Lumpipulse G CA19-9-N
Device Facts
| Record ID | K191973 |
|---|---|
| Device Name | Lumpipulse G CA19-9-N |
| Applicant | Fujirebio Dianostics, Inc. |
| Product Code | NIG · Immunology |
| Decision Date | Oct 22, 2019 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 866.6010 |
| Device Class | Class 2 |
Indications for Use
Lumipulse® G CA19-9-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA 19-9 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System. The assay is to be used as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable levels of CA19-9 at some point in their disease process. Serial testing for patient CA19-9 assay values should be used in conjunction with other clinical methods used for monitoring cancer of the exocrine pancreas.
Device Story
Lumipulse G CA19-9-N is a two-step chemiluminescent enzyme immunoassay (CLEIA) for quantitative measurement of CA 19-9 in human serum or plasma. Performed on the LUMIPULSE G1200 System; device uses anti-CA19-9 monoclonal antibody-coated particles to capture CA 19-9 from patient samples. Captured antigen is labeled with alkaline phosphatase (ALP)-conjugated anti-CA19-9 antibody. Addition of substrate (AMPPD) results in luminescence proportional to CA 19-9 concentration. Used by clinical laboratory professionals to monitor serial CA 19-9 levels in patients with exocrine pancreatic cancer. Results assist physicians in assessing disease progression or response to therapy when used alongside other clinical methods. Benefits include standardized serial monitoring for pancreatic cancer management.
Clinical Evidence
Clinical study assessed 83 patients with pancreatic cancer (374 serial observations). Sensitivity 64.29%, specificity 60.53%, total concordance 61.23%. Positive change (≥15%) in CA 19-9 correlated with disease progression in 65% of cases; no significant change correlated with no progression in 61% of cases.
Technological Characteristics
CLEIA technology; two-step immunoassay. Reagents: anti-CA19-9 monoclonal antibody (mouse)-coated particles, ALP-labeled anti-CA19-9 monoclonal antibody (mouse). Buffer: Tris/Bis-Tris. Substrate: AMPPD. Measuring range: 0.7-500 U/mL. Instrument: LUMIPULSE G1200 System. Storage: 2-10°C. Preservative: sodium azide.
Indications for Use
Indicated for the serial measurement of CA 19-9 to aid in the management of patients diagnosed with cancers of the pancreas. Not for cancer screening or diagnosis. Contraindicated in patients genotypically negative for Lewis blood group antigen as they cannot produce CA 19-9.
Regulatory Classification
Identification
A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.
Special Controls
*Classification.* Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.
Predicate Devices
- ARCHITECT® CA 19-9TM xR Assay (K052000)
Related Devices
- K200997 — Lumipulse G CA19-9-N · Fujirebio Diagnostics,Inc. · May 14, 2020
- K050231 — ELECSYS CA 19-9 IMMUNOASSAY, ELECSYS CA 19-9 CALSET · Roche Diagnostics Corp. · Jul 6, 2005
Submission Summary (Full Text)
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Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K191973
B Applicant
Fujirebio Diagnostics, Inc.
C Proprietary and Established Names
Lumipulse G CA19-9-N
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| NIG | Class II | 21 CFR 866.6010 - Tumor-Associated Antigen Immunological Test System | IM - Immunology |
## II Submission/Device Overview:
A Purpose for Submission:
New Device
B Measurand:
CA 19-9
C Type of Test:
Chemiluminescent Enzyme Immunoassay (CLEIA)
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III Intended Use/Indications for Use:
A Intended Use(s):
See Indication for Use below.
B Indication(s) for Use:
Lumipulse G CA19-9-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA 19-9 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.
The assay is to be used as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable levels of CA 19-9 at some point in their disease process. Serial testing for patient CA 19-9 assay values should be used in conjunction with other clinical methods used for monitoring cancer of the exocrine pancreas.
Warning Statement: The concentration of CA 19-9 in a given specimen, as determined by assays from different manufacturers, can vary due to differences in assay methods and reagent specificity. The results reported by the laboratory to the physician must include the identity of the assay for CA 19-9 used. Values obtained with different assay methods cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used for determining serial levels of CA 19-9 is changed, the laboratory must perform additional serial testing to confirm baseline values. Prior to changing assays, the laboratory MUST confirm baseline values for patients being serially monitored. Lumipulse G CA19-9-N should not be used for cancer screening or diagnosis.
Patients known to be genotypically negative for Lewis blood group antigen are unable to produce the CA 19-9 antigen even in the presence of malignant tissue. Phenotyping for the presence of the Lewis blood group antigen may be insufficient to detect true Lewis antigen negative individuals. Even patients who are genotype positive for the Lewis antigen may produce varying levels of CA 19-9 as the result of gene dosage effect.
C Special Conditions for Use Statement(s):
For Prescription Use Only
D Special Instrument Requirements:
Lumipulse G1200 System (K142895)
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## IV Device/System Characteristics:
### A Device Description:
#### Reagents
The Lumipulse G CA19-9-N Immunoreaction Cartridges (cat. # 235126) consists of $3 \times 14$ tests. Each kit contains the following:
1) Antibody-Coated Particle Solution: Liquid when used. The $250~\mu \mathrm{L}$ Immunoreaction Cartridge contains $150~\mu \mathrm{g / mL}$ anti-CA19-9 monoclonal antibody (mouse)-coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in $0.15\mathrm{M}$ sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at $15^{\circ}\mathrm{C}$ or lower. Preservative: sodium azide.
2) Enzyme-Labeled Antibody Solution: Liquid. The $350~\mu \mathrm{L}$ /Immunoreaction Cartridge contains $0.5~\mu \mathrm{g / mL}$ alkaline phosphatase (ALP: calf)-labeled anti-CA19-9 monoclonal antibody (mouse), protein stabilizers (bovine, calf, and mouse) and chemical stabilizers in $0.05\mathrm{M}$ sodium chloride/Bis-Tris buffer. Preservative: sodium azide.
#### Materials required but not provided:
1) Lumipulse G CA19-9-N Calibrators: Liquid, CAL 1 and CAL 2
2) Quality Control material
3) Lumipulse G Substrate Solution
4) Lumipulse G Wash Solution
5) Lumipulse G Specimen Diluent 1
6) Sampling tips for LUMIPULSE G System
7) Soda lime for LUMIPULSE G System
8) Lumipulse G Dilution Cartridges
### B Principle of Operation:
Lumipulse G CA19-9-N is an assay system, including a set of immunoassay reagents, for the quantitative measurement of CA 19-9 in human serum and plasma (sodium heparin, lithium heparin, or dipotassium EDTA) based on CLEIA technology by a two-step immunoassay method on the LUMIPULSE G1200 System. CA 19-9 in specimens specifically binds to anti-CA19-9 monoclonal antibody (mouse) on the particles, and antigen-antibody immunocomplexes are formed. The particles are washed and rinsed to remove unbound materials. Alkaline phosphatase (ALP: calf)-labeled anti-CA19-9 monoclonal antibody (mouse) specifically binds to CA 19-9 of the immunocomplexes on the particles, and additional immunocomplexes are formed. The
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particles are washed and rinsed to remove unbound materials. Substrate Solution is added and mixed with the particles.
AMPPD (3-(2'-spiroadamantane)-4-methoxy-4-(3''-phosphoryloxy)-phenyl-1, 2-dioxetane disodium salt) contained in the Substrate Solution is dephosphorylated by the catalysis of ALP indirectly conjugated to particles. Luminescence (at a maximum wavelength of 477 nm) is generate by the cleavage reaction of dephosphorylated AMPPD. The luminescent signal reflects the amount of CA 19-9.
V Substantial Equivalence Information:
A Predicate Device Name(s):
ARCHITECT CA 19-9XR Assay
B Predicate 510(k) Number(s):
K052000
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K191973 | K052000 |
| --- | --- | --- |
| Device Trade Name | Lumipulse G CA19-9-N | ARCHITECT CA 19-9XR |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Lumipulse G CA19-9-N is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative measurement of CA 19-9 in human serum or plasma (sodium heparin, lithium heparin, or dipotassium EDTA) on the LUMIPULSE G System.
The assay is to be used as an aid in the management of patients diagnosed with cancer of the exocrine pancreas who have detectable | The ARCHITECT CA 19-9XR assay is a Chemiluminescent Microparticle Immunoassay (CMIA) for the quantitative determination of 1116-NS-19-9 reactive determinants in human serum and plasma on the ARCHITECT i System.
The ARCHITECT CA 19-9XR assay is to be used as an aid in the management of pancreatic cancer patients with a detectable level of CA 19-9 at some point in their disease process and |
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| | levels of CA 19-9 at some point in their disease process. Serial testing for patient CA19-9 assay values should be used in conjunction with other clinical methods used for monitoring cancer of the exocrine pancreas. | in conjunction with other clinical methods. |
| --- | --- | --- |
| Classification | Class II | Same |
| Product Code | NIG | Same |
| Capture Antibody | monoclonal anti-CA19-9 antibody (mouse) | Same |
| Sample Type | human serum and plasma | Same |
| Reagent Storage | Store at 2–10°C | Store at 2–8°C |
| Sample Size | 100 μL | < 100 μL |
| Calibration Frequency | Every 30 days | Same |
| General Device Characteristic Differences | | |
| Instrument | LUMIPULSE G System | ARCHITECT i System |
| Methodology | CLEIA | CMIA |
| Analytical Measuring Range | 0.7–500 U/mL | 2–1200 U/mL |
| Capture | Monoclonal anti-CA19-9 antibody (mouse)-coated particles | Monoclonal anti-CA 19-9 antibody coated paramagnetic microparticles |
| Conjugate Antibody | ALP (calf)-labeled anti-CA19-9 monoclonal mouse antibody | Acridinium labeled monoclonal anti-CA 19-9 F(ab')2 conjugate |
| Calibrators | 2 level set (1 vial/level):
Cal 1: 0 U/mL
Cal 2: 500 U/mL | 6 level set:
Calibrator A: anti-microbial agent, protein stabilizers in TRIS buffer
Calibrator B-F: Recombinant human 1116-NS-19-9 in TRIS buffer |
| Calibration Range | 0–500 U/mL | 0–1200 U/mL |
| Controls | 2 levels | 3 levels |
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VI Standards/Guidance Documents Referenced:
- CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
- CLSI EP6-A Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline
- CLSI EP07 Interference Testing in Clinical Chemistry; Approved Guideline – Third Edition
- CLSI EP14-A2 Evaluation of Matrix Effects; Approved Guideline – Second Edition
- CLSI EP17-A2 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – Second Edition
- CLSI EP25-A Evaluation of Stability of In Vitro Diagnostic Reagents: Approved Guideline
- CLSI EP28-A3c Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline-Third Edition
- CLSI EP34 Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking;
VII Performance Characteristics (if/when applicable):
A Analytical Performance:
All results presented below met the manufacturer’s pre-determined acceptance criteria.
1. Precision/Reproducibility:
Precision: Six native human serum samples with various concentrations of CA 19-9 were tested for 20 non-consecutive days with two runs per day in two replicates per run using a single reagent and calibrator lot for a total of 80 (2x2x20) Lumipulse G CA19-9-N test results per sample. The mean Lumipulse G CA19-9-N test result was computed and the within-run, between-run, between-day, and total standard deviations (SD) and associated coefficients of variation (%CV) were calculated.
| | | Within-Run | | Between-Run | | Between-Day | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | Mean (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 2.9 | 0.1 | 2.7 | 0.0 | 1.6 | 0.1 | 4.3 | 0.2 | 5.3 |
| 2 | 20.0 | 0.3 | 1.6 | 0.3 | 1.3 | 0.8 | 3.8 | 0.9 | 4.3 |
| 3 | 38.9 | 0.6 | 1.6 | 0.4 | 1.0 | 0.8 | 2.2 | 1.1 | 2.9 |
| 4 | 173.9 | 2.1 | 1.2 | 1.3 | 0.8 | 2.6 | 1.5 | 3.6 | 2.1 |
| 5 | 318.9 | 3.9 | 1.2 | 3.3 | 1.0 | 3.6 | 1.1 | 6.3 | 2.0 |
| 6 | 452.8 | 4.7 | 1.0 | 3.3 | 0.7 | 4.7 | 1.0 | 7.5 | 1.6 |
Site-to-site Reproducibility: Six native human serum samples were tested at three sites with two runs per day in three replicates per run using a single reagent and calibrator lot for five non-consecutive days for a total of 30 Lumipulse G CA19-9-N test results per site. Three different LUMIPULSE G1200 Systems were used for testing (one per site) and there were 90
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replicates per sample across three sites (2x3x5x3). The mean Lumipulse G CA19-9-N test result was computed and the within-run, between-run, between-day, and total standard deviations (SD) and associated coefficients of variation (%CV) were calculated.
| | | Between-site | | Between-day | | Between-run | | Within-run | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | Mean (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 2.4 | 0.0 | 0.0 | 0.1 | 2.3 | 0.3 | 10.7 | 0.1 | 2.6 | 0.3 | 11.3 |
| 2 | 17.3 | 0.2 | 0.9 | 0.0 | 0.0 | 1.3 | 7.6 | 0.3 | 1.6 | 1.3 | 7.8 |
| 3 | 33.8 | 0.4 | 1.0 | 1.0 | 2.9 | 1.7 | 5.2 | 0.5 | 1.5 | 2.1 | 6.2 |
| 4 | 152.2 | 2.6 | 1.7 | 4.0 | 2.7 | 5.6 | 3.7 | 1.5 | 1.0 | 7.5 | 4.9 |
| 5 | 280.5 | 5.1 | 1.8 | 11.2 | 4.0 | 7.9 | 2.8 | 2.8 | 1.0 | 14.9 | 5.3 |
| 6 | 396.2 | 12.3 | 3.1 | 13.1 | 3.3 | 16.4 | 4.1 | 3.9 | 1.0 | 24.7 | 6.2 |
Lot-to-Lot Reproducibility: Six native human serum samples were tested at a single site with two runs per day in three replicates per run for five non-consecutive days for a total of 30 Lumipulse G CA19-9-N test results per lot. There were 90 replicates per sample across three lots (2x3x5x3). The mean Lumipulse G CA19-9-N test result was computed and the within-run, between-run, between-day, and total standard deviations (SD) and associated coefficients of variation (%CV) were calculated.
| | | Between-lot | | Between-day | | Between-run | | Within-run | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | Mean (U/mL) | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| 1 | 2.3 | 0.1 | 6.1 | 0.1 | 2.2 | 0.0 | 1.9 | 0.1 | 2.7 | 0.2 | 7.3 |
| 2 | 17.1 | 0.4 | 2.4 | 0.3 | 1.7 | 0.2 | 1.0 | 0.2 | 1.3 | 0.6 | 3.4 |
| 3 | 34.6 | 0.3 | 0.7 | 0.5 | 1.5 | 0.5 | 1.5 | 1.2 | 3.4 | 1.4 | 4.1 |
| 4 | 158.1 | 4.7 | 3.0 | 0.0 | 0.0 | 2.8 | 1.8 | 1.7 | 1.1 | 5.7 | 3.6 |
| 5 | 290.6 | 10.1 | 3.5 | 4.0 | 1.4 | 6.1 | 2.1 | 2.7 | 0.9 | 12.8 | 4.4 |
| 6 | 412.6 | 12.0 | 2.9 | 6.9 | 1.7 | 7.2 | 1.7 | 4.4 | 1.1 | 16.2 | 3.9 |
2. Linearity:
Two native human serum sample pools (high and low) were prepared. The high sample pool was diluted using the low sample pool in appropriate ratios to obtain 21 concentration levels (0.1 to 530 U/mL) of CA 19-9 that covers the full range of the assay from 0.7 to 500 U/mL. Four replicates were obtained at each concentration level to cover the assay measuring range. Data were analyzed using linear regression based on CLSI EP6-A Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline.
| Range (U/mL) | Slope (95% CI) | Intercept (95% CI) | R² |
| --- | --- | --- | --- |
| 1.11–486.19 | 1.033 (1.019, 1.047) | -0.008 (-0.080, 0.065) | 0.997 |
Dilution: A total of 15 native human serum sample pools at a known concentration of CA 19-9 were obtained and diluted at three different levels: five sample pools at each of 1:10, 1:100,
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and 1:200 dilutions. Each dilution was prepared by manual dilution and automatic on-board dilution. No differences were seen when comparing results from manual and on-board dilution. The recommended manual and automated dilution for Lumipulse G CA19-9-N is 1:10, 1:100 and 1:200 for samples up to 80,000 U/mL.
Hook Effect: The hook effect was evaluated for the Lumipulse G CA19-9-N on the LUMIPULSE G1200 System. No high dose effect was observed for samples containing approximately 200,000 U/mL of CA 19-9.
3. Analytical Specificity/Interference:
Native human serum samples at CA 19-9 concentrations of approximately 32.3 U/mL, 197.9 U/mL, and 344.7 U/mL were supplemented with a total of 10 potential endogenous and 12 therapeutic drug interferents as listed below.
| Endogenous Interferences | Test Concentration |
| --- | --- |
| Free Bilirubin (unconjugated) | 60 mg/dL |
| Conjugated Bilirubin | 60 mg/dL |
| Triglycerides (Intralipid 20% Emulsion) | 3,000 mg/dL |
| Hemoglobin | 500 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Total Protein (Human Serum Albumin) | 15 g/dL |
| Immunoglobulin G (IgG) | 5 g/dL |
| Biotin | 19.7 mg/dL |
| HAMA IgG | 1000 ng/dL |
| RF IgM | 1000 IU/mL |
| Therapeutic Drug Interferences | Test Concentration |
| 5-Fluorouracil | 39.0 mg/dL |
| Cisplatin | 5.70 mg/dL |
| Cyclophosphamide | 37.5 mg/dL |
| Cytarabine | 3.0 mg/dL |
| Doxorubicin HCl | 4.0 mg/dL |
| Gemcitabine | 38.2 mg/dL |
| Leucovorin | 11.4 mg/dL |
| Methotrexate | 90.9 mg/dL |
| Paclitaxel | 6.7 mg/dL |
| Pegylated Liposomal Doxorubicin (Doxil) | 5.2 mg/dL |
| Streptozotocin | 3.96 mg/dL |
| Tamoxifen | 6.0 mg/dL |
The Lumipulse G CA19-9-N on the LUMIPULSE G1200 System demonstrated an average interference of <10% from the test results in three replicates for each potential interferent.
4. Assay Reportable Range:
The analytical measuring interval (AMI) of the Lumipulse G CA19-9-N is 0.7 U/mL to 500.0 U/mL. When the test samples are diluted (1:200), the claimed reportable range of the Lumipulse G CA19-9-N is 0.7 U/mL to 80,000.0 U/mL.
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5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
a. Traceability: Calibration of the Lumipulse G CA19-9-N is traceable to in-house reference calibrators, whose values have been assigned to correlate to Fujirebio Diagnostics' CA19-9 radioimmunoassay.
b. Real Time Regent Stability: Six human serum samples at different levels of CA 19-9 were prepared for testing the real time stability of Lumipulse G CA19-9-N Immunoreaction Cartridges (IC) and the Lumipulse G CA19-9 Calibrators. Three lot combinations of Lumipulse G CA19-9-N ICs and Lumipulse G CA19-9-N Calibrators were utilized. The reagents were evaluated across four time points: Study Initiation, 6 months, 12 months, and 13 months. Each sample was tested in three runs and three replicates per run for a total of nine replicates at Study Initiation and in two runs and three replicates per run for a total of six replicates at 6 months, 12 months, and 13 months. The Lumipulse G CA19-9-N ICs and Calibrators are stable for 12 months at 2–10°C.
c. On board Reagent Stability: Six human serum samples at different levels of CA 19-9 were prepared for testing the on-board stability of Lumipulse G CA19-9-N Immunoreaction Cartridges (IC) and the Lumipulse G CA19-9 Calibrators on the LUMIPULSE G1200. A single lot of Lumipulse G CA19-9-N ICs and Lumipulse G CA19-9-N Calibrators were utilized. The reagents were evaluated in three replicates across four time points as follows: Study Initiation, 30 days, 12 months ± 5 days, and 13 months ± 5 days. The Lumipulse G CA19-9-N ICs and Calibrators on the LUMIPULSE G 1200 are stable up to 30 days on board. The study is ongoing.
d. Transport Conditions: The recommended transport condition for Lumipulse G CA19-9-N Immunoreaction Cartridges (IC) and the Lumipulse G CA19-9 Calibrators is at 2–10°C.
e. Sample Stability: Sample stability was tested using eight human serum samples collected across five tube types (SST serum, Red Top serum, K2 EDTA plasma, Lithium heparin plasma, and sodium heparin plasma). Two conditions for sample stability were evaluated: 2–10°C and –20±10°C. Five aliquots were stored at 2–10°C and tested at Day 1, Day 4, Day 7, Day 14, and Day 15. Three aliquots were stored at –20°C±10°C and tested at Day 7, Day 14, and Day 15. The samples were run on the LUMIPULSE G1200. The results demonstrated that:
- Samples collected across five tube types (SST serum, Red Top serum, K2 EDTA plasma, Lithium heparin plasma, and sodium heparin plasma) may be stored at 2–10°C for up to 4 days.
- Samples collected across five tube types (SST serum, Red Top serum, K2 EDTA plasma, Lithium heparin plasma, and sodium heparin plasma) may be stored at –20°C ±10°C for up to 14 days.
f. Expected Values: The calibrators are at two concentrations, 0 U/mL (CAL1) and 500 U/mL (CAL2).
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6. Detection Limit:
Limit of Blank (LoB):
Two blank samples were prepared by diluting normal healthy serum with human serum expressing ultra-low CA 19-9. Each sample was tested in ten replicates in each run with two runs per day for three days using two regent lots and two instruments. There was a total of 60 replicates per sample. The LoB was estimated as the 95th percentile of the distribution of test results using a non-parametric method. The highest estimate among the two lots was used as the claimed LoB. The LoB was determined to be 0.1 U/mL.
Limit of Detection (LoD):
Seven serum samples containing low levels of CA 19-9 were tested in ten replicates in two runs per day for three days using two regent lots and two instruments. Each lot was run on one LUMIPULSE G1200 instrument. For each lot combination, there was a total of 60 replicates per sample per reagent lot combination. The study design generated a total of 60 test determinations with each reagent lot and instrument combination. The study was conducted independently with two reagent lots and the highest estimate among the two lots was used as the claimed LoD. The LoD was determined to be 0.19 U/mL.
Limit of Quantification (LoQ):
Seven serum samples containing low levels of CA 19-9 were tested in ten replicates in two runs per day for three days using two regent lots and two instruments. Each lot was run on one LUMIPULSE G1200 instrument. For each lot combination, there was a total of 60 replicates per sample per reagent lot combination. The study design generated a total of 60 test determinations with each reagent lot and instrument combination. The LoQ was calculated to be 0.57 U/mL by identifying the measurand level at which a measurement procedure demonstrated total within-lab imprecision of 15 %CV. The claimed LoQ is 0.57 U/mL
7. Assay Cut-Off:
See Clinical Cut-off below.
B Comparison Studies:
1. Method Comparison:
A total of 130 human serum samples were obtained for the method comparison study. The test samples were collected in red-top or serum separator tubes (SST). Only the samples with the test results within the measuring range for both the Lumipulse G CA19-9-N and the ARCHITECT CA 19-9XR were included in the regression analysis (n=84). The samples tested ranged from 3.0 to 454.8 U/mL for Lumipulse G CA19-9 and 2.07 to 1056.05 U/mL for ARCHITECT CA 19-9XR assay. The linear regression analysis obtained from Passing-Bablok and Weighted Deming regression analysis comparing the Lumipulse G CA19-9 and ARCHITECT CA 19-9XR test results is shown below:
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| Regression Analysis | n | Correlation Coefficient (R) | Intercept (95% CI) | Slope (95% CI) | Average Bias (%) |
| --- | --- | --- | --- | --- | --- |
| Passing-Bablok | 84 | 0.6628 | 15.742 (4.770, 26.588) | 0.903 (0.706, 1.160) | 164.15 |
| Weighted Deming | 84 | 0.6628 | 1.865 (-0.931, 4.662) | 1.318 (1.011, 1.625) | 164.15 |
2. Matrix Comparison:
The Anticoagulant Matrix Comparison Study was conducted using 50 donor-matched sets of serum (red top and serum separator tubes (SST)) and plasma (K2EDTA, sodium heparin and lithium heparin) samples. The linear regression analysis obtained from Weighted Deming regression analysis comparing the Lumipulse G CA19-9-N test results of the control matrix sample (Red Top Serum) to the Lumipulse G CA19-9-N test results of each matrix sample (SST, K2EDTA, Lithium Heparin, and Sodium Heparin) is shown below:
| Tube Type | n | Concentration Range (U/mL) | Correlation Coefficient (R) | Intercept (95% CI) | Slope (95% CI) |
| --- | --- | --- | --- | --- | --- |
| SST | 50 | 3.7–441.2 | 0.994 | 0.776 (-3.026, 4.579) | 1.009 (0.963, 1.055) |
| K2 EDTA | 50 | 4.2–456.0 | 0.998 | -0.120 (-0.475, 0.235) | 1.004 (0.986, 1.022) |
| Lithium Heparin | 50 | 4.8–430.3 | 0.994 | 0.634 (0.008, 1.261) | 0.989 (0.961, 1.017) |
| Sodium Heparin | 50 | 3.9–470.2 | 0.998 | 0.768 (-0.078, 1.614) | 0.998 (0.975, 1.022) |
C Clinical Studies:
1. Clinical Sensitivity:
The clinical performance of the Lumipulse G CA19-9-N assay was determined on the LUMIPULSE G1200 System by assessing changes in CA 19-9 levels in serial serum samples from patients with exocrine pancreatic cancer and comparing the results to changes in the disease status. The patients were females and males with a historically/pathologically confirmed diagnosis of exocrine pancreatic cancers at any stage (Stage IA to IV). A minimum of three to a maximum of 12 serial blood draws were collected from each patient. The subject inclusion and exclusion criteria are as follows:
Inclusion criteria:
- Female or Male
- 22 years of age or older
- Diagnosed with exocrine pancreatic cancer
- Appropriate informed consent or remnant sample documentation
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Exclusion criteria:
- Less than 22 years old
- No diagnosis of exocrine pancreatic cancer
- Invalid informed consent or remnant sample documentation
The clinical data collected for each subject included the following: subject ID, age, gender, race/ethnicity, date of cancer diagnosis, histology, grade, and stage. For each subject sample draw, the following information will be collected, if available: chemotherapeutic treatment information (onset date, end date, regimen), imaging information (type, findings), physical exam date and findings, sample draw date, procedure information (type, date and findings), clinical disease status (see below for description), date or recurrence, and date of death (if subject expired).
Of the 83 patients, the age ranged from 47 to 87 years with a median of 65 years. Seventy-four subjects (89.2%) were Caucasian/White and the remaining subjects included six (7.2%) African American, two (2.4%) Asian/Pacific Islander, and one (1.2%) Other. A total of 374 pairs of observations were obtained from 83 patients with an average number of 5.6 observations per patient with a minimum of two follow up visits after the initial visit. Each patient's clinical disease status was evaluated by the clinical evidence which was identified by reviewing the compilation of procedures and clinical notes which may have included but were not limited to: imaging of various modalities, physical exam, physician transcription notes, and/or other laboratory data. The clinical disease status was categorized to NED (no evidence of disease), SD (stable disease), PD (progressive disease), or RD (Responding disease) based on the change in the clinical evidence at the follow up visit compared to the previous visit.
The CA 19-9 ratio distribution by clinical status is summarized below when the Lumipulse G CA19-9-N test result at a follow up visit was compared to the level at the previous visit.
| Clinical Disease Status | n | Minimum | 1st Quartile | Median | 3rd Quartile | Maximum |
| --- | --- | --- | --- | --- | --- | --- |
| NED | 37 | 0.35 | 0.81 | 0.92 | 1.42 | 4.15 |
| SD | 250 | 0.04 | 0.77 | 1.06 | 1.49 | 100.79 |
| PD | 70 | 0.10 | 0.98 | 1.43 | 2.41 | 22.85 |
| RD | 17 | 0.22 | 0.56 | 0.73 | 0.89 | 2.24 |
| Total | 374 | | | | | |
Based on the quantitative measures of CA 19-9 using the Lumipulse G CA19-9-N assay, a positive change in CA 19-9 was defined as an increase in the CA 19-9 level that was at least 15% greater at the follow up visit compared to the level at the previous value visit. Sixty-five percent (65%) or 45/70 of the patient samples with a positive change correlated with the disease progression in the disease status category (NED, SD, PD, and RD) while 61% (184/304) of the patient serial samples with no significant change in CA 19-9 value correlated with no progression. The total concordance was 61% (229/374).
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| Change in CA 19-9 Concentration | No Progression | Progression | Total |
| --- | --- | --- | --- |
| < 15% | 184 | 25 | 209 |
| ≥ 15% | 120 | 45 | 165 |
| Total | 304 | 70 | 374 |
The estimates of sensitivity, specificity, PPV, and NPV along with 95% confidence intervals were calculated for the Lumipulse G CA19-9-N assay using the cut-off of a ≥15% change in CA 19-9 concentration as shown below.
| Performance Measurement | Performance Measure % (95% CI) |
| --- | --- |
| Sensitivity | 64.29 (55.49, 73.08) |
| Specificity | 60.53 (55.60, 65.45) |
| Total Concordance | 61.23 (56.81, 65.65) |
| PPV | 27.27 (22.04, 32.50) |
| NPV | 88.04 (84.32, 91.76) |
2. Clinical Specificity:
See Section C.1 above.
3. Other Clinical Supportive Data:
The clinical performance of the Lumipulse G CA19-9-N assay on the LUMIPULSE G1200 System at different % change in CA 19-9 was evaluated against that of the predicate ARCHITECT CA 19-9XR (K052000) on the ACTHITECT i2000SR System using the test results obtained from the same patient cohort (See Section C.1 above). The CA 19-9 ratio distribution by clinical status was summarized below when the ARCHITECT CA 19-9XR test result at the follow up visit was compared to the level at the previous visit.
| Clinical Disease Status | n | Minimum | 1st Quartile | Median | 3rd Quartile | Maximum |
| --- | --- | --- | --- | --- | --- | --- |
| NED | 33 | 0.45 | 0.82 | 1.05 | 1.73 | 2.65 |
| SD | 202 | 0.04 | 0.68 | 1.00 | 1.58 | 376.15 |
| PD | 51 | 0.21 | 0.97 | 1.58 | 3.44 | 43.99 |
| RD | 15 | 0.19 | 0.44 | 0.68 | 0.84 | 2.05 |
| Total | 301 | | | | | |
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The estimates of sensitivity, specificity, PPV, and NPV along with 95% confidence intervals were calculated for the predicate assay, ARCHITECT CA 19-9xR. (K052000) using the cutoff of a ≥ 14% change in CA 19-9 concentration as shown below.
| Change in CA 19-9 Concentration | No Progression | Progression | Total |
| --- | --- | --- | --- |
| < 14% | 156 | 18 | 174 |
| ≥ 14% | 94 | 33 | 127 |
| Total | 250 | 51 | 301 |
| Performance Measurement | ARCHITECT CA 19-9xR Performance Measure % (95% CI) |
| --- | --- |
| Sensitivity | 64.71 (53.07, 76.34) |
| Specificity | 62.40 (57.29, 67.51) |
| Total Concordance | 62.79 (58.24, 67.34) |
| PPV | 25.98 (19.89, 32.08) |
| NPV | 89.66 (85.79, 93.52) |
The table below compared the clinical sensitivity and specificity for disease progression between the Lumipulse G CA19-9-N assay and the ARCHITECT CA 19-9xR assay for a series of % change in the CA 19-9 level within each assay's measuring range using the ROC curve analysis.
| | Lumipulse G CA19-9-N (N=374 paired observations) | | ARCHITECT CA 19-9xR (N=301 paired observations) | |
| --- | --- | --- | --- | --- |
| % Change in CA 19-9 | Sensitivity (%) | Specificity (%) | Sensitivity (%) | Specificity (%) |
| 10 | 67.1 | 55.6 | 66.7 | 60.8 |
| 20 | 62.9 | 62.8 | 64.7 | 64.4 |
| 30 | 55.7 | 68.8 | 62.8 | 68.4 |
| 40 | 52.9 | 73.0 | 54.9 | 70.4 |
| 50 | 44.3 | 76.6 | 54.9 | 72.8 |
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D Clinical Cut-Off:
See Expected Values below.
E Expected Values/Reference Range:
A total of 240 serum specimens obtained from an apparently healthy adult population (22 to 93 years old) were tested using the Lumipulse G CA19-9-N assay and the observed ranges are listed below. All Lumipulse G CA19-9-N concentrations are presented in U/mL.
| | Apparently Healthy Males and Females (Combined) | Apparently Healthy Males | Apparently Healthy Females |
| --- | --- | --- | --- |
| N | 240 | 120 | 120 |
| Mean (SD) | 11.0 (11.7) | 10.5 (11.4) | 11.5 (12.1) |
| Median | 6.7 | 6.2 | 7.6 |
| Range (min, max) | <0.7, 63.9 | <0.7, 63.9 | <0.7, 57.5 |
| Reference Interval (2.5th Percentile, 97.5th Percentile) | <0.7, 50.0 | <0.7, 40.1 | <0.7, 50.6 |
| N (%) with CA19-9 ≤ 25.0 | 88.8% | 88.3% | 89.2% |
| N (%) with CA19-9 ≤ 50.0 | 97.5% | 98.3% | 96.7% |
| N (%) with CA19-9 ≤ 75.0 | 100.0% | 100.0% | 100.0% |
In addition to the normal cohort, 75 serum samples from patients with benign pancreatic conditions and 120 from patients with exocrine pancreatic cancers were tested. The following tables summarize the sample distribution, diseases/conditions, and distribution of the Lumipulse G CA19-9-N assay results presented in U/mL.
| | Pancreatitis | Benign Lung Disease | Benign Renal Disease | Cirrhosis | Diabetes | Gallbladder Disease | Hepatitis | Rectal Polyps |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| N | 75 | 39 | 40 | 38 | 40 | 41 | 42 | 40 |
| Mean (SD) | 58.2 (227.0) | 31.9 (70.7) | 21.9 (31.1) | 33.3 (36.1) | 15.4 (15.1) | 45.3 (110.5) | 32.4 (37.1) | 20.0 (26.2) |
| Median | 18.5 | 13.8 | 12.6 | 20.6 | 9.9 | 12.0 | 21.6 | 8.8 |
| Range (min, max) | <0.7, 1966.0 | <0.7, 441.6 | <0.7, 180.6 | <0.7, 183.9 | <0.7, 69.5 | <0.7, 630.0 | <0.7, 159.3 | <0.7, 84.5 |
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| Reference Interval (2.5th Percentile, 97.5th Percentile) | <0.7, 181.4 | <0.7, 105.7 | <0.7, 68.3 | 4.7, 120.9 | <0.7, 56.0 | <0.7, 334.2 | <0.7, 151.6 | <0.7, 83.7 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| N (%) with CA 19-9 ≤25.0 | 62.7% | 71.8% | 70.0% | 57.9% | 80.0% | 68.3% | 61.9% | 80.0% |
| N (%) with CA 19-9 ≤50.0 | 84.0% | 87.2% | 90.0% | 84.2% | 95.0% | 82.9% | 78.6% | 85.0% |
| N (%) with CA 19-9 ≤75.0 | 89.3% | 89.7% | 97.5% | 89.5% | 100.0% | 90.2% | 90.5% | 87.5% |
| | Exocrine Pancreatic* | Biliary | Breast | CRC* | Gall-bladder | Liver | Lung | Ovarian | Stomach |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| N | 120 | 40 | 40 | 38 | 40 | 40 | 40 | 39 | 37 |
| Mean (SD) | 2873.1 (8721.0) | 2640.0 (9765.6) | 19.7 (31.2) | 254.7 (964.6) | 147.5 (349.3) | 732.2 (2431.9) | 21.0 (31.9) | 453.6 (2418.2) | 287.1 (1555.6) |
| Median | 182.7 | 73.3 | 6.9 | 8.5 | 20.4 | 24.4 | 10.8 | 12.8 | 6.3 |
| Range (min, max) | <0.7, >50000.0 | 7.1, >50000.0 | <0.7, 142.8 | <0.7, 5050.0 | <0.7, 1385.0 | <0.7, 11660.0 | <0.7, 181.4 | <0.7, 15130.0 | <0.7, 9480.0 |
| Reference Interval (2.5th Percentile, 97.5th Percentile) | <0.7, 32606.0 | 7.7, 37861.3 | <0.7, 129.4 | <0.7, 3434.9 | <0.7, 1216.3 | <0.7, 8335.2 | <0.7, 87.8 | 3.0, 1559.2 | <0.7, 1362.7 |
| N (%) with CA19-9 ≤25.0 | 21.7% | 25.0% | 77.5% | 68.4% | 60.0% | 52.5% | 80.0% | 61.5% | 83.8% |
| N (%) with CA19-9 ≤50.0 | 28.3% | 42.5% | 90.0% | 81.6% | 75.0% | 62.5% | 90.0% | 76.9% | 86.5% |
| N (%) with CA19-9 ≤75.0 | 34.2% | 50.0% | 95.0% | 84.2% | 82.5% | 70.0% | 95.0% | 82.1% | 86.5% |
*Treatment-Naive Exocrine Pancreatic; CRC - Colorectal;
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It is recommended that each laboratory establish its own range, which may be unique to the population it serves depending upon geographical, patient, and environmental factors.
## VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
## IX Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
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