(227 days)
Immunoassay for the in vitro quantitative determination of carcinoembryonic antigen (CEA) in human serum and plasma.
Measurements of CEA aid in the management of cancer patients by monitoring CEA concentrations.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on the Boehringer Mannheim Elecsys 2010 immunoassay analyzer.
The Elecsys® test principle is based on sandwich principle. Total duration of assay: 18 minutes (37° C).
• 1st incubation (9 minutes): Sample (30 µL), biotinylated monoclonal CEA-specific antibody (60 µL), and a monoclonal CEA-specific antibody labeled with a ruthenium complex (60 µL) react to form a sandwich complex.
• 2nd incubation (9 minutes): After addition of streptavidin-coated microparticles (50 µL), the complex is bound to the solid phase via interaction of biotin and streptavidin.
• The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier (0.4 second read frame).
• Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent bar code.
The provided document is a 510(k) summary for the "Elecsys® CEA Assay," a device for the in vitro quantitative determination of carcinoembryonic antigen (CEA). The document focuses on demonstrating substantial equivalence to a predicate device (Enzymun-Test CEA Assay) rather than establishing specific acceptance criteria for a new device and proving its performance against these criteria through a dedicated study.
Therefore, much of the requested information regarding acceptance criteria, a standalone study to prove acceptance, sample sizes for test/training sets, ground truth establishment, expert involvement, and MRMC studies is not explicitly stated in the document as it would be for a novel device undergoing a performance study.
However, I can extract information related to performance characteristics that were compared between the new device and the predicate device, which can be interpreted as demonstrating that the new device performs comparably to an already accepted device.
Here's the closest interpretation of your request based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not specify "acceptance criteria" in the sense of predefined thresholds that the Elecsys® CEA Assay must meet to be approved. Instead, it presents performance characteristics of the Elecsys® CEA Assay and directly compares them to a legally marketed predicate device (Enzymun-Test CEA Assay) to demonstrate substantial equivalence. The implication is that if the new device's performance characteristics are comparable to or better than the predicate, it is considered acceptable.
| Performance Characteristic | Elecsys® CEA Assay Performance | Predicate Device (Enzymun-Test CEA Assay) Performance | Implied Acceptance Criterion (Comparability to Predicate) |
|---|---|---|---|
| Precision | %CV and values comparable to predicate | ||
| Control 1 (5.10 ng/mL) | Within-Run %CV: 1.8%, Total %CV: 3.5% | Low (2.3 ng/mL) Within-Run %CV: 5.6%, Total %CV: 6.3% | Lower or comparable %CVs |
| Control 2 (35.51 ng/mL) | Within-Run %CV: 1.4%, Total %CV: 2.8% | Mid (12.4 ng/mL) Within-Run %CV: 3.7%, Total %CV: 4.1% | Lower or comparable %CVs |
| Pool 1 (3.99 ng/mL) | Within-Run %CV: 1.7%, Total %CV: 3.2% | High (26.4 ng/mL) Within-Run %CV: 3.3%, Total %CV: 3.7% | Lower or comparable %CVs |
| Pool 2 (17.16 ng/mL) | Within-Run %CV: 1.7%, Total %CV: 3.2% | N/A | |
| Pool 3 (546.00 ng/mL) | Within-Run %CV: 1.4%, Total %CV: 3.4% | N/A | |
| Lower Detection Limit | 0.2 ng/mL | 0.5 ng/mL | Lower or comparable detection limit |
| Linearity Range | 0.2 - 1000 ng/mL (±10% deviation) | 0.5 - 55 ng/mL (±10% deviation) | Wider or comparable linear range |
| Method Comparison (vs. Enzymun-Test® CEA) | 0-50 ng/mL: y=1.25x - 0.86, r=0.976 (N=397) | y=0.97x - 0.064, r=0.989 (N=69) | High correlation (r value) and acceptable regression parameters |
| 0-600 ng/mL: y=1.05x + 0.46, r=0.991 (N=446) | |||
| Interfering Substances (Bilirubin) | No interference at 25 mg/dL | No interference at 64.5 mg/dL | Comparable or higher tolerance for interference |
| Interfering Substances (Hemoglobin) | No interference at 1000 mg/dL | No interference at 50 mg/dL | Higher tolerance for interference |
| Interfering Substances (Lipemia) | No interference at 1000 mg/dL | No interference at 1250 mg/dL | Comparable or higher tolerance for interference |
| Interfering Substances (Biotin) | No interference at 30 ng/mL | No interference at 40 ng/mL | Comparable or higher tolerance for interference |
| Specificity (NCA 1 cross-reactivity) | < 0.7% | < 0.7% | Comparable or lower cross-reactivity |
| Specificity (NCA 2 cross-reactivity) | 70% | 70% | Comparable cross-reactivity |
| Hook Effect | No Hook Effect up to 49,100 ng/ml CEA | No Hook Effect up to 5,800 ng/ml CEA | Higher or comparable hook effect threshold |
| Clinical Performance (Colorectal Cancer) | Statistically significant association between clinical outcome and CEA test result (Chi square analysis) | N/A | Association between test result and clinical outcome |
2. Sample size used for the test set and the data provenance
- Precision Test Set N:
- For Elecsys® CEA: 60 samples at each of 5 levels (Control 1, Control 2, Pool 1, Pool 2, Pool 3). Total N = 300.
- For Enzymun-Test CEA: 120 samples at each of 3 levels (Low, Mid, High). Total N = 360.
- Method Comparison Test Set N:
- Elecsys® CEA vs. Enzymun-Test CEA (0-50 ng/mL): N = 397
- Elecsys® CEA vs. Enzymun-Test CEA (0-600 ng/mL): N = 446
- Clinical Specimens Test Set N: 50 patients with colorectal cancer.
- Data Provenance: Not specified (e.g., country of origin). The studies appear to be retrospective comparisons or internal validation studies.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
Not applicable. This is an immunoassay for quantitative measurement of a biomarker. The "ground truth" for method comparison would be the measurement by the predicate device or a reference method (not explicitly stated as an expert judgment in analytical performance studies). For clinical specimens, the "clinical outcome" serves as the reference, which is typically determined by medical professionals but not described as specific "experts" establishing a ground truth for individual test cases in this submission.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
Not applicable. Adjudication methods are typically for qualitative or subjective assessments (e.g., image interpretation), not for quantitative laboratory assays.
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
Not applicable. This is an in vitro diagnostic device (an immunoassay) and does not involve human readers or AI assistance in its current form.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the studies presented are essentially standalone performance evaluations of the Elecsys® CEA Assay, as it is a fully automated immunoassay on the Elecsys 2010 analyzer. Its performance is measured directly, without human intervention as part of the "device performance" itself.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
- For analytical performance (precision, linearity, detection limit, interference, specificity, hook effect): The "ground truth" is established through standard laboratory reference materials, spiked samples, and established analytical methods. For method comparison, the results from the predicate device (Enzymun-Test CEA Assay) serve as the comparative reference.
- For clinical specimens: "Clinical outcome" for 50 colorectal cancer patients was used to evaluate the association with CEA test results. This implies patient management data, medical records, and potentially pathology or follow-up data would contribute to defining the clinical outcome.
8. The sample size for the training set
Not applicable. The Elecsys® CEA Assay is a chemical/immunological assay, not a machine learning algorithm that requires a "training set" in the conventional sense. The "training" of the instrument would involve calibration using calibrators from the Elecsys® CEA CalSet and a master curve provided via the reagent bar code.
9. How the ground truth for the training set was established
Not applicable in the context of an AI/ML device. For this immunoassay, the "ground truth" in terms of calibration is established by:
- The use of calibrators (Elecsys® CEA CalSet) which share the same formulation as the predicate device's calibrators.
- Assay standardization based on the "1st WHO Reference Standard 73/601".
- A master curve provided via the reagent bar code is used for instrument-specific calibration via a 2-point calibration.
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P. 15
K964368
JUN 1 6 1997
510(k) Summary
| 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. |
|---|---|
| 1.Submitter name, address, contact | Boehringer Mannheim Corporation2400 Bisso LaneP.O. Box 4117Concord, CA 94524-4117(510) 674 - 0690, extension 8415Contact Person: Mary KoningDate Prepared: October 31, 1996 |
| 2.Device name | Proprietary name: Elecsys® CEA AssayCommon name: Electrochemiluminescence assay for the determination of Carcinoembryonic antigen (CEA).Classification name: Kit, Test, Carcinoembryonic antigen |
| 3.Predicate device | The Boehringer Mannheim Elecsys® CEA is substantially equivalent to other products in commercial distribution intended for similar use. Most notably it is substantially equivalent to the currently marketed Enzymun-Test CEA (P860058). |
| 4.Device Description | The Elecsys® test principle is based on sandwich principle. Total duration of assay: 18 minutes (37° C).• 1st incubation (9 minutes): Sample (30 µL), biotinylated monoclonal CEA-specific antibody (60 µL), and a monoclonal CEA-specific antibody labeled with a ruthenium complex (60 µL) react to form a sandwich complex.• 2nd incubation (9 minutes): After addition of streptavidin-coated microparticles (50 µL), the complex is bound to the solid phase via interaction of biotin and streptavidin. |
| 4.DeviceDescription,cont. | • The reaction mixture is aspirated into the measuring cell where themicroparticles are magnetically captured onto the surface of the electrode.Unbound substances are then removed with ProCell. Application of avoltage to the electrode then induces chemiluminescent emission which ismeasured by a photomultiplier (0.4 second read frame).• Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve providedvia the reagent bar code. |
| 5.Intended use | Immunoassay for the in vitro quantitative determination of carcinoembryonicantigen (CEA) in human serum and plasma.Measurements of CEA aid in the management of cancer patients bymonitoring CEA concentrations.The electrochemiluminescence immunoassay "ECLIA" is intended for use onthe Boehringer Mannheim Elecsys 2010 immunoassay analyzer. |
| 6.Comparison topredicatedevice | The Boehringer Mannheim Elecsys® CEA Assay is substantially equivalentto other products in commercial distribution intended for similar use. Mostnotably it is substantially equivalent to the currently marketed Enzymun-TestCEA Assay (P860058).The following table compares the Elecsys® CEA Assay with the predicatedevice, Enzymun-Test CEA Assay (P860058):Similarities:• Intended Use: Immunoassay for the in vitro quantitative determination ofCarcinoembryonic Antigen (CEA). The assay is further indicated for serialmeasurement of CEA to aid in the management of cancer patients.• Solid phase binding principle: Streptavidin/Biotin• Calibrators: Same formulation• Assay standardization: 1st WHO Reference Standard 73/601Continued on next page |
Continued on next page
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510(k) Summary, Continued
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510(k) Summary, Continued
Differences: 6. Comparison to predicate device, cont.
| Feature | Elecsys® CEA | Enzymun CEA |
|---|---|---|
| Reaction testprinciple | Electrochemiluminescence | ELISA/1-step sandwich assayusing streptavidin technology |
| Instrumentrequired | Elecsys® 2010 | ES 300 |
| Antibodies | Mouse/chimeric | Mouse/mouse |
| SampleMaterial | Serum and Plasma | Serum |
| CalibrationStability | A calibration is recommendedevery 7 days if kit is notconsumed; 8 weeks withsame reagent lot if reagent isconsumed within 7 days. | A calibration is required everyrun |
Performance Characteristics:
| Feature | Elecsys® CEA | Enzymun-Test CEA | ||||
|---|---|---|---|---|---|---|
| PrecisionLevel | Modified NCCLS (ng/mL): | Modified NCCLS (ng/mL): | ||||
| Control 1 | Control 2 | Pool 1 | Low | Mid | High | |
| N | 60 | 60 | 60 | 120 | 120 | 120 |
| Within-Run | 5.10 | 35.51 | 3.99 | 2.3 | 12.4 | 26.4 |
| %CV | 1.8 | 1.4 | 1.7 | 5.6 | 3.7 | 3.3 |
| Total | 5.10 | 35.51 | 3.99 | 2.3 | 12.4 | 26.4 |
| %CV | 3.5 | 2.8 | 3.2 | 6.3 | 4.1 | 3.7 |
| Modified NCCLS (ng/mL): | ||||||
| Pool 2 | Pool 3 | |||||
| N | 60 | 60 | ||||
| Within-Run | 17.16 | 546.00 | ||||
| %CV | 1.7 | 1.4 | ||||
| Total | 17.16 | 546.00 | ||||
| %CV | 3.2 | 3.4 |
Continued on next page
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510(k) Summary, Continued
Performance Characteristics:
Comparison to predicate device, cont.
| Feature | Elecsys® CEA | Enzymun-Test CEA |
|---|---|---|
| Lower Detection Limit | 0.2 ng/mL | 0.5 ng/mL |
| Linearity | 0.2 - 1000 ng/mL (with a deviation from a linear line of ±10%) | 0.5 - 55 ng/mL (with a deviation from a linear line of ±10%) |
| Method Comparison | Vs Enzymun-Test® CEA0 - 50 ng/mLLeast Squaresy=1.25x - 0.86r=0.976SEE = 1.421N=397Passing/Babloky=1.22x - 0.69r=0.976SEE = 0.471N=3970 - 600 ng/mLLeast Squaresy=1.05x + 0.46r=0.991SEE = 6.093N=446Passing/Babloky=1.13x - 0.53r=0.991SEE = 0.714N=446 | Vs Enzymun-Test® CEALeast Squaresy=0.97x - 0.064r=0.989SEE=1.649N=69 |
| Feature | Elecsys® CEA | Enzymun-Test CEA |
| Interferingsubstances | No interference at: | No interference at: |
| Bilirubin | 25 mg/dL | 64.5 mg/dL |
| Hemoglobin | 1000 mg/dL | 50 mg/dL |
| Lipemia | 1000 mg/dL | 1250 mg/dL |
| Biotin | 30 ng/mL | 40 ng/mL |
| SpecificityNon-specificcross reactingantigen | % Cross-reactivity | % Cross-reactivity |
| NCA 1 | < 0.7% | < 0.7% |
| NCA 2 | 70% | 70% |
| α, -acidglycoprotein | none | none |
| Hook Effect | No Hook Effect up to49,100 ng/ml CEA | No Hook Effect up to5,800 ng/ml CEA |
Continued on next page
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510(k) Summary, Continued
ર.
Performance Characteristics:
Comparison to predicate device, cont.
Clinical specimens
Comparison to predicate device, cont.
Serial samples from 50 patients with colorectal cancer were tested on the Elecsys CEA. Chi square analysis of the samples showed a statistically significant association between clinical outcome and CEA test result.
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Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo consists of a stylized eagle with three lines representing its wings and head. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle.
JUN 1 6 1997
Food and Drug Administration
Public Health Service
2098 Gaither Road Rockville MD 20850
Ms. Mary Koninq Regulatory Affairs Specialist Boehringer Mannheim Corporation 2400 Bisso Lane Concord, California 94524-4117
Re: K964368/S1
Trade Name: Elecsys® CEA Assay and Elecsys® CEA CalSet Calibrators Requlatory Class: II
Product Code: DHX 发 Dated: April 30, 1997 Received: May 1, 1997
Dear Ms. Koning:
We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to 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). 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.
If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Good Manufacturing Practice for Medical Devices: General (GMP) regulation (21 CFR Part 820) and that, through periodic GMP inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal Laws or Regulations.
Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770)488-7655.
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Page 2
This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll free number (800) 638-2041 or at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"
Sincerely yours,
Steven Sutman
Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
§ 862.1150 Calibrator.
(a)
Identification. A calibrator is a device intended for medical purposes for use in a test system to establish points of reference that are used in the determination of values in the measurement of substances in human specimens. (See also § 862.2 in this part.)(b)
Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.