(90 days)
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.
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) ●
The provided document describes the safety and effectiveness information for the VITROS Immunodiagnostic Products CEA Reagent Pack (K231517), which is intended for the quantitative measurement of carcinoembryonic antigen (CEA) in human serum and plasma to aid in the prognosis and management of cancer patients. The document primarily focuses on nonclinical performance studies to demonstrate substantial equivalence to a predicate device.
Here's a breakdown of the requested information based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" in a singular table alongside performance for all aspects. However, it implicitly defines acceptance by stating that certain studies were performed "consistent with CLSI document" guidelines and that "all results were acceptable" or "met the acceptance criteria." For linearity, it specifies "Allowable nonlinearity." For matrix comparison, it states "The results met the acceptance criteria."
Here's an attempt to synthesize the acceptance criteria and performance from the text for key analytical characteristics:
| Performance Characteristic | Acceptance Criteria (Implicit/Explicit) | Reported Device Performance |
|---|---|---|
| Stability (Shelf-life) | "supports a 52 week shelf-life" (implies acceptance of data over this period) | "Four runs have been performed on each time-point, monthly intervals, supports a 52 week shelf-life." |
| Stability (On-board) | "support the current claim of 8 weeks on-board stability" (implies acceptance of data over this period) | "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 (Repeatability) | Not explicitly stated as a separate acceptance criterion, but data is provided consistent with CLSI EP05-A3. | Repeatability (%CV) for 6.55 ng/mL: 1.7%; 41.4 ng/mL: 1.4%; 228 ng/mL: 1.9%; 390 ng/mL: 1.2%. Additional precision table shows within-run %CV ranging from 1.5% to 1.9%. |
| Precision (Within-Lab) | Not explicitly stated as a separate acceptance criterion, but data is provided consistent with CLSI EP05-A3. | Within-Lab (%CV) for 6.55 ng/mL: 2.7%; 41.4 ng/mL: 2.5%; 228 ng/mL: 2.7%; 390 ng/mL: 2.9%. Additional precision table shows within-laboratory %CV ranging from 3.1% to 3.6%. |
| Detection Capability (LoD) | "This supports the claimed LOD of 0.31ng/ml." (Implies the observed LoD must be ≤ 0.31 ng/mL) | Observed LoD: 0.15 ng/mL (ug/L) |
| Detection Capability (LoQ) | "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." (Implies observed LoQ must be ≤ 0.31 ng/mL at 20% CV) | Observed LoQ at 20% CV: 0.15 ng/mL (ug/L). Claimed LoQ: 0.31 ng/mL (ug/L). |
| Linearity | "Allowable nonlinearity: ±14.3%" | Linearity demonstrated from 0.22 ng/mL to 500 ng/mL (ug/L) with deviations from linearity within +/- 14.3%. All individual data points in the table are within ±14.3% deviation. |
| Matrix Comparison | "The results met the acceptance criteria for the comparison between serum and plasma (Li-Hep and EDTA) specimens spanning the expected measuring interval." (Specific criteria not provided, but statistical metrics like slope, intercept CIs, and correlation coefficient are presented). | The table shows for Li-Hep: Slope 0.998 (95% CI 0.9765-1.019), Intercept -0.1177 (95% CI -0.8353 to -0.5999), r=0.999. For EDTA: Slope 0.995 (95% CI 0.9459-1.044), Intercept -0.8768 (95% CI -3.056 to 1.302), r=0.998. Both passed. |
| Analytical Specificity (Interferents) | "Of the compounds tested, none were found to cause bias of >10%." (Implicit acceptance criterion for "Substances that do not Interfere"). | None of the numerous tested substances (e.g., Acetaminophen, Bilirubin, Biotin, Hemoglobin up to specified concentrations) caused bias >10% at CEA concentrations of 3.00 ng/mL and 15.0 ng/mL. |
| High Dose Hook | "The updated VITROS CEA assay has a high dose hook claim of up to 80,000ng/mL." (Implies the testing confirmed no hook effect below or at this concentration). The study assesses consistency with CLSI EP34. | High dose hook panel tested from 273 to 546,000 ng/mL to support the claim of up to 80,000 ng/mL. (No specific performance data presented, but implies successful demonstration). |
| Method Comparison (Accuracy) | Allowable difference of ±10% (as shown in the regression plot). | Passing-Bablok regression: y = 0.1059 + 1.006x, with 95% CI for slope (0.9972 to 1.012) and intercept (-0.01602 to -0.3729). Correlation coefficient (r): 0.999. The plot includes dashed lines indicating an allowable difference of ±10%, implying performance within this range. |
2. Sample Size Used for the Test Set and Data Provenance
- Precision:
- 5600 System (Table 1): 4 precision fluids. 2 replicates per fluid, 2 occasions per day, for 20 days. Total 80 data points per fluid.
- Additional Precision Analysis (Table 2): 4 precision fluids (PP1-PP4). 240 observations per sample (likely 2 replicates per run, multiple runs, over multiple days/lots as per CLSI guideline EP05-A3).
- Detection Capability (LoB): 4 endogenous fluids. 2 replicates per run, 2 runs per day, over 5 test days. Total 20 replicates per test fluid x 4 fluids = 80 replicates total for LoB. Tested on 3 lots, so 240 total replicates.
- Detection Capability (LoD & LoQ): 5 samples. 6 replicates per run, 2 runs per day, over 5 test days. Total 60 replicates per fluid x 5 fluids = 300 replicates total for LoD/LoQ. Tested on 3 lots, so 900 total replicates.
- Linearity: 13 levels, five replicates for each level.
- Matrix Comparison: Not specified precisely, but samples were "spanning the expected measuring interval."
- Analytical Specificity (Interferents): Not specified (e.g., number of replicates or distinct samples).
- High Dose Hook: Panel of ten fluids. Tested in singleton.
- Method Comparison (Accuracy): 110 human serum samples. Tested in singleton.
Data Provenance:
The document consistently refers to "human serum" or "patient samples." For the method comparison, it states "Human serum samples were obtained from certified vendors." For detection capability, it mentions "endogenous fluids" and "admixtures of serum samples containing endogenous CEA combined with CEA affinity stripped serum." For expected values, it refers to "healthy non-smokers (n=68)" and "healthy smokers (n=72)."
The country of origin is not specified but the submitter is Ortho-Clinical Diagnostics Inc. from the UK. The studies are nonclinical performance studies, often conducted in-house or by contract research organizations. These studies are prospective in nature, as they are designed experiments to evaluate specific performance characteristics.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
Ground truth for these studies is analytically derived, not expert consensus interpretation. For in vitro diagnostic devices like the CEA assay, the "ground truth" for test sets in nonclinical studies typically refers to:
- Reference values assigned by highly accurate reference methods or known concentrations of analytes (e.g., spiked samples) for linearity, detection, and accuracy studies.
- The known physiological state of samples (e.g., healthy non-smokers, healthy smokers) for reference intervals.
- The known presence/absence and concentration of interferents for specificity studies.
Therefore, the concept of "experts establishing ground truth" in the sense of clinical interpretation (like radiologists for imaging) is not applicable here. The ground truth is established by the design of the analytical experiment and the reference materials/methods used.
4. Adjudication Method for the Test Set
Adjudication methods (like 2+1, 3+1) are typically used in clinical studies where human interpretation of data (e.g., images) forms the ground truth, and discrepancies need to be resolved. This is not relevant for the analytical performance studies of a laboratory immunoassay described in this document.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No. An MRMC study is relevant for devices involving human interpretation (e.g., medical imaging) to assess how the device impacts human reader performance. This document describes the analytical performance of an in vitro diagnostic immunoassay.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, this entire submission describes the standalone performance of the VITROS Immunodiagnostic Products CEA Reagent Pack and the VITROS 5600 Integrated System. The data presented are purely analytical measurements performed by the device, without human interpretive input or assistance being part of its core function.
7. The Type of Ground Truth Used
- Stability: Time points with known age of reagents/calibrators/samples.
- Precision: Control materials or patient samples where inherent variability is being measured. No "ground truth" in the sense of an absolute true value is typically assigned for precision, but rather the repeatability and reproducibility of the measurements around a mean.
- Detection Capability: Samples confirmed to contain no measurable CEA (for LoB) or samples with targeted, known low concentrations of CEA (for LoD and LoQ), often prepared by spiking.
- Linearity: Samples covering a wide range of concentrations, often prepared by dilution of a high-concentration sample with known low-concentration diluent, such that the "expected value" is calculable.
- Matrix Comparison: Patient samples (serum vs. various plasma types) where a comparison between matrices is the objective, not an absolute ground truth value.
- Analytical Specificity: Samples spiked with known concentrations of potential interfering substances, with the expectation that the CEA measurement should not be significantly biased.
- High Dose Hook: Samples with extremely high, known CEA concentrations to ensure the device correctly reports high values and doesn't "hook" and report falsely low.
- Method Comparison (Accuracy): Patient samples compared against a legally marketed predicate device (VITROS CEA assay K041322) on the same system. The predicate device's results serve as the comparative measure, assumed to be accurate for the purpose of demonstrating equivalence.
- Expected Values: Clinically healthy subjects (non-smokers and smokers) categorized by their CEA levels.
In summary, the ground truth is primarily based on analytical reference materials, known spiked concentrations, and comparative measurements against a predicate device, all within the domain of quantitative laboratory measurements.
8. The Sample Size for the Training Set
This document describes nonclinical performance testing for an in vitro diagnostic device, not a machine learning or AI algorithm in the typical sense that would involve a "training set." The device is a chemical reagent pack used on an automated immunoassay system. While there were certainly development and validation phases during the device's creation (which might involve analogous processes to "training"), the document provided does not detail a "training set" in the context of an AI/ML algorithm. The studies described are validation studies of the finalized product.
9. How the Ground Truth for the Training Set Was Established
As noted in point 8, the concept of a "training set" with established ground truth as typically understood for AI/ML is not applicable to this kind of device and its regulatory submission. The document focuses on demonstrating the analytical performance of a developed immunoassay kit.
§ 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.