(237 days)
Elecsys CA 125 II is an immunoassay for the in vitro quantitative determination of OC 125 reactive determinants in human serum, Li heparin, K2-EDTA, as well as Li-heparin plasma tubes containing separating gel on the cobas e 411 analyzer.
These determinants are associated with a high molecular weight glycoprotein in serum and plasma of women with primary epithelial invasive ovarian cancer (excluding those with cancer of low malignant potential).
This immunoassay is indicated for use as an aid in the detection of recurrent ovarian carcinoma. This immunoassay is further indicated for use in monitoring patients for disease progress or response to therapy.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 411 immunoassay analyzers.
For use in the verification of the callbration established by the Elecsys CA 125 II reagent on the Elecsys and cobas e immunoassay analyzers.
The CA 125 II assay employs a sandwich test principle using biotinylated monoclonal CA 125-specific antibody and a monoclonal CA 125-specific antibody labeled with a ruthenium complex to form a sandwich complex. The use of streptavidin-coated microparticles serves as the solid phase for the electrochemiluminescence detection.
Results are determined using a calibration curve that is generated specifically on each instrument by a 2 point calibration and a master curve (5-point-calibration) provided with the reagent bar code.
The CA 125 II application is identical to the predicate assay (K972162). This submission is being done to modernize the labeling by adding the LoB, LoD and LoQ data and to change the sample:reagent ratio from 40:60μL to 20:70μL. Additionally, based on internal stability data the calibration frequency has been extended from 4 to 8 weeks.
The Elecsys CA 125 II CalCheck is a lyophilized product consisting of equine serum in level 1 and human serum matrix for levels 2 and 3. During manufacture, the analyte is spiked into the matrix at the desired concentration levels.
Here's a breakdown of the acceptance criteria and the study details for the Elecsys CA 125 II Assay, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document provides a comparison table (Table 1) between the predicate device (Elecsys CA 125 II, K972162) and the candidate device (Elecsys CA 125 II Assay), highlighting both similarities and differences, including labeled performance characteristics. Since explicit "acceptance criteria" are not given in a numerical form that can be directly compared to "reported performance" for each item, I will present the key performance characteristics detailed for the candidate device as its reported performance, implicitly indicating what was demonstrated to FDA for substantial equivalence.
| Acceptance Criteria (Implied / Predicate) | Reported Device Performance (Candidate Device) |
|---|---|
| General Assay Features | |
| Intended Use/Indications for Use | Largely similar indications, but explicitly mentions K2-EDTA and K3-EDTA, as well as Li-heparin plasma tubes with separating gel. Specific to cobas e 411 analyzer. |
| Assay Protocol | Same (sandwich test principle) |
| Detection Protocol | Same (Electrochemiluminescent Assay) |
| Applications | Same (18 minute application) |
| Instrument Platform | cobas e 411 analyzer (Predicate: Elecsys 2010, cobas e 411, MODULAR Analytics E170, cobas e 601 and cobas e 602 immunoassay analyzers) |
| Sample: Reagent Ratio | 20:70 μL (Predicate: 40:60 μL) |
| Sample Type | Human serum and Li-heparin, K2-EDTA and K3-EDTA, as well as Li-heparin plasma tubes containing separating gel (Predicate: Broader, including Na-NH4+-heparin, K2-EDTA, K3-EDTA, sodium citrate plasma). |
| Reagents | Same |
| Calibrator | Elecsys CA 125 II CalSet II (K140112) (Predicate: Elecsys CA 125 II CalSet (K003969)) |
| Calibration Interval | After 8 weeks when using the same reagent lot (Predicate: After 1 month (28 days)). Other conditions are similar. |
| Controls | Same (Elecsys PreciControl Tumor Marker) |
| Traceability/Standardization | Same (standardized against Enzymun-Test CA 125 II, which was standardized against CA 125 II RIA from Fujirebio Diagnostics). |
| Reagent Stability (on analyzers) | 6 weeks (Predicate: 4 weeks) |
| Labeled Performance Characteristics | |
| Measuring Range | 2 (LoQ) - 3000 U/mL (Predicate: 0.6 (LDL) - 5000 U/mL) |
| Precision (cobas e411 analyzers) | Intra-Assay/Within-run (Repeatability): 3.1% CV @ 14.70 U/mL 3.0% CV @ 3.07 U/mL 2.6% CV @ 2399 U/mL 1.9% CV @ 34.95 U/mL 0.9% CV @ 120.7 U/mL 1.1% CV @ 329.6 U/mLTotal (Intermediate): 4.1% CV @ 14.70 U/mL 4.2% CV @ 3.07 U/mL 3.4% CV @ 2399 U/mL 3.0% CV @ 34.95 U/mL 1.3% CV @ 120.7U/mL 1.3% CV @ 329.6U/mL |
| LoB | 0.6 U/mL (Predicate: Not Reported) |
| LoD | 1.2 U/mL (Predicate: Not Reported) |
| LoQ | 2 U/mL (Predicate: Not Reported) |
| Lower Detection Limit | N/A (Functional Sensitivity 0.6 U/mL for Predicate, but now explicit LoD/LoQ are reported for candidate). |
| Performance Characteristics | |
| Hook Effect | No high-dose hook effect at CA 125 concentrations up to 50,000 U/mL (Predicate: up to 20,000 U/mL). |
| Limitations (Interferences) | Unaffected by: Hemolysis < 3.2 g/dL, Bilirubin < 66 mg/dL, Lipemia < 2000 mg/dL, Biotin < 35 ng/mL, Rheumatoid factors < 1,200 IU/mL. (Predicate values are slightly different). 16 common + 23 special drugs tested with no interference. |
| Method Comparison (sample/reagent ratio) | n=80 samples, P/Blo_Slope: 0.981 (0.946–1.005), Intercept: 1.20 (0.296–1.77), Pearson: 0.995, Kendall (tau): 0.966. |
| Method Comparison (CalSet) | n=111 samples, P/Blo_Slope: 1.006 (1.006–1.006), Intercept: 0.827 (0.824–0.829), Pearson: 1.000, Kendall tau: 1.000. |
2. Sample Sizes Used for the Test Set and Data Provenance
The document details various studies performed, each with its own sample size and type:
- Precision: 4 serum samples + 2 additional serum samples for testing.
- Limit of Blank (LoB): 5 analyte-free human samples.
- Limit of Detection (LoD): 5 human samples with low analyte concentration.
- Limit of Quantitation (LoQ): 3 human sample pools.
- Linearity: 6 dilution series from 6 different spiked human samples (3 serum, 3 plasma), each with 15 dilutions.
- Dilution: 3 human samples spiked to concentrations above the measuring range.
- High Dose Hook Effect: 2 samples spiked with analyte to 50,000 U/mL, each with a dilution series.
- HAMA Effect: 1 HAMA serum and 1 basic serum (both spiked with analyte).
- Endogenous Interference: 5 interfering substances (Intralipid, Biotin, Bilirubin, Rheumatic Factor, Hemolysis) tested using 3 spiked human samples (low, medium, high) to prepare 11 dilutions.
- Exogenous Interference (Drugs): 16 common and 23 additional pharmaceutical compounds, each spiked into 2 human samples (low and high CA125 concentration).
- Exogenous Interference (Anticoagulants): 51 or 52 serum/plasma pairs for each sample material type (Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma, Li-Heparin Plasma Separation Tubes).
- Method Comparison (Sample/Reagent Ratio Change): 80 human serum samples (native single donors).
- Method Comparison (CalSet Change): 111 human serum samples (native single donors).
- Reagent Stability:
- After first opening: 5 human serum samples (native single donors) and 2 controls.
- On-board: 5 human samples (pooled and single donor) and 2 controls.
- Shelf-life: PreciControl Tumor Marker 1 and 2, using 3 reagent lots (154355-Lot, 157240, 158725).
- Sample Stability:
- 2 to 8°C: 10 human samples for each of 4 sample types (Serum, K2-EDTA-plasma, K3-EDTA-plasma, Li-Heparin-plasma).
- Room Temperature: 10 human samples for each of 4 sample types.
- -20°C: 10 human samples for each of 4 sample types.
- Freeze/Thaw: 10 human samples for each of 4 sample types.
- Calibration Stability:
- Lot calibration: 4 human serum samples (pooled patient samples) and 2 controls.
- On-board calibration: 5 human serum samples (pooled and single donor) and 2 controls.
Data Provenance: The document generally refers to "human samples," "human serum samples," "pooled patient samples," and "native single donors." It does not explicitly state the country of origin, but given the submitter (Roche Diagnostics) and the nature of the device (in vitro diagnostic), it's highly likely to be a combination of commercially available human samples and samples collected in clinical settings in regions where such studies are commonly performed, potentially including the US or Europe. All studies appear to be prospective for the purpose of device validation, as they involve specific experimental designs to evaluate performance characteristics.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This information is not provided in the document. For an immunoassay like Elecsys CA 125 II, "ground truth" typically refers to the true concentration of the analyte (CA 125) in the samples. This is usually established through reference methods, certified reference materials, or highly characterized control materials, rather than expert consensus on diagnostic images or clinical outcomes. The document mentions standardization against the Enzymun-Test CA 125 II method, which in turn was standardized against the CA 125 II RIA from Fujirebio Diagnostics. This implies a chain of reference methods rather than expert panels establishing ground truth for individual samples.
4. Adjudication Method for the Test Set
This information is not applicable/not provided as the device is an immunoassay for quantitative determination of CA 125, not a device requiring interpretation or adjudication by multiple experts (like radiology images). The "ground truth" for quantitative assays is typically established through analytical methods and reference standards, not by an adjudication process.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance
This information is not applicable/not provided. The Elecsys CA 125 II Assay is an in vitro diagnostic immunoassay that quantifies a biomarker. It does not involve human readers interpreting cases or AI assistance in the context of image analysis.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
This information is not applicable/not provided in the context of an "algorithm only" as generally understood for AI/imaging devices. The device is a standalone automated immunoassay system (Elecsys CA 125 II Assay on the cobas e 411 analyzer) that provides quantitative results. Its "performance" is inherently "standalone" in the sense that the analyzer directly processes samples and generates results without human diagnostic interpretation input into the result generation itself. However, a clinician then interprets these results in conjunction with other clinical findings.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
The ground truth for the quantitative measurement of CA 125 in the test samples is implicitly established by:
- Reference Methods/Standardization: The method has been standardized against the Enzymun-Test CA 125 II method, which in turn was standardized against the CA 125 II RIA from Fujirebio Diagnostics. This indicates that the "true" values used for comparison (e.g., in method comparison studies) are derived from these established reference methods.
- Spiking: For studies like linearity, dilution, hook effect, and interference, samples were "spiked" with known concentrations of the analyte, establishing a known "ground truth" for the added analyte.
- Assigned Values: For controls (e.g., PreciControl Tumor Marker), "assigned values" are used, which are derived from comprehensive characterization processes.
8. The Sample Size for the Training Set
This information is not explicitly provided in the document. For an immunoassay, "training set" might refer to data used during the assay development phase to optimize reagent concentrations, reaction times, and calibration algorithms. This type of data is usually part of internal R&D and not typically detailed in 510(k) summaries as a "training set" in the same way it would be for a machine learning model. The document primarily focuses on validation/verification studies.
9. How the Ground Truth for the Training Set Was Established
Since the document does not explicitly mention a "training set" in the context of a machine learning algorithm, the establishment of ground truth for such a set is not applicable/not provided. If an analogous "training set" were considered to be the samples used during assay development for parameter optimization, the ground truth would likely be established using similar methods as noted in point 7 (reference methods, spiking, assigned values for controls).
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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle or bird-like symbol with three curved lines forming its body and head. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the symbol.
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
August 6, 2015
Roche Professional Diagnostics Linda McCammack Regulatory Program Manager 9115 Hague Road Indianapolis, IN 46250
Re: K143534
Trade/Device Name: Elecsys CA 125 II Assay Elecsys CA 125 II CalCheck Regulation Number: 21 CFR 866.6010 Regulation Name: Tumor-associated antigen immunological test system Regulatory Class: II Product Code: LTK, JJX Dated: July 6, 2015 Received: July 7, 2015
Dear Ms. McCammack:
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 of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the
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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/Resourcesfor You/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
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
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,
Leonthena R. Carrington -S
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) K143534
Device Name Elecsys CA 125 II Assay
Indications for Use (Describe)
Elecsys CA 125 II is an immunoassay for the in vitro quantitative determination of OC 125 reactive determinants in human serum, Li heparin, K2-EDTA, as well as Li-heparin plasma tubes containing separating gel on the cobas e 411 analyzer.
These determinants are associated with a high molecular weight glycoprotein in serum and plasma of women with primary epithelial invasive ovarian cancer (excluding those with cancer of low malignant potential).
This immunoassay is indicated for use as an aid in the detection of recurrent ovarian carcinoma. This immunoassay is further indicated for use in monitoring patients for disease progress or response to therapy.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e 411 immunoassay analyzers.
X Prescription Use (Part 21 CFR 801 Subpart D)
Over-The-Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
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Indications for Use
510(k) Number (if known) K143534
Device Name Elecsys CA 125 II CalCheck
Indications for Use (Describe)
For use in the verification of the callbration established by the Elecsys CA 125 II reagent on the Elecsys and cobas e immunoassay analyzers.
Type of Use (Select one or both, as applicable)
X Prescription Use (Part 21 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
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510(k) Summary for the Elecsys CA 125 II assay and Elecsys CA 125 II CalCheck
| Introduction | According to the requirements of 21 CFR 807.92, the following information provides sufficient detail to understand the basis for a determination of substantial equivalence. |
|---|---|
| Submitter Name, Address, Contact | Roche Diagnostics9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0415 |
| Contact Person: Linda McCammackPhone: (317) 521-7144 Fax: (317) 521-2324 Email: linda.mccammack@roche.com | |
| Secondary Contact Person: Angelo PereiraPhone: (317) 521-3544 Fax: (317) 521-2324 Email: angelo.pereira@roche.com | |
| Date Updated: August 6, 2015 | |
| Purpose | In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).The purpose of this premarket notification is to modernize the label for the Elecsys CA 125 II assay, which currently does not contain information on LoB, LoD or LoQ. In addition, we would like to include new data for precision on the cobas e instruments in our product labeling.Information is also provided on a new Elecsys CA 125 II CalCheck product. |
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510(k) Summary for Elecsys CA 125 II assay, continued
| Device Name | Proprietary name: | Elecsys CA 125 II Assay |
|---|---|---|
| Common name: | CA 125 II assay | |
| Classification name: | Test, Epithelial Ovarian Tumor Associated Antigen(Ca125) | |
| Product Code: | LTK | |
| Predicate Device: | Elecsys CA 125 II (K972162) | |
| Device Name | Proprietary name: | Elecsys CA 125 II CalCheck |
| Common name: | CA 125 II CalCheck | |
| Classification name: | Single (specified) analyte controls (assayed andunassayed) | |
| Product Code: | JJX | |
| Predicate Device: | Elecsys CA 125 II CalCheck 5 (K102086) | |
| EstablishmentRegistration | For the Elecsys CA 125 II assay and the CA 125 II CalCheck, theestablishment registration number for Roche Diagnostics GmbH inMannheim, Germany, is 9610126 and for Penzberg, Germany, is 9610529.The establishment registration number for Roche Diagnostics in the UnitedStates is 1823260 | |
| DeviceDescription | The CA 125 II assay employs a sandwich test principle using biotinylatedmonoclonal CA 125-specific antibody and a monoclonal CA 125-specificantibody labeled with a ruthenium complex to form a sandwich complex. Theuse of streptavidin-coated microparticles serves as the solid phase for theelectrochemiluminescence detection. | |
| Results are determined using a calibration curve that is generated specificallyon each instrument by a 2 point calibration and a master curve (5-point-calibration) provided with the reagent bar code. | ||
| The CA 125 II application is identical to the predicate assay (K972162). Thissubmission is being done to modernize the labeling by adding the LoB, LoDand LoQ data and to change the sample:reagent ratio from 40:60μL to20:70μL. Additionally, based on internal stability data the calibrationfrequency has been extended from 4 to 8 weeks. |
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The Elecsys CA 125 II CalCheck is a lyophilized product consisting of equine Device serum in level 1 and human serum matrix for levels 2 and 3. During Description, manufacture, the analyte is spiked into the matrix at the desired concentration continued levels.
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510(k) Summary for Elecsys CA 125 II assay, continued
| Intended Use/Indicationsfor Use | Elecsys CA 125 II Assay:Immunoassay for the in vitro quantitative determination of OC 125 reactivedeterminants in human serum, Li-heparin, K2-EDTA and K3-EDTA, as wellas Li-heparin plasma tubes containing separating gel on the cobas e 411analyzer. |
|---|---|
| These determinants are associated with a high molecular weight glycoproteinin serum and plasma of women with primary epithelial invasive ovariancancer (excluding those with cancer of low malignant potential). | |
| This immunoassay is indicated for use as an aid in the detection of residual orrecurrent ovarian carcinoma. This immunoassay is further indicated for use inmonitoring patients for disease progress or response to therapy. | |
| The electrochemiluminescence immunoassay “ECLIA” is intended for use onthe cobas e 411 immunoassay analyzers. | |
| Elecsys CA 125 II CalCheck: | |
| For use in the verification of the calibration established by the Elecsys CA125 II reagent on the indicated Elecsys and cobas e immunoassay analyzers. | |
| SubstantialEquivalence | The Elecsys CA 125 II assay is equivalent to Elecsys CA 125 II assay(K972162). |
| The Elecsys CA 125 II CalCheck is equivalent to the Elecsys CA 125 IICalCheck 5 (K102086) | |
| SubstantialEquivalence -Comparison | The following table compares the Elecsys CA 125 II Assay with its predicatedevice (K972162). |
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510(k) Summary for Elecsys CA 125 II, continued
Comparison of Assays, Similarities and Differences Table 1
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:Roche Elecsys CA 125 II (K972162) | Candidate Device:Elecsys CA 125 II Assay |
| General Assay Features | ||
| Intended Use/Indicationsfor Use | Immunoassay for the in vitro quantitativedetermination of OC 125 reactive determinants inhuman serum and plasma. These determinants areassociated with a high molecular weightglycoprotein in serum and plasma of women withprimary epithelial invasive ovarian cancer(excluding those with cancer of low malignantpotential).The Elecsys CA 125 II assay is indicated for use asan aid in the detection of residual or recurrentovarian carcinoma in patients who have undergonefirst-line therapy and would be considered forsecond-look procedures. The Elecsys CA 125 IIassay is further indicated for serial measurement ofCA 125 to aid in the management of cancerpatients.The electrochemiluminescence immunoassay"ECLIA" is intended for use on Elecsys and cobase immunoassay analyzers. | Immunoassay for the in vitroquantitative determination ofOC 125 reactive determinantsin human serum, Li-heparin,K2-EDTA and K3-EDTA, aswell as Li-heparin plasmatubes containing separating gelon the cobas e 411 analyzer.These determinants areassociated with a highmolecular weight glycoproteinin serum and plasma ofwomen with primary epithelialinvasive ovarian cancer(excluding those with cancerof low malignant potential).This immunoassay is indicatedfor use as an aid in detection ofresidual or recurrent ovariancarcinoma. This immunoassayis further indicated for use inmonitoring patients for diseaseprogress or response totherapy.The electrochemiluminescenceimmunoassay "ECLIA" isintended for use on the cobas e411 immunoassay analyzers. |
| AssayProtocol | The CA 125 II Assay employs a sandwich testprinciple using biotinylated monoclonal CA 125-specific antibody and a monoclonal CA 125-specific antibody labeled with a rutheniumcomplex to form a sandwich complex. The use ofstreptavidin-coated microparticles serves as thesolid phase for the electrochemiluminescencedetection. | Same. |
| Assay Comparison | ||
| Feature | Predicate Device:Elecsys CA 125 II (K972162) | Candidate Device:Elecsys CA 125 II Assay |
| General Assay Features | ||
| DetectionProtocol | Electrochemiluminescent Assay | Same. |
| Applications | 18 minute application | Same. |
| InstrumentPlatform | Elecsys 2010, cobas e 411, MODULAR AnalyticsE170, cobas e 601 and cobas e 602 immunoassayanalyzers. | cobas e 411 analyzer |
| Sample:ReagentRatio | 40:60 μL | 20:70 μL |
| SampleType | Human serum and plasma treated with Li-, Na-.NH4+-heparin, K2-EDTA, K3-EDTA, sodiumcitrate plasma as well as Li-heparin plasma tubescontaining separating gel. When sodium citrate isused, the results must be corrected by +10%. | Human serum and Li-heparin, K2-EDTA and K3-EDTA, as well as Li-heparinplasma tubes containingseparating gel |
| Reagents | The sample is incubated with a biotinylatedmonoclonal CA 125-specific antibody, and amonoclonal CA 125 specific antibody labeled witha ruthenium complex to form a sandwich complex.Steptavidin-coated microparticles are added in thesecond incubation. | Same. |
| Calibrator | Elecsys CA 125 II CalSet (K003969) | Elecsys CA 125 II CalSet II(K140112) |
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510(k) Summary for Elecsys CA 125 II, continued
Table 1, continued
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Table 1, continued
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:Elecsys CA 125 II (K972162) | Candidate Device:Elecsys CA 125 II Assay |
| General Assay Features | ||
| CalibrationInterval | 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 1 month (28 days) whenusing the same reagent lot.After 7 days (when using thesame reagent kit on theanalyzer).As required: e.g. quality controlfindings outside the specifiedlimits | Calibration must be performed onceper reagent lot using fresh reagent (i.e.not more than 24 hours since thereagent kit was registered on theanalyzer). Renewed calibration isrecommended as follows:After 8 weeks when using thesame reagent lotAfter 7 days (when using thesame reagent kit on theanalyzer)As required, e.g. qualitycontrol findings outside thedefined limits. |
| Controls | Elecsys PreciControl Tumor Marker(K972235). | Same. |
| Traceability/Standardiz-ation | The method has been standardizedagainst the Enzymun-Test CA 125 IImethod. This in turn has beenstandardized against the CA 125 II RIAfrom Fujirebio Diagnostics. | Same. |
| ReagentStability | Store at 2-8 °C. Store the reagent kitupright in order to ensure completeavailability of the microparticles duringautomatic mixing prior to use.Stability:Unopened at 2-8 °C—up to the statedexpiration dateAfter opening at 2-8 °C—12 weeksOn the analyzers—4 weeks | Store at 2-8 °C. Store the reagent kitupright in order to ensure completeavailability of the microparticlesduring automatic mixing prior to use.Stability:Unopened at 2-8 °C—up to the statedexpiration dateAfter opening at 2-8 °C—12 weeksOn the analyzers—6 weeks |
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Table 1, continued
| Assay Comparison | ||
|---|---|---|
| Predicate Device: | Candidate Device: | |
| Feature | Elecsys CA 125 II (K972162) | Elecsys CA 125 II Assay |
| Labeled Performance Characteristics | ||
| MeasuringRange | 0.6 (LDL) - 5000 U/mL | 2 (LoQ) -3000 U/mL |
| Precision | Elecsys 2010 | cobas e411 analyzers |
| Intra-Assay | Within-run (Repeatability) | |
| 3.3% CV @ 7.83 U/mL | 3.1% CV @ 14.70 U/mL | |
| 2.1% CV @ 38.30 U/mL | 3.0% CV @ 3.07 U/mL | |
| 2.1% CV @ 70.80 U/mL | 2.6% CV @ 2399 U/mL | |
| 1.9% CV @ 39.00 U/mL | 1.9% CV @ 34.95 U/mL | |
| 1.4% CV @ 121.41 U/mL | 0.9% CV @ 120.7 U/mL | |
| 1.1% CV @ 329.6 U/mL | ||
| Total | Total (Intermediate) | |
| 4.2% CV @ 7.83 U/mL | 4.1% CV @ 14.70 U/mL | |
| 3.1% CV @ 38.30 U/mL | 4.2% CV @ 3.07 U/mL | |
| 2.5% CV @ 70.80 U/mL | 3.4% CV @ 2399 U/mL | |
| 2.5% CV @ 39.00 U/mL | 3.0% CV @ 34.95 U/mL | |
| 2.7% CV @ 121.41 U/mL | 1.3% CV @ 120.7U/mL | |
| 1.3% CV @ 329.6U/mL | ||
| LoB | Not Reported | 0.6 U/mL |
| LoD | Not Reported | 1.2 U/mL |
| LoQ | Not Reported | 2 U/mL |
| LowerDetectionLimit | Functional Sensitivity: 0.6 U/mL | N/A |
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Table 1, continued
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:Elecsys CA 125 II | Candidate Device:Elecsys CA 125 II Assay |
| Performance Characteristics | ||
| Hook Effect | There is no high-dose hook effect at CA125 concentrations up to 20,000 U/mL. | There is no high-dose hook effect atCA 125 concentrations up to 50,000U/mL. |
| Limitations | The assay is unaffected by:Hemoglobin < 3.2 g/dL Bilirubin < 75 mg/dL Triglycerides < 3,800 mg/dL Biotin < 50 ng/mL Rheumatoid factors < 1,500 IU/mL In-vitro tests were performed on 27commonly used pharmaceuticals. No interference with the assay wasfound. In rare cases, interference due toextremely high titers of antibodies toanalyte-specific antibodies,streptavidin or ruthenium can occur. These effects are minimized bysuitable test design. For diagnostic purposes, the resultsshould always be assessed inconjunction with the patient'smedical history, clinicalexamination and other findings. | The assay is unaffected by:Hemolysis < 3.2 g/dL Bilirubin < 66 mg/dL Lipemia < 2000 mg/dL Biotin < 35 ng/mL Rheumatoid factors < 1,200 IU/mL In-vitro tests were performed on 16commonly used pharmaceuticalsand 23 special drugs. Nointerference with the assay wasfound. In rare cases, interference due toextremely high titers of antibodiesto analyte-specific antibodies,streptavidin or ruthenium canoccur. These effects are minimizedby suitable test design. For diagnostic purposes, the resultshould always be assessed inconjunction with the patient'smedical history, clinicalexamination and other findings. |
| MethodComparison(sample/reagentratio) | n = 80Min = 4.7 U/mLMax = 2680 U/mL | Passing/Bablok |
| Slope (95% confidence limits) | 0.981 (0.946 – 1.005) | |
| Intercept (95% confidence limits) | 1.20 (0.296 – 1.77) | |
| Correlation (Pearson) | 0.995 | |
| Kendall (tau) | 0.966 |
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Table 1, continued
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device:Elecsys CA 125 II (K972162) | Candidate Device:Elecsys CA 125 II Assay |
| Performance Characteristics | ||
| MethodComparison(CalSet) | n= 111 | Passing/ Bablok |
| Min = 3.19 U/mL | Max = 2621 U/mL | |
| Slope | 1.006 | |
| (95% confidence limits) | (1.006-1.006) | |
| Intercept | 0.827 | |
| (95% confidence limits) | (0.824-0.829) | |
| Correlation (Pearson) | 1.000 | |
| Kendall tau | 1.000 |
The table below compares Elecsys CA 125 II CalCheck with the predicate CA 125 II CalCheck 5
Comparison of CalCheck Products, Similarities and Differences Table 2
| Characteristic | Predicate Device:Elecsys CA 125 II CalCheck 5(K102086) | Candidate Device:Elecsys CA 125 II CalCheck |
|---|---|---|
| Intended Use | The Elecsys CA 125 II CalCheck 5is an assayed control for use incalibration verification and for usein the verification of the assayrange established by the ElecsysCA 125 II reagent on the indicatedElecsys and cobas e immunoassayanalyzers | For use in the verification of thecalibration established by theElecsys CA 125 II reagent on theindicated Elecsys and cobas eimmunoassay analyzers. |
| Analyte | CA 125 | Same |
| Levels | Five | Three |
| Format | Lyophilized | Same |
| Handling | Reconstitute Check 1, Check 2,Check 3, Check 4 and Check 5 withexactly 1.0mL distilled ordeionized water. Allow to standclosed for 15 minutes, then mixgently by inversion. | Reconstitute Check 1, Check 2, andCheck 3 with exactly 1.0mLdistilled or deionized water. Allowto stand closed for 15 minutes, thenmix gently by inversion. |
| Stability | Unopened :• Store at 2-8°C untilexpiration date | Same |
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| Reconstituted: | ||
|---|---|---|
| • 20-25°C: 4 hours | ||
| Matrix | Level 1: Equine serumLevels 2-5: Human serum matrix | Level 1: Equine serumLevels 2 & 3: Human serum matrix |
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The Elecsys CA 125 II reagent was evaluated for several performance Evaluations Summary characteristics, including precision, limit of blank, limit of detection, limit of quantitation, linearity, dilution, high dose hook effect, HAMA effect, interferences, method comparison, stability, and control recovery.
Precision
Precision of the Elecsys CA125 II assay was evaluated on the cobas e 411 immunoassay analyzer according to CLSI EP5-A2 guideline.
Precision was determined for 4 serum samples at one site using one Elecsys reagent lot and controls; 2 runs per day in duplicate each for 20 days (n=80). Precision was determined at another site for the remaining 2 serum samples using the same protocol. The measurements were performed on the cobas e 411 analyzer, with one reagent lot, performing rackpack calibration according to the instructions for use.
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| EvaluationsSummary,continued | Limit of BlankLoB of the Elecsys CA125 II assay has been determined according to CLSIEP17-A2.Limit of Blank is the highest observed measured value for samples free of analyte. The Limit of Blank was determined as the 95th percentile of the measurement of blank samples.The distribution of values for five analyte-free human samples was determined with three reagent lots on two cobas e 411 analyzers with six runs distributed over a period of up to 5 days.The sample was measured in one-fold determination in each run. In summary, 30 measuring points were collected per instrument. for a total of 60 measured values.Limit of DetectionLoD of the Elecsys CA125 II assay has been determined according to CLSI EP17-A2.LoD determines the lower limit for samples with analyte. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability.The distribution of values for five human samples with low analyte concentration has been determined with three reagent lots on two cobas e 411 analyzers with six runs distributed over a period of up to 5 days.Samples were measured in one-fold determination in each run. In summary, 30 measuring points were collected per instrument, for a total of 60 measured values. The sum of standard deviations (SD total) of the five samples was calculated. The LoD was determined according to the following EP17-A2 calculation: |
|---|---|
| EvaluationsSummary,continued | Limit of Quantitation |
| LoQ of the Elecsys CA125 II assay was determined according to CLSIGuideline EP17-A2. | |
| LoQ determines the lowest amount of analyte that can be quantitativelydetermined with stated accuracy and stated experimental conditions. TheLoQ was determined as the lowest concentration of analyte which can bequantified with a total within-laboratory precision CV< 20%. | |
| The distribution of values for three human sample pools each diluted toconcentrations which covered the range between LoB and 2x LoQ has beendetermined with three reagent lot on two cobas e 411 analyzers with six runsdistributed over three to five days. Each run was calibrated separately using atwo point calibration. | |
| Samples were measured in one-fold determination in each run. In summary,a total of 54 measuring points were collected per instrument, for a total of108 measured values. |
LoD = LoB + 1.653 x SD total (of low analyte samples)
{17}------------------------------------------------
{18}------------------------------------------------
| EvaluationsSummary,continued | LinearityLinearity of the Elecsys CA125 II assay was assessed on the cobas e 411immunoassay analyzer according to CLSI EP6-A. |
|---|---|
| Six dilution series were prepared from six different spiked human samples.The first three dilution series were performed with serum samples and theother three with plasma samples. Each dilution series included 15 dilutions.Each sample was measured 3-fold within one run and the measuredconcentrations were plotted against the expected sample concentration. | |
| DilutionThe dilution study for the Elecsys CA125 II assay was performed on thecobas e 411 using three human samples spiked to analyte concentrationsabove the measuring range and diluted automatically. These measurementswere compared against manual dilutions.The samples were diluted with the Elecsys Diluent Universal. The dilutedand undiluted samples were measured in triplicate. |
Testing was performed on two cobas e 411 analyzers.
Percent recoveries were calculated between the median of the manual and automated dilution.
{19}------------------------------------------------
| EvaluationsSummary,continued | High Dose Hook Effect |
|---|---|
| The high dose hook effect of the Elecsys CA125 II assay was assessed on the cobas e 411 analyzer | |
| Two samples were spiked with analyte to a concentration of 50000U/mL.For each sample a dilution series was performed using Diluent Universal (Id. Nr. 175912) resulting in 5 to 6 samples above the measuring range. Each dilution was tested in single determination. | |
| The hook concentration reported corresponds to the analyte concentration with a signal corresponding to at least 10% above the highest master calibrator. | |
| HAMA Effect | |
| The effect of the presence of human anti-mouse antibodies on the Elecsys CA125 II assay was assessed on the cobas e 411 analyzer | |
| A specified HAMA serum and the related basic serum without interferent were spiked with the analyte to a concentration of 13.0 U/mL. These two samples were measured in duplicates. |
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| EvaluationsSummary,continued | Endogenous InterferenceThe effect on quantitation of analyte in the presence of endogenousinterfering substances using the Elecsys CA125 II was determined on thecobas e 411 analyzer for the following 5 interfering substances Intralipid,Biotin, Bilirubin, Rheumatic Factor and Hemolysis using three spiked humansamples (one low, one medium, and one high) to prepare dilution series of 11 dilutions that were tested with one reagent lot. |
|---|---|
| -------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
Exogenous Interference
-
- Drugs
16 common and 23 additional pharmaceutical compounds were spiked into each of two human samples containing CA125 (low and high concentration). The spiked samples (spiked with 10.7 U/mL and 313 U/mL CA125) were evaluated at drug concentrations defined as 5- fold daily dose and tested for interference by the Elecsys CA125 II assay on cobas e 411 analyzer.
- Drugs
Testing was performed in 3-fold determination with one reagent lot in one run on one cobas e 411 analyzer. The mean value is used to calculate the absolute deviation (U/mL, for samples ≤ 15 U/mL) and percentage deviation (%, for samples > 15 U/mL) of the drug sample to the reference.
{21}------------------------------------------------
| EvaluationsSummary,continued | Exogenous Interference, continued2) AnticoagulantsThe effect on quantitation of analyte in the presence of anticoagulants with the Elecsys CA125 II assay was determined by comparing values obtained from native samples (single donors) drawn into Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma primary tubes and Li-Heparin Plasma SeparationTubes. |
|---|---|
| 51 or 52 serum/plasma pairs per sample material were tested in duplicateswith one reagent lot on one cobas e 411 analyzer. |
Potential effects are assessed by Passing/Bablok regression analyses.
Method Comparison
A method comparison was performed to evaluate the change in the sample/reagent ratio. The sample to reagent ratio has changed from 40 uL of sample and 60 µL of R1 and R2 on the formulation cleared under K972162 to 20uL of sample and 70 uL of R1 and R2 with the new assay. The method comparison proves the safety and effectiveness of the sample to reagent volumes has not affected the performance of the assay.
The study was performed on the Elecsys 2010 analyzer using the Elecsys CA125 II assay (sample/reagent ratios as cleared under K972162) and the CA125 II Cal Set (K003969)(X) against the Elecsys CA 125 II assay with the new sample/reagent ratios and the Elecsys CA125 II CalSet (K003969) (Y). A total of 80 human serum samples (all native single donors) with CA125 values from 4.7 -2680U/mL (X) and 4.8 -2594U/mL (Y) were measured in order to cover the entire measuring range.
{22}------------------------------------------------
| EvaluationsSummary,continued | Method Comparison (CalSet) |
|---|---|
| A method comparison was performed using the Elecsys CA125 II assay incombination with the Elecsys CA125 II CalSet (cleared under K003969) aspredicate device and in combination with the new cleared Elecsys CA125 IICalSet II (K140112). | |
| The Elecsys CA125 II Assay is standardized against the Enzymun-Test CA125 II method. This in turn was standardized against the CA 125 II RIA fromFujirebio Diagnostics. | |
| The study was performed on the cobas e 411 analyzer using the ElecsysCA125 II assay with the CA125 II Cal Set(X) and the Elecsys CA 125IIassay with the new Elecsys CA125 II CalSet II assay (Y) | |
| A total of 111 human serum samples (all native single donors) with CA125values from 3.19–2621U/mL (X) and 4.05–2641U/mL (Y) were measuredin order to cover the entire measuring range. |
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| EvaluationsSummary,continued | The reagent stability was performed in three different studies and they are:Study 1: Reagent stability after first openingReagent stability after first opening for the Elecsys CA125 II assay wasdetermined on a cobas e 411 analyzer by comparing the reagent stabilityfor four kits of the same lot. All reagent kits were opened on day 0. One kitwas placed on the analyzer and calibrated and reference values for thesamples tested were determined. |
|---|---|
| The other three kits were stored at 2 to 8°C. After 5, 9 and 13 weeks, oneof the stored kits was placed on the analyzer and calibrated, and theoriginal test samples were measured. | |
| Samples tested in duplicate include five human serum (HS) samples andtwo controls. The human serum samples used were native single donors. | |
| Study 2: On-board reagent stabilityOn-board reagent stability for the CA125 II assay was tested on onecobas e 411 immunoassay analyzer. A fresh kit was placed on the analyzer. |
cobas e 411 immunoassay analyzer. A fresh kit was placed on the and calibrated. Reference values for the samples tested were determined. After measurement, the kit was closed and kept at 20℃ ± 3℃ for 6 weeks to simulate on-board conditions. Measurements were repeated every week for nine weeks (64 days). The kit was placed on the analyzer again utilizing the calibration curve from seven days earlier for determinations of stability, and the original test samples were measured. The recovery was compared to the measurements from day zero. Samples were tested with one reagent lot in one run per day on one cobas e 411 analyzer in duplicate.
Samples tested included five human samples (pooled patient samples and single donor samples spiked with CA125) and two controls (PreciControl Tumormarker Level 1 and 2).
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| EvaluationsSummary, | Reagent Stability, continued |
|---|---|
| continued | Study 3: Shelf life stabilityIn addition, real-time stability was used to determine CA125 II shelf-lifestability. |
| In the real-time stability study, the CA125 II assay material was stored at 2to 8°C. The stored assay reagents were tested at time point T=0 and atspecified intervals over the shelf life of the device up to the planned shelflife plus one month. Testing was performed using PreciControl TumorMarker 1 and 2 (stored at -20°C). | |
| For the 154355-Lot, data for the time-points at 0, 9, 15 and 19 monthswere tested in duplicates. For the second and third lot (production lots157240 and 158725) data for the time point at 0, 7, 13 and 19 months weretested in duplicates. | |
| The average on-test recovery was calculated as percent recovery comparedto the reference value (Assigned value for PreciControl Tumor Marker 1and 2). |
{25}------------------------------------------------
| EvaluationsSummary,continued | The sample stability was performed with four different studies and theyare: |
|---|---|
| Study 1: Sample stability at 2 to 8°C | |
| Ten human samples for each sample type (Serum, K2-EDTA-plasma, K3-EDTA-plasma, Li-Heparin-plasma) were collected and stored at -80°C(reference). | |
| After the first measurement (reference value), the samples were tested afterstorage at 2 to 8°C after 6 days. | |
| Measurements were performed with three-fold determination on cobas e411 analyzer. The median was used to calculate the percent recovery orabsolute deviation to the reference value. | |
| Study 2: Sample stability at room temperature | |
| Ten human samples for each sample type (Serum, K2-EDTA-plasma, K3-EDTA-plasma, Li-Heparin-plasma) were collected and stored at -80°C(reference). | |
| After the first measurement (reference value), the samples were tested after 9hours at room temperature. | |
| Measurements were performed with three-fold determination on cobas e 411analyzer. The median was used to calculate the percent recovery or absolutedeviation to the reference value. | |
| Continued on next page |
{26}------------------------------------------------
| EvaluationsSummary,continued | Sample Stability- continued |
|---|---|
| continued | Study 3: Sample stability at -20°CTen human samples for each sample type (Serum, K2-EDTA-plasma, K3-EDTA-plasma, Li-Heparin-plasma) were measured fresh (reference) and after storage at -20°C for 25 weeks. |
| Measurements were performed with three-fold determination on cobas e 411 analyzer. The median was used to calculate the percent recovery or absolute deviation to the reference value. | |
| Study 4: Sample stability through freeze/thaw cyclesTen human samples for each sample type (Serum, K2-EDTA-plasma, K3-EDTA-plasma, Li-Heparin-plasma) were collected and stored at -80°C (reference). | |
| After the first measurement (reference value), the samples were tested after 4 freeze/thaw cycles. | |
| Measurements were performed with three-fold determination on cobas e 411 analyzer. The median was used to calculate the percent recovery or absolute deviation to the reference value. |
{27}------------------------------------------------
| EvaluationsSummary,continued | Calibration Stability was performed with two different studies and they are: |
|---|---|
| Study 1: Lot calibration stability:The stability of lot calibration was determined by comparing the calibrationfor four kits of the same lot. On day 0, the first reagent kit was opened andcalibrated, and samples were measured. The same samples were alsomeasured with fresh opened kits of the same lot, using the same calibrationestablished by the first kit, after 5 and 9 weeks on one cobas e 411. | |
| Four human serum samples (pooled patient samples spiked with CA125)and two controls were measured in duplicate with one reagent lot in onerun per day. | |
| Study 2: On-board calibration stability:On-board calibration stability for the ElecsysCA125 II assay was tested onone cobas e 411 analyzer. One reagent kit was opened and samples weremeasured on day 0. The same samples were then retested after 8 days witha new opened reagent bottle kept at 20±3°C (on-board condition) usingthe calibration from day 1. Recovery was calculated based on the initialvalues. | |
| Five human serum samples (pooled patient samples and single donor |
samples spiked with CA125 II) and two controls were tested in duplicate with one reagent lot on one cobas e 411 in one run per day.
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| Evaluations Summary, continued | Recovey of Controls A set of PreciControl Tumor Marker was evaluated in duplicate with one reagent lot on two cobas e 411 analyzers. Two runs were performed on each analyzer. The results were compared against the target ranges of the PreciControl Tumor Marker. |
|---|---|
| The measuring range is defined to meet CLSI guideline EP17-A2 requirements. | |
| Performance Characteristics of CA 125 II CalCheck The Elecsys CA 125 II Calcheck was evaluated for value assignment and stability. | |
| Conclusion | Based on performance data described above the Elecsys CA 125 II assay and CA 125 II CalCheck devices were found to have safety and effectiveness profiles similar to the predicate devices. |
§ 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.