(575 days)
The NMR LipoProfile® -2 test, used with the NMR Profiler, an automated NMR spectrometer, measures lipoprotein particles to quantify LDL particle number (LDL-P), HDL cholesterol (HDL-C), and triglycerides in serum and plasma using nuclear magnetic resonance (NMR) spectroscopy. LDL-P and these NMR-derived concentrations of triglycerides and HDL-C are used in conjunction with other lipid measurements and clinical evaluation to aid in the management of lipoprotein disorders associated with cardiovascular disease. This test is performed and provided as a service by LipoScience Laboratory.
The NMR LipoProfile Test involves measurement of the 400 MHz proton NMR spectrum of a plasma or serum sample, deconvolution of the composite signal at ~0.8 ppm to produce the signal amplitudes of the lipoprotein subclasses that contribute to the composite plasma signal, and conversion of these subclass signal amplitudes to lipoprotein subclass concentrations. The 0.8 ppm plasma NMR signal arises from the methyl group protons of the lipids carried in the VLDL, and HDL subclasses of varying diameter. The NMR signals from the various lipoprotein subclasses have unique and distinctive frequencies and lineshapes, each of which are accounted for in the deconvolution analysis model. Each subclass signal amplitude is proportional to the number of subclass particles emitting the signal, which enables subclass particle concentrations to be calculated from the subclass signal amplitudes derived from the spectral deconvolution analysis. LDL subclass particle concentrations, in units of nanomoles of particles per liter (nmol/L), are summed to give the reported total LDL particle concentration (LDL-P). By employing conversion factors that assume that the various lipoprotein subclass particles have cholesterol and triglyceride contents characteristic of normolipidemic individuals, HDL cholesterol and triglyceride concentrations are also derived.
AI Device Acceptance Criteria and Study Summary
Here's an analysis of the provided text regarding the NMR LipoProfile-2 Assay and NMR Profiler Instrument Test System:
1. Acceptance Criteria and Reported Device Performance
The document describes several analytical and clinical performance aspects. While explicit "acceptance criteria" for all metrics are not always stated with numerical thresholds, they are implied through the performance data and comparisons to predicate devices. For analytical sensitivity and linearity, specific ranges are provided.
Table 1: Acceptance Criteria (Implied/Stated) and Reported Device Performance
| Metric | Acceptance Criteria (Implied/Stated) | Reported Device Performance |
|---|---|---|
| Analytical Sensitivity: | Acceptable precision and accuracy with total error ≤20%. | |
| - LDL-P (LOQ) | - | 300 nmol/L |
| - HDL-C (LOQ) | - | 10 mg/dL |
| - Triglycerides (LOQ) | - | 25 mg/dL |
| Assay Precision: | Acceptable intra-assay and inter-assay variability. (No explicit numeric criteria stated, but low CVs are implied as acceptable) | |
| - LDL-P (Intra-assay) | Pool 1: Mean 2222 nmol/L, SD 49.1, %CV 2.2; Pool 2: Mean 1042 nmol/L, SD 47.7, %CV 4.6 | |
| - LDL-P (Inter-assay) | Pool 1: Mean 1925 nmol/L, SD 66.7, %CV 3.5; Pool 2: Mean 1053 nmol/L, SD 68.4, %CV 6.5 | |
| - HDL-C (Intra-assay) | Pool 1: Mean 41 mg/dL, SD 0.54, %CV 1.3; Pool 2: Mean 57 mg/dL, SD 0.42, %CV 0.7 | |
| - HDL-C (Inter-assay) | Pool 1: Mean 42 mg/dL, SD 1.17, %CV 2.8; Pool 2: Mean 56 mg/dL, SD 0.83, %CV 1.5 | |
| - Trig (Intra-assay) | Pool 1: Mean 189 mg/dL, SD 2.0, %CV 1.1; Pool 2: Mean 75 mg/dL, SD 1.2, %CV 1.5 | |
| - Trig (Inter-assay) | Pool 1: Mean 219 mg/dL, SD 2.9, %CV 1.3; Pool 2: Mean 80 mg/dL, SD 1.7, %CV 2.1 | |
| Linearity: | Wide varying target concentrations with acceptable percent bias. | |
| - LDL-P (Linear Range) | - | 300-6000 nmol/L |
| - HDL-C (Linear Range) | - | 7-160 mg/dL |
| - Triglycerides (Linear Range) | - | 5-2700 mg/dL |
| Reportable Range: | - | |
| - LDL-P | - | 300 - 3500 nmol/L |
| - HDL-C | - | 7 - 140 mg/dL |
| - Triglycerides | - | 5 - 1100 mg/dL |
| Interfering Substances: | No appreciable interference at clinically relevant concentrations. | No appreciable interference by Endogenous substances (Bilirubin, Creatinine, Hemoglobin, Urea, Uric acid) or Exogenous substances (Acetaminophen, Aspirin, Clopidogrel, Enalapril, Fenofibrate, Furosemide, Glipizide, Hydralazine, Hydrochlorothiazide, Ibuprofen, Isosorbide dinitrate, Metformin, Metoprolol, Naproxen, Niacin, Nifedipine, Piroxicam, Simvastatin, Thiazolidinedione, Triamterene) at tested concentrations. The concentrations tested were representative of the highest blood concentrations expected for the highest therapeutic doses of these compounds. |
| Method Comparison (HDL-C): | Demonstrate substantial equivalence to a predicate chemistry analyzer system. (Implicit: strong correlation and similar mean values.) | 5,362 plasma samples tested. R-squared = 0.897. NMR LipoProfile mean: 50.7 mg/dL; Predicate mean: 51.3 mg/dL. |
| Method Comparison (Triglycerides): | Demonstrate substantial equivalence to a predicate chemistry analyzer system. (Implicit: strong correlation and similar mean values.) | 5,362 plasma samples tested. R-squared = 0.929. NMR LipoProfile mean: 128.7 mg/dL; Predicate mean: 123.9 mg/dL. |
| Clinical Performance (LDL-P): | Statistically significant relationship to CVD risk, aiding in the management of lipoprotein disorders. (Implicit: demonstrating predictive value for cardiovascular events). | VA-HIT Study (Baseline): Odds Ratio 1.31 (95% CI, 1.09-1.57), p=0.004 for a new CHD event with 1-SD increment of LDL-P in placebo group. EPIC-Norfolk Study (Multivariable): Statistically significant association of LDL-P quartiles with incident CAD events (p=0.02, highest quartile HR 1.37 (1.04-1.83)). Women's Health Study: Statistically significant association of LDL-P quintiles with incident CVD events (p<0.001, highest quintile HR 2.51 (1.91-3.30)). |
2. Sample Sizes and Data Provenance
Test Set (for method comparison):
- Sample Size: 5,362 plasma samples (for HDL-C and Triglycerides method comparison).
- Data Provenance: From individuals who were part of the Multi-Ethnic Study of Atherosclerosis (MESA). The specific country of origin is not explicitly stated, but MESA is a US-based study. This data is retrospective.
Test Set (for clinical performance of LDL-P measurement):
- VA-HIT Study: 1,061 plasma samples (364 cases, 697 controls). Data is retrospective from a previous randomized placebo-controlled clinical trial. The trial was conducted in the US (Veterans Affairs).
- EPIC-Norfolk Study: 2,888 serum samples (1,003 cases, 1,885 controls). Data is retrospective from the prospective EPIC-Norfolk study conducted in Norfolk, United Kingdom.
- Women's Health Study: 27,673 plasma samples (1,015 CVD events). Data is retrospective from a randomized, double-blind, placebo-controlled trial of US-based female healthcare professionals.
Test Set (for analytical performance - sensitivity, precision, linearity, interfering substances):
- Analytical Sensitivity: Serum specimens with low initial concentrations were serially diluted. 20 replicates of each dilution were analyzed. Exact number of initial specimens not stated.
- Assay Precision: 2 patient serum pools tested with 20 replicates each (intra-assay) and over 20 different runs (inter-assay).
- Linearity: 2 serum pools prepared and diluted to produce 12 different samples. 6 replicates analyzed for each.
- Interfering Substances: 6 plasma pools spiked with potential interferents.
3. Number of Experts and Qualifications for Ground Truth
The document does not mention the use of experts to establish ground truth for the test sets in the context of radiologists or similar clinical diagnosticians. The ground truth for the method comparison studies was established by commercially available chemistry analyzer systems which are considered standard clinical methods.
For the clinical outcome studies (VA-HIT, EPIC-Norfolk, Women's Health Study), the "ground truth" for disease events (e.g., CHD event, CAD, CVD event) would have been established by clinical adjudication committees or established diagnostic criteria within those long-term epidemiological studies. The qualifications of these individuals are not specified in this 510(k) summary, but they would typically involve cardiologists and other medical specialists.
4. Adjudication Method for the Test Set
Since the ground truth for clinical outcomes was based on events recorded in large epidemiological studies, there was no "adjudication method" in the sense of comparing human reads against an AI output. The lipid measurements from the NMR LipoProfile device were used as a predictor for these retrospectively determined clinical events. For the method comparison studies, the comparison was directly against existing commercial chemistry analyzer systems.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was mentioned. The device is an in vitro diagnostic device, not an imaging AI designed to assist human readers. Its performance is measured directly against established lab methods and its predictive power for clinical outcomes.
6. Standalone Performance Study
Yes, the studies described are primarily standalone (algorithm only without human-in-the-loop performance).
- The "Method Comparison" studies (HDL-C, Triglycerides) directly compare the device's output to that of predicate devices.
- The "Clinical Performance of NMR LipoProfile test for LDL-P Measurement" studies assess the association of the device's LDL-P output with future cardiovascular events directly, not in conjunction with human interpretation.
7. Type of Ground Truth Used
- Analytical Performance (Sensitivity, Precision, Linearity, Interfering Substances): Ground truth was established internally using laboratory standards, dilutions, and spiked samples, often by comparing observed values to target values or calculated expected values.
- Method Comparison (HDL-C, Triglycerides): Ground truth was established by predicate commercial chemistry analyzer systems.
- Clinical Performance (LDL-P): Ground truth for the outcomes (CHD events, CAD, CVD events) was established by outcomes data (clinical events recorded during follow-up in the respective large-scale epidemiological studies: VA-HIT, EPIC-Norfolk, Women's Health Study).
8. Sample Size for the Training Set
The document does not specify a distinct "training set" size. The NMR LipoProfile Test involves "deconvolution of the composite signal at ~0.8 ppm" and relies on an "algorithm resident on the LipoProfile Analysis Server [which] is the foundation of the LipoProfile assay." This suggests that the algorithm was developed and likely trained using a set of data, but details about this training dataset (size, ground truth, etc.) are not provided in this 510(k) summary, as is common for in vitro diagnostic devices where the focus is often on analytical and clinical validation of the final product.
9. How the Ground Truth for the Training Set Was Established
As no specific training set is detailed, the method for establishing its ground truth is not explicitly mentioned. However, based on the technology description (deconvolution of NMR spectra), the "ground truth" for developing the algorithm would likely involve characterized lipoprotein standards and/or meticulously analyzed human samples where lipoprotein subclass concentrations were determined by established gold-standard methods or extensive biochemical profiling. These are typically developed through iterative research and development processes by the manufacturer.
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LIPOSCIENCE
JUL 2 8 2008
2500 Sumner Boulevard Raleigh, NC 27616
Main Number: 919.212.1999 Customer Service: 877.547.6837
510(k) Summary
LipoScience NMR LipoProfile-2 Assay and NMR Profiler Instrument Test System
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
Assigned 510(k) Number: K063841
Submitter's Name, Address, Telephone Number, Contact Person, and Date Prepared
Submitter: LipoScience, Incorporated 2500 Sumner Boulevard Raleigh, NC 27616
919-256-1236 Phone: Facsimile: 919-256-1039
Contact Person: E. Duffy McDonald, SPHR Vice President, Operations LipoScience, Incorporated Phone: 919-256-1236 Facsimile: 919-256-1039
Date Prepared: September 18, 2006 (summary revised July 17, 2008)
Name of Device and Name/Address of Sponsor
Name of Device NMR LipoProfile-2 Assay and NMR Profiler Test System
Sponsor:
LipoScience, Incorporated 2500 Sumner Boulevard Raleigh, NC 27616
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Common or Usual Name
NMR LipoProfile test
Classification Name (s)
Lipoprotein test system (21CFR 862.1475, product codes MRR and LBS) Triglyceride test system (21CFR 862.1705, product code CDT) Quality control material (21 CFR 862.1660, product code JJY) Calibrator (21 CFR 862.1150, JIT)
Predicate Device(s)
| Device Name: | Dimension Automated LDL Cholesterol Flex Reagent |
|---|---|
| Manufacturer: | Dade Behring, Inc. |
| 510(k) Number: | K020724 |
| Device Name: | Triglycerides Reagent |
| Manufacturer: | Carolina Liquid Chemistries |
| 510(k) Number: | K971324 |
| Device Name: | Liquid N-geneous HDL Cholesterol Kit |
| Manufacturer: | Genzyme Corporation |
| 510(k) Number: | K971162 |
Intended Use / Indications for Use
The NMR LipoProfile® -2 test, used with the NMR Profiler, an automated NMR spectrometer, measures lipoprotein particles to quantify LDL particle number (LDL-P), HDL cholesterol (HDL-C), and triglycerides in serum and plasma using nuclear magnetic resonance (NMR) spectroscopy. LDL-P and these NMR-derived concentrations of triglycerides and HDL-C are used in conjunction with other lipid measurements and clinical evaluation to aid in the management of lipoprotein disorders associated with cardiovascular disease. This test is performed and provided as a service by LipoScience Laboratory.
Device Description
Principle of Operation
The NMR LipoProfile Test involves measurement of the 400 MHz proton NMR spectrum of a plasma or serum sample, deconvolution of the composite signal at ~0.8 ppm to produce the signal amplitudes of the lipoprotein subclasses that contribute to the composite plasma signal, and conversion of these subclass signal amplitudes to lipoprotein subclass concentrations. The 0.8 ppm plasma NMR signal arises from the methyl group protons of the lipids carried in the VLDL, and HDL subclasses of varying diameter. The NMR signals from the various lipoprotein subclasses have unique and distinctive frequencies and lineshapes, each of which are accounted for in the deconvolution analysis model. Each subclass signal amplitude is proportional to the number of subclass particles emitting the signal, which enables subclass particle
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concentrations to be calculated from the subclass signal amplitudes derived from the spectral deconvolution analysis. LDL subclass particle concentrations, in units of nanomoles of particles per liter (nmol/L), are summed to give the reported total LDL particle concentration (LDL-P). By employing conversion factors that assume that the various lipoprotein subclass particles have cholesterol and triglyceride contents characteristic of normolipidemic individuals, HDL cholesterol and triglyceride concentrations are also derived.
Types of Specimen
Freshly drawn serum collected in an NMR LipoTube is the preferred specimen. Freshly drawn serum collected in plain red-top blood collection tubes and EDTA or heparin plasma are also acceptable specimens. The optimum volume is ≥0.5 mL. Patient fasting is not necessary prior to the blood draw, except for determination of fasting triglyceride concentrations.
Testing Procedure
Each patient specimen is diluted 2-fold using the NMR Diluent, mixed thoroughly, and placed in separate specimen vials in predefined locations of the bar-coded measurement racks. Automated testing is then initiated according to the operating instructions.
Result Calculation
The NMR Profiler test system performs all calculations necessary to produce the final reported results. These calculations include the linear least squares spectral deconvolution analysis which gives the NMR signal amplitudes of each lipoprotein subclass, the conversion of these signal amplitudes to subclass particle concentrations and calculated subclass cholesterol and triglyceride concentrations, and summation of the appropriate subclass concentrations to give the reported values of LDL-P. HDL-C. and triglycerides.
Software and Hardware
The NMR Profiler test system contains a Rack Reader, a Nuclear Magnetic Resonance (NMR) system, and a LipoProfile Analysis Server. These three core systems manage information through databases and file systems. The algorithm resident on the LipoProfile Analysis Server is the foundation of the LipoProfile assay. The NMR system and Rack reader are configured off-the-shelf components. The remaining software serves to transmit data, store data, and report the results of the LipoProfile analysis. The LipoProfiler System may be configured as a stand alone system or integrated into a Laboratory Information System (LIS).
Technological Characteristics and Substantial Equivalence
The NMR LipoProfile test, when used with the NMR Profiler, is as safe and effective as the Dade Dimension Automated LDL Cholesterol Flex Reagent, Carolina Liquid Chemistries Triglycerides Reagent, and Genzyme Liquid N-geneous HDL Cholesterol
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test. The NMR LipoProfile test has the same intended uses and similar indications and principles of operation as its predicate devices. The minor technological differences between the NMR LipoProfile test and its predicate devices raise no new issues of safety or effectiveness. Performance data further demonstrate that the NMR LipoProfile test is as safe and effective as its predicate devices. Thus, the NMR LipoProfile test is substantially equivalent.
Similarity to Predicates
As with the predicate assays, the NMR LipoProfile test is intended for the separation and quantitation of LDL, HDL, and triglycerides in serum and plasma, measurements of which are used in conjunction with other lipid measurements and clinical evaluation to aid in the management of lipoprotein disorders associated with cardiovascular disease.
Therefore, substantial equivalence of the NMR LipoProfile Test to the claimed predicate devices is based upon the following:
- substantially similar intended use and indications for use, .
- use of the same clinical specimen (serum and plasma)
- substantial similar safety and effectiveness; i.e.; no new questions of safety � and effectiveness are raised when the tests are used as intended
Differences from Predicate
The NMR LipoProfile Test differs from its predicates in three ways, related to the primary technological characteristic difference of the NMR LipoProfile Test, which uses nuclear magnetic resonance (NMR) spectroscopy as compared to chemistry-based spectrophotometric detection.
- NMR uses a different energy source magnetic resonance versus . photometric,
- . NMR directly measures lipoprotein particles - direct measure of particle number concentration versus chemistry-based lipid assay, and
- NMR does not require chemical or enzymatic reactions to measure lipoprotein . concentrations.
Therefore, fundamentally the NMR LipoProfile Test and predicates are intended to measure substantially similar information by way of different methods, by evaluating the quality and quantity of lipoproteins in biological specimens using proprietary algorithms. physical measurements, and calculations. Although the NMR LipoProfile Test differs in technological characteristics, the performance of this assays has been shown to be equivalent through the testing of clinical specimens. For LDL-P, substantial equivalence and clinical utility was demonstrated in the target population utilizing appropriate clinical outcome measures and for the measurement of triglycerides and HDL-C, comparing the NMR test results to standard chemical methods for TRIG and HDL-C determination.
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Performance Data - Non-Clinical
Analytical Sensitivity
The analytical sensitivity of the NMR LipoProfile test measurements of LDL-P. HDL-C. and triglycerides was determined as the lowest concentration measurable with acceptable precision and accuracy. Serum specimens with low initial concentrations LDL-P, HDL-C, and triglycerides were serially diluted and 20 replicates of each were analyzed. CVs and % bias between observed and target values were determined and acceptance criteria are based on total error ≤20%. Limits of quantification (LOQ) are 300 nmol/L for LDL-P, 10 mg/dL for HDL-C, and 25 mg/dL for triglycerides.
Assay Precision
Intra-assay and inter-assay variability were determined by testing 20 replicates of two patient serum pools in the same run (intra-assay) and in 20 different runs over 4 days (inter-assay). The results of this testing are summarized below:
| Intra-assay Precision | Inter-assay Precision | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pool 1 | Pool 2 | Pool 1 | Pool 2 | |||||||||
| Mean | SD | % CV | Mean | SD | % CV | Mean | SD | % CV | Mean | SD | % CV | |
| LDL-P (nmol/L) | 2222 | 49.1 | 2.2 | 1042 | 47.7 | 4.6 | 1925 | 66.7 | 3.5 | 1053 | 68.4 | 6.5 |
| HDL-C (mg/dL) | 41 | 0.54 | 1.3 | 57 | 0.42 | 0.7 | 42 | 1.17 | 2.8 | 56 | 0.83 | 1.5 |
| Trig (mg/dL) | 189 | 2.0 | 1.1 | 75 | 1.2 | 1.5 | 219 | 2.9 | 1.3 | 80 | 1.7 | 2.1 |
Linearity
Two serum pools were prepared from patient specimens with high or low values of LDL-P, HDL-C, and triglycerides as determined by NMR LipoProfile analysis. Each were mixed and diluted in different proportions to produce 12 different samples with widely varying target concentrations. Mean values from analysis of 6 replicates were compared to the expected target values to determine the percent bias for each sample. Linear ranges were determined as follows:
| LDL-P | 300-6000 nmol/L |
|---|---|
| HDL-C | 7-160 mg/dL |
| Triglycerides | 5-2700 mg/dL |
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Reportable Range
The following are the reportable ranges for LDL-P, HDL-C and triglycerides.
| LDL-P | 300 - 3500 nmol/L |
|---|---|
| HDL-C | 7 - 140 mg/dL |
| Triglycerides | 5 - 1100 mg/dL |
Interfering Substances
Endogenous substances normally found in blood and exogenous substances (common and prescription drugs) were evaluated for potential interference with the NMR LipoProfile test. Six plasma pools with LDL-P, HDL-C, and triglyceride values spanning the clinically-relevant range were spiked with potential interferents. No appreciable interference was produced by the substances at the spiked levels tested, which were representative of the highest blood concentrations expected for the highest therapeutic doses of these compounds.
| Potential Interferent | Test Concentration |
|---|---|
| Endogenous | |
| Bilirubin | 20 mg/dL |
| Creatinine | 20 mg/dL |
| Hemoglobin | 500 mg/dL |
| Urea | 300 mg/dL |
| Uric acid | 40 mg/dL |
| Exogenous | |
| Acetaminophen | 1050 µmol/L |
| Aspirin | 880 µmol/L |
| Clopidogrel | 28 µmol/L |
| Enalapril | 13 µmol/L |
| Fenofibrate | 70 µmol/L |
| Furosemide | 38 µmol/L |
| Glipizide | 7 µmol/L |
| Hydralazine | 60 µmol/L |
| Hydrochlorothiazide | 27 µmol/L |
| Ibuprofen | 550 µmol/L |
| Isosorbide dinitrate | 80 µmol/L |
| Metformin | 960 µmol/L |
| Metoprolol | 23 µmol/L |
| Naproxen | 470 µmol/L |
| Niacin | 2200 µmol/L |
| Nifedipine | 37 µmol/L |
| Piroxicam | 10 µmol/L |
| Simvastatin | 30 µmol/L |
| Thiazolidinedione | 61 µmol/L |
| Triamterene | 31 µmol/L |
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Performance Data - Clinical
Method Comparison - HDL Cholesterol
Method comparison was evaluated by split-sample comparison of HDL-C values measured by the NMR LipoProfile test with those analyzed on a commercially available chemistry analyzer system. The data below summarize the results of analyses performed on 5,362 plasma samples from individuals who were part of the Multi-Ethnic Study of Atherosclerosis (MESA). HDL-C concentrations ranged from 15 to approximately 140 mg/dL and the mean values observed for the predicate and the NMR LipoProfile test were 51.3 and 50.7 mg/dL, respectively.
Image /page/6/Figure/3 description: This image is a scatter plot that compares NMR LipoProfile HDL-C to Predicate HDL-C, both measured in mg/dL. The x-axis represents Predicate HDL-C, ranging from 0 to 160 mg/dL, while the y-axis represents NMR LipoProfile HDL-C, also ranging from 0 to 160 mg/dL. A diagonal line runs through the plot, and the data points are clustered closely around this line. The R-squared value, indicating the goodness of fit, is given as 0.897.
Method Comparison - Triglycerides
Method comparison was evaluated by split-sample comparison of triglyceride values measured by the NMR LipoProfile test with those analyzed on a commercially available chemistry analyzer system. The data below summarize the results of analyses performed on 5,362 plasma samples from individuals who were part of the Multi-Ethnic Study of Atherosclerosis (MESA). Triglyceride concentrations ranged from 21 to 400 mg/dL and the mean values observed for the predicate and the NMR LipoProfile test were 123.9 and 128.7 mg/dL, respectively ..
Image /page/6/Figure/6 description: This image is a scatter plot that compares NMR LipoProfile Triglycerides to Predicate Triglycerides, both measured in mg/dL. The data points are clustered tightly around a diagonal line, indicating a strong positive correlation between the two variables. The R-squared value is 0.929, which suggests that the model explains 92.9% of the variance in the data. The x and y axis range from 0 to 500 mg/dL.
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Clinical performance of NMR LipoProfile test for LDL-P Measurement
Three external clinical outcome studies were conducted to evaluate the clinical performance of the NMR Lipoprofile measurement of LDL-P. The studies estimated the prediction of future (incident) cardiovascular disease (CVD) events by previously measured values of LDL-P. Results of all three studies indicated that LDL-P was statistically significantly related to CVD risk
Veterans Affairs HDL Intervention Trial (VA-HIT)
A prospective, nested case-control study was conducted using 1061 plasma samples collected from male patients enrolled in the randomized placebocontrolled Veterans Affairs HDL Intervention Trial (VA-HIT), a secondary prevention trial examining the efficacy of gemfibrozil for prevention of new CHD events among men with known CHD and low levels of both HDL and LDL cholesterol. Fasting EDTA plasma samples were collected at baseline and after 7 months from 2,531 men. Case subjects (n=364) were men who experienced a CHD event (cardiac death or nonfatal myocardial infarction) during the mean 5,1 year follow-up period. Control subjects (n=697) were men matched for age who remained free of CHD events during follow-up.
Table 1 shows the odds ratios (OR) for a new CHD event associated with a 1- SD increment of LDL-P in the subjects treated with placebo (n=546). Baseline levels of LDL-P were statistically significantly associated with incident CHD events (odds ratio 1.31 (95% CI, 1.09-1.57, p=0.004), while on-trial LDL-P values had a somewhat weaker association .
| Baseline | On-Trial | |
|---|---|---|
| LDL-P | ||
| Odds Ratio (95% CI) | 1.31 (1.09-1.57) | 1.19 (0.99-1.43) |
| p value | 0.004 | 0.054 |
Table 1: Prediction of CHD Events by LDL-P in the Placebo Group
EPIC -Norfolk study
A nested case-control study was performed in the prospective EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study, which was carried out between 1993 and 1997 to investigate dietary and other determinants of cancer. Additional data were obtained to enable the assessment of determinants of other diseases, including coronary artery disease (CAD). The study population comprised 25,663 men and women inhabitants of Norfolk, United Kingdom, aged 45 to 79 years, who completed a baseline questionnaire survey and attended a clinic visit. At this baseline visit, non-fasting serum samples were obtained from participants and stored at -80℃ before NMR LipoProfile testing. Participants were followed for six years for the development of CAD, defined as CAD death, myocardial infarction, and angina. Samples
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tested (n=2,888; 36% women; average age 65 years) were from cases (n=1,003) who developed CAD during the 6-year follow-up period and controls (n=1,885) who did not develop CAD, matched for age, gender, and enrollment time. None of the cases or controls were taking any lipid altering medications.
LDL-P values measured in this study spanned the range of 485-4156 nmol/L. Conditional logistic regression was used to calculate odds ratios for future (incident) CAD, adjusted for smoking and blood pressure plus matching for age, gender, and enrollment time. Table 2 shows the odds ratios for development of CAD by increasing quartiles of LDL-P. LDL-P was statistically significantly associated with an incident CAD events in both univariable analyses and multivariable analyses adjusted for HDL-C and triglycerides.
| Quartiles | |||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | p§ | |
| Range (nmol/L) | <1278 | 1278-1525 | 1526-1812 | >1812 | |
| UnivariableOdds Ratio (95% CI) | 1.00 | 1.23(0.97-1.56) | 1.48(1.17-1.87) | 2.00(1.58-2.59) | <0.0001 |
| MultivariableOdds Ratio (95% CI) | 1.00 | 1.13(0.89-1.44) | 1.21(0.94-1.54) | 1.37(1.04-1.83) | 0.02 |
Table 2: Association of Incident Coronary Artery Disease Events by Quartile of LDL-P
Women's Health Study
A study was conducted using 27,673 baseline nonfasting EDTA plasma samples from participants enrolled in the Women's Health Study, a randomized, double blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease (CVD) and cancer in women. Participants were apparently healthy female health care professionals, ages 45 years and older, who were free of self-reported CVD and cancer at study entry and were followed for incident CVD over a mean of 11 years. The CVD endpoint was a composite of nonfatal myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, nonfatal ischemic stroke, and cardiovascular death. 1,015 CVD events occurred during the follow-up period (Mean ± SD = 11 ± 1.6 years; range 0.003 to 12.8 years).
LDL-P values measured in this study spanned the range of 276-4590 nmol/L. Cox proportional hazard regression models were used to examine the association of LDL-P by quintile with incident CVD events. The Cox models were adjusted for age, randomized treatment assignment (to aspirin, vitamin E or placebo), smoking status, menopausal status, postmenopausal hormone use, blood pressure, diabetes, and body mass index. The results, shown in Table 3, indicate that baseline concentrations of LDL-P were statistically significantly associated with incident CVD events (p<0.001).
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| Quintiles | ||||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | p § | |
| Range(nmol/L) | <963 | 963-1165 | 1166-1387 | 1388-1703 | >1703 | |
| HR(95% CI) | 1.00 | 1.37(1.01-1.85) | 1.35(1.01-1.81) | 1.80(1.36-2.38) | 2.51(1.91-3.30) | <0.001 |
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Association with Incident Cardiovascular Disease Events by Table 3: Quintile of LDL-P
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Image /page/10/Picture/1 description: The image shows the seal of the Department of Health & Human Services (HHS) of the United States. The seal features a stylized eagle with its head turned to the left, and its wings forming three abstract shapes. Encircling the eagle is the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" in a circular arrangement.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
JUL 2 3 2008
Liposcience Inc. c/o Mr. E. Duffy McDonald Vice President Operations, Liposcience 2500 Sumner Blvd., Raleigh, NC 27616
Re: K063841
Trade/Device Name: NMR Profiler and NMR LipoProfile® Test Regulation Number: 21 CFR 862.1475 Regulation Name: Lipoprotein Test System Regulatory Class: Class I, subject to limitation of excmption in 21 CFR 862.9(c)(4) Product Code: MRR, JJY, CDT, LBS, JIT Dated: April 23, 2008 Received: April 24, 2008
Dear Mr. McDonald:
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.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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This letter will allow you to begin marketing your device as described in your Section 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 information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Jean M. Cooper, M.S., D.V.M.
Yean M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indication for Use
510(k) Number (if known): K063841
Device Name: NMR Profiler and NMR LipoProfile® Test
Indication For Use:
The NMR LipoProfile®-2 test, used with the NMR Profiler, an automated NMR spectrometer, measures lipoprotein particles to quantify LDL particle number (LDL-P), HDL cholesterol (HDL-C), and triglycerides in serum and plasma using nuclear magnetic resonance (NMR) spectroscopy. LDL-P and these NMR-derived concentrations of triglycerides and HDL-C are used in conjunction with other lipid measurements and clinical evaluation to aid in the management of lipoprotein disorders associated with cardiovascular disease. The test is performed and provided as a service by Liposcience Laboratory.
Prescription Use / (21 CFR Part 801 Subpart D)
And/Or
Over the Counter Use (21 CFR Part 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OVD)
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K063811
§ 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.