(257 days)
Elecsys CYFRE 21-1:
Immunoassay for the in vitro quantitative determination of tragments of cytokeratin 19 in human serum and plasma (Li-Heparin. K2-EDTA and K3-EDTA). The assay is to be used as an aid in monitoring disease progression during the course of disease and treatment in lung cancer patients. Serial testing for patient CYFRA 21-1 assay values should be used in conjunction with other clinical methods used for monitoring lung cancer.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Elecsys CYFRA 21-1 CalSet:
CYFRA 21-1 is used for calibrating the quantitative Elecsys CYFRA 21-1 assay on the Elecsys and cobas e immunoassay analyzers.
Elecsys PreciControl Tumor Marker:
PreciControl Tumor Marker is used for quality control of Elecsys immunoassays on Elecsys and cobas e immunoassay analyzers.
(1) The Elecsys CYFRA 21-1 Immunoassay is a two-step sandwich immunoassay with streptavidin microparticles, a biotinylated monoclonal cytokeratin 19-specific antibody, and a monoclonal cytokeratin 19-specific antibody labeled with a ruthenium complex and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration master curve (5-pointcalibration) provided with the reagent bar code.
(2) The Elecsys CYFRA 21-1 CalSet is a lyophilized product consisting of Cytokeratin from cell culture of the cell line MCF-7 in two concentration ranges (approximately 0 ng/mL and 50 ng/mL) in a cytokeratin free human serum matrix with preservative. During manufacture, the analyte is spiked ito the matrix at the desired concentration levels.
(3) The Elecsys PreciControl Tumor Marker (CYFRA 21-1) is a lyophilized control serum in two concentration ranges (approximately 3.29 ng/mL and 27.2 ng/mL).
Note: The reagent, calibrator, and the quality control materials are all packaged separately.
The provided document describes the Elecsys CYFRA 21-1 Immunoassay, a device intended for quantitative determination of cytokeratin 19 fragments in human serum and plasma, used as an aid in monitoring disease progression and treatment for lung cancer patients.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The FDA clearance for this in-vitro diagnostic device does not typically specify "acceptance criteria" in the same way a medical image analysis AI might have specific sensitivity/specificity thresholds. Instead, it demonstrates substantial equivalence to a predicate device by comparing various performance characteristics. The acceptance is implied by demonstrating performance that is comparable to or better than the predicate device across critical analytical and clinical metrics.
| Performance Characteristic | Acceptance Criteria (Implied by Predicate/Regulatory Standards) | Reported Device Performance (Elecsys CYFRA 21-1) |
|---|---|---|
| Intended Use/Indications | Aid in monitoring disease progression during course of disease and treatment in lung cancer patients (for serum) | Aid in monitoring disease progression during course of disease and treatment in lung cancer patients (for human serum and plasma, Li-Heparin, K2-EDTA and K3-EDTA) |
| Measuring Range | 0.5 - 50 ng/mL | 0.5 – 100 ng/mL |
| Precision (Within-run CV) | Predicate: 2.40% - 5.10% CV | 0.7% - 4.8% CV |
| Precision (Total/Intermediate CV) | Predicate: 4.90% - 8.40% CV | 0.7% - 9.6% CV |
| Limit of Blank (LoB) | Not determined for predicate | 0.0946 ng/mL |
| Limit of Detection (LoD) | 0.12 ng/mL | 0.1813 ng/mL |
| Limit of Quantitation (LoQ) | 0.21 ng/mL with 17.78% imprecision | 0.286 ng/mL with 30% total allowable error |
| Hook Effect | No high-dose hook effect up to 1100 ng/mL | No high-dose hook effect up to 2427 ng/mL |
| Cross-Reactivity/Interference | Limited information on specific thresholds for predicate; generally, minimal interference expected. | Largely unaffected by common interferents (e.g., Lipemia, Biotin, Bilirubin, Hemoglobin, Rheumatoid Factor, HAMA). Recovery of spiked HAMA serum: 98.51%. |
| Method Comparison (vs. Predicate) | High correlation (implied by good slope and correlation coefficient) | Slope 0.911 (95% CI: 0.86, 0.96); Intercept -1.4 (95% CI: -2.86, 0.06); Pearson r 0.955 |
| Clinical Sensitivity (at 50% change) | 45.9% | 44.1% |
| Clinical Specificity (at 50% change) | 87.3% | 91.0% |
| Expected Values (Normal Population) | Predicate: Primarily ≤ 2.37 ng/mL | Elecsys: 228/240 (95%) of apparently healthy individuals had values ≤ 2.37 ng/mL |
| Normal Range (Benign Conditions) | Predicate: Primarily ≤ 2.37 ng/mL | Elecsys: Varies by condition, but generally low for benign lung disease, higher for CHF & benign kidney/liver disease. |
2. Sample Size Used for the Test Set and Data Provenance
The document details numerous analytical validation studies. Here's a breakdown for key performance metrics:
- Precision (Human Sera):
- Internal: Seven-member panel (5 patient samples, 2 controls). Tested in single determination, 4 aliquots, over 21 operating days. Total measurements: 7 samples * 4 aliquots/day * 21 days = 588 measurements (at least, assuming single determination each aliquot).
- External: Two replicates of each control (PC TM 1 & 2) and six human serum samples per run, two runs per day for 20 days at three external sites. Total measurements: (2 controls + 6 HS) * 2 replicates * 2 runs/day * 20 days * 3 sites = 1,920 measurements.
- Provenance: Not explicitly stated, but common for such studies to use mixtures of human serum/controls which could be sourced from various regions due to ethical and availability considerations. Prospective data collection for these specific tests.
- Limit of Blank (LoB): 5 analyte-free serum samples. 60 measuring points collected (implies 5 samples * 2-fold determination/run * 6 runs = 60).
- Limit of Detection (LoD): 5 low-level human serum samples. 60 measuring points collected (implies 5 samples * 2-fold determination/run * 6 runs = 60).
- Limit of Quantitation (LoQ): 8 spiked human serum samples. 200 measuring points collected (implies 8 samples * 5 runs * single determination = 40, assuming some dilutions).
- Linearity: Six dilution series (3 serum, 3 plasma), each with at least 11 dilutions.
- Endogenous Interferences: Three human serum samples (low, mid, high CYFRA 21-1) for each of six interfering substances.
- HAMA Effect: One HAMA serum and one control serum, both spiked to two different analyte concentrations. Each concentration had 11 dilutions, measured in duplicate.
- High-Dose Hook Effect: Human serum pools spiked up to 2,470ng/mL.
- Exogenous Interferences - Drugs: Two human serum samples, spiked with 27 pharmaceutical compounds. Samples tested in three-fold determination.
- Serum/Plasma Comparison: At least 44 serum/plasma pairs per sample type. For Serum/Plasma Separation Tube comparison, 5 samples in duplicate.
- Clinical Performance (Monitoring): 83 patients with lung cancer, 398 samples measured (86 baseline, 315 monitoring values). Patients had ≥ 3 blood draws over time.
- Provenance: Not explicitly stated, but implies clinical samples from lung cancer patients, likely retrospective from a patient cohort or collected prospectively for the study.
- Expected Values (Normal Population):
- 240 apparently healthy men and women (equally divided into smokers and non-smokers).
- 195 benign disease conditions.
- 440 cancer cases (including 120 lung cancer, 40 bladder, breast, cervical, ESCC, GI tract, head and neck, prostate, and ovarian cancer each).
- Provenance: This data represents cohort studies, likely retrospective collection from various institutions.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
For this type of immunoassay, "ground truth" is typically defined by the actual analyte concentration in the samples or by established clinical diagnoses/disease progression based on a combination of clinical assessment, imaging, and potentially pathology.
- Clinical Performance (Monitoring): The document states that clinical effectiveness was assessed by "comparing changes in CYFRA 21-1 levels in serial serum samples from 83 patients compared to changes in disease status." The "disease status" would be the ground truth for clinical progression. However, the number and qualifications of experts (e.g., oncologists, radiologists) establishing this disease status ground truth are NOT specified in the provided text.
4. Adjudication Method for the Test Set
Not applicable in the typical sense for an immunoassay. The clinical performance study relies on a comparison of assay values to "disease status," which is a clinical endpoint rather than an adjudicated radiological finding or similar interpretation. The judgment of disease progression would be based on standard clinical practice for lung cancer, likely involving follow-up imaging, biopsy results, and physician assessment, but no specific adjudication panel or method (e.g., 2+1) is described for the clinical endpoint data.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
Not applicable. This is an in-vitro diagnostic device for quantitative measurement of a biomarker, not an AI for image interpretation that augments human readers. Therefore, an MRMC study comparing human readers with and without AI assistance is not relevant to this device's evaluation.
6. Standalone Performance Study (Algorithm Only Without Human-in-the-Loop Performance)
Yes, the entire submission is a standalone performance study of the Elecsys CYFRA 21-1 immunoassay. The device generates quantitative results (ng/mL) without human interpretation as part of its primary function. The clinical performance section assesses how these quantitative results_correlate_ with disease status, but the assay itself doesn't have a "human-in-the-loop" component in its operation.
7. Type of Ground Truth Used
- Analytical Studies (Precision, LoB, LoD, LoQ, Linearity, Interference, Calibration, Stability): The ground truth is the actual concentration of the analyte (CYFRA 21-1) in spiked samples, known concentrations in controls, or the absence of the analyte in blank/interferent-free samples. This is established through highly controlled laboratory procedures and reference methods.
- Clinical Performance (Monitoring): The ground truth is the "disease status" (progression or no progression) of lung cancer patients. The method for establishing this status is not detailed beyond "changes in disease status," but it inherently relies on a combination of medical evidence and clinical assessment over time.
- Expected Values (Normal Population & Cancer/Benign Cohorts): The ground truth is the clinical diagnosis/health status of the individuals in those cohorts (e.g., "apparently healthy," "benign lung disease," "lung cancer").
8. Sample Size for the Training Set
For an immunoassay, the concept of a "training set" as understood in machine learning (where an algorithm learns from labeled data) doesn't directly apply. However, the development and optimization of the assay (e.g., antibody selection, reagent formulation, instrument parameters) would involve extensive internal testing. The submission here focuses on validation, demonstrating performance on independent (test) samples. The assay itself has pre-defined chemical and electrical principles, not an adaptive learning algorithm.
9. How the Ground Truth for the Training Set Was Established
As explained above, "training set" doesn't directly apply. However, during the initial development and optimization phase, the ground truth would be established through:
- Reference materials: Samples with precisely known concentrations of CYFRA 21-1 (traceable to internal or international standards).
- Clinical samples: Use of various clinical samples (e.g., from healthy individuals, various disease states) to understand the assay's behavior and define preliminary measuring ranges and expected values. This preliminary testing would inform the design of the formal validation studies presented in the 510(k). The "Enzymun-Test CYFRA 21-1 method" is mentioned as a method against which the Elecsys CYFRA 21-1 has been standardized, indicating a reference for comparison during development.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
December 14, 2016
Roche Diagnostics Mr. Adam Clark Regulatory Affairs Consultant 9115 Hague Road Indianapolis, IN 46250
Re: K160915
Trade/Device Name: Elecsys CYFRA 21-1 Elecsys CYFRA 21-1 CalSet Elecsys PreciControl Tumor Marker Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-Associated Antigen Immunological Test System Regulatory Class: II Product Code: OVK, JIT Dated: November 7, 2016 Received: November 8, 2016
Dear Mr. Clark:
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. 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 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements
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as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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
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You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
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FOR
Leonthena R. Carrington, MS, MBA, MT(ASCP) Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K160915
Device Name Elecsys CYFRA 21-1 Elecsys CYFRA 21-1 CalSet Elecsys PreciControl Tumor Marker
Indications for Use (Describe)
Elecsys CYFRE 21-1:
Immunoassay for the in vitro quantitative determination of tragments of cytokeratin 19 in human serum and plasma (Li-Heparin. K2-EDTA and K3-EDTA). The assay is to be used as an aid in monitoring disease progression during the course of disease and treatment in lung cancer patients. Serial testing for patient CYFRA 21-1 assay values should be used in conjunction with other clinical methods used for monitoring lung cancer.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Elecsys CYFRA 21-1 CalSet:
CYFRA 21-1 is used for calibrating the quantitative Elecsys CYFRA 21-1 assay on the Elecsys and cobas e immunoassay analyzers.
Elecsys PreciControl Tumor Marker:
PreciControl Tumor Marker is used for quality control of Elecsys immunoassays on Elecsys and cobas e immunoassay analyzers.
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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510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague RoadIndianapolis, IN 46250 |
| Contact | Adam ClarkPhone317)521-4371Email: adam.clark@roche.com |
| Date Prepared | November 7, 2016 |
| Proprietary Name | 1. Elecsys CYFRA 21-12. Elecsys CYFRA 21-1 CalSet3. Elecsys PreciControl Tumor Marker |
| Common Name | 1. CYFRA 21-12. CYFRA 21-1 CalSet3. Tumor Marker Control |
| Classification Name | 1. Tumor-Associated antigen immunological test system2. Secondary, calibrator3. Multi-analyte controls, all kinds (assayed and unassayed) |
| Product Codes | 1. OVK; 866.60102. JIT; 862.11503. JJY; 862.1660 |
| Predicate Devices | 1. Fujirebio CYFRA 21-1 EIA kit2. Elecsys HE4 CalSet3. Elecsys PreciControl Tumor Marker |
| Establishment Registration | Roche Diagnostics GmbH in Mannheim, Germany: 9610126Roche Diagnostics GmbH in Penzberg, Germany: 9610529Roche Diagnostics in the United States: 1823260 |
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1. DEVICE DESCRIPTION
(1) The Elecsys CYFRA 21-1 Immunoassay is a two-step sandwich immunoassay with streptavidin microparticles, a biotinylated monoclonal cytokeratin 19-specific antibody, and a monoclonal cytokeratin 19-specific antibody labeled with a ruthenium complex and electrochemiluminescence detection. Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration master curve (5-pointcalibration) provided with the reagent bar code.
(2) The Elecsys CYFRA 21-1 CalSet is a lyophilized product consisting of Cytokeratin from cell culture of the cell line MCF-7 in two concentrations ranges (approximately 0 ng/mL and 50 ng/mL) in a cytokeratin free human serum matrix with preservative. During manufacture, the analyte is spiked ito the matrix at the desired concentration levels.
(3) The Elecsys PreciControl Tumor Marker (CYFRA 21-1) is a lyophilized control serum in two concentration ranges (approximately 3.29 ng/mL and 27.2 ng/mL).
Note: The reagent, calibrator, and the quality control materials are all packaged separately.
INDICATIONS FOR USE 2.
(1) Immunoassay for the in vitro quantitative determination of fragments of cytokeratin 19 in human serum and plasma (Li-Heparin, K2-EDTA and K3-EDTA). The assay is to be used as an aid in monitoring disease progression during the course of disease and treatment in lung cancer patients. Serial testing for patient CYFRA 21-1 assay values should be used in conjunction with other clinical methods used for monitoring lung cancer.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
(2) CYFRA 21-1 CalSet is used for calibrating the quantitative Elecsys CYFRA 21-1 assay on the Elecsys and cobas e immunoassay analyzers.
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(3) PreciControl Tumor Marker is used for quality control of Elecsys immunoassays on Elecsys and cobas e immunoassay analyzers.
TECHNOLOGICAL CHARACTERISTICS 3.
| Comparison of Assays, Similarities and Differences |
|---|
| Table 1 |
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:Fujirebio CYFRA 21-1 EIA(K100831) | Candidate Device:Elecsys CYFRA 21-1 |
| General Assay Features | ||
| Intended Use/Indicationsfor Use | The CYFRA 21-1 EIA kit is intendedfor the quantitative determination ofsoluble cytokeratin 19 fragments inhuman serum. The assay is to be used asan aid in monitoring disease progressionduring the course of disease andtreatment in lung cancer patients. Serialtesting for patient CYFRA 21-1 assayvalues should be used in conjunctionwith other clinical methods used formonitoring lung cancer. | Immunoassay for the in vitroquantitative determination of fragmentsof cytokeratin 19 in human serum andplasma (Li-Heparin, K2-EDTA and K3-EDTA). The assay is to be used as anaid in monitoring disease progressionduring the course of disease andtreatment in lung cancer patients. Serialtesting for patient CYFRA 21-1 assayvalues should be used in conjunctionwith other clinical methods used formonitoring lung cancer.The electrochemiluminescenceimmunoassay “ECLIA” is intended foruse on Elecsys and cobas eimmunoassay analyzers. |
| AssayProtocol | Quantitative enzyme immunometricassay | Quantitative sandwichimmunoassay |
| DetectionProtocol | Spectrophotometry | Electrochemiluminescence |
| Applications | Manual assay | 18 minute application |
| Assay Comparison | ||
| Feature | Predicate Device:Fujirebio CYFRA 21-1 EIA(K100831) | Candidate Device:Elecsys CYFRA 21-1 |
| General Assay Features | ||
| InstrumentPlatform | Microtiter plate | cobas e 411 |
| SampleVolume | 50 μL | 20 μL |
| SampleType | Human serum | Human serum and plasma (Li-Heparin, K2-EDTA and K3-EDTA) |
| Reagents | The Fuijirebio CYFRA 21-1 EIA is asolid phase, non-competitiveimmunoassay based on two monoclonalantibodies (derived from mice) directedagainst two separate antigenicdeterminants of soluble fragments ofcytokeratin 19. Calibrators, controls andpatient samples are incubated togetherwith biotinylated Anti-CYFRA 21-1MAb and horseradish peroxidase (HRP)labeled Anti-CYFRA 21-1 MAb instreptavidin coated microstrips. Afterwashing, bufferedSubstrate/Chromogen reagent(hydrogen peroxide and 3, 3', 5, 5'tetramethylbenzidine) is added to eachwell and the enzyme reaction is allowedto proceed. During the enzyme reactiona blue color will develop if antigen ispresent. The color intensity isdetermined in a microplatespectrophotometer at 620 nm. | The Elecsys CYFRA 21-1 assay isa sandwhich immunoassaybiotinylated monoclonalcytokeratin 19-specific antibodyand a monoclonal cytokeratin 19-specific antibody labeled with aruthenium complex [Tris(2,2'- bipyridyl)ruthenium(II)-complex(Ru(bpy))] |
| Calibrator | CYFRA 21-1 A, B, C, D, E and F | Elecsys CYFRA 21-1 CalSet |
| Assay Comparison | ||
| Feature | Predicate Device:Fujirebio CYFRA 21-1 EIA(K100831) and Elecsys HE4PreciControl (K112624) | Candidate Device:Elecsys CYFRA 21-1 |
| General Assay Features | ||
| CalibrationInterval | Calibration curves are determinedfrom the 6 calibrators and are runin duplicate with each assay run. | Calibration must be performed once perreagent lot using fresh reagent (i.e. notmore than 24 hours since the reagent kitwas registered on the analyzer.)Renewed Calibration is recommended asfollows:After 8 weeks when using the samereagent lotAfter 7 days when using the samereagent kit on the analyzerAs required: e.g. quality controlfindings outside the specified limits |
| Controls | Elecsys HE4 PreciControl (K112624) | Elecsys PreciControl Tumor Marker |
| Traceability/Standardization | In K100831, the sponsor states:There is no recognized referencestandard for CYFRA 21-1. Theconcentration of the CYFRA 21-1EIA primary calibrators has beenassigned by using Roche CK19antigen. The methods used forvalue assignment of the CYFRA21 primary and secondarycalibrators were provided. | Elecsys CYFRA 21-1 has beenstandardized against the Enzymun-TestCYFRA 21-1 method. |
| Reagent Stability | Microplate – 2-8°C until expirydate stated on the plateBiotin Anti-CYFRA 21-1 – 2-8°Cuntil expiry date stated on the vialTracer, HRP Anti-CYFRA 21-1 –2-8°C until expiry date stated onthe vialTMB HRP-Substrate – 2-8°C untilexpiry date stated on the vial | Unopened at 2-8°C – up to statedexpiration date.After opening at 2-8°C – 12 weeks.On the analyzer – 8 weeks |
| Assay Comparison | ||
| Feature | Predicate Device:Fujirebio CYFRA 21-1 EIA(K100831) | Candidate Device:Elecsys CYFRA 21-1 |
| Labeled Performance Characteristics | ||
| MeasuringRange | 0.5 - 50 ng/mL | 0.5 – 100 ng/mL |
| Precision | On the Fujirebio Test SystemWithin-runn=1603.70% CV @ 2.69 ng/mL5.10% CV @ 2.91 ng/mL4.30% CV @ 7.28 ng/mL4.10% CV @ 7.63 ng/mL2.40% CV @ 17.4 ng/mL2.60% CV @ 18.6 ng/mL2.60% CV @ 33.4 ng/mL3.80% CV @ 35.7 ng/mLTotal6.10% CV @ 2.69 ng/mL8.40% CV @ 2.91 ng/mL6.90% CV @ 7.28 ng/mL7.30% CV @ 7.63 ng/mL5.30% CV @ 17.4 ng/mL4.90% CV @ 18.6 ng/mL4.90% CV @ 33.4 ng/mL5.60% CV @ 35.7 ng/mL | cobas e 411Within-run (will be labeled repeatability)n=84HS1: 4.8% CV @ 0.53 ng/mLHS2: 2.1% CV @ 1.31 ng/mLHS3: 2.1% CV @ 1.37 ng/mLHS4: 1.9% CV @ 2.80 ng/mLHS5: 1.3% CV @ 18.98 ng/mLHS6: 1.3% CV @ 79.37 ng/mLPC 1: 1.2% CV @ 2.66 ng/mLPC 2: 0.7% CV @ 21.73 ng/mLTotal (will be labeled Intermediate)HS1: 9.6% CV @ 0.53 ng/mLHS2: 4.0% CV @ 1.31 ng/mLHS3: 4.6% CV @ 1.37 ng/mLHS4: 2.6% CV @ 2.80 ng/mLHS5: 2.2% CV @ 18.98 ng/mLHS6: 2.4% CV @ 79.37 ng/mLPC 1: 4.3% CV @ 2.66 ng/mLPC 2: 0.7% CV @ 21.73 ng/mL |
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Table 1, continued
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| Assay Comparison | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Feature | Predicate Device:Fujirebio CYFRA 21-1 EIA(K100831) | Candidate Device:Elecsys CYFRA 21-1 | |||||||||
| Labeled Performance Characteristics | |||||||||||
| LoB | Not determined | 0.0946 ng/mL | |||||||||
| LoD | 0.12 ng/mL | 0.1813 ng/mL | |||||||||
| LoQ | 0.21 ng/mL with the highestallowable imprecision of 17.78% | 0.286 ng/mL with a total allowable errorof 30% | |||||||||
| LowerDetectionLimit | 0.5 ng/mL | 0.5 ng/mL | |||||||||
| HookEffect | No high-dose hook effect in samplesup to 1100 ng/mL | There is no high-dose hook effect atanalyte concentrations up to 2427 ng/mL | |||||||||
| Limitations | The assay is inaffected by:Triglycerides ≤ 30 mg/mL Bilirubin1 ≤ 0.2 mg/mL Hemoglobin ≤ 5.0 mg/mL Total Protein ≤ 120 mg/mL The CYFRA 21-1 EIA assay wasevaluated using specimens withHAMA and Rheumatoid Factor (FR)to further assess the assay specificity.Six specimens positive for HAMAand five specimens positive for RFwere evaluated for % recovery withCYFRA 21-1 antigen spiked intoeach specimen at approximately 5and 25 ng/mL. Mean recoveryresults are summarized in thefollowing table:ClinicalCondition Numberofspecimens Mean %Recovery HAMA 6 98 RF 5 101 1A mixture of conjugated (10%) andunconjugated (90%) bilirubin. | The assay is unaffected by:Lipemia (Intralipid®) ≤ 1500 mg/dL Biotin ≤ 50 ng/mL Bilirubin ≤ 66 mg/dL Hemoglobin ≤ 1500 mg/dL Rheumatoid Factor ≤ 1500 IU/mL Human Serum Albumin ≤ 7 g/dL The CYFRA 21-1 assay was evaluatedusing specimens with HAMA to furtherassess the assay specificity. A specifiedHAMA serum was spiked with analyte totwo different analyte concentrations (3.21ng/mL and 96.3 ng/mL). As a control, aserum without interferent (related basicserum) was spiked analogously. Thesamples were measured in duplicates.The Mean result was 98.51% recovery. |
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| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:Fujirebio CYFRA 21-1 EIA(K100831) | Candidate Device:Elecsys CYFRA 21-1 |
| Labeled Performance Characteristics | ||
| ExternalMethodComparison(Fujirebio vs.Elecsys) | SlopeUnweighted 0.911Deming (95% CI: 0.86, 0.96) | Intercept Pearson r-1.4 0.955(95% CI: -2.86, 0.06) |
| ClinicalSensitivity andSpecificity | The following table shows theresulting sensitivities andspecificities of the CYFRA 21-1EIA at various percent changes inCYFRA 21-1 EIA concentrations,together with the positive predictivevalues (PPV) and negativepredictive values (NPV) for thepopulation tested (85 sequentialpairs from patients with diseaseprogression and 229 sequential pairsfrom patients with no progression). | The following table shows the resultingsensitivities and specificities of theElecsys CYFRA 21-1 assay comparedto the disease status at various changesin concentration over time. Sensitivity isrepresented as a concordance of theElecsys CYFRA 21-1 to progression ofdisease. Specificity is represented as aconcordance of the Elecsy CYFRA 21-1to no progression of disease. |
| PercentChange inCYFRA 21-1 | Sensitivity Specificity(%) (%) | |
| 30 | 52.9 84.3 | |
| 40 | 48.2 85.6 | |
| 50 | 45.9 87.3 | |
| 60 | 44.7 88.2 | |
| 70 | 43.5 89.5 | |
| PercentChange inCYFRA 21-1 | Sensitivity Specificity(%) (%) | |
| 30 | 49.2 87.1 | |
| 40 | 44.1 89.8 | |
| 50 | 44.1 91.0 | |
| 60 | 39.0 91.4 | |
| 70 | 35.6 93.4 |
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| CalSet Comparison | ||
|---|---|---|
| Feature | Predicate Device:Elecsys HE4 CalSet (K112624) | Candidate Device:Elecsys CYFRA 21-1 CalSet |
| Intended Use | Elecsys HE4 CalSet is used forcalibrating the quantitative ElecsysHE4 assay on the Elecsys and cobase immunoassay analyzers. | CYFRA 21-1 CalSet is used forcalibrating the quantitative ElecsysCYFRA 21-1 assay on the Elecsys andcobas e immunoassay analyzers. |
| Levels | Two | Two |
| Matrix | Human Serum | Human Serum |
| Format | Lyophilized | Lyophilized |
| Stability | Unopened:• Store at 2-8°C up to thestated expiration date.After reconstitution:• At 2-8°C: 7 days• At -20°C: 8 weeks (freezeonly once).• On Elecsys 2010/cobas e411 at 20-25°C: Up to 5hours.• On MODULARANALYTICS E170/cobas e601: Use only once. | Unopened:• Store at 2-8°C up to the statedexpiration date.After reconstitution:• At 2-8°C: 7 days• At -15--25°C: 8 weeks (freezeonly once).• On cobas e 411 at 20-25°C: Upto 5 hours. |
| Handling | Dissolve the contents of one bottlecarefully by adding exactly 1.0mLof distilled water and allow to standclosed for 15 minutes to reconstitute.Mix carefully, avoiding theformation of foam. Transfer thereconstituted calibrator into theempty labeled snap-cap bottlessupplied. | Dissolve the contents of one bottlecarefully by adding exactly 1.0mL ofdistilled water and allow to stand closedfor 15 minutes to reconstitute. Mixcarefully, avoiding the formation offoam. Transfer the reconstitutedcalibrator into the empty labeled snap-cap bottles supplied. |
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Table 1, continued
| Feature | Predicate Device:PreciControl Tumor Marker(K050387) | Candidate Device:PreciControl Tumor MarkerModified to Include CYFRA 21-1 |
|---|---|---|
| Intended Use | PreciControl Tumor Marker is usedfor quality control of Elecsysimmunoassays on Elecsysimmunoassay analyzers. | PreciControl Tumor Marker is used forquality control of Elecsysimmunoassays on Elecsys and cobas eimmunoassay analyzers. |
| Analyte | AFP: approx.. 8 & 100 IU/mLCEA: approx.. 5 & 50 mLCA 15-3 II: approx. 20 & 100 U/mLCA 125 II: approx. 35 & 100 U/mLFerritin: approx.. 25 & 200 ng/mLfPSA: approx.. 1 & 10 ng/mLtPSA: approx.. 4 & 40 ng/mLCA 19-9: approx.. 20 & 100 U/mL | AFP: approx. 8 & 100 IU/mLCEA: approx. 5 & 50 mLCA 15-3 II: approx. 20 & 100 U/mLCA 125 II: approx. 35 & 100 U/mLFerritin: approx. 25 & 200 ng/mLfPSA: approx. 1 & 10 ng/mLtPSA: approx. 4 & 40 ng/mLCA 19-9: approx. 20 & 100 U/mLCYFRA 21-1: approx. 3 & 27 ng/mL |
| Levels | Two | Same |
| Matrix | Human Serum | Same |
| Format | Lyophilized | Same |
| Handling | Dissolve the contents of one bottlecarefully by adding exactly 3.0mLof distilled water and allow to standclosed for 30 minutes to reconstitute.Mix carefully, avoiding theformation of foam. Transfer thereconstituted calibrator into theempty labeled snap-cap bottlessupplied. | Same |
| Stability | On the analyzer: up to 5 hours20-25°C: 24 hours2-8°C: 2 weeks-20°C: 1 month (freeze only once) | Same |
NON-CLINICAL PERFORMANCE EVALUATION 4.
Non-clinical performance evaluations for the Elecsys CYFRA 21-1 assay executed with the study briefly summarized.
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Precision (Human Sera) 4.1.
Internal precision of the Elecsys CYFRA 21-1 assay was evaluated with a seven-member panel consisting of five pooled patient samples and two controls (Precicontrol TM Level 1 and 2) were measured. The protocol consisted of testing the samples in single determination in four separate aliquots (divided in two runs per day) for 21 operating days. The measurements were performed on the cobas e 411 with one reagent lot, performing rackpack calibration according to instruction for use.
External precision consisted of testing two replicates of each control (PC TM 1 and PC TM 2) and six human serum samples per run, two runs per day for 20 days at three external sites. The samples were run in randomized order on the analyzer.
Repeatability and Intermediate precision were calculated according to CLSI EP5-A3.
4.2. Limit of Blank (LoB)
For the analytical sensitivity studies, the Limit of Blank was determined according to CLSI EP17-A2. The LoB was determined as the 95th percentile of blank-sample measurements. The distribution of values for five analyte-free serum samples was determined with one reagent lot on one cobas e 411 anaylzer over three days for six runs total.
The samples were measured in two-fold determination for each run. A total of 60 measuring points were collected.
4.3. Limit of Detection (LoD)
For the analytical sensitivity studies, the Limit of Detection was determined according is the smallest amount of analyte that can be detected with 95% probability. The distribution of values for five low-level human serum samples was determined with one reagent lot on one cobas e 411 anaylzer over three days for six runs total.
The samples were measured in two-fold determination for each run. A total of 60 measuring points were collected.
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4.4. Limit of Quantitation (LoQ)
LoO of the CYFRA 21-1 assay has been determined according to CLSI EP17-A2.
The distribution of values for 8 spiked human serum samples each diluted to concentrations which covered the range between LoB and 2x LoQ has been determined with one reagent lot on one cobas e411 analyzer with five runs distributed over five days. Each run was calibrated separately using a two-point calibration. Samples were measured in single determination in each run. In summary, a total of 200 measuring points were collected.
4.5. Linearity
The linearity of the CYFRA 21-1 assay was assessed on the cobas e 411 immunoassay analyzer; six dilution series were prepared from six different spiked human samples. Three dilution series were performed with serum samples and the other three with plasma samples. Each dilution series included at least 11 dilutions. Each sample was measured 3-fold within one run and the measured concentrations were plotted against the expected sample concentration.
The linearity data was determined in accordance with CLSI EP6-A. In a first step, a linearity check was performed with a first order (linear) regression and then with higher order models (quadratic and cubic).
Analytical Specificity 4.6.
The specificity of the Elecsys CYFRA 21-1assay was determined using human serum samples spiked with potential cross-reacting compounds. The spiked and unspiked reference samples were measured in duplicate or triplicate on one cobas e411 analyzer. Specificity was determined using three spiked human samples to prepare dilution series of 11 dilutions that were tested with one reagent lot. Samples were spiked with potential cross-reactant compounds at three different concentrations each. Cross-reactivity results will be reported in the method sheet.
4.7. Endogenous Interferences
The effect on quantitation of CYFRA 21-1 in the presence of six endogenous interfering substances (Hemoglobin, Biotin, Intralipid, Bilirubin', and Rheumatoid Factor) was tested using one cobas e 411 analyzer. Spiked serum pools were used for testing.
For each potential interferent, three human serum samples (containing low, mid, and high concentrations of CYFRA 21-1) were tested. 1 A mixture of conjugated (10%) and unconjugated (90%) bilirubin.
4.8. HAMA Effect
The effect of the presence of human anti-mouse antibodies (HAMA) on the Elecsys CYFRA 21-1assay was assessed on the cobas e411 analyzer.
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A suitable HAMA serum was spiked with CYFRA 21-1 analyte to two different analyte concetrations (3.21 ng/mL and 96.3 ng/mL. In parallel, a control (human serum) sample was spiked with the same levels of analyte. For each analyte concentration, a series of 11 dilutions of the HAMA sample and control sample were each prepared and measured in duplicate. The recovery for each sample was calculated by comparison to the reference (no HAMA) sample.
4.9. High-Dose Hook Effect
The high-dose hook effect of the Elecsys CYFRA 21-1assay was assessed on the cobas e 411 analyzer. Human serum pools were spiked with analyte up to a concentration of 2,470ng/mL. These samples were subsequently diluted with negative human serum.
The expected values for the diluted samples were calculated using the known spiked CYFRA 21-1 analyte concentration of the undiluted sample and the appropriate dilution factor.
The hook concentration reported corresponds to the analyte concentration that generates a signal ≥10% above the upper limit of the measuring range
4.10. Exogenous Interferences - Drugs
The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 27 pharmaceutical compounds into two human serum samples at differing analyte concentrations and tested on the cobas e 411 analyzer.
The CYFRA 21-1 concentration of the spiked aliquots was tested in three-fold determination and compared to the CYFRA 21-1 concentration for the reference aliquot (also tested in three-fold determination).
4.11. Serum/Plasma Comparison
The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys CYFRA 21-1 assay was determined by comparing values obtained from samples drawn into Serum Separator Tubes (SST). Serum, Li-Heparin Plasma, K2-, K3-EDTA and Plasma primary tubes and Plasma Separation Tubes (PST). At least 44 serum/plasma pairs per sample type were tested on one cobas e 411 analyzer. For Serum / Plasma Separation Tube comparison, measurements were performed on five samples in duplicate on the cobas e 601 assay. Potential effects were assessed by Passing/Bablok regression analysis.
4.12. Reagent Stability
To test reagent stability, three studies were executed.
4.12.1. Study 1. Reagent Stability (On Board)
Reagent on-board stability for the Elecsys CYFRA 21-1 assay was tested on one cobas e 411 analyzer.
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A fresh reagent Rack Pack was placed on the analyzer and calibrated. Reference values for the samples tested were determined. On day 36, 50 and day 64 the same samples were determined with the same reagent kit (kept on board the instrument) using the calibration curve of day 0 and day 64 respectively.
Samples tested in duplicate include four spiked human serum samples.
4.12.2. Study 2. Reagent Stability (After Opening)
Reagent stability after first opening for the Elecsys CYFRA 21-1 assay was determined on a cobas e 411 immunoassay analyzer by comparing the reagent stability for three kits of the same lot. All reagent kits were opened on day 0. One kit was placed on the analyzer and calibrated and reference values for the samples tested were determined.
The other two kits were stored at 2 to 8°C. After 50 and 92 days, one of the stored kits was placed on the analyzer and calibrated, and the original test samples were measured.
Samples tested in duplicate include five human serum (HS) samples.
4.12.3. Study 3. Reagent Stability (Real-Time Shelf Life)
In the real-time, shelf-life stability study, the Elecsys CYFRA 21-1assay reagent was stored at 2-8°C. The stored reagent was tested at time point 0 (at manufacture), then again at specified intervals over the shelf life of the device (up to the planned shelf life plus one month). The average on-test recovery was calculated as percent recovery compared to the reference value.
Samples tested in duplicate included two controls.
4.13. Sample Stability
To test reagent stability, four studies were executed.
4.13.1. Study 1. Sample Stability (Freeze/Thaw Cycles)
Four samples of each human serum and plasma types were collected and stored at -80°C. The samples were tested after one freeze/thaw cycle with the Elecsys CYFRA 21-1 assay.
Measurement were performed in three-fold determination on one cobas e 411 analyzer, and recovery was calculated as percent of the reference value or as a deviation in ng/mL.
4.13.2. Study 2. Sample Stability (at -15 to -25°C)
Four samples of each human serum and plasma types were collected and stored at -80°C. The samples were tested after storage at -15 to -25°C for 6 and 12 weeks with the Elecsys CYFRA 21-1 assay.
Measurement were performed in three-fold determination on one cobas e 411 analyzer, and recovery was calculated as percent of the reference value or as a deviation in ng/mL.
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4.13.3. Study 3. Sample Stability (at 2-8°C)
Four samples of each human serum and plasma types were collected and stored at -80°C. The samples were tested after storage for up to14 days at 2-8°C with the Elecsys CYFRA 21-1assay.
Measurement were performed in three-fold determination on one cobas e 411 analyzer, and recovery was calculated as percent of the reference value or as a deviation in ne/mL.
4.13.1. Study 4. Sample Stability (at 15-25°C)
Four samples of each human serum and plasma types were collected and stored at -80°C. The samples were tested after storage for up to 5 days at 15-25℃ with the Elecsys CYFRA 21-1 assay.
Measurement were performed in three-fold determination on one cobas e 411 analyzer, and recovery was calculated as percent of the reference value or as a deviation in ng/mL.
4.14. Calibration Stability
To test calibration stability, two studies were executed.
4.14.1. Study 1. Calibration (Lot) Stability
The stability of lot calibration was determined by comparing the calibration for three kits of the same lot. On day 0, the first reagent kit was opened and calibrated, and samples were measured. The same samples were also measured with fresh opened kits of the same lot, using the same calibration established by the first kit, after 36 and 64 days on one cobas e 411.
Five human serum samples (samples ≥ 1 ng/mL spiked with CYFRA 21-1) were measured in duplicate with one reagent lot in one run per day.
4.14.2. Study 2. Calibration (On Board) Stability
On-board calibration stability for the CYFRA 21-1 assay was tested on one cobas e 411 immunoassay analyzer. One reagent kit was opened and samples were measured on day 0. The same samples were then retested after 8 days with a new opened reagent bottle kept at 20 ± 3℃ (on-board condition) using the calibration from day 0. Recovery was calculated based on the initial values.
Four human serum samples > 1 ng/mL spiked with CYFRA 21-1) were measured in duplicate with one reagent lot on a cobas e 411 in one run per day..
4.15. Calibrator Stability
The CYFRA 21-1 CalSet was evaluated for value assignment and stability: five studies were executed.
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4.15.1. Calibrator Value Assignment
Roche Diagnostics maintains a set of master calibrators for each assay that has values assigned that are traceable to various method "gold standards". These standards can either be WHO, NIST, or in-house developed standards.
The Elecsys CYFRA 21-1 CalSet is assayed and compared to these reference preparations, and target values and ranges are assigned.
In the case of this submission, the CYFRA 21-1 assay has been standardized against an in-house reference system.
Values are assigned using the cobas e 411 analyzer. Six independent series are performed. All samples are tested in duplicate. The sample recovery (%) is calculated as the median of each sample as a reference to the target value.
4.15.2. Study 1. Calibrator Stability (On-Board)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept on-board at 20 to 25°C for 6 hours. On-test recovery was calculated as the signal (counts) of the reference value.
4.15.3. Study 2. Stress Stability (Post Reconstitution at 35°C)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept at 35°C for 3 weeks.
On-test recovery was calculated as the signal (counts) of the reference value.
4.15.4. Study 3. Post Reconstitution Storage Stability(2-8°C)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept at 2 to 8°C for 8 days.
On-test recovery was calculated as the signal (counts) of the reference value.
4.15.5. Study 4. Post Reconstitution Stability(-15 to -25°C)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept at -25°C to -15°C for 9 weeks.
On-test recovery was calculated as the signal (counts) of the reference value.
4.15.6. Study 5. Real-time Shelf Life Stability
In the real-time stability study, the CYFRA 21-1 CalSet material was stored at 2 to 8°C. The stored CalSet reagents were tested at time point T=0 and at specified intervals over the shelf life of the device up to 30 months in duplicate. Testing was performed using PreciControl Turnor Marker 1 and 2 (stored at -20℃).
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The average on-test recovery was calculated as percent recovery compared to the reference value (Assigned value for PreciControl Tumor Marker 1 and 2).
4.16. PreciControl Tumor Marker
PreciControl Tumor Marker was evaluated for value assignment and stability; five studies were executed.
4.16.1. PreciControl Value Assignment
Values are assigned using the cobas e 411 Immunoassay Analyzer. Six independent series are performed. All samples are tested in duplicate. The sample recovery (%) is calculated as the median of each sample as a reference to the target value.
4.16.2. Study 1. Calibrator Stability (On-Board)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept on-board at 20 to 25°C for 6 hours.
4.16.3. Study 2. Open-Vial Stability (Post Reconstitution at 20-25°C)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept at 20 to 25°C for 25 hours.
4.16.4. Study 3. Post Reconstitution Storage Stability(2-8°C)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept at 2 to 8°C for 15 days.
4.16.5. Study 4. Post Reconstitution Stability(-15 to -25°C)
Reference and on-test materials were tested in duplicate with one reagent lot in one run per day on one cobas e 411 analyzer. The on-test material was opened and kept at -25°C to -15°C for 5 weeks.
4.16.6. Study 5. Real-time Shelf Life Stability
In the real-time stability study, the PreciControl material was stored at 2 to 8°C. The stored PreciControl reagents were tested at time point T=0 and at specified intervals over the shelf life of the device up to 39 months in duplicate. Testing was performed using PreciControl Turnor Marker 1 and 2 (stored at -20℃).
The average on-test recovery was calculated as percent recovery compared to the reference value (Assigned value for PreciControl Tumor Marker 1 and 2).
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5. CLINICAL PERFORMANCE EVALUATION
Expected values
Normal CYFRA 21-1 values are expected to be ≤ 2.37 ng/mL.
The following table shows the results of three separate cohorts. The first study represents the distribution of expected results from 240 apparently healthy men and women equally divided into smokers and nonsmokers. The second study represents the distribution of expected results from 195 benign disease conditions other than cancers, and the third study represents the distribution of expected results from different cancers, including lung cancer.
| No. ofsubjects | 0.3- 2.37ng/mL | 2.38- 5.0ng/mL | 5.01- 20.0ng/mL | 20.01- 100ng/mL | > 100ng/mL | |
|---|---|---|---|---|---|---|
| Apparentlyhealthy | 240 | |||||
| All normals | 240 | 228 | 12 | 0 | 0 | 0 |
| Nonsmokers | 120 | 111 | 9 | 0 | 0 | 0 |
| Smokers | 120 | 117 | 3 | 0 | 0 | 0 |
| Normal females | 125 | 119 | 6 | 0 | 0 | 0 |
| Nonsmokers | 63 | 59 | 4 | 0 | 0 | 0 |
| Smokers | 62 | 60 | 2 | 0 | 0 | 0 |
| Normal males | 115 | 109 | 6 | 0 | 0 | 0 |
| Nonsmokers | 57 | 52 | 5 | 0 | 0 | 0 |
| Smokers | 58 | 57 | 1 | 0 | 0 | 0 |
| No. ofsubjects | 0.3-2.37ng/mL | 2.38- 5.0ng/mL | 5.01- 20.0ng/mL | 20.01- 100ng/mL | > 100ng/mL | |
| Investigational Elecsys CYFRA 21-1 distribution of values by cohort | ||||||
| Benign conditions | 195 | |||||
| Benign lungdisease | 75 | 70 | 5 | 0 | 0 | 0 |
| CHFb) | 40 | 29 | 11 | 0 | 0 | 0 |
| Benign kidneydisease | 40 | 8 | 24 | 8 | 0 | 0 |
| Benign liverdisease | 40 | 35 | 4 | 1 | 0 | 0 |
| Cancer | 440 | |||||
| Lung cancer | 120 | 53 | 33 | 27 | 5 | 2 |
| Bladder cancer | 40 | 13 | 9 | 12 | 5 | 1 |
| Breast cancer | 40 | 32 | 5 | 3 | 0 | 0 |
| Cervical cancer | 40 | 28 | 11 | 1 | 0 | 0 |
| ESCCc) | 40 | 21 | 12 | 6 | 1 | 0 |
| GI tract cancer | 40 | 23 | 10 | 6 | 1 | 0 |
| Head and neckcancer | 40 | 29 | 11 | 0 | 0 | 0 |
| Prostate cancer | 40 | 37 | 1 | 2 | 0 | 0 |
| Ovarian cancer | 40 | 25 | 8 | 5 | 2 | 0 |
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b) CHF = Congestive heart failure
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c) ESCC = Esophageal squamous cell carcinoma
Each laboratory should investigate the transferability of the expected values to its own patient population and if necessary determine its own reference ranges.
Specific performance data
Representative performance data on the analyzers are given below. Results obtained in individual laboratories may differ.
Clinical performance data
The effectiveness of the Elecsys CYFRA 21-1 assay as an aid in monitoring of disease status in lung cancer patients was determined by assessing changes in CYFRA 21-1 levels in serial serum samples from 83 patients compared to changes in disease status. A total of 398 samples were measured, including 86 baseline values and 315 monitoring values. Subjects had ≥ 3 blood draws over time.
A positive change in CYFRA 21-1 was defined as an increase in the value that was at least 50 % greater than the previous value of the test. This level of change takes into account the analytical variability of the assay. 44.1 % (26/59) of the patient samples with a positive change correlated with the disease progression while 91.0 % (233/256) of the patient serial samples with no significant change in CYFRA 21-1 value correlated with no progression. The following table presents the data in a 2 x 2 format.
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| Investigational Elecsys CYFRA 21-1 elevation vs. disease progression | ||||
|---|---|---|---|---|
| Disease progression | ||||
| No progression | Progression | Total | ||
| Investigational ElecsysCYFRA 21-1 elevation | Not elevated | 233 | 33 | 267 |
| Elevated | 23 | 26 | 48 | |
| Total | 256 | 59 | 315 |
No set cutoff exists for CYFRA 21-1. The clinical performance of other percent changes in serial samples are presented below. Clinicians may choose to use these other values to enhance the sensitivity or specificity of the assay, depending on their needs.
| Cutoff values and corresponding performance measurements | ||||||||
|---|---|---|---|---|---|---|---|---|
| Percent (%)change inElecsys CYFRA21-1 | Sensitivity (%) | Specificity (%) | NPVa) | PPVb) | ||||
| 30 | 49.2 | 87.1 | 88.1 | 46.8 | ||||
| 40 | 44.1 | 89.8 | 87.5 | 50.0 | ||||
| 50 | 44.1 | 91.0 | 87.6 | 53.1 | ||||
| 60 | 39.0 | 91.4 | 86.7 | 51.1 | ||||
| 70 | 35.6 | 93.4 | 86.3 | 55.3 |
a) NPV = negative predictive value
b) PPV = positive predictive value
CONCLUSIONS 6.
The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys CYFRA 21-1 test system. The data supports a safe, effective device which performs as well as or better than the predicate device.
§ 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.