(220 days)
The Axis Homocysteine Enzyme Immunoassay is intended for the quantitative measurement of total L-homocysteine in human serum or plasma. The device can assist in the diagnosis and treatment of patients suspected of having hyperhomocysteinemia and homocysteinuria.
The Axis Homocysteine Enzyme Immunoassay is designed for the quantitative determination of total homocysteine in plasma or serum. In the Axis Homocysteine Enzyme Immunoassay, protein bound homocysteine is reduced to free homocysteine, enzymatically converted to S-adenosyl-L-homocysteine (SAH), and detected in competitive immunoassay with monoclonal anti-SAH antibody.
The Axis Homocysteine Enzyme Immunoassay (Axis Homocysteine EIA) underwent an evaluation to establish its substantial equivalence to an existing device, the University of Bergen Homocysteine by HPLC method, and thus confirm its safety and effectiveness.
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria (Implied by Predicate Device Performance) | Axis Homocysteine Enzyme Immunoassay Performance |
|---|---|---|
| Precision | ||
| - Within-run %CV (Low) | Similar to or better than predicate | 7.3% |
| - Within-run %CV (Medium) | Similar to or better than predicate | 6.8% |
| - Within-run %CV (High) | Similar to or better than predicate | 5.2% |
| - Total precision (Low) | Similar to or better than predicate | 9.3% |
| - Total precision (Medium) | Similar to or better than predicate | 8.1% |
| - Total precision (High) | Similar to or better than predicate | 7.1% |
| Measuring Range | Not explicitly stated, but within clinically relevant range | 2 - 50 µmol/L |
| Limit of Quantification | Not explicitly stated, but clinically acceptable | < 0.5 µmol/L |
| Accuracy (Correlation to HPLC) | High correlation (r² close to 1, slope close to 1, Y-intercept close to 0) | r² = 0.94, Slope = 0.94, Y-Intercept = -0.09 |
2. Sample Size Used for the Test Set and Data Provenance
The document does not explicitly state the sample size for the test set used in the correlation study.
The study was a comparative study against the University of Bergen Homocysteine by HPLC method. The data provenance is not explicitly mentioned (e.g., country of origin, retrospective or prospective), but given the comparison to a specific university's method, it suggests samples were likely from a clinical setting where that method was in use.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
Not applicable for this type of device. The ground truth was established by a reference analytical method (HPLC), not through expert interpretation of images or clinical cases.
4. Adjudication Method for the Test Set
Not applicable. The "ground truth" was an analytical measurement from a reference method (HPLC). There was no human adjudication involved in this comparison study.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done. This study focuses on the analytical performance of an in vitro diagnostic device, comparing its measurements to a reference method, not on human reader performance with or without AI assistance.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
Yes, the study primarily assessed the standalone performance of the Axis Homocysteine Enzyme Immunoassay. It's an in vitro diagnostic device, and its output is a quantitative measurement. The comparison was to another analytical method (HPLC), not to human interpretations.
7. The Type of Ground Truth Used
The ground truth used for performance evaluation (specifically accuracy) was the measurements obtained from a well-established and accepted reference method, the University of Bergen Homocysteine by HPLC method. This is considered an analytical gold standard for homocysteine quantification.
8. The Sample Size for the Training Set
The document does not provide details on a separate "training set" for the Axis Homocysteine EIA. Immunoassays are typically developed through a detailed R&D process involving reagent optimization, calibration, and validation, rather than a "training set" in the machine learning sense. The reported performance metrics (precision, measuring range, limit of quantification, and accuracy) appear to be derived from validation studies.
9. How the Ground Truth for the Training Set Was Established
Not explicitly described as a discrete "training set" in the context of machine learning. The development and calibration of the immunoassay would have relied on known concentrations of homocysteine, likely prepared using highly pure standards, to establish its measurement characteristics (e.g., standard curve for quantitative determination). These standards would effectively serve as the "ground truth" for the assay's development.
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OCT 16 1998
510(k) Summary
Axis® Homocysteine Enzyme Immunoassay
:
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510(k) Summarv
Axis Homocysteine Enzyme Immunoassay
Summary of Safety and Effectiveness Information Supporting a Substantially Equivalent Determination
The Axis Homocysteine Enzyme Immunoassay is designed for the quantitative determination of total homocysteine in plasma or serum.
Homocysteine is a thiol-containing amino acid produced by the intracellular demethylation of methionine. Homocysteine is metabolized to either cysteine or to methionine. In the vitamin Bo dependent trans-sulphuration pathway homocysteine is irreversibly catabolised to cysteine. A major part of homocysteine is remethylated to methionine, mainly by the folate and cobalamindependent enzyme methionine synthase. Homocysteine accumulates in the cell and is exported to the circulation when these reactions are impaired. Homocysteine circulates in plasma mostly in its oxidized form bound to proteins and is measured as total homocysteine (tHcy) the sum of free and protein bound fractions.
In the Axis " Homocysteine Enzyme Immunoassay, protein bound homocysteine is reduced to free homocysteine, enzymatically converted to S-adenosyl-L-homocysteine (SAH), and detected in competitive immunoassay with monoclonal anti-SAH antibody.
There are several 510(k) cleared methods for measurement of amino acids'13 . All these methods are based on HPLC separation and either traditional post-column derivitization (LKB, Beckman) or pre-column derivitization (Waters). Homocysteine can be analyzed using a traditional HPLC method with post-column derivatization. For example, Poele-Pothoff et al used a traditional system with 3 hours analysis for this purpose (LKB analyzer). Sera were reduced using dithiotreitol, then proteins were precipitated as would normally be done for this instrument. Candito et al also published an analysis of homocysteine using a Beckman Amino Acid Analyzer, after reduction with dithiotreitol. Both of these methods are based on earlier work by Andersson , which used a modified separation on an amino acid analyzer.
To establish substantial equivalence to an existing device, and thus establish the safety and effectiveness of the Axis® Homocysteine Enzyme Immunoassay, the Axis® Homocysteine Enzyme Immunoassay was compared to the University of Bergen Homocysteine by HPLC method'. This method uses pre-column derivatization and permits rapid analysis. In the work of Poele-Pothoff, a similar pre-column method was compared to an amino acid analyzer method and was shown to give an excellent correlation.
The performance of the Axis® Homocysteine Enzyme Immunoassay was evaluated for precision, measuring range, accuracy and limit of quantification. The precision studies were done according to NCCLS Evaluation protocol. Vol. 12, No. 4, EP5-T2. Using this protocol. precision of the system was determined using Low, Medium and High controls. The Within-run %CV for the Low was 7.3%, for the Medium 6.8%, and for the High 5.2%. Total precision was
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9.3% for the Low, 8.1% for the Medium and 7.1% for the High. The assay is linear within the measuring range: 2 - 50 umol/L and has a limit of homocysteine quantification of < 0.5 µmol/L.
A correlation study, to determine accuracy of the Axis® Homocysteine Enzyme Immunoassay. was done against the University of Bergen Homocysteine by HPLC method. The study followed NCCLS Document EP9-T. The r2 for the correlation was 0.94, the Slope was 0.94, and the Y-Intercept was - 0.09.
When considering an excellent correlation between the Axis® Homocysteine Enzyme Immunoassay and the University of Bergen Homocysteine by HPLC method, it can be concluded that the Axis Homocysteine Enzyme Immunoassay is substantially equivalent to the HPLC method. Based on the establishment of substantial equivalence, the safety and effectiveness of the Axis® Homocysteine Enzyme Immunoassay is confirmed.
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- LKB Instruments Inc. 4150 Alpha Amino Acid Analyzer. 510(k) Number: K820415, 02/11/82.
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- Beckman Instruments Inc. System 6300 Series High Performance Amino Acid Analyzer. 510(k) Number: K92093, 11/16/92.
- Waters Chromatography Division. Waters Pico Tag Chem Pack. Free Amino Acid 3 . Analysis Kit. 510(k) Number: K943978, 05/02/95.
- Poele-Pothoff et al, Ann. Clin. Biochem., 1995, 32: 218-220. 4.
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- Andersson et al, Scand. J. Clin Lab Invest, 1989, 49: 445-449.
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- Candito et al. Journal of Chromatography, 1997, 692: 213-216.
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- Fiskerstrand et al, Clin. Chem. 1993, 39: 263-271.
In conclusion, these data demonstrate that the Axis Homocysteine Enzyme Immunoassay is as safe and effective as, and is substantially equivalent to the Beckman System 6300 Series High Performance Amino Acid Analyzer, K 92093
Prepared and Submitted by:
Fred B. Kennedy, March 5, 1998
Ronald G. Leonardi, Ph. D. President R & R Registrations P.O. Box 262069 San Diego, CA 92196 1-619-586-0751
for AXIS BIOCHEMICALS, NORWAY
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Food and Drug Administration 2098 Gaither Road Rockville MD 20850
OCT 16 1998
Ronald G. Leonardi, Ph.D. . President R & R Registrations P.O. Box 262069 San Diego, California 92196-2069
Re : K980907 AXIS® Homocysteine Enzyme Immunoassay Regulatory Class: I & II Product Code: JJX, LPS, DFC Dated: September 10, 1998 Received: September 11, 1998
Dear Dr. Leonardi:
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 The general controls provisions of the Act of the Act. include requirements for annual reqistration, 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 requlations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. ਸ substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory In addition, FDA may publish further announcements action. 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 requlations.
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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.
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 (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".
Sincerely yours,
Steven Litman
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
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510(k) Number (lf Known): K980907
Axis® Homocysteine Enzyme Immunoassay Device Name:
Indications for Use:
The Axis Homocysteine Enzyme Immunoassay is intended for the quantitative measurement of total L-homocysteine in human serum or plasma.
The device can assist in the diagnosis and treatment of patients suspected of having hyperhomocysteinemia and homocysteinuria.
(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED) Concurrence of CDHR, Office of Device Evaluation (ODE)
Prescription Use
(Per 21 CFR 801 109)
OR
Over-The- Counter Use ________________________________________________________________________________________________________________________________________________________
(Optional Format 1-2-96)
(Division Sign-Off)
Division of Clinical Laboratory Devices
Division of Clinical Laboratory Devices
510(k) Number K950907
§ 862.1377 Urinary homocystine (nonquantitative) test system.
(a)
Identification. A urinary homocystine (nonquantitative) test system is a device intended to identify homocystine (an analogue of the amino acid cystine) in urine. The identification of urinary homocystine is used in the diagnosis and treatment of homocystinuria (homosystine in urine), a heritable metabolic disorder which may cause mental retardation.(b)
Classification. Class II.