededucationallevelforintendedusersatCLIAwaived
laboratories.
Table5.2.Operatorinformation
Site
Operator
Age
Gender
Education
DelfinenPrimaryCare
41
female
Assistantnurse
DelfinenPrimaryCare
65
female
Assistantnurse
DelfinenPrimaryCare
2
3
42
female
Assistantnurse
MunkaPrimaryCare
55
female
Assistantnurse
MunkaPrimaryCare
55
female
Assistantnurse
SjcronaPrimaryCare
40
female
Assistantnurse
SjcronaPrimaryCare
47
female
Assistantnurse
PTCatngelholmhospital*
27
female
Assistantnurse
PTCatngelholmhospital*
31
female
Assistantnurse
PTCatngelholmhospital*
10
28
female
Assistantnurse
NrlundaPrimaryCare
11
*PTC=PatientServiceCenteratngelholmhospital
52
female
Assistantnurse
Page 16 of 38
5.4.2 Procedure
TheintendeduserswereprovidedwiththeHemoCueWBCSystemQuickReferenceGuide(Attachment2),the
draftHemoCueWBCPackageInsert(Attachment3),andtheHemoCueWBCSystemOperatingManual
(Attachment4).Theassistantnursesdidnotreceiveanytraining,coaching,prompting,writtenorverbal
instructionsbeyondthewrittentestprocedureandthesuppliedinstructionsforuse.
EachsamplewasanalyzedaccordingtoinstructionsforusewiththeHemoCueWBCSystembytheassistant
nurse(intendeduser)andinduplicatewiththeSysmexXS1000ibytheprofessionaluserfromHemoCue.All
samplesweremasked,i.e.theoperatorsdidnotreceiveanyinformationabouttheWBClevelforthesample.
Theevaluationtimewas4thofAprilto17thofOctober2007,during31workingdays.
Afterthestudywascompletedalltheintendedusersweregivenaquestionnaireinordertoevaluateifthe
participantsunderstoodhowtousethedevicecorrectlyandifitwaseasytouseandwhetheritfollowedthe
operatingmanualandpackageinsert.Thequestionnairecontainedquestionsconcerning:
1. themicrocuvette
2. theanalyzer
3. generalaspectsofthesystemandtheprovidedinstructionsforuse
4. theoverallimpressionofthesystemanditssimplicity
5.4.3 SampleMaterial
Intotal415humanbloodsampleswerecollectedandanalyzed.Thetestmaterialusedinthestudywere
capillaryandvenousbloodsamples:
LeftovervenousbloodsamplesfromClinicalChemistryLaboratoriesatngelholm,Halmstadand
HelsingborgHospitals.
CapillarybloodsamplesfrompatientsatDelfinenandMunkaPrimaryCareCenters
SpikedcapillarysamplesfromemployeesatHemoCueAB
5.4.4 FinancialDisclosure
SeeAttachment6.
5.4.5 SelectionofComparativeMethod(CM)
Thechosencomparativemethod(CM)istheSysmexXS1000i.TheSysmexXS1000iisanautomated
hematologyanalyzerforinvitrodiagnosticuseinclinicallaboratories.
TheSysmexXS1000iisacomparativemethodoftypeBwhichhastraceabilitytothemanuallightmicroscopic
WBCmethod(theReferenceMethod,RM).Themathematicalrelationshipisdefinedas1:1,seeTable5.3and
Figure5.3below.
Page 17 of 38
Table5.3.RelationshipbetweenCMandRM
Meanvalues,x109/L
Difference
between
Number
Manuallight methods
SysmexXS
of
microscopic
1000i
samples
WBCmethod
9
(CM)
x10 /L %
(RM)
WBC
level
x109/L
SD,x109/L
Sysmex
XS1000i
(CM)
CV,%
Manuallight
Manuallight
microscopic SysmexXS microscopic
WBCmethod 1000i(CM) WBCmethod
(RM)
(RM)
04.0
4.16.5
6.612.0
>12.0
19
33
23
34
2.52
5.46
8.98
22.59
2.23
5.36
8.91
22.48
0.29
0.10
0.07
0.11
13.0
1.9
0.8
0.5
0.04
0.09
0.19
0.26
0.25
0.43
0.38
0.50
1.6
1.6
2.1
1.2
11.2
8.0
4.3
2.2
Total
109
11.03
10.90
0.13
1.2
0.18
0.42
1.6
3.9
70
bo = 0.109 0.095
b1 = 1.002 0.006
r2 = 0.998
Syx = 0.501
N = 109
60
50
40
30
20
10
------- Y = X
0
0
10
20
30
40
50
60
70
Figure5.3.Regressionanalysis,SysmexXS1000i(CM)andManuallightmicroscopicWBCmethod
(RM)
Page 18 of 38
5.4.6 Specimencollectionandsampleanalysis
SamplinghasbeendoneaccordingtoCDCRecommendationsandReportsGoodLaboratoryPracticesfor
WaivedTestingSitesSurveyFindingsfromTestingSitesHoldingaCertificateofWaiverUndertheClinical
LaboratoryImprovementAmendmentsof1988andRecommendationsforPromotingQualityTestingVol.54
/RR13.Note:thisisnotapplicableforthespikedcapillarysamplesfromHemoCue.
Capillary sampling:
Patients visiting
Primary Care
Patient identified
samples (age,
gender)
Result from
intended user
(WM)
Result from
professional user
(CM)
Intended user at
intended use site
collect sample in
microtube
Samples collected
in tubes
Intended user
performs analysis
on WM
Samples spiked
by HemoCue
Sample
transported to
HemoCue within 4
hours
Professional user
performs analysis
on CM
(in duplicate)
Professional user
performs analysis
on CM
(in duplicate)
Venous sampling:
Left over samples from patients
where WBC testing has been
ordered by physician
Capillary sampling:
Spiked samples from
HemoCue
Identified samples
(age, gender)
Result from
professional user
(CM)
Sample
transported to
intended user site
within 4 hours
Intended user
performs analysis
on WM
Result from
professional user
(CM)
Professional user
performs analysis
on CM
(in duplicate)
Result from
intended user
(WM)
Sample
transported to
intended use site
within 4 hours
Intended user
performs analysis
on WM
Result from
intended user
(WM)
Figure5.4.Flowchartofthespecimencollectionandsampleanalysisusedinthefieldstudy
5.4.7 StatisticalAnalysis(foreachsiteandcombined)
5.4.7.1 StatisticalMethods
DescriptivestatisticsaccordingtoCLIADraftGuidanceof2005
o Mean,min,median,max,boxandwhiskerplots
o Scatterplot
Regressionanalysis
TotalAnalyticalError(TAE)
5.4.7.2 ExclusionofResults
Calculationswereperformedon411samples.ForsamplesP37,S12andH6thesamplevolumeweretoosmall
foranalysiswithSysmexXS1000i.SampleH49showedHHHontheHemoCueWBCsystem.Measurements
above30.0x109/LaredisplayedasHHHontheHemoCueWBC.ThemeanvalueonSysmexXS1000iwas
29.475forsampleH49.
5.4.7.3 DescriptiveStatistics
Thesampleshavebeendividedintothemedicalrelevantintervalsbasedonthemeanvaluesofthe
comparativemethod,i.e.SysmexXS1000i.
Page 19 of 38
Table5.4.SummaryrawdataMulticenterstudy
SysmexXS1000i,x109/L
HemoCueWBC,x109/L
WBC
Numberof
%of
x109/L
samples
total
Mean
values
Minvalues
Median
values
Max
values
Min
values
Median
values
Max
values
5.0
5.110.0
10.130.0
112
181
118
27
44
29
2.86
7.29
18.15
0.34
5.09
10.06
2.79
7.11
17.19
5.02
10.04
28.74
0.4
4.2
9.7
2.7
7.2
17.3
13.3
11.5
29.0
Total:
411
100
9.20
0.34
7.19
28.74
0.4
7.4
29.0
Table5.5.SummaryrawdataDelfinenPrimaryCare
WBC
Number
of
SysmexXS1000i,x109/L
%of
HemoCueWBC,x109/L
Mean
values
Min
values
Median
values
Max
values
Min
values
Median
values
Max
values
x109/L
samples
total
5.0
5.110.0
10.130.0
37
45
42
30
36
34
3.15
7.54
18.08
0.85
5.35
10.21
2.98
7.38
16.53
4.96
10.04
27.91
1.0
4.8
11.0
2.8
7.6
17.2
13.3
11.5
28.7
Total:
124
100
9.80
0.85
7.75
27.91
1.0
8.2
28.7
Table5.6.SummaryrawdataMunkaPrimaryCare
WBC
Number
of
SysmexXS1000i,x109/L
%of
HemoCueWBC,x109/L
Mean
values
Min
values
Median
values
Max
values
Min
values
Median
values
Max
values
x109/L
samples
total
5.0
5.110.0
10.130.0
34
79
39
22
52
26
2.80
7.24
17.44
1.18
5.09
10.06
2.74
7.03
17.08
5.01
9.96
28.61
1.3
4.2
9.7
2.9
7.1
17.3
4.7
10.6
28.5
Total:
152
100
8.86
1.18
7.12
28.61
1.3
7.3
28.5
Table5.7.SummaryrawdataSjcronaPrimaryCare
WBC
Number
of
SysmexXS1000i,x109/L
%of
HemoCueWBC,x109/L
Mean
values
Min
values
Median
values
Max
values
Min
values
Median
values
Max
values
109/L
samples
total
5.0
5.110.0
10.130.0
18
31
21
26
44
30
2.79
7.13
17.83
0.72
5.32
10.20
2.44
7.06
15.69
4.50
10.04
28.50
0.7
4.2
10.9
2.6
7.0
16.8
5.3
10.0
29.0
Total:
70
100
9.22
0.72
7.15
28.50
0.7
7.4
29.0
Page 20 of 38
Table5.8.SummaryrawdataPatientServiceCenter
Number
of
WBC
SysmexXS1000i,x109/L
%of
Mean
values
HemoCueWBC,x109/L
Min
values
Median
values
Max
values
Min
values
Median
values
Max
values
109/L
samples
total
5.0
5.110.0
10.130.0
19
26
15
32
43
25
2.54
7.22
20.55
0.34
5.25
12.80
2.34
6.93
20.02
5.02
9.89
28.74
0.4
4.4
13.0
2.3
6.8
18.2
4.8
10.2
27.0
Total:
60
100
9.07
0.34
6.74
28.74
0.4
6.4
27.0
Table5.9.SamplesanalyzedatNrlundaPrimaryCare(toofewresultstocalculatestatisticsforthissubgroup,
butthedataareincludedinTable5.4above.)
SysmexXS1000i,x109/L
repl1
repl2
mean
Sample
KH16
KH17
KH18
KH32
KH33
18.91
2.04
2.25
2.39
3.39
19.33
2.07
2.61
2.48
3.57
19.12
2.06
2.43
2.44
3.48
HemoCueWBC
x109/L
18.7
2.1
2.7
2.6
3.7
WBC count
30
20
10
HemoCue
WBC, single
replicate
Sysmex
XS-1000i, all
replicates
Figure5.5.BoxandwhiskersplotforMulticenterstudy,HemoCueWBCandSysmexXS1000i,x109/L.
Page 21 of 38
WBC count
30
20
10
HemoCue
WBC, single
replicates
Sysmex
XS-1000i, all
replicates
Figure5.6.BoxandwhiskersplotforDelfinenPrimaryCareCenter,HemoCueWBCandSysmexXS1000i,
x109/L.
WBC count
30
20
10
HemoCue
WBC, single
replicates
Sysmex
XS-1000i, all
replicates
Figure5.7.BoxandwhiskersplotforMunkaPrimaryCareCenter,HemoCueWBCandSysmexXS1000i,x109/L
Page 22 of 38
WBC count
30
20
10
HemoCue
WBC, single
replicate
Sysmex
XS-1000i, all
replicates
Figure5.8.BoxandwhiskersplotforSjcronaPrimaryCareCenter,HemoCueWBCandSysmexXS1000i,
x109/L.
WBC count
30
20
10
HemoCue
WBC, single
replicates
Sysmex
XS-1000i, all
replicates
Figure5.9.BoxandwhiskersplotforPatientServiceCenter,HemoCueWBCandSysmexXS1000i,x109/L.
Page 23 of 38
30
Coefficients:
b0 = 0.056 0.131
b1 = 1.008 0.012
25
r2 = 0.986
Syx = 0.799
N = 411
20
15
10
-------- X = Y
0
0
10
15
20
25
30
Figure5.10.RegressionanalysisandscatterplotforMulticenterstudy,HemoCueWBCvsSysmexXS1000i.
30
Coefficients:
b0 = 0.047 0.326
b1 = 1.027 0.027
2
25
r = 0.979
Sxy = 1.078
N =124
20
15
10
----- X=Y
0
0
10
15
20
25
30
Page 24 of 38
Figure5.11.RegressionanalysisandscatterplotforDelfinenPrimaryCareCenter,HemoCueWBCvsSysmex
XS1000i.
30
Coefficients:
b0 = 0.028 0.132
b1 = 1.015 0.012
r2 = 0.994
Sxy = 0.466
N = 152
25
20
15
10
----- X=Y
0
0
10
15
20
25
30
Figure5.12.RegressionanalysisandscatterplotforMunkaPrimaryCareCenter,HemoCueWBCvsSysmexXS
1000i.
30
Coefficients:
b0 = -0.017 0.275
b1 = 1.012 0.024
r2 = 0.990
Sxy = 0.673
N =70
25
20
15
10
5
----- X=Y
0
0
10
15
20
25
30
Page 25 of 38
Figure5.13.RegressionanalysisandscatterplotforSjcronaPrimaryCareCenter,HemoCueWBCvsSysmex
XS1000i.
30
Coefficients:
b0 = 0.121 0.281
b1 = 0.954 0.024
r2 = 0.991
Sxy = 0.692
N = 60
25
20
15
10
5
------ X=Y
0
0
10
15
20
25
30
Figure5.14.RegressionanalysisandscatterplotforPatientServiceCenter,HemoCueWBCvsSysmexXS
1000i.
5.4.8 TotalAnalyticalError
10
-5
-10
0
10
20
30
9
Figure5.15.BlandAltmanplotforHemoCueWBCuservsSysmexXS1000i,absolutedifferences,x109/L
Page 26 of 38
40
20
-20
-40
10
20
30
Figure5.16.BlandAltmanplotforHemoCueWBCuservsSysmexXS1000i,relativedifferences,%.Sample
KM18(155.3%)andH20(189.1%)areexcludedinthisplot.
0.6
0.4
0.2
0.0
-20
-10
10
20
30
Figure5.17.Mountainplotforlowrange.Noacceptancelimits(0.4x109/L,15%)hasbeenincludedinthis
figure.SampleKM18(155.3%)andH20(189.1%)areexcludedinthisplot.
Page 27 of 38
0.6
0.4
0.2
0.0
-20
-10
10
20
30
Figure5.18.Mountainplotformediumrange.
0.6
0.4
0.2
0.0
-20
-10
10
20
30
Figure5.19.Mountainplotforhighrange.
Page 28 of 38
5.4.9 AllowableTotalError(ATE)
TheanalyticqualitygoalforWBCisestablishedinseveralpublicationsincludingCLIAtoallowatotalerror
(ATE)at15%Ref.1,2,3,4,5.
SuggestionofclinicalactionlimitshasbeenmadeinCLSI(NCCLS)H26ARef.6:
ClinicalRelevance:AbnormalResultsMayReflecttheFollowingConditions
<3x109/L Sepsis,chemotherapy,radiotherapy,agranulocytosis,marrowhypoplasia,cobalamin,folate,
irondeficiency.
>12x109/L Acutestress(includingsurgery),infection,malignancy,lymphoma,leukemia.
5.4.9.1 EstablishmentofanErrorGridforWBC
ThereexistsnoconsensuserrorgridforWBCcomparabletotheClarkeerrorgridforglucose.Accordingtothe
newCLIAguidelines,HemoCuethereforehasestablishedagridbasedonpatientriskandclinicalrelevance.
Atotalleukocytecountismeasuredindifferentsituationsinhealthcare:
Oneofthemostcommonsituationsistodetermineifaninfectionisbacterialorviral,ifthepatient
shouldbetreatedwithantibioticsornot.Usuallyacutoffvalueof12x109g/Lisused.Itcouldbea
severeconditionforthepatientifafalselowresultisreceivedandthetrueWBCisveryelevated.
Differenttypesofacuteleukemiawouldbecriticaltomiss.Patientswithacuteleukemiahavea
massiveincreaseofleucocytes.Gettinganormaloronlyaslightlyelevatednumberofleucocytes
missingacuteleukemiawouldbefatal.
AnotherpossiblesituationistomonitortheWBCduringchemotherapyorothercytotoxictreatment.
Avalueof3x109g/Lservesasadecisionleveltopermitcontinuationofthetreatment.Small
differencesherecouldcauserelativesevereconditions.EspeciallymissingapatientwithaWBCbelow
1x109g/Lorevenworse<0.5x109g/Lbecauseoftheincreasedinfectionrisk.
Withthisbackground,HemoCueestablishedthefollowingerrorgridwithzonesofATEandLER:
ATE:<15%or0.4x109g/Ltheallowabletotalerrorofdeviation.95%ofallsamplesshouldfall
withinthiszone.
LER:0%ofthesamplesmayfallintothesezones.TheupperleftLERzonecorrespondstoarisktomiss
patientswithleucopenia(<3x109g/L)duringchemotherapyorothercytotoxictreatment.Thelower
LERzonecorrespondstoarisktomisssevereinfectionsorleukemia.
Page 29 of 38
WBC grid
30
25
ATE
LER
HemoCue
20
15
10
LER
0
0
10
15
20
25
30
Figure5.20.EstablishedWBCErrorGrid
LiteraturereferencestosupportestablishmentofWBCerrorgrid:
1. FraserC.G.,HyltoftPetersenP.,Qualitygoalsinexternalqualityassessmentarebestbasedonbiology,
ScandJClinLabInvest1993;53suppl212.ChapterI.Qualityplanning
2. FraserC.G.,TheNecessityofAchievingGoodLaboratoryPerformance,DiabeticMedicine1990;7:
490493.
3. FraserG.F.andPetersenP.H.,AnalyticalPerformanceCharacteristicsShouldBeJudgedagainst
ObjectiveQualitySpecifications.,ClinChem1999;45:3,321323.
4. RicsC.etal.,Currentdatabasesonbiologicalvariation,ScandJClinLabInvest1999,59:491500.
5. SebastinGambaroM..etal.,IntraandInterIndividualBiologicalVariabilityDataBank,EurJClin
ChemClinBiochem1997;35(11):845852
ThisdatabankisalsoavailableonthefollowingInternetaddress:http://www.westgard.com
6. NCCLSH26APerformanceGoalsfortheInternalQualityControlofMultichannelHematology
Analysers;ApprovedStandard.Vol.9No.9.December1996.
Page 30 of 38
5.4.9.2
ResultFieldStudyATE
30
ATE
25
ATE
20
LER
15
10
LER
-------- X = Y
0
0
10
15
20
25
30
Figure5.21.ScatterplotinErrorgrid,HemoCueWBCvsSysmexXS1000i,x109/L
Table5.10.NumberofsampleswithinATEandLERforeachWBCintervalandtotally
WBC
x109/L
Numberof
samples
%ofsampleswithinATE
%ofsampleswithinLER
5.0
5.110.0
10.030.0
112
181
118
93.8
97.2
98.3
0.0
0.0
0.0
Total
411
96.6
0.0
Page 31 of 38
5.4.10 ResultfromQuestionnaire
1
(Strongly
disagree)
5
(Totally
agree)
2.Itiseasytoplacethecuvette
intotheanalyzer
11
3.Itiseasytoreadthevalue
fromthedisplay
11
4.Itiseasytounderstandthe
instructionforuseforthesystem
10
5.Itiseasytofollowthe
instructionforuseforthesystem
10
6.Itispossibletohandlethesystemusing
onlyQuickReferenceGuide
7.Itiseasytofindinformationabouthow
torectifyanerrorcodeiftheanalyzer
displaysone
Statement
1.Itiseasytofillthecuvette
Statement
8.IneededhelpthefirsttimeI
performedthetest
1
(Totally
agree)
5
(Strongly
disagree)
11
5.5 ConclusionoftheFieldStudy
TheresultfromthefieldstudyclearlyshowsthattheHemoCueWBCSystemissimpletouseinthehandsof
theintendeduserandthatthereisaninsignificantriskofreceivingerroneousresults.Thisisbasedonthe
factsthat96.6%ofallresultsfallswithintheATEzoneandtheintendedusersbelievesthatthedeviceisan
easysystemtouse.
Page 32 of 38
ProposedLabelling
TheHemoCueWBCSystemisdeliveredtotheuserincludinganoperatingmanual,aquickreferenceguide,a
packageinsertaswellaslabelsshownbelow.Allapplicablelabellingispresentedinthischapter.
ProvidedwiththeHemoCueWBCSystemis:
QuickReferenceGuideHemoCueWBCsystemprovidedinAttachment2
PackageInsertHemoCueWBCMicrocuvettesprovidedinAttachment3
OperatingManualHemoCueWBCAnalyzerprovidedinAttachment4
TrainingCDHemoCueWBCSystemprovidedinAttachment5
TheHemoCueWBCSystemutilizesthelabelsshownonthefollowingpages.
Page 33 of 38
Label,HemoCueWBCAnalyzer:DrawingCEandS/Nlabel,box
Page 34 of 38
Label,HemoCueWBCAnalyzerboxlabel
Label,HemoCueWBCAnalyzerboxdrawing
Page 35 of 38
Label,HemoCueWBCMicrocuvetteviallabel
Page 36 of 38
Label,HemoCueWBCMicrocuvetteboxdrawing
Page 37 of 38
Label,HemoCueWBCMicrocuvetteboxlabel(boxcontains4vials)
Attachments
Attachment1SafetyRiskAnalysisUserandSystemforHemoCueWBCSystemfollowup
Attachment2QuickReferenceGuideHemoCueWBCsystem
Attachment3PackageInsertHemoCueWBCMicrocuvettes
Attachment4OperatingManualHemoCueWBCAnalyzer
Attachment5TrainingCDHemoCueWBCSystem
Attachment6FinancialDisclosureStatement
Attachment7Rawdatasheetfromfieldstudy
Page 38 of 38