(77 days)
for the quantitative determination of high-density lipoprotein Cholesterol (HDL-C) n human serum and plasma.
for in vitro diagnostic use.
for the calibration of the Liquid N-geneous HDL Cholesterol assay.
for in vitro diagnostic use.
The Genzyme Liquid N-geneous™ HDL Cholesterol Kit is a two-reagent homogeneous method for the direct quantitative determination of high density lipoprotein cholesterol (HDL-C) in human serum and plasma.
In both user settings, the principle of the test is based upon a unique detergent which selectively solubilizes only the HDL. This unique detergent also strongly inhibits the reaction of the enzymes with cholesterol contained in the low density lipoprotein (LDL), very low density lipoprotein (VLDL) and chylomicron particles. Consequently, only the cholesterol in the resultant micell complexes of the detergent and lipids is subject to the enzyme reactions, leading to the selective determination of HDL cholesterol.
This document describes the submission for the Genzyme Liquid N-geneous™ HDL Cholesterol Kit, a device designed for the quantitative determination of high-density lipoprotein cholesterol (HDL-C) in human serum and plasma. The study aims to demonstrate that the device is substantially equivalent to existing reference methods.
1. Table of Acceptance Criteria (Implied) and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" but rather presents comparative performance data against established reference methods. The implicit acceptance criteria are that the Genzyme Liquid N-geneous™ HDL Kit should perform comparably to these reference methods in terms of correlation, slope, intercept, and mean differences, as well as meeting NCEP precision goals.
| Performance Metric | Acceptance Criteria (Implied by Comparison) | Genzyme Liquid N-geneous™ HDL vs. Phosphotungstate (n=92) | Genzyme Liquid N-geneous™ HDL vs. CDC Method (n=54) | Precision: Within-Run %CV (Low/Mid/High) | Precision: Between-Run %CV (Low/Mid/High) | POL Study: Coeff. (r) vs. Reference Lab (Site 1/2/3) | POL Study: NCEP Goals Achieved |
|---|---|---|---|---|---|---|---|
| Slope | Close to 1.0 | 0.960 | 1.056 | N/A | N/A | 1.11 / 1.12 / 0.93 | N/A |
| Intercept (mg/dL) | Close to 0.0 | 3.97 | -0.736 | N/A | N/A | -1.44 / -5.90 / 1.25 | N/A |
| Correlation Coefficient (r) | High (e.g., >0.95) | 0.991 | 0.992 | N/A | N/A | 0.97 / 0.99 / 0.99 | N/A |
| Mean Difference (mg/dL) | Small | 2.0 | 2.2 | N/A | N/A | N/A | N/A |
| Mean Percent Difference (%) | Small | 4.7% | 4.1% | N/A | N/A | N/A | N/A |
| Within-Run %CV | Low; ≤6% (≥42mg/dL), ≤2.5mg/dL SD (<42mg/dL) | 0.99 (Low), 0.79 (Mid), 0.28 (High) | N/A | N/A | N/A | N/A | Achieved |
| Between-Run %CV | Low; ≤6% (≥42mg/dL), ≤2.5mg/dL SD (<42mg/dL) | 1.49 (Low), 1.31 (Mid), 1.17 (High) | N/A | N/A | N/A | N/A | Achieved |
2. Sample Sizes and Data Provenance:
- Test Set (Comparative Performance):
- N=92 serum samples for comparison with the Sodium Phosphotungstate MgCl2 (PTA) method.
- N=54 of these 92 samples were tested with the CDC Designated Comparison Method (DCM) or the HDL reference method (ultracentrifugation, chemical precipitation, and Abell-Kendall) for samples with triglyceride levels >200 mg/dL.
- N=40 serum samples for the Physician Office Laboratories (POL) comparative studies. These were "split samples" from the same 40 specimens, with a reference laboratory (Genzyme) also analyzing them.
- Data Provenance: The studies were conducted at Genzyme Corporation. The origin of the patient samples (e.g., country of origin) is not explicitly stated. The data is retrospective as it involves testing existing serum samples.
3. Number of Experts and Qualifications for Ground Truth:
- The document does not mention the use of "experts" in the traditional sense for establishing ground truth for individual cases. For this type of diagnostic test, the "ground truth" is provided by established, accepted reference methods rather than human interpretation.
4. Adjudication Method for the Test Set:
- Not applicable. As the ground truth is established by chemical/instrumental reference methods, there is no need for expert adjudication of results. The comparison is quantitative.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No. This is an in vitro diagnostic (IVD) device for chemical analysis (HDL-C measurement), not an imaging or interpretive device that would typically involve human readers. Therefore, an MRMC study is not relevant or performed.
6. Standalone (Algorithm Only) Performance Study:
- Yes, in essence. The comparative performance studies directly evaluate the Genzyme Liquid N-geneous™ HDL Cholesterol Kit (the "algorithm/device") against reference methods, operating without direct human interpretation influencing the numerical result. These studies are standalone in that they assess the device's accuracy in producing a quantitative value.
7. Type of Ground Truth Used:
- The ground truth was established by established reference methods for HDL cholesterol measurement:
- Sodium Phosphotungstate MgCl2 (PTA) method.
- Center for Disease Control (CDC) Designated Comparison Method (DCM).
- HDL reference method (ultracentrifugation, chemical precipitation, and Abell-Kendall) for samples with triglyceride levels >200 mg/dL.
- The selection of samples was based on the Lipid Research Clinics (LRC) population studies, using patient serum samples with HDL values between 27-91 mg/dL (5th and 95th percentile).
8. Sample Size for the Training Set:
- The document does not explicitly describe a separate "training set" in the context of machine learning. The Liquid N-geneous™ HDL Cholesterol Kit is a reagent kit based on a chemical principle rather than an AI/ML algorithm that requires a training phase.
9. How the Ground Truth for the Training Set Was Established:
- Not applicable. As the device is a chemical reagent kit and not an AI/ML system, a training set with established ground truth in the machine learning sense is not described or relevant for this type of submission. The development of the kit would rely on chemical principles and validation against known standards and reference methods during its R&D phase, rather than a "training set" for an algorithm.
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510(k) PREMARKET NOTIFICATION
Cambridge, MA 02139
June 16, 1997
Liquid N-geneous™ HDL
Cholesterol Reagent Kit
March 28, 1997
ATTACHMENT 1
510(k) Summary Of Safety and Effectiveness Information Upon Which An Equivalence Determination Could be Made
| Trade or Proprietary Name: | Genzyme Liquid N-geneous™ HDL Cholesterol Kit |
|---|---|
| Common or Usual Name: | Homogeneous assay for high density lipoproteincholesterol |
| Classification Name: | High density lipoprotein cholesterol test |
| Manufacturer: | Genzyme DiagnosticsOne Kendall SquareCambridge, MA 02139-1562 |
| Contact Person: | Nancy E. Isaac, Associate Director, Regulatory Affairs (617) 374-7431 orBeth A. Crowley, Regulatory Associate (617) 252-7669. |
The use of the Liquid Genzyme N-geneous™ HDL Cholesterol Kit in clinical and physician's office laboratory settings is substantially equivalent to the Sodium Phosphotungstate MgCl2 (PTA) method. The Genzyme Liquid N-geneous™ HDL Cholesterol Kit is a two-reagent homogeneous method for the direct quantitative determination of high density lipoprotein cholesterol (HDL-C) in human serum and plasma.
In both user settings, the principle of the test is based upon a unique detergent which selectively solubilizes only the HDL. This unique detergent also strongly inhibits the reaction of the enzymes with cholesterol contained in the low density lipoprotein (LDL), very low density lipoprotein (VLDL) and chylomicron particles. Consequently, only the cholesterol in the resultant micell complexes of the detergent and lipids is subject to the enzyme reactions, leading to the selective determination of HDL cholesterol.
Comparative performance studies were conducted using the Liquid N-geneous™ HDL Cholesterol Kit and two reference methods: Sodium Phosphotungstate MgCly and the Center for Disease Control (CDC) designated comparison method (DCM). When samples contained triglyceride levels >200 mg/dL, the HDL reference method (ultracentrifugation, chemical precipitation and Abell-Kendall) was performed. Based on the Lipid Research Clinics (LRC) population studies, patient serum samples with HDL values between 27-91 mg/dL (5th and 95th percentively) were used for these comparative studies.
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Ninety two serum samples, with HDL values between 25 and 91 mg/dL, were tested at Genzyme Corporation using the Liguid N-geneous™ HDL and the PTA precipitation methods. Of these 92 samples, 54 were tested with the CDC Designated Comparison Method for samples with trighyceride levels <200 mg/dL and the HDL reference method (ultracentrifugation, precipitation and Abell-Kendall) for samples with triglyceride levels >200 mg/dL.
| Liquid N-geneous™ HDL | vs.Phosphotungstate(n = 92) | vs.CDC Method(n = 54) |
|---|---|---|
| Slope | 0.960 | 1.056 |
| Intercept (mg/dL) | 3.97 | -0.736 |
| Correlation Coefficient (r) | 0.991 | 0.992 |
| Mean (mg/dL) | Ng: 51.3PTA: 49.3 | Ng: 54.3CDC: 52.0 |
| Standard Deviation (mg/dL) | Ng: 13.7PTA: 14.1 | Ng: 12.2CDC: 11.5 |
| Mean Difference (mg/dL) | 2.0 | 2.2 |
| Mean Percent Difference | 4.7% | 4.1% |
Precision studies were conducted using the Liquid N-geneous™ HDL Cholesterol Test Kit. Both within-run and between-run studies were performed using frozen serum pools at three target levels of HDL cholesterol as determined by the National Cholesterol Education Program (NCEP): <35 mg/dL (low); 35-60 mg/dL (mid); and >60 mg/dL (high).
| Within-Run | Low(<35 mg/dL) | Mid(35-60 mg/dL) | High(>60 mg/dL) |
|---|---|---|---|
| n | 20 | 20 | 20 |
| Sample Range (mg/dL) | 22.6 - 23.5 | 55.1 - 56.7 | 84.3 - 85.0 |
| Mean (mg/dL) | 22.9 | 55.8 | 84.7 |
| SD (mg/dL) | 0.23 | 0.44 | 0.24 |
| %CV | 0.99 | 0.79 | 0.28 |
| Between-Run | Low(<35 mg/dL) | Mid(35-60 mg/dL) | High(>60 mg/dL) |
|---|---|---|---|
| n | 40 | 40 | 40 |
| Sample Range (mg/dL) | 22.6 - 24.1 | 54.5 - 57.1 | 83.7 - 87.8 |
| Mean (mg/dL) | 23.4 | 55.7 | 85.6 |
| SD (mg/dL) | 0.35 | 0.73 | 1.00 |
| %CV | 1.49 | 1.31 | 1.17 |
In separate comparative performance studies, three physician office laboratories (POL) analyzed separate sets of 40 serum samples using the lyophilized format of Genzyme's N-geneous™ HDL Cholesterol Reagent Kit. Split samples from the same 40 specimens were also analyzed at
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Genzyme, which acted as the reference laboratory. The correlation coefficient between the reference testing site and the POL testing sites for this study were:
| Parameter | Site #1 | Site #2 | Site #3 |
|---|---|---|---|
| Slope | 1.11 | 1.12 | 0.93 |
| Intercept (mg/dL) | -1.44 | -5.90 | 1.25 |
| Correlation Coefficient (r) | 0.97 | 0.99 | 0.99 |
In the same study, the three POL sites compared their Genzyme N-geneous™ HDL Cholesterol Reagent Kit results to their respective current HDL methods for each of these 40 patient samples. The correlation coefficient for these comparisons were:
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Precision studies were conducted using the Ivophilized N-geneous™ HDL Cholesterol Test Kit. Both within-run and between-run studies were performed using frozen serum pools at three target levels of HDL cholesterol as determined by the National Cholesterol Education Program (NCEP): <35 mg/dL (low); 35-60 mg/dL (mid); and >60 mg/dL (high). It was determined that each POL site achieved the NCEP goals of CVs ≤6% at ≥42 mg/dL, and ≤2.5 mg/dL SD at <42 mg/dL, when using the Genzyme N-geneous™ HDL Cholesterol Kit.
These data demonstrate that the performance of the N-geneous™ HDL Cholesterol Kit in both the clinical and physician office laboratories is substantially equivalent to the performance of the Sodium Phosphotungstate MgCl2 and CDC Designated Comparison Methods.
In lieu of a 510(k) statement under 513(i) of the Act, this information is provided as a 510(k) summary for disclosure to any other persons/companies without the specific written authorization from Genzyme Corporation.
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Image /page/3/Picture/1 description: The image shows the seal for the Department of Health & Human Services - USA. The seal is circular and contains the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. In the center of the seal is an abstract image of an eagle with three heads.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
JUN 16 107
Nancy E. Isaac Associate Director, Regulatory Affairs Genzyme Corporation One Kendall Square Cambridge, Massachusetts 02139
K971162 Re: Liquid N-geneous™ HDL Cholesterol Kit/Cholesterol Calibrator Regulatory Class: I & II Product Code: LBS, JIS March 28, 1997 Dated: March 31, 1997 Received:
Dear Ms. Isaac:
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 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 Requlations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Good Manufacturing Practice for Medical Devices: General (GMP) requlation (21 CFR Part 820) and that, through periodic GMF inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP requlation 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 requlations.
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Paqe 2
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 requlation (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 Gutman
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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Page 1 of 1
(k) Number (if known): _______________________________________________________________________________________________________________________________________________________
vice Name: Liquid N-geneous HDL Cholesterol Kit and N-geneous HDL Cholesterol Calibrator
ications For Use:
for the quantitative determination of high-density lipoprotein Cholesterol (HDL-C) n human serum and plasma.
or in vitro diagnostic use. 学
or the calibration of the Liquid N-geneous HDL Cholesterol assay.
or in vitro diagnostic use.
(Division Sign-Off)
Division of Clinical Laboratory Devices
510(k) Number 5971162
LEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF EDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
escription Use
er 21 CFR 801.109)
ાર
RECEIVED
4 APR 97 09 356
FDA/CDRH/ODE\IDM
Over-The-Counter User
(Optional Format 1-2-96)
§ 862.1475 Lipoprotein test system.
(a)
Identification. A lipoprotein test system is a device intended to measure lipoprotein in serum and plasma. Lipoprotein measurements are used in the diagnosis and treatment of lipid disorders (such as diabetes mellitus), atherosclerosis, and various liver and renal diseases.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.