(75 days)
Not Found
No
The device description details a standard immunometric immunoassay technique and the performance studies focus on analytical performance characteristics, with no mention of AI, ML, or related concepts.
No
The device is for in vitro diagnostic use, intended to measure a defined antigen in human serum and plasma to aid in the management and monitoring of patients with pancreatic cancer. It does not directly treat or mitigate a disease.
Yes
The device is explicitly stated as being "For in vitro diagnostic use only" in the "Intended Use / Indications for Use" section. It measures a defined antigen in human serum and plasma to aid in the management and monitoring of patients diagnosed with and confirmed to have pancreatic cancer, which are diagnostic purposes.
No
The device description clearly outlines physical components like reagent packs, coated wells, calibrators, and the VITROS 5600 System, which is a hardware platform. The assay involves chemical reactions and light measurement, indicating a hardware-dependent process.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Explicit Statement: The "Intended Use / Indications for Use" section explicitly states: "For in vitro diagnostic use only."
- Purpose: The device is intended for the quantitative measurement of a specific antigen (1116-NS-19-9 defined antigen) in human serum and plasma. This is a laboratory test performed on biological samples outside of the body.
- Clinical Application: The test is used to aid in the management of patients diagnosed with cancers of the exocrine pancreas and to monitor disease status. This indicates a clinical purpose for the test results.
- Device Description: The description details an immunoassay technique performed on a laboratory system (VITROS 5600), using reagents and calibrators. This is characteristic of an in vitro diagnostic test.
N/A
Intended Use / Indications for Use
For in vitro diagnostic use only.
For the quantitative measurement of 1116-NS-19-9 defined antigen in human serum and plasma (EDTA or heparin), using the VITROS 5600 Integrated System. The VITROS CA 19-9 test is to be used to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The VITROS CA 19-9 test can be used to monitor the disease status in patients with confirmed pancreatic cancer who show measurable CA 19-9 values over the course of their disease. Serial CA 19-9 test results should be used in conjunction with all other available clinical and laboratory data before a medical decision is determined.
Product codes (comma separated list FDA assigned to the subject device)
NIG
Device Description
The VITROS Immunodiagnostic Products CA 19-9 assay (test) is performed using the VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack and VITROS CA 19-9 Calibrators on the VITROS 5600 System.
An immunometric immunoassay technique is used, which involves the simultaneous reaction of 1116-NS-19-9 defined antigen present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-1116-NS-19-9 defined antigen) bound to Streptavidin. In a second incubation a Horseradish Peroxidase (HRP)- labelled antibody conjugate (Mouse monoclonal anti-1116-NS-19-9 defined antigen) binds to the immobilized 1116-NS-19-9 defined antigen. Unbound materials are removed by washing.
The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of conjugate bound is directly proportional to the concentration of 1116-NS-19-9 defined antigen present in the sample.
VITROS Immunodiagnostic Products CA 19-9™ Reagent Pack contains:
1 reagent pack containing:
- 100 coated wells (antibody, mouse monoclonal anti-1116-NS-19-9 defined antigen, binds >49 U 1116-NS-19-9 defined antigen/well)
- 13.4 mL assay reagent (buffer containing bovine gamma globulin and antimicrobial agent)
- 20.0 mL conjugate reagent (HRP-mouse monoclonal anti-1116-NS-19-9 defined antigen, binds ≥326 U 1116-NS-19-9 defined antigen/mL) in buffer with bovine serum albumin, bovine gamma globulin and antimicrobial agent.
VITROS CA 19-9 Calibrator contains:
- 1, 2, and 3 (OC 1116-NS-19-9 defined antigen in buffer with bovine serum albumin and antimicrobial agent, 1.75 mL); nominal values 15; 60 and 700 U 1116-NS-19-9 defined antigen/mL
- 24 calibrator bar code labels (8 for each calibrator)
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Nonclinical Performance
Several nonclinical tests were performed.
Stability Studies
Long term stability and on-board storage performance was evaluated consistent with methods based on CLSI EP25-A.
Long Term Stability: Four runs have been performed on each of 3 Lots at each time-point, monthly intervals, data supports a 20 week shelf-life.
On-board Stability: Three Lots of the VITROS CA19-9 assay were stored opened refrigerated for up to 12 weeks. Four runs were performed on the each Lot at each time-point for fresh and open, all result were acceptable and support the current claim of 8 weeks on-board stability.
Precision
Precision was evaluated on the VITROS 5600 Integrated System consistent with CLSI document EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. Six (6) precision fluids, covering the analytical measuring interval, were evaluated for performance. For one reagent lot, two (2) replicates of each precision fluid were run on two (2) occasions per day for twenty (20) days, for a total of 80 data points per fluid.
Detection Capability
Detection studies for the VITROS CA 19-9 Assay were evaluated on the VITROS 5600 Integrated System consistent with CLSI document EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition. Four endogenous fluids containing no measurable 1116-NS-19-9 defined antigens (CA19-9) were used for determining the LoB. The study design was 2 replicates per run, 2 runs per day over 5 test days = 20 reps per test fluid x 4 fluids = 80 replicates x 3 lots = 240 total replicates. Five samples were used for establishing the LoD, which were targeted at 1 to 5 times the LoB concentration. The LoD samples were admixtures of serum samples containing endogenous CA 19-9 to achieve the approximate target CA 19-9 concentrations. The LoD fluids were used to determine the LoQ. All samples were run using three reagent lots on one VITROS 5600 System, 6 replicates per run, 2 runs per day over 5 test days = 60 reps per fluid x 5 fluids = 300 replicates x 3 lots = 900 total replicates.
The Limit of Detection (LoD) for the VITROS CA 19-9 test is 1.4 U/mL, determined consistent with CLSI document EP17-A2. The Limit of Quantification (LoQ) for the VITROS CA19-9 test was designed to be less than or equal to 1.4 U/mL at 20%CV. The existing LoB product claim of 1.05 U/mL has been verified.
Linearity
Linearity was established in accordance with the CLSI document EP06 2nd Edition. The linearity test panel was comprised of 16 levels, five replicates of each linearity level were run on three reagent lots on one VITROS 5600 Integrated System over 2 days. Linearity Interval 0.9 to 1152 U/mL.
Matrix Comparison
Serum and plasma (Li-Hep and EDTA) specimen matrices was determined to be equivalent. The results met the acceptance criteria for the comparison between serum and plasma (Li-Hep and EDTA) specimens spanning the expected measuring interval. Based on the analysis serum and plasma (Li-Hep and EDTA) are suitable specimen matrices for use with the VITROS CA 19-9 assay.
For VITROS 5600 System comparing Li-Hep, Slope: 0.97, Correlation Coefficient (r): 0.99, n: 41, Pass/Fail Status: Pass.
For VITROS 5600 System comparing EDTA, Slope: 0.98, Correlation Coefficient (r): 1.00, n: 41, Pass/Fail Status: Pass.
Analytical Specificity / Known Interferences
The VITROS CA 19-9 assay was screened for interfering substances at CA 19-9 concentrations of approximately 5.0 U/mL and 50.0 U/mL following CLSI EP07+ and EP37.2.
Interferents with bias ≥ 10%:
Hemoglobin: 1000 mg/dL (0.155 mmol/L) with Analyte Conc. 7.1 U/mL showed 190.1% bias; 125 mg/dL (0.0194 mmol/L) with Analyte Conc. 45.2 U/mL showed 30.5% bias.
Rheumatoid Factor: 1035 U/mL with Analyte Conc. 5.0 U/mL showed 27.4% bias.
Dilution
The dilution recovery and dilution imprecision product requirements were met for the VITROS Immunodiagnostic Products CA 19-9 Reagent. The 20-fold dilution has been demonstrated on samples with a concentration up to 10,000 U/mL.
Expected Values
The adult reference interval was verified following CLSI document EP28-A3c. The number of test results from 60 normal blood donors that fell outside the reference limit of >37 UlmL are shown in Table 1, for each reagent lot and instrument combination. As no more than 10% of the test results were outside the limit, the expected values claim of the current VITROS CA 19-9 will be transferred to the updated VITROS CA 19-9 assay.
Table 1: Test results for the modified VITROS CA 19-9 assay
Normal Subjects: 60
VITROS 5600: 57 (≤37 U/mL), 2 (37.1-70 U/mL), 1 (>70 U/mL).
Method Comparison
Accuracy was evaluated consistent with CLSI document EP09. The plot and table show the results of a method comparison study using patient serum samples analyzed on the VITROS 5600 Integrated System compared with those analyzed using the VITROS CA 19-9 assay. The relationship between the 2 methods was determined by Weighted Deming regression.
VITROS 5600 Modified CA19-9 vs Comparative Method VITROS CA19-9: n=118, Sample Range (U/mL) 2.8 - 934, Slope 95% (Confidence Interval) 0.97 (0.95-0.99), Intercept 95% (Confidence Interval) 0.15 (-0.03-0.32), R2 0.989.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Not Found
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 866.6010 Tumor-associated antigen immunological test system.
(a)
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.(b)
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.
0
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
August 9, 2023
Ortho Clinical Diagnostics Declan Hynes Senior Regulatory Affairs Manager Felindre Meadows Pencoed Bridgend. CF35 5PZ United Kingdom
Re: K231525
Trade/Device Name: VITROS CA 19-9 Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: NIG Dated: May 26, 2023 Received: May 26, 2023
Dear Declan Hynes:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal
1
statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Ying Mao -S
Ying Mao, Ph.D. Branch Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known) K231525
Device Name
VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack
Indications for Use (Describe) For in vitro diagnostic use only.
For the quantitative measurement of 1116-NS-19-9 defined antigen in human serum and plasma (EDTA or heparin), using the VITROS 5600 Integrated System. The VITROS CA 19-9 test is to be used to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The VITROS CA 19-9 test can be used to monitor the disease status in patients with confirmed pancreatic cancer who show measurable CA 19-9 values over the course of their disease. Serial CA 19-9 test results should be used in conjunction with all other available clinical and laboratory data before a medical decision is determined.
Type of Use (Select one or both, as applicable)X Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
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3
510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is: K231525
Submitter's Information
Ortho-Clinical Diagnostics Inc.
Felindre Meadows,
Pencoed,
UK CF35 5PZ Phone: +44 07505 370257
Fax: (585) 453-3368 Contact Person: Declan Hynes
Preparation Date
August 01, 2023
Device Proprietary Name(s)
VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack
Common Name(s) VITROS CA19-9 Assay
Classification Names
| Product Code | Class | Regulation Section | Panel |
|---|---|---|---|
| NIG | II | 21 CFR 866.6010 | |
| Tumor-associated antigen immunological test | |||
| system | Immunology |
Predicate Device(s)
| Predicate Device | FDA 510(k) Number |
|---|---|
| VITROS Immunodiagnostic Products CA 19-9 Assay | K052889 |
Device Description
The VITROS Immunodiagnostic Products CA 19-9 assay (test) is performed using the VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack and VITROS CA 19-9 Calibrators on the VITROS 5600 System.
An immunometric immunoassay technique is used, which involves the simultaneous reaction of 1116-NS-19-9 defined antigen present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-1116-NS-19-9 defined antigen) bound to Streptavidin. In a second incubation a Horseradish Peroxidase (HRP)- labelled antibody conjugate (Mouse monoclonal anti-1116-NS-19-9 defined antigen) binds to the immobilized 1116-NS-19-9 defined antigen. Unbound materials are removed by washing.
The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The
4
VITROS CA 19-9 Traditional 510(k)
HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of conjugate bound is directly proportional to the concentration of 1116-NS-19-9 defined antigen present in the sample.
VITROS Immunodiagnostic Products CA 19-9™ Reagent Pack contains:
1 reagent pack containing:
- 100 coated wells (antibody, mouse monoclonal anti-1116-NS-19-9 defined antigen, binds >49 U 1116-NS-19-9 defined antigen/well)
- 13.4 mL assay reagent (buffer containing bovine gamma globulin and antimicrobial agent) ●
- 20.0 mL conjugate reagent (HRP-mouse monoclonal anti-1116-NS-19-9 defined antigen, binds ≥326 U ● 1116-NS-19-9 defined antigen/mL) in buffer with bovine serum albumin, bovine gamma globulin and antimicrobial agent.
VITROS CA 19-9 Calibrator contains:
- 1, 2, and 3 (OC 1116-NS-19-9 defined antigen in buffer with bovine serum albumin and ● antimicrobial agent, 1.75 mL); nominal values 15; 60 and 700 U 1116-NS-19-9 defined antigen/mL
- 24 calibrator bar code labels (8 for each calibrator) ●
5
Intended Use Statement(s):
Rx ONLY
For in vitro diagnostic use only.
For the quantitative measurement of 1116-NS-19-9 defined antigen in human serum and plasma (EDTA or heparin), using the VITROS 5600 Integrated System. The VITROS CA 19-9 test is to be used to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The VITROS CA 19-9 test can be used to monitor the disease status in patients with confirmed pancreatic cancer who show measurable CA 19-9 values over the course of their disease. Serial CA 19-9 test results should be used in conjunction with all other available clinical and laboratory data before a medical decision is determined.
Comparison to Predicate Devices
The following tables provide a summary of the key features of the new device assessed against the predicate.
| Device
Characteristic | Predicate Device
VITROS Immunodiagnostic Products
CA 19-9 Assay, K052889, cleared 20
December 2005 | Modified Device
VITROS Immunodiagnostic Products
CA 19-9TM Reagent Pack |
|--------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | Rx ONLY
For in vitro diagnostic use only. | Rx ONLY
For in vitro diagnostic use only. |
| | For the quantitative measurement of 1116-NS-
19-9 defined antigen concentration in human
serum and plasma (EDTA or heparin) using
the VITROS ECi/ECiQ/3600
Immunodiagnostic Systems and the VITROS
5600/XT 7600 Integrated Systems. The
VITROS CA 19-9 assay is to be used as an aid
in management of patients diagnosed with caners
of the exocrine pancreas. The VITROS CA 19-9
test can be used to monitor disease status in
patients with confirmed pancreatic cancer who
show measurable CA 19-9 values over the
course of their disease. Serial CA 19-9 test
results should be used in conjunction with
other clinical and laboratory data before a
medical decision is determined. | For the quantitative measurement of 1116-NS-
19-9 defined antigen concentration in human
serum and plasma (EDTA or heparin) using
the VITROS 5600 Integrated System. The
VITROS CA 19-9 test is to be used to aid in the
management of patients diagnosed with cancers
of the exocrine pancreas. The VITROS CA
19-9 test can be used to monitor the disease
status in patients with confirmed pancreatic
cancer who show measurable CA 19-9 values
over the course of their disease. Serial CA 19-9
test results should be used in conjunction with
all other available clinical and laboratory data
before a medical decision is determined. |
| Assay Principle | Immunometric. | Same. |
| Antibody | Mouse Monoclonal anti-1116-NS-19-9
antigen. | Same. |
| Sample Type | Serum and Plasma. | Same. |
| Sample Volume | 35 µL. | Same. |
6
VITROS CA 19-9 AssayTraditional 510(k)
| Traceability | Calibration of the VITROS CA 19-9 test is
traceable to in-house reference calibrators
which have been value assigned to correlate
to another commercially available test. | Same. |
|-------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|
| Measuring Range | 1.4-1000 (U/mL) | Same. |
| Detect on Limit | LOB: 1.05 (U/mL)
LOD: 1.4 (U/mL)
LOQ: 1.4 (U/mL) | LOB: Same.
LOD: Same.
LOQ: Same |
| Calibrator Levels | 3. | Same. |
Differences:
| Basic Principle | Sandwich immunoassay | Sandwich immunoassay.
In the modified CA 19-9
assay, the mouse anti-
1116-NS-19-9 has been
removed from the Biotin
Reagent and coated
directly onto the well.
The modification to allow
the biotinylated antibody
capture conjugate to be
pre- bound to the well,
eliminates the risk of
biotin interference. |
|-----------------|----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Instrumentation | VITROS 5600 Integrated System
VITROS XT7600 Integrated System
VITROS 3600 Immunodiagnostic System
VITROS ECi/ECiQ Immunodiagnostic System | VITROS 5600 Integrated System |
7
Nonclinical Performance
Several nonclinical tests were performed.
Stability Studies
Long term stability and on-board storage performance was evaluated consistent with methods based on CLSI EP25-A.
Long Term Stability: Four runs have been performed on each of 3 Lots at each time-point, monthly intervals, data supports a 20 week shelf-life.
On-board Stability: Three Lots of the VITROS CA19-9 assay were stored opened refrigerated for up to 12 weeks. Four runs were performed on the each Lot at each time-point for fresh and open, all result were acceptable and support the current claim of 8 weeks on-board stability.
Precision
Precision was evaluated on the VITROS 5600 Integrated System consistent with CLSI document EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. Six (6) precision fluids, covering the analytical measuring interval, were evaluated for performance. For one reagent lot, two (2) replicates of each precision fluid were run on two (2) occasions per day for twenty (20) days, for a total of 80 data points per fluid.
The data presented are a representation of test performance and are provided as a guideline. Variables such as sample handling and storage, reagent handling and storage, laboratory environment, and system maintenance can affect reproducibility of test results.
| VITROS
System | Units = U/mL | | | | | No. of
Obs. | No. of
Days |
|------------------|--------------------------|----------------|------|--------------|------|----------------|----------------|
| | Mean
CA 19-9
Conc. | Repeatability* | | Within Lab** | | | |
| | | SD | %CV | SD | %CV | | |
| 5600 | 29.0 | 0.5 | 1.8% | 1.9 | 6.6% | 80 | 20 |
| | 107 | 2.0 | 1.9% | 6.3 | 5.9% | 80 | 20 |
| | 223 | 4.4 | 2.0% | 9.2 | 4.1% | 80 | 20 |
| | 301 | 5.8 | 1.9% | 14.0 | 4.6% | 80 | 20 |
| | 708 | 12.1 | 1.7% | 27.6 | 3.9% | 80 | 20 |
| | 6.7 | 0.1 | 2.2% | 0.3 | 4.2% | 80 | 20 |
*Repeatability (formerly called within-run precision) was determined using two replicates per run.
** Within Lab precision was determined using a single reagent lot and a single calibration.
8
Detection Capability
Detection studies for the VITROS CA 19-9 Assay were evaluated on the VITROS 5600 Integrated System consistent with CLSI document EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition. Four endogenous fluids containing no measurable 1116-NS-19-9 defined antigens (CA19-9) were used for determining the LoB. The study design was 2 replicates per run, 2 runs per day over 5 test days = 20 reps per test fluid x 4 fluids = 80 replicates x 3 lots = 240 total replicates
Five samples were used for establishing the LoD, which were targeted at 1 to 5 times the LoB
concentration. The LoD samples were admixtures of serum samples containing endogenous CA 19-9 to achieve the approximate target CA 19-9 concentrations. The LoD fluids were used to determine the LoQ. All samples were run using three reagent lots on one VITROS 5600 System,
6 replicates per run, 2 runs per day over 5 test days = 60 reps per fluid x 5 fluids = 300 replicates x 3 lots = 900 total replicates.
The Limit of Detection (LoD) for the VITROS CA 19-9 test is 1.4 U/mL, determined consistent with CLSI document EP17-A2 . The Limit of Quantification (LoQ) for the VITROS CA19-9 test was designed to be less than or equal to 1.4 U/mL at 20%CV. The existing LoB product claim of 1.05 U/mL has been verified.
Linearity
Linearity was established in accordance with the CLSI document EP06 2nd Edition. The linearity test panel was comprised of 16 levels, five replicates of each linearity level were run on three reagent lots on one VITROS 5600 Integrated System over 2 days.
| Slope | Intercept | ||||||
|---|---|---|---|---|---|---|---|
| Lot | Dilution | ||||||
| Range | % Recovery | Estimate | 95% CI | Estimate | 95% CI | R | |
| તે તે તે તે તે તે તે તે તે તે તે તે તે આ ગામમાં પ્રાથમિક શાળા, આંગણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં પ્રાથમિક શાળા, આંગણવાડી તેમ જ દૂધની ડેરી જેવી | 0.9 to 1152 | 93.0% to | |||||
| 125% | 0.973 | 0.957 to | |||||
| 0.989 | 0.145 | 0.103 to | |||||
| 0.186 | 0.999 |
9
| Weighted Least Squares Regression | ||||||
|---|---|---|---|---|---|---|
| Level | %HP | Measured | ||||
| Result | ||||||
| (U/mL) | Predicted | |||||
| Result | ||||||
| (U/mL) | Deviation | |||||
| from | ||||||
| Linearity | Allowable | |||||
| Deviation | ||||||
| from | ||||||
| Linearity | ||||||
| (±) | Pass / | |||||
| Fail | ||||||
| 1 | 0.00 | 0.861 | 0.981 | -12.3% | 15.0% | Pass |
| 2 | 0.03 | 1.516 | 1.328 | 14.1% | 15.0% | Pass |
| 3 | 0.05 | 1.59 | 1.52 | 5.0% | 15.0% | Pass |
| 4 | 0.10 | 2.35 | 2.08 | 13.0% | 15.0% | Pass |
| 5 | 0.50 | 6.81 | 6.60 | 3.1% | 15.0% | Pass |
| 6 | 1.00 | 12.2 | 12.1 | 0.3% | 15.0% | Pass |
| 7 | 2.99 | 33.5 | 34.5 | -2.8% | 15.0% | Pass |
| 8 | 5.01 | 54.6 | 57 | -4.3% | 15.0% | Pass |
| 9 | 10 | 108 | 113 | -4.5% | 15.0% | Pass |
| 10 | 30 | 332 | 337 | -1.5% | 15.0% | Pass |
| 11 | 40 | 441 | 449 | -1.7% | 15.0% | Pass |
| 12 | 50 | 557 | 561 | -0.6% | 15.0% | Pass |
| 13 | 60 | 668 | 672 | -0.6% | 15.0% | Pass |
| 14 | 80 | 904 | 896 | 0.8% | 15.0% | Pass |
| 15 | 95 | 1074 | 1064 | 0.9% | 15.0% | Pass |
| 16 | 100 | 1152 | 1121 | 2.8% | 15.0% | Pass |
| Linearity Interval 0.9 to 1152 U/mL |
Linearity/Measuring Range
| VITROS System | Measuring (Reportable) Range |
|---|---|
| 5600 | 1.4–1000 U/mL |
10
VITROS CA 19-9 AssayTraditional 510(k) Matrix Comparison
Serum and plasma (Li-Hep and EDTA) specimen matrices was determined to be equivalent. The results met the acceptance criteria for the comparison between serum and plasma (Li-Hep and EDTA) specimens spanning the expected measuring interval. Based on the analysis serum and plasma (Li-Hep and EDTA) are suitable specimen matrices for use with the VITROS CA 19-9 assay.
Specimens Recommended
-
Serum and Plasma ●
Specimens Not Recommended -
Do not use turbid specimens. Turbidity in specimens may affect test results. ●
| VITROS 5600 System | ||
|---|---|---|
| Ordinary | ||
| Deming | Li-Hep | EDTA |
| Slope | 0.97 | 0.98 |
| Correlation | ||
| Coefficient (r) | 0.99 | 1.00 |
| n | 41 | 41 |
| Pass/Fail | ||
| Status | Pass | Pass |
Analytical Specificity
Known Interferences
The VITROS CA 19-9 assay was screened for interfering substances at CA 19-9 concentrations of approximately 5.0 U/mL and 50.0 U/mL following CLSI EP07+ and EP37.2 The substances listed in the table demonstrated observed bias of ≥ 10% when tested at the concentrations shown.
For substances that were tested and did not interfere, refer to "Substances that do not Interfere."
| Interferent | Interferent Concentration | Analyte Conc.* (U/mL) | Bias %** | |
|---|---|---|---|---|
| Hemoglobin | 1000 mg/dL | 0.155 mmol/L | 7.1 | 190.1 |
| 125 mg/dL | 0.0194 mmol/L | 45.2 | 30.5 | |
| 125 mg/dL | 0.0194 mmol/L | 47.5 | 0.8 | |
| 100 mg/dL | 0.0155 mmol/L | 6.1 | 2.0 | |
| Rheumatoid Factor | 1035 U/mL | N/A | 5.0 | 27.4 |
| 981 U/mL | 43.4 | 2.8 | ||
| 900 U/mL | 32.5 | 5.2 | ||
| 199 U/mL | 5.0 | 5.2 |
- Average test concentration of replicate determinations using 3 different lots of reagent, on the VITROS 5600 platform
**Estimate of the average difference observed
11
Substances that do not Interfere
The substances listed in the table below were tested with the VITROS CA 19-9 assay following CLSI EP07 and EP372 and found not to cause bias > 10% at CA 19-9 concentrations of approximately 5.0 U/mL at the test concentrations shown.
| Substance | Concentration | |
|---|---|---|
| Conventional Units | SI Units | |
| Acetaminophen | 50 mg/dL | 3.3 mmol/L |
| N-Acetylcysteine | 15.0 mg/dL | 0.919 mmol/L |
| Acetylsalicylic acid | 50 mg/dL | 2.78 mmol/L |
| Alpha-tocopherol | 6.45 mg/dL | 0.150 mmol/L |
| Amoxicillin | 5.40 mg/dL | 0.148 mmol/L |
| Ascorbic acid | 300 mg/dL | 17.0 mmol/L |
| Bilirubin, conjugated | 40 mg/dL | 0.475 mmol/L |
| Bilirubin, unconjugated | 40 mg/dL | 0.684 mmol/L |
| Biotin | 0.351 mg/dL | 0.014 mmol/L |
| Cefoxitin sodium | 695 mg/dL | 15.5 mmol/L |
| Cetuximab | 70.5 mg/dL | 0.00464 mmol/L |
| Cholecalciferol (D3) | 19.2 $ μg $ /dL | 0.499 $ μmol $ /L |
| Cholesterol, total | 400 mg/dL | 10.3 mmol/L |
| Cisplatin | 5.7 mg/dL | 0.19 mmol/L |
| Codeine | 0.141 mg/dL | 0.005 mmol/L |
| Cotinine | 0.24 mg/dL | 0.014 mmol/L |
| Coumadin | 1.4 mg/dL | 0.042 mmol/L |
| Cyclophosphamide | 54.9 mg/dL | 1.97 mmol/L |
| Cytarabine | 3 mg/dL | 0.123 mmol/L |
| Dextran 40 | 2400 mg/dL | 0.600 mmol/L |
| Dextromethorphan | 0.00156 mg/dL | 0.057 $ μmol $ /L |
| Doxorubicin hydrochloride | 4 mg/dL | 0.053 mmol/L |
| Enoxaparin - Low molecular weight Heparin | 360 U/dL | N/A |
| Ethanol | 600 mg/dL | 130 mmol/L |
| Eribulin | 1.12 $ μg $ /mL | 0.00136 mmol/L |
| 5-Fluorouracil | 39 mg/dL | 3.0 mmol/L |
| Furosemide | 1.59 mg/dL | 0.048 mmol/L |
| Gemcitabine | 38.2 mg/dL | 1.28 mmol/L |
| HAMA (Human Anti-Mouse Antibodies) | 800 $ μg $ /L | 0.053 $ μmol $ /L |
| Hydralazine | 1.44 mg/dL | 0.073 mmol/L |
| Substance | Concentration | |
| Conventional Units | SI Units | |
| Hydrocodone | 0.0072 mg/dL | 0.241 µmol/L |
| Ibuprofen | 40 mg/dL | 1.94 mmol/L |
| Intralipid | 2000mg/dL | 0.0192 mol/L |
| Leucovorin | 11.4 mg/dL | 0.386 mmol/L |
| Levothyroxine | 0.0429 mg/dL | 0.552 µmol/L |
| Loratadine | 0.0087 mg/dL | 0.227 µmol/L |
| Megestrol Acetate | 2.26 µg/mL | 0.0058 mmol/L |
| Methotrexate | 136 mg/dL | 3.0 mmol/L |
| Mitomycin C | 300 µg/dL | 0.009 mmol/L |
| Morphine | 0.780 mg/dL | 0.010 mmol/L |
| Naproxen | 36.0 mg/dL | 1.56 mmol/L |
| Omeprazole | 0.840 mg/dL | 0.024 mmol/L |
| Paclitaxel | 6.7 mg/dL | 0.080 mmol/L |
| Phenytoin | 6.00 mg/dL | 0.238 mmol/L |
| Prednisone | 0.010 mg/dL | 0.280 µmol/L |
| Salicylic acid | 2.86 mg/dL | 0.207 mmol/L |
| Streptozocin | 114 mg/dL | 4.30 mmol/L |
| Tamoxifen | 51.9 ug/dL | 1.40 µmol/L |
| Theophylline | 6.0 mg/dL | 0.333 mmol/L |
| Total Protein | 15 g/dL | N/A |
| Triglycerides, total | 3000 mg/dL | 33.8 mmol/L |
| Vancomycin hydrochloride | 12.3 mg/dL | 0.083 mmol/L |
| Vinblastine | 0.0084 mg/dL | 0.092 µmol/L |
| Vincristine | 0.00162 mg/dL | 0.0176 µmol/L |
| Vinorelbine | 0.19 mg/dL | 0.002 mmol/L |
12
VITROS CA 19-9 AssayTraditional 510(k)
N/A = Not applicable, alternate units not available
Dilution
The dilution recovery and dilution imprecision product requirements were met for the VITROS Immunodiagnostic Products CA 19-9 Reagent. Serum or plasma (EDTA or heparin) samples with concentrations greater than the measuring range may be automatically diluted on the system up to 20-fold (1 partsample with 19 parts diluent) by the VITROS 5600 Integrated System with the VITROS High Sample Diluent B Reagent Pack prior to test. Refer to the VITROS High Sample Diluent B Reagent Pack instructions for use. The 20-fold dilution has been demonstrated on samples with a concentration up to 10,000 U/mL.
Expected Values
Adult Reference Interval
The adult reference interval was verified following CLSI document EP28-A3c Defining,
13
VITROS CA 19-9 AssayTraditional 510(k) Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.
| Unit (U/L) |
|---|
| $\u2264$ 37 U/mL |
The number of test results from 60 normal blood donors that fell outside the reference limit of >37 UlmL are shown in Table 1, for each reagent lot and instrument combination. As no more than 10% of the test results were outside the limit, the expected values claim of the current VITROS CA 19-9 will be transferred to the updated VITROS CA 19-9 assay.
Table 1: Test results for the modified VITROS CA 19-9 assay
| Normal Subjects | N | ≤37 U/mL | 37.1-70 U/mL | >70 U/mL |
|---|---|---|---|---|
| VITROS 5600 | 60 | 57 | 2 | 1 |
Traceability of Calibration
Calibration of the VITROS CA 19-9 assay is traceable to in-house reference calibrators which have been value assigned to correlate to another commercially available test.
14
Method Comparison
Accuracy was evaluated consistent with CLSI document EP09. The plot and table show the results of a method comparison study using patient serum samples analyzed on the VITROS 5600 Integrated System compared with those analyzed using the VITROS CA 19-9 assay. The relationship between the 2 methods was determined by Weighted Deming regression.
Image /page/14/Figure/3 description: This image is a regression plot comparing two methods of measuring CA19-9 levels. The x-axis represents the Comparative Method CA19-9 (Current) in U/mL, ranging from 0 to 1000. The y-axis represents the VITROS CA19-9 Modified in U/mL, also ranging from 0 to 1000. A red regression line is plotted through the data points, with gray dashed lines indicating the confidence interval.
| Single Lot Analyses | n | Sample Range
(U/mL) | Slope 95%
(Confidence Interval) | Intercept 95%
(Confidence
Interval) | R2 |
|-----------------------------------------------------------------------|-----|------------------------|------------------------------------|-------------------------------------------|-------|
| VITROS 5600 Modified
CA19-9 vs Comparative
Method VITROS CA19-9 | 118 | 2.8
934 | 0.97 (0.95-0.99) | 0.15 (-0.03-0.32) | 0.989 |
Conclusion
The conclusions drawn from the nonclinical tests (discussed above) demonstrate the VITROS Immunodiagnostic Products CA 19-9 Assay is as safe, effective, and performs as well as the cleared predicate device. The information submitted in the premarket notification is complete and supports a substantial equivalence decision.