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Roles and responsibilities in Roles and responsibilities in
verification of traceability of in vitro verification of traceability of in vitro
medical diagnostics (IVD)medical diagnostics (IVD)
Federica BragaFederica Braga
University of Milan Medical School University of Milan Medical School
Centre for Metrological Traceability in Laboratory Centre for Metrological Traceability in Laboratory
Medicine (CIRME)Medicine (CIRME)
Laboratory measurement paradigm:Laboratory measurement paradigm:
•• Assays that claim to measure the same Assays that claim to measure the same analyteanalyte
should give equivalent measurement results (for should give equivalent measurement results (for
long term and within clinically meaningful limits)long term and within clinically meaningful limits)
Measurement results should be independent of:Measurement results should be independent of:
−− TimeTime
−− Location/laboratoryLocation/laboratory
−− Assay systemAssay system
Laboratory results should be
equivalent no matter where
they are performed
ISO/EN 17511 ISO/EN 17511 -- MeasurementMeasurement of of quantitiesquantities in in samplessamples of of biologicalbiological originorigin -- MetrologicalMetrological traceabilitytraceability of of
valuesvalues assignedassigned toto calibratorscalibrators and control and control materialsmaterials..
→→ To becomeTo become equivalent for long equivalent for long termterm, results must be traceable to , results must be traceable to higherhigher--order references.order references.
ObjectiveObjective of of traceabilitytraceability
implementationimplementation::
toto enableenable the the resultsresults obtainedobtained byby the the
calibratedcalibrated routine procedure routine procedure toto bebe
expressedexpressed in in termsterms of the of the valuesvalues obtainedobtained at at
the the highesthighest availableavailable levellevel of the of the calibrationcalibration
hierarchyhierarchy..
EU 98/79/ECEU 98/79/EC--IVD IVD DirectiveDirective
•• Establishment of a calibration hierarchy Establishment of a calibration hierarchy
starting from the unequivocal definition of starting from the unequivocal definition of
the the measurandmeasurand
•• Elimination of measurement biasElimination of measurement bias
•• Adequate estimation of measurement Adequate estimation of measurement
uncertaintyuncertainty
Basic requirements to Basic requirements to
establish traceability establish traceability
Primary Ref. ProcedurePrimary Ref. Procedure
Secondary Ref. Secondary Ref.
ProcedureProcedure
ManufacturerManufacturer’’ss
Internal ProcedureInternal Procedure
EndEnd--useruser’’s Routines Routine
ProcedureProcedure
Primary Reference MaterialPrimary Reference Material
(e.g. pure (e.g. pure analyteanalyte))
Secondary Ref. MaterialSecondary Ref. Material
(matrix(matrix--based)based)
ManufacturerManufacturer’’s Calibrators Calibrator
Routine SampleRoutine Sample
Test ResultTest Result
SI UnitsSI Units
Tra
cea
bility
Tra
cea
bility
*Adapted from ISO 17511
Reference Measurement SystemReference Measurement SystemU
nce
rtain
tyU
nce
rtain
ty
ProfessionProfession (e.g., IFCC, JCTLM):(e.g., IFCC, JCTLM): DefineDefine analyticalanalytical objectivesobjectives: : referencereference
measurementmeasurement systemssystems ((traceabilitytraceability chainchain) )
and and associatedassociated clinicallyclinically acceptableacceptable
uncertaintyuncertainty ((fitfit forfor purposepurpose))
DiagnosticDiagnostic manufacturersmanufacturers:: ImplementImplement suitablesuitable measuringmeasuring systemssystems
((platformplatform, , reagentsreagents, , calibratorscalibrators, , controlscontrols) )
fulfillingfulfilling the the aboveabove establishedestablished goalsgoals
End End usersusers ((clinicalclinical laboratorieslaboratories):): Survey assay and laboratory performance Survey assay and laboratory performance
through:through:
-- IQC component I: testing system controls IQC component I: testing system controls
to confirm and verify manufacturerto confirm and verify manufacturer’’s s
declared performance (CE marked declared performance (CE marked ––
virtually unbiased)virtually unbiased)
-- EQA: true value in commutable materials EQA: true value in commutable materials
for defining measurement error of for defining measurement error of
laboratorylaboratory
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
ProfessionProfession (e.g., IFCC, JCTLM):(e.g., IFCC, JCTLM): DefineDefine analyticalanalytical objectivesobjectives: : referencereference
measurementmeasurement systemssystems ((traceabilitytraceability chainchain) )
and and associatedassociated clinicallyclinically acceptableacceptable
uncertaintyuncertainty ((fitfit forfor purposepurpose))
DiagnosticDiagnostic manufacturersmanufacturers:: ImplementImplement suitablesuitable measuringmeasuring systemssystems
((platformplatform, , reagentsreagents, , calibratorscalibrators, , controlscontrols) )
fulfillingfulfilling the the aboveabove establishedestablished goalsgoals
End End usersusers ((clinicalclinical laboratorieslaboratories):): Survey assay and laboratory performance Survey assay and laboratory performance
through:through:
-- IQC component I: testing system controls IQC component I: testing system controls
to confirm and verify manufacturerto confirm and verify manufacturer’’s s
declared performance (CE marked declared performance (CE marked ––
virtually unbiased)virtually unbiased)
-- EQA: true value in commutable materials EQA: true value in commutable materials
for defining measurement error of for defining measurement error of
laboratorylaboratory
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
�� UnequivocalUnequivocal definitiondefinition of the of the measurandmeasurand asas the the
quantityquantity subjectsubject toto measurementmeasurement
�� DefinitionDefinition of the of the referencereference measurementmeasurement systemsystem
�� DefinitionDefinition of of analyticalanalytical performance performance
specificationsspecifications
Role of ProfessionalRole of Professional OrganizationOrganization::
MeasurandMeasurand
TYPE A MEASURANDSTYPE A MEASURANDS
• Well defined compounds;• Traceable to SI units;• Results are not method-dependent;• Approx. 65 analytes(metabolites, electrolytes,steroid hormones);
TYPE B MEASURANDSTYPE B MEASURANDS
• Not well defined (often heterogeneous mixtures);• Analytes can be bound or in free state;• Not traceable to SI units, but to arbitrary units (e.g. WHO International Units);• Immunochemical procedures show inherent variability (different epitopes);• 400-600 analytes (tumour markers, viral antigens, clotting factors);
PanteghiniPanteghini M. M. ClinClin BiochemBiochem 2009;42:2362009;42:236
Joint Committee for Traceability in Joint Committee for Traceability in
Laboratory Medicine (JCTLM)Laboratory Medicine (JCTLM)
The WorldThe World’’s only qualitys only quality--assured database of:assured database of:
a)a) Higher Order Reference MaterialsHigher Order Reference Materials
b)b) Higher Order Reference Measurement ProceduresHigher Order Reference Measurement Procedures
c)c) Accredited Laboratory Reference Measurement Services Accredited Laboratory Reference Measurement Services
For use by (primarily):For use by (primarily):
a) IVD industry (a) IVD industry (to assist them in following the EU Directive on to assist them in following the EU Directive on
compliance and traceability of commercial systemscompliance and traceability of commercial systems))
b) Regulators (to verify that results produced by b) Regulators (to verify that results produced by IVDsIVDs are are
traceable to)traceable to)
Reference measurement systemReference measurement system
The definition and use of the reference systemThe definition and use of the reference system
concept for standardization of measurements must concept for standardization of measurements must
be closely associated with the setting of targets for be closely associated with the setting of targets for
uncertainty and error of measurement in order to uncertainty and error of measurement in order to
make it clinically acceptablemake it clinically acceptable
L L ThienpontThienpont et al., et al., ClinClin ChemChem Lab Med 2004;42:842Lab Med 2004;42:842
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
If these goals are not objectively defined and fulfilled, there If these goals are not objectively defined and fulfilled, there is a risk of letting is a risk of letting
error gain the upper hand, thus obscuring the clinical informatierror gain the upper hand, thus obscuring the clinical information supplied by on supplied by
the result and possibly nullifying the theoretical advantages ofthe result and possibly nullifying the theoretical advantages of metrological metrological
traceability and even causing negative effects on patients' outctraceability and even causing negative effects on patients' outcome.ome.
Analytical performance specificationsAnalytical performance specifications
Model 1: Based on the effect of analytical Model 1: Based on the effect of analytical
performance on clinical outcomeperformance on clinical outcome
Model 2: Based on components of biological Model 2: Based on components of biological
variation of the variation of the measurandmeasurand
Model 3: Based on state of the art of the Model 3: Based on state of the art of the
measurement (i.e., the highest level of measurement (i.e., the highest level of
analytical performance technically analytical performance technically
achievable) achievable)
Some models are better suited for certain Some models are better suited for certain
measurandsmeasurands than for others. The attention is than for others. The attention is
therefore primarily directed towards the therefore primarily directed towards the
measurandmeasurand and its biological and clinical and its biological and clinical
characteristics.characteristics.
1.1. The The measurandmeasurand hashas a a centralcentral rolerole in in diagnosisdiagnosis and and
monitoringmonitoring of a of a specificspecific diseasedisease⇒⇒ outcomeoutcome
modelmodel
2.2. The The measurandmeasurand hashas a high a high homeostatichomeostatic control control ⇒⇒biologicalbiological variabilityvariability modelmodel
3.3. NeitherNeither centralcentral diagnosticdiagnostic rolerole nornor sufficientsufficient
homeostatichomeostatic control control ⇒⇒ state state ofof--thethe--artart modelmodel
Biologic
al
Biologic
al
Variati
onVar
iation
approa
chapp
roach
a. Done by direct outcome studies – investigating the impact of analytical
performance of the test on clinical outcome.
b. Done by indirect outcome studies – investigating the impact of analytical
performance of the test on clinical classifications or decisions and thereby on
the probability of patient outcome, e.g., by simulation analysis.
a. Done by direct outcome studies a. Done by direct outcome studies –– investigating the impact of analytical investigating the impact of analytical
performance of the test on clinical outcome.performance of the test on clinical outcome.
b. Done by indirect outcome studies b. Done by indirect outcome studies –– investigating the impact of analytical investigating the impact of analytical
performance of the test on clinical classifications or decisionsperformance of the test on clinical classifications or decisions and thereby on and thereby on
the probability of patient outcome, e.g., by simulation analysisthe probability of patient outcome, e.g., by simulation analysis..
IMPRECISION:IMPRECISION: ≤≤ 0.25 CV0.25 CVII (O)(O)
≤≤ 0.5 CV0.5 CVII (D)(D)
≤≤ 0.75 CV0.75 CVI I (M)(M)
BIAS: BIAS: < 0.125 (CV< 0.125 (CVII22 + CV+ CV
GG22))1/21/2 (O)(O)
< 0.25 (CV< 0.25 (CVII22 + CV+ CV
GG22))1/21/2 (D)(D)
< 0.375 (CV< 0.375 (CVII22 + CV+ CV
GG22))1/21/2 (M) (M)
Outcome
Outcome
approach
approach
IntraIntra--individualindividual BV: BV: CVCVII%%
InterInter--individualindividual BV: BV: CVCVGG%%
<0.75 x CV<0.75 x CVII (Minimum)(Minimum)
<0.50 x CV<0.50 x CVII ((DesirableDesirable))
<0.25 x CV<0.25 x CVII (Optimum)(Optimum)
UNCERTAINTYUNCERTAINTYUNCERTAINTY [Note that these are goals for [Note that these are goals for random variabilityrandom variability, as , as at the at the
calibrator level the systematic error (bias), in agreement calibrator level the systematic error (bias), in agreement
with the metrological traceability theory, must be corrected with the metrological traceability theory, must be corrected
if present in a non negligible amount]if present in a non negligible amount]
<(0.75 x CV<(0.75 x CVII) x 2 (Minimum)) x 2 (Minimum)
<(0.50 x CV<(0.50 x CVII) x 2 () x 2 (DesirableDesirable))
<(0.25 x CV<(0.25 x CVII) x 2 (Optimum)) x 2 (Optimum)
kuU ×=EXPANDED UNCERTAINTYEXPANDED UNCERTAINTYEXPANDED UNCERTAINTY
Total uncertainty budget that should be fulfilled
when combining the uncertainty of the measuring
system employed in the individual laboratory
(random uncertainty) to that accumulated along all
the steps of metrological traceability chain.
Total uncertainty budget that should be fulfilled
when combining the uncertainty of the measuring
system employed in the individual laboratory
(random uncertainty) to that accumulated along all
the steps of metrological traceability chain.
Biological Biological
VariationVariation
approachapproach
UncertaintyUncertainty of of measurementmeasurement thatthat
fitsfits forfor purposepurpose mustmust bebe defineddefined
acrossacross the the entireentire traceabilitytraceability chainchain, ,
→→ startingstarting withwith the provider of the provider of
referencereference materialsmaterials, ,
→→ extendingextending through the IVD through the IVD
manufacturersmanufacturers and and theirtheir processesprocesses forfor
assignmentassignment of of calibratorcalibrator valuesvalues, and , and
→→ ultimatelyultimately toto the final the final resultresult
reportedreported toto cliniciansclinicians byby end end usersusers (i.e. (i.e.
clinicalclinical laboratorieslaboratories).).
[[PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2012;50:1237]2012;50:1237]
Braga F & Braga F & PanteghiniPanteghini M. M. ClinClin ChemChem Lab Lab MedMed 2013;51:17192013;51:1719
HbAHbA1c1c: Metrological traceability chain: Metrological traceability chain
Uncertainty budgetUncertainty budget
Clinical Clinical
laboratorylaboratory
IVD ManufacturerIVD ManufacturerReference providerReference provider
System imprecision
System calibration
uncertainty
Individual lab
performance
(IQC safety margin)
Total measurement
uncertainty
budget
Total measurement
uncertainty
budget
Uncertainty of
references
Patient result
33%33%
50%50%
100%100%
Measurand definitionMeasurand definition
ProfessionProfession (e.g., IFCC, JCTLM):(e.g., IFCC, JCTLM): DefineDefine analyticalanalytical objectivesobjectives: : referencereference
measurementmeasurement systemssystems ((traceabilitytraceability chainchain) )
and and associatedassociated clinicallyclinically acceptableacceptable
uncertaintyuncertainty ((fitfit forfor purposepurpose))
DiagnosticDiagnostic manufacturersmanufacturers:: ImplementImplement suitablesuitable measuringmeasuring systemssystems
((platformplatform, , reagentsreagents, , calibratorscalibrators, , controlscontrols) )
fulfillingfulfilling the the aboveabove establishedestablished goalsgoals
End End usersusers ((clinicalclinical laboratorieslaboratories):): Survey assay and laboratory performance Survey assay and laboratory performance
through:through:
-- IQC component I: testing system controls IQC component I: testing system controls
to confirm and verify manufacturerto confirm and verify manufacturer’’s s
declared performance (CE marked declared performance (CE marked ––
virtually unbiased)virtually unbiased)
-- EQA: true value in commutable materials EQA: true value in commutable materials
for defining measurement error of for defining measurement error of
laboratorylaboratory
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
IVD manufacturers should IVD manufacturers should define adefine a calibration calibration
hierarchyhierarchy to assign traceable values to their system to assign traceable values to their system
calibrators and to fulfil during this processcalibrators and to fulfil during this process
uncertainty limits,uncertainty limits,
Role of IVD manufacturersRole of IVD manufacturers
which represent a proportion which represent a proportion
of the uncertainty budget of the uncertainty budget
allowed for clinical laboratory allowed for clinical laboratory
results.results.
ParadigmParadigm shiftshift in the in the thinkingthinking
•• IfIf the the manufacturermanufacturer assumesassumes total total responsibilityresponsibility forfor supplyingsupplying productsproducts of of acceptableacceptable qualityquality in in termsterms of of traceabilitytraceability and and uncertaintyuncertainty of the system (of the system (““CE CE markedmarked””), ), itit isisno no longerlonger possiblepossible toto considerconsider separatelyseparately the the componentscomponents of of eacheach measuringmeasuring system (system (i.ei.e., ., platformplatform, , reagentsreagents, , calibratorscalibrators and control and control materialsmaterials), ), whichwhich in in termsterms of performance can of performance can onlyonly bebe guaranteedguaranteed and and certifiedcertified byby the the manufacturermanufacturer asas a a wholewhole..
•• AnyAny changechange introducedintroduced byby usersusers or or thirdthirdpartiesparties ((e.ge.g., the ., the useuse of of reagentsreagents, , calibratorscalibrators or or control control materialsmaterials fromfrom otherother supplierssuppliers) ) maymaysignificantlysignificantly alter the alter the qualityquality of the of the measuringmeasuringsystem performance, system performance, removingremoving anyanyresponsibilityresponsibility fromfrom the the manufacturermanufacturer and and deprivingdepriving the system (and, the system (and, consequentlyconsequently, the , the producedproduced resultsresults) of the ) of the certificationcertification originallyoriginallyprovidedprovided through CE through CE markingmarking..
ProfessionProfession ((e.ge.g., IFCC, JCTLM):., IFCC, JCTLM): DefineDefine analyticalanalytical objectivesobjectives: : referencereference
measurementmeasurement systemssystems ((traceabilitytraceability chainchain) )
and and associatedassociated clinicallyclinically acceptableacceptable
uncertaintyuncertainty ((fitfit forfor purposepurpose))
DiagnosticDiagnostic manufacturersmanufacturers:: ImplementImplement suitablesuitable measuringmeasuring systemssystems
((platformplatform, , reagentsreagents, , calibratorscalibrators, , controlscontrols) )
fulfillingfulfilling the the aboveabove establishedestablished goalsgoals
End End usersusers ((clinicalclinical laboratorieslaboratories):): SurveySurvey assayassay and and laboratorylaboratory
performance through:performance through:
-- IQC IQC componentcomponent I: I: testingtesting system system
controlscontrols toto confirmconfirm and and verifyverify
manufacturermanufacturer’’s s declareddeclared performance performance
(CE (CE markedmarked –– virtuallyvirtually unbiasedunbiased))
-- EQA: EQA: truetrue valuevalue in in commutablecommutable
materialsmaterials forfor definingdefining measurementmeasurement
error of error of laboratorylaboratory
PostPost--marketing marketing
surveillance of IVD surveillance of IVD
metrological traceabilitymetrological traceability
AdaptedAdapted fromfrom PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
The role of the endThe role of the end--usersusers
1. Availability and quality of information about IVD
metrological traceability and uncertainty
2. Daily surveillance of IVD system traceability
3. Estimating the measurement uncertainty due to
the random effects
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Post-marketingsurveillance
PostPost--marketing
marketingsurveillance
surveillance
The role of the endThe role of the end--usersusers
1. Availability and quality of information about IVD
metrological traceability and uncertainty
2. Daily surveillance of IVD system traceability
3. Estimating the measurement uncertainty due to
the random effects
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Post-marketingsurveillance
PostPost--marketing
marketingsurveillance
surveillance
In principle, laboratory users should be able to In principle, laboratory users should be able to
access the following:access the following:
a) an indication of higher order references (materials and/or procedures) used to assign traceable values to calibrators,
b) which internal calibration hierarchy has been applied by the manufacturer, and
c) a detailed description of each step,
d) the expanded combined uncertainty value of commercial calibrators, and
e) which, if any, acceptable limits for uncertainty of calibrators were applied in the validation of the analytical system.
a) an indication of higher order references (materials and/or procedures) used to assign traceable values to calibrators,
b) which internal calibration hierarchy has been applied by the manufacturer, and
c) a detailed description of each step,
d) the expanded combined uncertainty value of commercial calibrators, and
e) which, if any, acceptable limits for uncertainty of calibrators were applied in the validation of the analytical system.
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
(ideally all this information should be available in (ideally all this information should be available in
the assay or calibrator package inserts)the assay or calibrator package inserts)
Some Some organisationsorganisations are are frequentlyfrequently
mentionedmentioned ((oftenoften withoutwithout explanationexplanation): ):
usedused asas a a ““trustedtrusted brandbrand””
•• NIST, IRMM, IFCC, CLSI (NIST, IRMM, IFCC, CLSI (protocolsprotocols))
GCGC--IDMS @ NISTIDMS @ NIST
NIST SRM 917NIST SRM 917
ManufacturerManufacturer’’s s
internal procedureinternal procedure
Commercial Commercial
systemsystem
NIST SRM 965NIST SRM 965
(glucose in human serum)(glucose in human serum)
CommercialCommercial
calibratorcalibrator
PatientPatient’’s sample resultss sample results
GCGC--IDMS IDMS [accredited reference laboratory][accredited reference laboratory]
ManufacturerManufacturer’’s internals internal
procedureprocedure
CommercialCommercial
systemsystem
CommercialCommercial
calibratorcalibrator
PatientPatient’’s sample resultss sample results
ComparisonComparison onon
biologicalbiological samplessamples
AA BB
CC DD NIST SRM 917NIST SRM 917
ManufacturerManufacturer’’s s
internal procedureinternal procedure
NIST SRM 917NIST SRM 917
CDC CDC HexokinaseHexokinase[accredited reference laboratory][accredited reference laboratory]
ManufacturerManufacturer’’s internals internal
procedureprocedure
CommercialCommercial
systemsystem
CommercialCommercial
calibratorcalibrator
PatientPatient’’s sample resultss sample results
ComparisonComparison onon
biologicalbiological samplessamples
NIST SRM 917NIST SRM 917
Commercial Commercial
systemsystem
CommercialCommercial
calibratorcalibrator
PatientPatient’’s sample resultss sample results
Types of metrological chains that can be used to implement the tTypes of metrological chains that can be used to implement the traceability of blood glucose results*raceability of blood glucose results*
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
*all*all JCTLM JCTLM recognizedrecognized
Chain A = 1.45% vs. Chain C = 3.26%
Are the Are the measuringmeasuring systemssystems commerciallycommercially availableavailable forfor glucoseglucose determinationdetermination ableable toto
achieveachieve the the desirabledesirable limitlimit forfor combinedcombined uncertaintyuncertainty in a in a clinicalclinical settingsetting??
uurefref
(u(u22refref ++ uu22
calcal))½½
((uu22ref ref + + uu22
calcal + + uu22randomrandom))½½
System imprecision
System calibration
uncertainty
Individual lab
performance
(IQC safety margin)
Measurement
uncertainty
budget
Uncertainty of
references
Measurand definition
Patient result
5.4%5.4% desirabledesirable
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Pasqualetti S, Braga F, Panteghini M, Clin Biochem 2017 Mar 11. Pasqualetti S, Braga F, Panteghini M, Clin Biochem 2017 Mar 11. pii: S0009pii: S0009--9120(17)301169120(17)30116--99
L M H
•• Measured in triplicate in 3 consecutive Measured in triplicate in 3 consecutive
daysdays byby participatingparticipating laboratorieslaboratories59
.9 U
/L5
9.9
U/L
18
6.9
U/L
18
6.9
U/L
40
1.5
U/L
40
1.5
U/L
•• ALP target values ALP target values
assigned with assigned with IFCC RMPIFCC RMP
Desirable and minimum APS for bias: 8.3% and 5.5%Desirable and minimum APS for bias: 8.3% and 5.5%
The importance of the postThe importance of the post--marketing surveillancemarketing surveillance
EQA experimentEQA experiment
(performed 5(performed 5 years later years later the availability of the IFCC RMPthe availability of the IFCC RMP) )
to evaluate the level of ALP standardizationto evaluate the level of ALP standardization
ID
Lab
Measuring
system
Bias Regression parameters
Pool L Pool
M
Pool H Slope Intercepts
1 Roche
Cobas 6000
-7.2% -9.0% -9.6% 0.8998
(P=0.0005)
1.8
(P=0.065)
2 Roche
Cobas 6000
-5.4% -5.9% -7.0% 0.9271
(P=0.0029)
1.7
(P=0.37)
3 Beckman
AU5800
5.9% 6.6% 5.8% 1.0573
(P=0.0029)
0.7
(P=0.69)
4 Roche
Cobas 8000
-5.2% -6.8% -8.6% 0.9074
(P=0.0047)
3.3
(P=0.31)
5 Roche
Cobas
6000/8000
-3.0% -4.0% -5.1% 0.9452
(P=0.0028)
2.0
(P=0.32)
6 Beckman
AU680
4.4% 5.6% 3.1% 1.0263
(P=0.0086)
2.8
(P=0.57)
7 Beckman
AU6800
8.6% 8.3% 4.3% 1.0320
(P=0.012)
5.7
(P=0.46)
8 Beckman
AU5800
6.3% 7.4% 5.9% 1.0566
(P=0.0055)
1.5
(P=0.63)
9 Siemens
Advia
-2.3% -2.9% -4.5% 0.9500
(P=0.0049)
2.5
(P=0.41)
10 Roche
Cobas 8000
-5.0% -5.6% -6.8% 0.9275
(P=0.0037)
2.0
(P=0.38)
11 Roche
Cobas 8000
-5.8% -6.8% -8.6% 0.9075
(P=0.0056)
3.0
(P=0.38)
12 Siemens
Vista
-6.1% -1.4% -2.0% 0.9868
(P=0.0054)
1.9
(P=0.54)
13 Abbott
Architect
c16000
2.3% -1.0% -0,6% 0.9895
(P=0.0039)
1.3
(P=0.57)
The ability to meet or not the desirable APS for
bias is clearly dependent on the measuring
system used.
The ability to meet or not the desirable APS for
bias is clearly dependent on the measuring
system used.
Schumann G, et al.
Clin Chem Lab Med 2011;49:1439-46
Schumann G, et al.Schumann G, et al.
ClinClin ChemChem Lab Lab MedMed 2011;49:14392011;49:1439--4646
The importance of the postThe importance of the post--marketing surveillancemarketing surveillance
CompanyCompany PlatformPlatformPrinciple of Principle of
commercial methodcommercial methodCalibratorCalibrator
Declared standard Declared standard
uncertaintyuncertainty
HigherHigher--order reference order reference
employedemployed
Abbott Abbott ArchitectArchitect pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA IFCC reference method (2011)IFCC reference method (2011)
pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA Molar extinction coefficientMolar extinction coefficient
Beckman Beckman AUAU IFCC (1983)IFCC (1983) System calibratorSystem calibrator 6.00%6.00% Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator
pp--NPP/DEANPP/DEA System calibratorSystem calibrator NANA Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator
SynchronSynchron pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 6.22%6.22% IFCC reference method (2011)IFCC reference method (2011)
Enzyme Enzyme ValidatorValidator level 2level 2 1.86%1.86% IFCC reference method (2011)IFCC reference method (2011)
pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 3.64%3.64% DGKC standard methodDGKC standard method
Enzyme Enzyme ValidatorValidator level 2level 2 1.27%1.27% DGKC standard methodDGKC standard method
Roche Roche CobasCobas cc IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s.. 0.59%0.59% IFCC reference method (1983)IFCC reference method (1983)
IntegraIntegra IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s 1.22%1.22% IFCC reference method (1983)IFCC reference method (1983)
ModularModular IFCC liquidIFCC liquid C.f.a.sC.f.a.s 1.65%1.65% IFCC reference method (1983)IFCC reference method (1983)
SiemensSiemens Dimension VistaDimension Vista pp--NPP/AMPNPP/AMP ALPI calibratorALPI calibrator 4.51%4.51%cc IFCC reference method (2011)IFCC reference method (2011)
AdviaAdvia pp--NPP/AMPNPP/AMP Chemistry calibrator control 1Chemistry calibrator control 1 3.70%3.70% IFCC reference method (2011)IFCC reference method (2011)
Chemistry calibrator control 2Chemistry calibrator control 2 1.00%1.00% IFCC reference method (2011)IFCC reference method (2011)
pp--NPP/DEANPP/DEA Chemistry calibrator control 1Chemistry calibrator control 1 1.40%1.40%cc Molar extinction coefficientMolar extinction coefficient
Chemistry calibrator control 2Chemistry calibrator control 2 1.30%1.30%cc Molar extinction coefficientMolar extinction coefficient
The importance of the postThe importance of the post--marketing surveillancemarketing surveillance
CompanyCompany PlatformPlatformPrinciple of Principle of
commercial methodcommercial methodCalibratorCalibrator
Declared standard Declared standard
uncertaintyuncertainty
HigherHigher--order reference order reference
employedemployed
Abbott Abbott ArchitectArchitect pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA IFCC reference method (2011)IFCC reference method (2011)
pp--NPP/AMPNPP/AMP Calibration factorCalibration factor NANA Molar extinction coefficientMolar extinction coefficient
Beckman Beckman AUAU IFCC (1983)IFCC (1983) System calibratorSystem calibrator 6.00%6.00% Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator
pp--NPP/DEANPP/DEA System calibratorSystem calibrator NANA Beckman Coulter Master CalibratorBeckman Coulter Master Calibrator
SynchronSynchron pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 6.22%6.22% IFCC reference method (2011)IFCC reference method (2011)
Enzyme Enzyme ValidatorValidator level 2level 2 1.86%1.86% IFCC reference method (2011)IFCC reference method (2011)
pp--NPP/AMPNPP/AMP Enzyme Enzyme ValidatorValidator level 1level 1 3.64%3.64% DGKC standard methodDGKC standard method
Enzyme Enzyme ValidatorValidator level 2level 2 1.27%1.27% DGKC standard methodDGKC standard method
Roche Roche CobasCobas cc IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s.. 0.59%0.59% IFCC reference method (1983)IFCC reference method (1983)
IntegraIntegra IFCC gen. 2IFCC gen. 2 C.f.a.sC.f.a.s 1.22%1.22% IFCC reference method (1983)IFCC reference method (1983)
ModularModular IFCC liquidIFCC liquid C.f.a.sC.f.a.s 1.65%1.65% IFCC reference method (1983)IFCC reference method (1983)
SiemensSiemens Dimension VistaDimension Vista pp--NPP/AMPNPP/AMP ALPI calibratorALPI calibrator 4.51%4.51%cc IFCC reference method (2011)IFCC reference method (2011)
AdviaAdvia pp--NPP/AMPNPP/AMP Chemistry calibrator control 1Chemistry calibrator control 1 3.70%3.70% IFCC reference method (2011)IFCC reference method (2011)
Chemistry calibrator control 2Chemistry calibrator control 2 1.00%1.00% IFCC reference method (2011)IFCC reference method (2011)
pp--NPP/DEANPP/DEA Chemistry calibrator control 1Chemistry calibrator control 1 1.40%1.40%cc Molar extinction coefficientMolar extinction coefficient
Chemistry calibrator control 2Chemistry calibrator control 2 1.30%1.30%cc Molar extinction coefficientMolar extinction coefficient
• The availability of an internationally agreed reference The availability of an internationally agreed reference
measurement system does not automatically mean that measurement system does not automatically mean that
the traceability to it is implemented!the traceability to it is implemented!
•• If a postIf a post--marketing surveillance is lacking alternatives marketing surveillance is lacking alternatives
that do not comply with the EU Directive can remain that do not comply with the EU Directive can remain
undisturbed on the market.undisturbed on the market.
•• Some manufacturers continue to offer assays based on Some manufacturers continue to offer assays based on
different experimental conditions (e.g. use of different experimental conditions (e.g. use of
diethanolaminediethanolamine instead of 2instead of 2--aminoamino--22--methylmethyl--11--propanol propanol
as reaction buffer for ALP) that may significantly influence as reaction buffer for ALP) that may significantly influence
the measurement selectivity and, ultimately, the the measurement selectivity and, ultimately, the
measurandmeasurand definition, one of the indispensable definition, one of the indispensable
prerequisites in the field of enzyme standardization.prerequisites in the field of enzyme standardization.
• The alkaline picrate method is unable to measure solely creatinine
• Endogenous and exogenous substances may significantly interfere
• Interfering substances in serum, particularly proteins, can lead to significant overstimation with various alkaline picrate methods
• Interference from glucose and ketonesparticularly important in diabetics who are at high-risk for CKD
The issue of analytical nonThe issue of analytical non--
selectivity: selectivity:
the case of serum the case of serum creatininecreatinine
Reference System for CreatinineReference System for Creatinine
PanteghiniPanteghini M M etet al., al., ClinClin ChemChem Lab Lab MedMed 2006;44:11872006;44:1187
10,7%
-0,1%-2,0%
-2,8%-1,5%
-2,9%-2,1%
5,3%
-10%
-5%
0%
5%
10%
15%
50 100 150 200 250
Creatinine (µmol/L)
Bia
s b
etw
een o
vera
ll
mean a
nd t
arg
et
valu
e
Picrate Enzymatics
Traceability implementation does not correct for Traceability implementation does not correct for
creatininecreatinine analytical nonanalytical non--selectivity problems!selectivity problems!
Percent bias of overall means for the two method macro-categories based on different
analytic principle in post-standardization years (2010-2011). The dotted and the dashed
line indicate the maximum acceptable bias at desirable (±4.0%) and at minimum quality
level (±6.0%), respectively.
Carobene A et al., Clin Chim Acta 2014;427:100Carobene A et al., Clin Chim Acta 2014;427:100
The role of the endThe role of the end--usersusers
1. Availability and quality of information about IVD
metrological traceability and uncertainty
2. Daily surveillance of IVD system traceability
3. Estimating the measurement uncertainty due to
the random effects
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Post-marketingsurveillance
PostPost--marketing
marketingsurveillance
surveillance
Daily surveillance of IVD system traceability Daily surveillance of IVD system traceability
1.1. Verification of the consistency of declared performance Verification of the consistency of declared performance
during routine operations performed in accordance with the during routine operations performed in accordance with the
manufacturermanufacturer’’s instructionss instructions
(checking of system alignment by (checking of system alignment by IQC component IIQC component I))
2.2. Participation to appropriately structured EQASParticipation to appropriately structured EQAS
((““that meet metrological criteriathat meet metrological criteria””))
Braga F & Panteghini M, Braga F & Panteghini M,
Clin Chim Acta 2014;432:55Clin Chim Acta 2014;432:55
IVDIVD
TraceabilityTraceability
SurveillanceSurveillance
Daily surveillance of IVD system traceability Daily surveillance of IVD system traceability
1.1. Verification of the consistency of declared performance Verification of the consistency of declared performance
during routine operations performed in accordance with the during routine operations performed in accordance with the
manufacturermanufacturer’’s instructionss instructions
(checking of system alignment by (checking of system alignment by IQC component IIQC component I))
2.2. Participation to appropriately structured EQASParticipation to appropriately structured EQAS
((““that meet metrological criteriathat meet metrological criteria””))
Braga F & Panteghini M, Braga F & Panteghini M,
Clin Chim Acta 2014;432:55Clin Chim Acta 2014;432:55
IVDIVD
TraceabilityTraceability
SurveillanceSurveillance
Analytical quality
of measurement
Check alignment Imprecision
qualify
Reliability of the analytical system
AnalyticalAnalytical QualityQuality Control in the Control in the TraceabilityTraceability EraEra
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
10-M
ay
25-M
ay
28-J
un
13-Jul
28-J
ul
11-A
ug
27-Aug
11-Sep
26-Sep
13-O
ct
24
+3SD
+2SD
+1SD
19
29
34
Monitoring the reliability of the measuring system through IQC: Monitoring the reliability of the measuring system through IQC:
Component I. Check alignment (Component I. Check alignment (““system traceabilitysystem traceability””))A
cce
pta
ble
Acc
ep
tab
lera
ng
era
ng
eo
f co
ntr
ol
ma
teri
al
of
con
tro
l m
ate
ria
l
This program checks whether in the course of an analytical run tThis program checks whether in the course of an analytical run the performance of a he performance of a
measuring system complies with the set goals, represented by themeasuring system complies with the set goals, represented by the acceptable acceptable
ranges of control materials. ranges of control materials.
Clinical laboratories must verify the consistency of declared peClinical laboratories must verify the consistency of declared performance during routine operations rformance during routine operations
performed in accordance with the manufacturerperformed in accordance with the manufacturer’’s instructions, by s instructions, by checking that values of control checking that values of control
materials provided by the manufacturer as component of the measumaterials provided by the manufacturer as component of the measuring system are in the ring system are in the
established control rangeestablished control range, with no clinically significant changes in the assumed traceabl, with no clinically significant changes in the assumed traceable results.e results.
PlatformPlatform
CalibratorsCalibratorsReagentsReagents
Control material(s)Control material(s)
PlatformPlatform
CalibratorsCalibratorsReagentsReagents
PlatformPlatform
CalibratorsCalibratorsReagentsReagents
Control material(s)Control material(s)
Acceptance/rejection of
the analytical run in
“real time”
Acceptance/rejection of Acceptance/rejection of
the analytical run in the analytical run in
““real timereal time””
Internal Quality Control
(Component I)
Internal Quality Control Internal Quality Control
(Component I)(Component I)
Testing alignmentTesting alignment
[[““system traceabilitysystem traceability””]]
Any “out of control” signal must be made available with
sufficient time to allow immediate corrective actions
to bring again the situation under control (virtually
“unbiased”) and before reports related to the samples
analyzed in the affected analytical run are issued.
Any Any ““out of controlout of control”” signal must be made available with signal must be made available with
sufficient time to allow immediate corrective actions sufficient time to allow immediate corrective actions
to bring again the situation under control (virtually to bring again the situation under control (virtually
““unbiasedunbiased””) and before reports related to the samples ) and before reports related to the samples
analyzed in the affected analytical run are issued.analyzed in the affected analytical run are issued.
Daily surveillance of IVD system traceability Daily surveillance of IVD system traceability
1.1. Verification of the consistency of declared performance Verification of the consistency of declared performance
during routine operations performed in accordance with the during routine operations performed in accordance with the
manufacturermanufacturer’’s instructionss instructions
(checking of system alignment by (checking of system alignment by IQC component IIQC component I))
2.2. Participation to appropriately structured EQASParticipation to appropriately structured EQAS
((““that meet metrological criteriathat meet metrological criteria””))
Braga F & Panteghini M, Clin Braga F & Panteghini M, Clin
Chim Acta 2014;432:55Chim Acta 2014;432:55
IVDIVD
TraceabilityTraceability
SurveillanceSurveillance
Analytical quality
of measurement
Check alignment Imprecision
qualify
Reliability of the analytical system
AnalyticalAnalytical QualityQuality Control in the Control in the TraceabilityTraceability EraEra
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Requirements for the applicability of EQAS results in the Requirements for the applicability of EQAS results in the
evaluation of the performance of participating laboratories evaluation of the performance of participating laboratories
in terms of traceability of their measurementsin terms of traceability of their measurements
FeatureFeature AimAim
EQAS EQAS materialsmaterials valuevalue--assignedassigned
withwith referencereference proceduresprocedures byby
anan accreditedaccredited refref. . laboratorylaboratory
ToTo checkcheck traceabilitytraceability of of
commercial system commercial system toto referencereference
systemsystem
ProvedProved commutabilitycommutability of EQAS of EQAS
materialsmaterials
ToTo allowallow transferabilitytransferability of of
participatingparticipating laboratorylaboratory
performance performance toto the the measurementmeasurement
of of clinicalclinical samplessamples
Definition and use of the Definition and use of the
clinically allowable clinically allowable
measurement errormeasurement error
ToTo verifyverify the the suitabilitysuitability of of
laboratorylaboratory measurementsmeasurements in in
clinicalclinical settingsetting
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:7 2010;48:7
InfusinoInfusino I I etet al., al., ClinClin ChemChem Lab Lab MedMed 2010;48:3012010;48:301
Braga F & Braga F & PanteghiniPanteghini M. M. ClinClin ChemChem Lab Lab MedMed 2013;51:17192013;51:1719
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
The role of the endThe role of the end--usersusers
1. Availability and quality of information about IVD
metrological traceability and uncertainty
2. Daily surveillance of IVD system traceability
3. Estimating the measurement uncertainty due to
the random effects
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Post-marketingsurveillance
PostPost--marketing
marketingsurveillance
surveillance
Analytical quality
of measurement
Check alignment Imprecision
qualify
Reliability of the analytical system
AnalyticalAnalytical QualityQuality Control in the Control in the TraceabilityTraceability EraEra
PanteghiniPanteghini M, M, ClinClin ChemChem Lab Lab MedMed 2010;48:72010;48:7
Braga F & Panteghini M, Clin Chim Acta 2014;432:55Braga F & Panteghini M, Clin Chim Acta 2014;432:55
Internal Quality Control
(Component II)
Internal Quality Control Internal Quality Control
(Component II)(Component II)
Testing the uncertainty Testing the uncertainty
due to the random effectsdue to the random effects
((““imprecisionimprecision””))
System stability at
medium/long term
System stability at System stability at
medium/long termmedium/long term
This program provides, through
mechanisms of retrospective
evaluation, data useful to the
knowledge of variability of
measuring system and of its use by
the individual laboratory.
This program provides, through This program provides, through
mechanisms of retrospective mechanisms of retrospective
evaluation, data useful to the evaluation, data useful to the
knowledge of variability of knowledge of variability of
measuring system and of its use by measuring system and of its use by
the individual laboratory.the individual laboratory.
System
Reagent lots
Laboratory
0,0
2,5
5,0
7,5
10,0
12,5
15,0
august-
09octo
ber-0
9dec
ember-
09febru
ary-10
april-1
0june-10
august-
10octo
ber-1
0dec
ember-
10febru
ary-11
April-11
july-11
septem
ber-1
1Monitoring the reliability of the measuring system through IQC: Monitoring the reliability of the measuring system through IQC:
Component II. Evaluate the system + individual lab imprecisionComponent II. Evaluate the system + individual lab imprecision
System imprecision
System calibration
(combined) uncertainty
Individual lab
performance
(IQC safety margin)
Measurement
uncertainty
budget
[adopted cut[adopted cut--off for myocardial necrosis >15 off for myocardial necrosis >15 ngng/L]/L]Cumulative mean, 17 Cumulative mean, 17 ngng/L/L
CV, %CardiacCardiac troponintroponin T high sensitiveT high sensitive
MonthlyMonthly monitoringmonitoring of of imprecisionimprecision byby IQC materialIQC material
Requirements for IQC material
(Component II)
RequirementsRequirements forfor IQC material IQC material
((ComponentComponent II)II)
RequirementRequirement CommentComment
MatrixedMatrixed material from a thirdmaterial from a third--
party independent source party independent source
should be used (e.g., freshshould be used (e.g., fresh--
frozen pool)frozen pool)
Material must be different from the Material must be different from the
system control material used for system control material used for
checking alignmentchecking alignment
Specimens closely resembling Specimens closely resembling
authentic patient samples authentic patient samples
(commutability)(commutability)
Commercial nonCommercial non--commutable controls commutable controls
may provide a different impression of may provide a different impression of
imprecision performanceimprecision performance
Specimens of concentrations Specimens of concentrations
appropriate to the clinical appropriate to the clinical
application of the application of the analyteanalyte
When clinical decision cutWhen clinical decision cut--points are points are
employed, samples around these employed, samples around these
concentrations should preferentially be concentrations should preferentially be
selected selected