(90 days)
Not Found
No
The device description details a standard immunometric immunoassay technique. There is no mention of AI, ML, or any computational methods beyond standard data processing for calculating results from light signals. The performance studies focus on traditional analytical validation metrics.
No
The device is for in vitro diagnostic use only and measures CEA levels to aid in the prognosis and management of cancer patients, not to treat them.
Yes
Explanation: The "Intended Use / Indications for Use" section explicitly states "For In Vitro Diagnostic Use Only" and describes its purpose as "to aid in the prognosis and management of cancer patients," which are characteristics of a diagnostic device.
No
The device is a reagent pack and calibrators used with a specific hardware system (VITROS 5600). The description details physical components (coated wells, assay reagent, conjugate reagent, calibrators) and a chemical reaction process, indicating it is not software-only.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Explicit Statement: The "Intended Use / Indications for Use" section clearly states: "For In Vitro Diagnostic Use Only".
- Nature of the Test: The device measures the concentration of carcinoembryonic antigen (CEA) in human serum and plasma. This is a laboratory test performed on biological samples taken from the body, which is the definition of an in vitro diagnostic test.
- Purpose: The intended use is to "aid in the prognosis and management of cancer patients in whom changing concentrations of CEA are observed." This indicates the test is used to provide information for medical diagnosis and management, which is a key characteristic of an IVD.
N/A
Intended Use / Indications for Use
For In Vitro Diagnostic Use Only
For the quantitative measurement of carcinoembryonic antigen (CEA) concentration in human serum and plasma (EDTA or heparin) using the VITROS 5600 Integrated System, to aid in the prognosis and management of cancer patients in whom changing concentrations of CEA are observed.
Product codes (comma separated list FDA assigned to the subject device)
DHX
Device Description
The VITROS Immunodiagnostic Products CEA Reagent Pack (test) is performed using the VITROS CEA Reagent Pack and VITROS CEA Calibrators on the VITROS 5600 System.
An immunometric immunoassay technique is used, which involves the reaction of CEA present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-CEA) bound to Streptavidin, and a Horseradish Peroxidase (HRP)-labelled antibody conjugate (Mouse monoclonal anti- CEA). Unbound (HRP)-labeled anti-CEA antibody conjugate is 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 HRP conjugate bound is directly proportional to the concentration of CEA present in the sample.
VITROS CEA Reagent Pack contains:
1 reagent pack containing:
- 100 coated wells (antibody, mouse monoclonal anti-CEA, binds >=8ng CEA/well);
- 9.7 mL assay reagent (buffer containing bovine serum albumin, bovine gamma globulin and . antimicrobial agent).
- 9.7 mL conjugate reagent (HRP-mouse monoclonal anti-CEA, binds >=123ng CEA/mL).
VITROS CEA Calibrator contains:
- 1 set of VITROS CEA Calibrators 1 and 2 (human CEA in bovine serum with antimicrobial agent, 2 mL); nominal values 3 and 250 ng/mL (us/L)
- 16 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:
Stability Studies:
- Long term stability: Evaluated consistent with CLSI EP25-A, supports a 52 week shelf-life.
- On-board Stability: Three Lots were studied, supports 8 weeks on-board stability.
Precision:
- Evaluated consistent with CLSI document EP05-A3.
- Four precision fluids covering the analytical measuring interval were evaluated.
- For one reagent lot, two replicates of each fluid were run on two occasions per day for twenty days (total 80 data points per fluid).
- Repeatability and Within Lab precision data are provided in tables.
- Additional precision analysis (Within-laboratory precision including repeatability, between-run, between-day and between-lot) was determined using three reagent lots.
Detection Capability:
- Evaluated consistent with CLSI document EP17-A2.
- Limit of Blank (LoB): Four endogenous fluids containing no measurable CEA were used. LoB = 0.08 ng/mL.
- Limit of Detection (LoD): Five samples targeted at 1 to 5 times the LoB concentration were used. Observed LoD = 0.15 ng/mL, supporting claimed LoD of 0.31 ng/mL.
- Limit of Quantitation (LoQ): LoQ at 20% CV was observed to be 0.15 ng/mL, supporting claimed LoQ of 0.31 ng/mL.
Linearity:
- Performed according to CLSI document EP06 2nd edition.
- Study with 13 levels and five replicates for each level on 1 reagent lot on one VITROS 5600 Integrated System.
- Linearity demonstrated from 0.22 ng/mL to 500 ng/mL with deviations from linearity within +/- 14.3%.
- Regression analysis: Slope = 1.04275 (95% CI: 1.025 to 1.061), Intercept = -0.06678 (95% CI: -0.085 to -0.049), R2 = 0.999.
Matrix Comparison:
- Serum and plasma (Li-Hep and EDTA) specimen matrices were determined to be equivalent.
- Met acceptance criteria for comparison between serum and plasma.
- Ordinary Deming Regression for Li-Hep vs. Serum: Slope = 0.998, Intercept = -0.1177, Correlation Coefficient (r) = 0.999 (n=40).
- Ordinary Deming Regression for EDTA vs. Serum: Slope = 0.995, Intercept = -0.8768, Correlation Coefficient (r) = 0.998 (n=40).
Analytical Specificity - Known Interferents:
- Screened for interfering substances at CEA concentrations of approx. 3.00 ng/mL and 15.0 ng/mL following EP07 3rd ed and EP37 1st ed.
- None of the tested compounds caused bias of >10%. List of 48 substances provided with concentrations.
Cross-Reactivity:
- Evaluated by adding Non-specific Cross-reacting Antigen 1 (NCA 1) at 500 ng/mL.
- VITROS 5600 % Cross Reactivity: ND (Not Detectable) for three master lots.
Dilution:
- Dilution recovery and dilution imprecision requirements were met.
- Samples >400 ng/mL may be automatically diluted up to 100-fold.
Expected Values (Adult Reference Interval):
- Validated following CLSI document EP28-A3c.
- Distribution of CEA values for healthy non-smokers (n=68) and healthy smokers (n=72) showed equivalency to the expected values claim published in the IFU of the current US VITROS CEA assay.
High Dose Hook:
- Assessment consistent with CLSI document EP34.
- High dose hook panel prepared with CEA concentrations up to 546,000 ng/mL.
- The updated VITROS CEA assay has a high dose hook claim of up to 80,000 ng/mL.
Traceability of Calibration:
- Traceable to in-house reference calibrators which are value assigned to correlate to a commercially available test with reference to the 1st International Preparation 73/601.
Method Comparison:
- Accuracy evaluated consistent with CLSI documents EP09c and EP21.
- 110 human serum samples were tested in singleton using one reagent lot and one VITROS 5600 Integrated System.
- Comparison of the updated VITROS CEA assay vs. predicate (K041322) on the VITROS 5600.
- Passing and Bablok regression results (vs. Comparative Method):
- n = 110
- Slope (95% CI) = 1.01 (0.9972 to 1.012)
- Correlation Coefficient = 0.999
- Range of Samples = 0.56-396 U/mL (ng/mL)
- Intercept (95% CI) = 0.106 (-0.01602 to -0.3729)
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.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food & Drug Administration (FDA). On the left, there is a seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged in a circular pattern around a stylized image. To the right of the seal, there is a blue square with the letters "FDA" in white. Next to the square, the words "U.S. FOOD & DRUG" are written in blue, with the word "ADMINISTRATION" written in a smaller font size below.
August 23, 2023
Ortho Clinical Diagnostics Rebecca Lewis Senior Regulatory Affairs Associate Felindre Meadows Pencoed Bridgend, CF35 5PZ United Kingdom
Re: K231517
Trade/Device Name: VITROS Immunodiagnostic Products CEA Reagent Pack Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: Class II Product Code: DHX Dated: May 23, 2023 Received: May 25, 2023
Dear Rebecca Lewis:
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.
1
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 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
2
Indications for Use
510(k) Number (if known) K231517
Device Name
VITROS Immunodiagnostic Products CEA Reagent Pack
Indications for Use (Describe) For In Vitro Diagnostic Use Only
For the quantitative measurement of carcinoembryonic antigen (CEA) concentration in human serum and plasma (EDTA or heparin) using the VITROS 5600 Integrated System, to aid in the prognosis and management of cancer patients in whom changing concentrations of CEA are observed.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| ☑ 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: K231517.
Submitter's Information
Ortho-Clinical Diagnostics Inc.
Felindre Meadows,
Pencoed.
UK CF35 5PZ Phone: +44 (0) 7971 427649
Fax: (585) 453-3368 Contact Person: Rebecca Lewis
Preparation Date
Aug 23, 2023
Device Proprietary Name(s)
VITROS® Immunodiagnostic Products CEA Reagent Pack
Common Name(s) VITROS Immunodiagnostic Products CEA
Reagent Pack
Classification Names
| Product Code | Class | Regulation Section | Panel |
|---|---|---|---|
| DHX | II | 21 CFR 866.6010 | Immunology |
Predicate Device(s)
| Predicate Device | FDA 510(k) Number |
|---|---|
| VITROS Immunodiagnostic Products CEA Reagent Pack | K041322 |
Device Description
The VITROS Immunodiagnostic Products CEA Reagent Pack (test) is performed using the VITROS CEA Reagent Pack and VITROS CEA Calibrators on the VITROS 5600 System.
An immunometric immunoassay technique is used, which involves the reaction of CEA present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-CEA) bound to Streptavidin, and a Horseradish Peroxidase (HRP)-labelled antibody conjugate (Mouse monoclonal anti- CEA). Unbound (HRP)-labeled anti-CEA antibody conjugate is 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
QuidelOrtho
4
VITROS CEA Reagent Traditional 510(k) 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 HRP conjugate bound is directly proportional to the concentration of CEA present in the sample.
VITROS CEA Reagent Pack contains:
1 reagent pack containing:
- 100 coated wells (antibody, mouse monoclonal anti-CEA, binds ≥8ng CEA/well); ●
- 9.7 mL assay reagent (buffer containing bovine serum albumin, bovine gamma globulin and . antimicrobial agent).
- 9.7 mL conjugate reagent (HRP-mouse monoclonal anti-CEA, binds ≥123ng CEA/mL). ●
VITROS CEA Calibrator contains:
- 1 set of VITROS CEA Calibrators 1 and 2 (human CEA in bovine serum with ● antimicrobial agent, 2 mL); nominal values 3 and 250 ng/mL (us/L)
- 16 calibrator bar code labels (8 for each calibrator) ●
Intended Use Statement(s):
Rx ONLY
For in vitro diagnostic use only.
For the quantitative measurement of carcinoembryonic antigen (CEA) concentration in human serum and plasma (EDTA or heparin) using the VITROS 5600 Integrated System, to aid in the prognosis and management of cancer patients in whom changing concentrations of CEA are observed.
Comparison to Predicate Devices
The following table provides a summary of the key features of the new device assessed against the predicate.
| Device
| Characteristic | Predicate Device | Modified Device |
|---|---|---|
| Device | ||
| Characteristic | VITROS Immunodiagnostic Products | |
| CEA Reagent Pack, K041322, cleared 17 | ||
| June 2004 | VITROS Immunodiagnostic Products CEA | |
| Reagent Pack | ||
| Intended Use | Rx ONLY | |
| For in vitro diagnostic use only. |
For the quantitative measurement of
carcinoembryonic antigen (CEA)
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, to aid in the prognosis and
management of cancer patients in
whom changing concentrations of
CEA are observed. | Rx ONLY
For in vitro diagnostic use only.
For the quantitative measurement of
carcinoembryonic antigen (CEA) concentration in
human serum and plasma (EDTA or heparin)
using the VITROS 5600 Integrated System, to aid
in the prognosis and management of cancer
patients in whom changing concentrations of CEA
are observed. |
| Antibody | Mouse Monoclonal anti-CEA antibody. | Same. |
| Sample Type | Serum and Plasma. | Same. |
5
VITROS CEA Reagent
Traditional 510(k)
| Traditional 510(k)
| Sample Volume | 20 µL. | Same. |
|---|---|---|
| Traceability | Traceable to in-house reference | |
| calibrators which have been value | ||
| assigned to | ||
| correlate to another commercially | ||
| available test with reference to the | ||
| 1st International Preparation | ||
| 73/601. | Same. | |
| Measuring Range | Analytical Measuring Interval: | |
| 0.31-400 ng/mL (µg/L) | Analytical Measuring Interval: | |
| 0.31-400 ng/mL (µg/L) | ||
| Extended Measuring Interval: | ||
| 400 - 40,000 ng/mL (µg/L) | ||
| Reportable Measuring Interval: | ||
| 0.31-40,000 ng/mL (µg/L) | ||
| Detect on Limit | LOB: 0.06 ng/mL (µg/L) | |
| LOD: 0.31 ng/mL (µg/L) | LOB: 0.08 ng/mL (µg/L) | |
| LOD: Same. | ||
| LOQ: 0.31 ng/mL (µg/L) | ||
| Calibrator Levels | 2. | Same. |
| Instrumentation | VITROS 5600 Integrated System | Same. |
Differences:
| Assay Principle | Sandwich immunoassay | Sandwich immunoassay. In the modified CEA assay, the
mouse anti- CEA antibody 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. |
|-----------------|--------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Assay Reagent | 0.5% BSA, no Tween 20 or EDTA. | The modified product utilizes the same capture and
detection antibodies. The modified product includes the
addition of 0.6% Tween 20, 25 mM EDTA and an increase
in BSA concentration from 0.5% to 3% in the CEA assay
reagent.
These modifications have improved the CEA assay:
The purpose of BSA in the assay reagent
formulation is to minimize matrix effects, reduce
non-specific binding (NSB) and improve the
stability of the biotin conjugate. Hemoglobin in
samples may adsorb to the wells and introduce an
additional peroxidase activity, resulting in
elevated signals and therefore a positive bias.
Increase in BSA concentration of the assay
reagent reduces the NSB, and therefore addresses
the hemoglobin interference with the current
assay.
Improvement to the serum/plasma equivalence which
previously required a limitation on bias for EDTA in the
previously cleared product IFU. |
6
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 time-point, monthly intervals, supports a 52 week shelf-life. data
On-board Stability: Three Lots of the VITROS CEA assay were stored opened refrigerated for up to 12 weeks. Four runs were performed on each Lot at each time-point for fresh and open, all results were acceptable and support the current claim of 8 weeks on-board stability.
Precision
Precision was evaluated consistent with CLSI document EP05-A3. Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. Four (4) 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.
| System | Mean
CEA
Conc. | Repeatability* | | Within Lab** | | No. of
Obs. | No. of
Days |
|--------|----------------------|----------------|------|--------------|------|----------------|----------------|
| | | SD | %CV | SD | %CV | | |
| 5600 | 6.55 | 0.114 | 1.7% | 0.175 | 2.7% | 80 | 20 |
| | 41.4 | 0.58 | 1.4% | 1.02 | 2.5% | 80 | 20 |
| | 228 | 4.4 | 1.9% | 6.2 | 2.7% | 80 | 20 |
| | 390 | 4.6 | 1.2% | 11.4 | 2.9% | 80 | 20 |
| Product Claim | |||||
|---|---|---|---|---|---|
*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.
7
| Units = ng/mL (µg/L) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample | N | Mean | Within-run | |||||||||
| (Repeatability) | Between- | |||||||||||
| Run | Between- | |||||||||||
| Day | Between-Lot | Within- | ||||||||||
| Laboratory* | ||||||||||||
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| PP1 | 240 | 6.44 | 0.107 | 1.7% | 0.096 | 1.5% | 0.095 | 1.5% | 0.132 | 2.1% | 0.217 | 3.4% |
| PP2 | 240 | 40.8 | 0.59 | 1.5% | 0.84 | 2.1% | 0.62 | 1.5% | 0.45 | 1.1% | 1.28 | 3.1% |
| PP3 | 240 | 223 | 4.3 | 1.9% | 3.4 | 1.5% | 3.2 | 1.4% | 4.5 | 2.0% | 7.8 | 3.5% |
| PP4 | 240 | 381 | 5.6 | 1.5% | 6.6 | 2.1% | 6.0 | 1.6% | 8.7 | 2.3% | 13.7 | 3.6% |
Additional Precision Analysis Summarv
*Within-laboratory precision includes following components:
repeatability, between-run, between-day and between-lot was determined using three reagent lots.
Detection Capability
Detection studies for the VITROS CEA Reagent were evaluated 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 carcinoembryonic antigen (CEA) 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 CEA combined with CEA affinity stripped serum to achieve the approximate target CEA 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 observed Limit of Detection (LoD) for the VITROS CEA test is 0.15 ng/mL (ug/L), determined consistent with CLSI document EP17. This supports the claimed LOD of 0.31ng/ml. The Limit of Quantitation (LoQ) for the VITROS CEA test was designed to be less than or equal to currently claimed low end of the measuring range of 0.31 ng/mL (ug/L) at 20% CV. The observed LoO at 20% CV was determined to be 0.15 ng/mL (ug/L), consistent with CLSI document EP17. The claimed LQ is set at 0.31 ng/mL (ug/L). The representative LoB is 0.08 ng/mL.
8
VITROS CEA Reagent Traditional 510(k) Linearity
Linearity studies were performed according to CLSI document EP06 2ªd edition. In a study with 13 levels and five replicates for each level on 1 reagent lot on one VITROS 5600 Integrated System, linearity was demonstrated from 0.22 ng/mL (ug/L) to 500 ng/mL (ug/L) with deviations from linearity within +/- 14.3%.
| Slope | Intercept | ||||||
|---|---|---|---|---|---|---|---|
| Dilution | |||||||
| Range | % Recovery | Estimate | 95% CI | Estimate | 95% CI | R2 | |
| 0.22 to 500 | 82.1% to 109% | 1.04275 | 1.025 to | ||||
| 1.061 | -0.06678 | -0.085 to - | |||||
| 0.049 | 0.999 |
| Sample ID | % HP | Expected
value
(ng/mL) | Measured
Value
(ng/mL) | Predicted
Value
(ng/mL) | Deviation
(ng/mL) | % Deviation | Allowable
nonlinearity | Within
Allowable
nonlinearity |
|-----------|--------|------------------------------|------------------------------|-------------------------------|----------------------|-------------|---------------------------|-------------------------------------|
| Lin-2 | 0.04 | 0.267 | 0.219 | 0.212 | 0.008 | 3.6% | ±14.3% | Yes |
| Lin-3 | 0.05 | 0.317 | 0.262 | 0.264 | -0.002 | -0.8% | ±14.3% | Yes |
| Lin-4 | 0.50 | 2.565 | 2.632 | 2.608 | 0.024 | 0.9% | ±14.3% | Yes |
| Lin-5 | 1.01 | 5.11 | 5.26 | 5.26 | -0.006 | -0.1% | ±14.3% | Yes |
| Lin-6 | 5.00 | 25.0 | 26.2 | 26.0 | 0.19 | 0.7% | ±14.3% | Yes |
| Lin-7 | 14.99 | 74.95 | 81.6 | 78.1 | 3.48 | 4.5% | ±14.3% | Yes |
| Lin-8 | 34.98 | 175 | 186 | 182 | 4.2 | 2.3% | ±14.3% | Yes |
| Lin-9 | 50.00 | 250 | 266 | 260 | 5.4 | 2.1% | ±14.3% | Yes |
| Lin-10 | 69.99 | 350 | 351 | 365 | -13.6 | -3.7% | ±14.3% | Yes |
| Lin-11 | 80.00 | 400 | 398 | 417 | -18.3 | -4.4% | ±14.3% | Yes |
| Lin-12 | 89.96 | 449 | 455 | 469 | -13.4 | -2.9% | ±14.3% | Yes |
| Lin-13 | 100.00 | 500 | 500 | 521 | -21.3 | -4.1% | ±14.3% | Yes |
Linearity/Measuring Range
| VITROS System | Measuring (Reportable) Range |
|---|---|
| 5600 | 0.31-400 ng/mL( µg/L) |
The extended measuring interval is 400-40,000 ng/mL (ug/L). Results with concentrations greater than 40,000 ng/mL (ug/L) will be reported as >40,000 ng/ mL(ug/L).
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 CEA assay.
Specimens Recommended
-
Serum and Plasma
Specimens Not Recommended. -
Do not use turbid specimens. Turbidity in specimens may affect test results. ●
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| VITROS 5600
| System | ||
|---|---|---|
| Li-Hep | EDTA | |
| Ordinary | ||
| Deming | ||
| Slope | 0.998 | 0.995 |
| 95% CI (Slope) | 0.9765 to 1.019 | 0.9459 to 1.044 |
| Intercept | -0.1177 | -0.8768 |
| 95% CI | ||
| (Intercept) | -0.8353 to -0.5999 | -3.056 to 1.302 |
| Correlation | ||
| Coefficient (r) | 0.999 | 0.998 |
| n | 40 | 40 |
| Pass/Fail Status | Pass | Pass |
Analytical Specificity
Known Interferents
The VITROS CEA assay was screened for interfering substances at CEA concentrations of approximately 3.00 ng/mL(ug/L) and 15.0 ng/mL(ug/L) following EP07 3rd ed – Interference Testing in Clinical Chemistry and EP37 1st ed - Supplemental Tables for Interference Testing in Clinical Chemistry. Commonly encountered substances were tested. Of the compounds tested, none were found to cause bias of >10%.
For substances that were tested and did not interfere, refer to "Substances that do not Interfere."
Substances that do not Interfere
The substances listed in the table below were tested with the VITROS CEA test following CLSI EP07and EP37 and found not to cause bias > 10% at CEA concentrations of approximately 3.00 ng/mL(ug/L) and 15.0 ng/mL(ug/L) at the test concentrations shown.
| Substance | Concentration |
|---|---|
| Acetaminophen | 20.3 mg/dL |
| N-Acetylcysteine | 15.0 mg/dL |
| Acetylsalicylic acid | 50 mg/dL |
| Alpha-tocopherol | 6.45 mg/dL |
| Aminoglutethimide | 39.8 mg/dL |
| Amoxicillin | 5.40 mg/dL |
| Ascorbic acid | 6.00 mg/dL |
| Bilirubin, conjugated | 100 mg/dL |
| Bilirubin, unconjugated | 100 mg/dL |
| Biotin | 0.351 mg/dL |
| Bleomycin | 300 mg/dL |
| onal 510(k) | |
| Carbamazepine | 4.50 mg/dL |
| Cefoxitin sodium | 695 mg/dL |
| Cholecalciferol (D3) | 19.2 µg/dL |
| Cholesterol | 400 mg/dL |
| Cisplatin | 1.3 mg/dL |
| Codeine | 0.141 mg/dL |
| Cotinine | 0. 24 mg/dL |
| Cyclophosphamide | 54.9 mg/dL |
| Dextran 40 | 1200 mg/dL |
| Dextromethorphan | 0.00156 mg/dL |
| Doxorubicin hydrochloride | 5.2 mg/dL |
| Enoxaparin | 360 U/dL |
| Ethanol | 600 mg/dL |
| Etoposide | 83 mg/dL |
| 5-Fluorouracil | 34.8 mg/dL |
| Furosemide | 1.59 mg/dL |
| Gamma globulin | 6 g/dL |
| HAMA (Human Anti-Mouse Antibodies) | 800 µg/L |
| Hemoglobin | 1000 mg/dL |
| Hydralazine | 1.44 mg/dL |
| Hydrocodone | 0.0072 mg/dL |
| Ibuprofen | 71.0 mg/dL |
| Intralipid | 2000 mg/dL |
| Levothyroxine | 0.0429 mg/dL |
| Loratadine | 0.0087 mg/dL |
| Methotrexate | 136 mg/dL |
| Mitomycin C | 5.52 mg/dL |
| Morphine | 0.78 mg/dL |
| Naproxen | 36.0 mg/dL |
| Omeprazole | 0.840 mg/dL |
| Phenytoin | 6.00 mg/dL |
| Prednisone | 0.010 mg/dL |
| Rheumatoid Factor | 900 IU/mL |
| Tamoxifen | 4.8 mg/dL |
| Theophylline | 6.0 mg/dL |
| Total protein | 15.0 g/dL |
| Triglycerides | 1500 mg/dL |
| Vancomycin hydrochloride | 12.3 mg/dL |
| Vinblastine | 138 mg/dL |
| Vincristine | 140 mg/dL |
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VITROS CEA Reagent
Traditional 510(k)
Cross-Reactivity
The cross-reactivity of the VITROS CEA test was evaluated by adding the following substance to a sample containing no CEA.
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| Substance | Tested
Concentration | VITROS 5600
% Cross Reactivity | | |
|-------------------------------------------------------|-------------------------|-----------------------------------|-----------------------|-----------------------|
| | | Master
Lot
9991 | Master
Lot
9992 | Master
Lot
9993 |
| Non- specific Cross- reacting
Antigen 1
(NCA 1) | 500 ng/mL
(µg/L) | ND | ND | ND |
ND = Not Detectable; mean result is below the measuring interval of the assay
Other Limitations
- · The VITROS CEA test is not recommended as a screening procedure for cancer detection.
- · Patients with confirmed carcinoma frequently have CEA levels in the same range as normal patients. Elevated levels of CEA may be found in smokers or patients with nonmalignant conditions. Based on these observations, CEA levels in serum and plasma, regardless of level, should not be interpreted as absolute evidence of the presence or absence of malignant disease.
- · Certain drugs and clinical conditions are known to alter CEA concentrations in vivo. For additional information, refer to one of the published summaries.
- · The results from this test should be used and interpreted only in the context of the overall clinical picture.
- · Heterophile, as well as human anti-animal antibodies (most common being human antimouse antibodies or HAMA) in serum or plasma of certain individuals are known to cause interference with immunoassays. The anti-animal antibodies may be present in blood samples from individuals regularly exposed to animals or who have received preparations of mouse monoclonal antibodies for diagnosis or therapy. Results inconsistent with clinical observations indicate the need for additional testing.
Dilution
The dilution recovery and dilution imprecision product requirements were met for the VITROS Immunodiagnostic Products CEA Reagent Pack. Serum or Plasma (EDTA or heparin) samples with concentrations greater than the measuring range will be reported as >400 ng/mL(ug/L) and may be automatically diluted on the system up to 100-fold (1 part sample with 99 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.
Expected Values
Adult Reference Interval
The adult reference interval was validated following CLSI document EP28-A3c Defining. Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition.
The distribution of CEA values for healthy non-smokers (n=68) and healthy smokers (n=72) showed equivalency to the expected values claim published in the Instructions for Use of the current US VITROS CEA
12
VITROS CEA Reagent Traditional 510(k) assay, therefore the current distribution of results for healthy subjects will be transferred to the updated VITROS CEA assay.
Product Claim:
| Percent (%) | |||||
|---|---|---|---|---|---|
| Category | N | 0-3.0 ng/mL (µg/L) | >3.0-5.0 ng/mL (µg/L) | >5.0-10.0 ng/mL (µg/L) | >10.0 ng/mL (µg/L) |
| Healthy Subjects | |||||
| Nonsmokers | 149 | 91.9 | 6.0 | 0.7 | 1.3 |
| Smokers | 101 | 67.3 | 22.8 | 8.9 | 1.0 |
| Total | 250 | 82.0 | 12.8 | 4.0 | 1.2 |
Distribution of Healthy Subjects Results for the updated VITROS CEA assay:
| Category | n | Percent (%) | |||
|---|---|---|---|---|---|
| 0-3.0 ng/mL | |||||
| (µg/L) | >3.0-5.0 ng/mL | ||||
| (µg/L) | >5.0-10.0 ng/mL | ||||
| (µg/L) | >10.0 ng/mL | ||||
| (µg/L) | |||||
| Healthy Subjects | |||||
| Non-smokers | 68 | 89.7 | 7.4 | 2.9 | 0 |
| Smokers | 72 | 72.2 | 22.2 | 5.6 | 0 |
High Dose Hook
The assessment was consistent with the high dose hook guidance found in CLSI document EP34. The high dose hook panel was prepared with VITROS High Sample Diluent B (HSDB), containing no measurable CEA, spiked with endogenous CEA antigen to produce a fluid with a concentration of approximately 546,000 ng/mL(ug/L). This fluid was diluted with VITROS HSDB to produce a set of ten fluids (the High Dose Hook Panel) with concentrations spanning between 273 and 546,000 ng/mL (ug/L). The high dose hook panel samples were tested in singleton using one reagent lot on one VITROS 5600 System.
The updated VITROS CEA assay has a high dose hook claim of up to 80,000ng/mL.
Traceability of Calibration
The Calibration of the VITROS CEA assay is traceable to in-house reference calibrators which have been value assigned to correlate to another commercially available test with reference to the 1st International Preparation 73/601.
Method Comparison
Accuracy was evaluated consistent with CLSI documents Measurement Procedure Comparison and Bias Estimation Using Patient Samples. 3rd ed. CLSI guideline EP09c; and Evaluation of Total Analytical Error for Quantitative medical laboratory Measurement Procedures. 2nd ed. CLSI guideline EP21. Human serum samples were obtained from certified vendors and tested neat. A total of 110 samples were tested in singleton using one reagent lot and one VITROS 5600 Integrated System.
Accuracy was evaluated consistent with CLSI document EP09c. The plot and table show the results of a method comparison study using patient (serum) samples analyzed on the VITROS CEA assay QuidelOrtho
13
compared with those analyzed on the VITROS CEA assay (K041322) on the VITROS 5600 Integrated System. The relationship between the 2 methods was determined by a Passing and Bablok regression as shown in the Figure below.
Image /page/13/Figure/2 description: The image is a regression plot for CEA (GEM.1110A) Lot 9993 versus a comparative method. The x-axis represents the comparative method VITROS CEA (GEM.1110) in ng/mL, while the y-axis represents 5600 PM 118 Lot 9993 in ng/mL. The plot includes a Passing-Bablok fit line represented by the equation y = 0.1059 + 1.006x, and dashed lines indicating the allowable difference of ±10%.
14
| System | n | Slope
(95% CI) | Correlation
Coefficient | Conventional Units (U/mL) | |
|--------------------------------|-----|------------------------------|----------------------------|---------------------------|------------------------------------|
| | | | | Range of
Samples | Intercept (95%
CI) |
| 5600 vs. Comparative
Method | 110 | 1.01
(0.9972 to
1.012) | 0.999 | 0.56-396 | 0.106
(-0.01602 to -
0.3729) |
Conclusion
The conclusions drawn from the nonclinical tests (discussed above) demonstrate the updated VITROS Immunodiagnostic Products CEA Reagent pack 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.