March 4 2021 Fingerstick Blueprint Public Comment Announcement MDIC is a 501 c3 and publicprivate partnership created with the sole objective of advancing regulatory science of medical devices for patient benefit ID: 933109
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Slide1
Comment Period: March 4 – April 5, 2021
March 4, 2021
Fingerstick Blueprint – Public Comment Announcement
Slide2MDIC is a 501 (c)(3) and public-private partnership created with the sole objective of advancing regulatory science of medical devices for patient benefit.
Who We Are
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Slide3Timothy Stenzel, MD, PhD
, Director of Office of In Vitro Diagnostics and Radiological Health | OHT7 | CDRH | FDA
Shridhara Alva, PhD,
Senior Director, Clinical Affairs | Abbott Diabetes Care (Working Group Chair)Corinne Fantz, PhD
, Director, Medical and Scientific Affairs-POC | Roche Diagnostics CorporationRex Astles, PhD, Acting Lead, Data Science Team | Center for Disease Control and Prevention
MDICx Panelists
Slide4Director of Office of In Vitro Diagnostics and Radiological Health | OHT7 | CDRH | FDA
Timothy Stenzel, MD, PhD
Slide5Increasing need for scientifically sound and practical study design recommendations when evaluating analytical performance characteristics of POC devices, including CLIA waived and non-CLIA waived devices, utilizing capillary whole blood specimens (fingerstick specimens)
The Issue:
Slide6Advantages for POC testing
small sample volume
ease of sample collection
fast sample collection and testing
Challenges for assay validation
small sample volume
subject recruitmentsample stabilitybiological variations Fingerstick samples
Slide7MDIC | Program Director, Clinical Dx
Carolyn Hiller, MBA
Slide8Subject Matter Experts from:
FDA | CDRH | OIR
CDC
Industry
Expert Advisors
Working Group Assembled
Slide9Industry:
*Shridhara Alva, PhD, Abbott Jacqueline Barrows, RN, ICON plc
Corinne Fantz, PhD, Roche
Maria Figueroa, AbbottPam Frank, Abbott
Ian Giles, MD, SysmexEileen Hiller, BDGordon McFarlane, PhD, ICONPeter Shearstone, Thermo Fisher Scientific
Government:J. Rex Astles, PhD, CDCMarina Kondratovich, PhD, FDA | CDRH | OIRMarianela Perez-Torres, PhD, FDA | CDRH | OIR
Expert Advisors:Susan Alpert, PhD, MDAlberto Gutierrez, PhD MDIC:Carolyn Hiller, Program Director, Clinical Diagnostics *Working Group ChairMDIC Fingerstick Blueprint Working Group:
Slide10We heard from:
IVD Industry
Regulatory Agency: such as FDA, Health Canada, etc.
Contract Clinical Research Organizations
Regulatory consultants
Survey of experience
Slide11Precision
Method Comparison
Survey Illuminated Greatest Pain Points:
Slide12Definitions/Acronyms
Regulatory Considerations for POCT Devices
Study Designs for Candidate Device Clearance/Approval
(both Non-Waived and CLIA Waived Tests)
Considerations for the Use of Surrogate SamplesConsiderations for Data Analysis in Method Comparison and Precision StudiesAdditional Considerations for Precision Studies with Fingerstick Samples
The Blueprint includes:
Slide13Senior Director, Clinical Affairs | Abbott Diabetes Care | MDIC Fingerstick Blueprint Working Group Chair
Shridhara Alva, PhD
Slide14A study design blueprint for using data from capillary whole blood collected by fingerstick for analytical validation of IVD tests.
General guidance on considerations for study design.
Specific devices may require modifications in order to implement these studies.
Reading and following this document neither guarantees FDA approval/clearance nor payment from insurance companies.
Purpose of the Blueprint
Slide15Two Approaches for CLIA Waiver
Slide16Fingerstick only
Study Design for a Non-Waived Test
Test environment
Site
Studies to be performed at each site
POCT site1
Method ComparisonCandidate device tested with fingerstick by trained operators Vs Comparator method by laboratory professionals Precision Evaluation
Reproducibility study using plasma/serum or liquid control AND Reproducibility study with fingerstick samplesDesign A (method comparison + precision study) ORDesign B (a separate precision study)
2
3 Internal siten/a
Matrix Comparison study of fingerstick vs. plasma/serum or liquid control for analytical performance evaluation by laboratory professionalsEvaluation of between-lot and between-instrument variability using plasma/serum or liquid control
Slide17Fingerstick and Venous Samples
Study Design for a Non-Waived Test
Test environment
Site
Studies to be performed at each site
POCT site1
Method ComparisonCandidate device tested with fingerstick and venous sample (with one anticoagulant) by trained operators Vs Comparator method by laboratory professionals
Precision EvaluationReproducibility study using plasma/serum or liquid control AND Reproducibility study with fingerstick samples and venous samples Design A (method comparison + precision study) OR
Design B (a separate precision study)2
3 Internal siten/a
Matrix Comparison study of fingerstick and venous samples vs. plasma/serum or liquid control for analytical performance evaluation by laboratory professionals
Matrix comparison study for different anticoagulants (anticoagulant 1 vs. anticoagulant 2…)Evaluation of between-lot and between-instrument variability using plasma/serum or liquid control
Slide18Fingerstick and Venous Samples: Special Situations
Study Design for a Non-Waived Test
Test environment
Site
Studies to be performed at each site
POCT site1
Method ComparisonCandidate device tested with venous sample (with one anticoagulant) by trained operators Vs Comparator method by laboratory professionals
Precision EvaluationReproducibility study using plasma/serum or liquid control AND Reproducibility study with venous samples Design A (method comparison + precision study) ORDesign B (a separate precision study)
2
3 Internal siten/a
Matrix Comparison study of fingerstick and venous samples vs. plasma/serum or liquid control for analytical performance evaluation by laboratory professionalsEvaluation of between-lot and between-instrument variability using plasma/serum or liquid control
Consult regulatory agency for acceptability of this study design
Slide19Precision studies should be able to provide estimates of following components of variance:
repeatabilitybetween-runbetween-daybetween-lot
between-calibration
between-instrumentbetween-operator between-site
Precision Studies
Slide20Different studies for different components of Variance
Precision Studies for non-Waived Test
Sample
Repeatability
Between-day
Between-
lotBetween-instrumentBetween-operatorBetween-site
Surrogate sampleStudy 1
Study 1Study 3
Study 3Study 1
Study 1Fingerstick sampleStudy 2 Study 2 POCT Sites: Study 1: Test with surrogate samples, different components of variance such as repeatability, between-run (if applicable), between-day, between-operator, and between-site components can be evaluated.
Study 2: Test FS samples, repeatability with FS and between-POCT operator components can be evaluated.Manufacturer’s siteStudy 3: In addition, precision between lots and between instruments should be determined at the manufacturer’s internal site in a separate precision study.
Slide21Fingerstick Samples
Design A: Method Comparison + Precision Study
Test environment
Site
Studies to be performed at each site
POCT site1
Method Comparison + Precision StudyCandidate POCT device, Patient 1, Test 1, Operator 1Candidate POCT device, Patient 1, Test 2, Operator 2vs. Comparator method by laboratory professionals
Precision EvaluationReproducibility study using plasma/serum or liquid control2
3
Slide22Fingerstick Samples
Design B: Precision Study
Test environment
Site
Studies to be performed at each site
POCT site1
Each subinterval has five patients Each patient is tested by two operatorsTotal of four fingerstick for each patient Candidate POCT device, Patient 1, Test 1, Operator 1
Candidate POCT device, Patient 1, Test 2, Operator 1Candidate POCT device, Patient 1, Test 3, Operator 2Candidate POCT device, Patient 1, Test 4, Operator 2Precision Evaluation
Reproducibility study using plasma/serum or liquid control2
3
Slide23Fingerstick Samples
Study Design for a Waived Test
Test environment
Site
Studies to be performed at each site
POCT site1
Operator ComparisonCandidate device, Patient 1; Sample 1, untrained operatorvs.
Candidate device, Patient 1, Sample 2, trained operator Comparison of PrecisionPrecision comparison of untrained and trained operators Design A (operator comparison + precision study) or
Design B (a separate precision study)2
3
Slide24Fingerstick + Venous Samples
Study Design for a Waived Test
Test environment
Site
Studies to be performed at each site
POCT site1
Operator Comparison for Fingerstick Candidate device, untrained operator (2 operators per patient) Vs trained operator(2 operators per patient) for each patientOperator Comparison for Venous samples (each anticoagulant)
Candidate device, anticoagulant 1, untrained operator Vs anticoagulant 1, trained operator for each patient Comparison of Precision with Fingerstick and Venous SamplesPrecision comparison of untrained and trained operators Design A (operator comparison + precision study) or
Design B (a separate precision study)2
3
Slide25Design A
Each patient is tested
4 Fingerstick tests per patient
3 untrained operators and 2 trained operators per site
Operators are randomizedDesign B
Each site test 5 patients per subinterval
5 Fingerstick tests per patient3 untrained operators and 2 trained operators per siteOperators are randomizedPrecision Study Design for a Waived Test
Slide26Fingerstick only
CLIA Waiver Studies for a New Device
Test environment
Site
Studies to be performed at each site
POCT site1
Method ComparisonCandidate device tested with fingerstick by untrained operators Vs Comparator method by laboratory professionals Precision Evaluation by untrained operator
Reproducibility study using plasma/serum or liquid control AND Reproducibility study with fingerstick samplesDesign A (method comparison + precision study) ORDesign B (a separate precision study)
2
3 Internal siten/a
Matrix Comparison study of fingerstick vs. plasma/serum or liquid control for analytical performance evaluation by laboratory professionalsEvaluation of between-lot and between-instrument variability using plasma/serum or liquid control
Slide27Test method
Test levels should cover the measurement range + medical decision levels
Number of test devices, reagent lots, test sites, test days
Presentation of different components of variability
Design Considerations for Precision Studies
Slide28Director, Medical and Scientific Affairs |
Roche Diagnostics Corporation
Corinne Fantz, PhD
Slide29Design Considerations
Combined data set should have samples spanning the measurement range, approximately uniformly
Each site should try to include samples across the span of the measurement range
A total of
120 patients should be enrolled for the method comparison study for a nonwaived testSurrogate samples are not recommended
Minimum 3 test sites and 2 operators per site
Method Comparison – Non-Waived Test
Slide30Sequential Approach
Combined data set should have samples spanning the measurement range, approximately uniformly
Each site should try to include samples across the span of the measurement range
A total of
240 patients should be enrolled for the method comparison study for a waived testSurrogate samples are not recommended
Minimum 3 test sites and 1-3 untrained operators per site (total 9 untrained operators)
Method Comparison – Waived test
Slide31Dual Approach
Combined data set should have samples spanning the measurement range, approximately uniformly
A total of
360 patients
should be enrolled for the method comparison study for a waived testProvisions are provided for situations where only trained operators are allowed to perform test for some subintervalsTakes into account systematic difference between trained operator and untrained operator established in a different subinterval
Method Comparison –Waived test
Slide32Use of Surrogate Samples
Unmodified patient samples provide best assessment of performance
When surrogate samples are used, evidence that surrogate samples are true representation of the unmodified fingerstick samples should be provided.
Different design approaches are provided
Method Comparison
Consult regulatory agency for acceptability of this study design
Slide33Legally marketed traceable calibration method or well validated method
In the absence of a reliable laboratory analyzer, another cleared POCT device may be used
Consider sample type variations – not all comparator methods are validated to use fingerstick samples
Understand the concentration difference between sample types and adequately address
Comparator Method
Consult regulatory agency for acceptability of this study design
Slide34Data Analysis and Presentation
Minimize oversampling
In study design
After study completion
Not performing comparator test on excessive samplesWeighted regressionRandom deletion of excessive samples for overfilled bins
Method Comparison
Slide35Design Considerations
Matrix comparisons are done
Between fingerstick and surrogate samples
Venous samples with different anticoagulants
40 pairs of results in each sample type covering the measurement rangeFor repeatability testing, two replicates are requiredThis study can be performed at one site or at the manufacturer’s internal site
Matrix Comparison
Slide36Additional Questions? Diagnostics@mdic.org
Download the Draft Blueprint here:
https://mdic.org/fingerstickdraft