(84 days)
HiChem Glucose/HK Reagent (product no. 70007) is for the quantitative determination of glucose in serum, plasma, cerebrospinal fluid and urine.
The HiChem Glucose/HK Reagent determines glucose by enzymatic phosphorylation using ATP in the presence of hexokinase. The extent of this reaction, and the quantity of glucose in the specimen, is determined through the measurement of the resulting glucose-o-phosphate by producing NADH in the presence of glucose-o-phosphate dehydrogenase. The reagent is supplied as two liquid-stable components which are combined, either before or during use, in the approximate ratio of 1 part Glucose Enzyme Reagent and 8 parts Glucose Reagent Buffer. The Glucose Enzyme Reagent can also be used as a start reagent and combined with the Reagent Buffer following sample addition.
Here's an analysis of the provided text regarding the HiChem Glucose/HK Reagent, focusing on acceptance criteria and supporting studies.
Based on the provided document, the device is a reagent for quantitative determination of glucose. The "acceptance criteria" can be inferred from the performance characteristics presented for both manual and automated methods, as the goal is to demonstrate substantial equivalence to predicate devices. The study is a series of laboratory experiments designed to characterize the reagent's performance.
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" as a distinct set of pass/fail thresholds. Instead, it presents performance characteristics (linearity, precision, and correlation with predicate devices) which are implicitly the metrics by which its performance is deemed acceptable and substantially equivalent to existing devices.
Inferred Acceptance Criteria & Reported Device Performance
| Performance Characteristic | Inferred Acceptance Standard (Qualitative / Implied) | Reported HiChem Glucose/HK Reagent Performance (Manual Method) | Reported HiChem Glucose/HK Reagent Performance (Automated Method on Hitachi 704) |
|---|---|---|---|
| Linearity | Should be linear over clinically relevant range and comparable to predicate. | Linear to at least 500 mg/dL: (HiChem Results) = 2.1 mg/dL + 0.9769 x (Standard Value), r = 0.9999, Sy.x = 2.6 mg/dL. | Linear to at least 1000 mg/dL: (HiChem Results) = 1.4 mg/dL + 0.986 × (Standard Value), r = 1.0000, Sy.x = 2.7 mg/dL. |
| Precision | Acceptable within-run and total SD for various glucose levels in different specimen types. (Comparison to predicate implied) | See Table below for detailed values. | See Table below for detailed values. |
| Method Comparison (Serum/Plasma) | Strong correlation (high r-value, low Sy.x) and minimal bias with predicate (Boehringer Mannheim Corp. (BMD) Glucose/HK Reagent or Sigma Glucose (HK) Reagent). | Vs. Sigma: (HiChem Results) = 0.2 mg/dL + 1.013 x (Sigma Results), r = 0.999, Sy.x = 2.3 mg/dL. | Vs. BMD: (HiChem Results) = -1.1 mg/dL + 1.004 × (BMD Results), r = 0.999, sy.x = 1.61 mg/dL. |
| Method Comparison (Urine) | Strong correlation (high r-value, low Sy.x) and minimal bias with predicate (BMD Glucose/HK Reagent). | Vs. BMD: (HiChem Results) = 4.1 mg/dL + 0.944 x (BMD Results), r = 0.998, Sy.x = 5.58 mg/dL. | Vs. BMD: (HiChem Results) = -1.4 mg/dL + 0.989 × (BMD Results), r = 0.999, sy.x = 3.3 mg/dL. |
| Method Comparison (CSF) | Strong correlation (high r-value, low Sy.x) and minimal bias with predicate (BMD Glucose/HK Reagent). | Vs. BMD: (HiChem Results) = 1.9 mg/dL + 0.972 x (BMD Results), r = 0.997, Sy.x = 1.8 mg/dL. | Vs. BMD: (HiChem Results) = 0.1 mg/dL + 0.978 × (BMD Results), r = 0.999, sy.x = 1.1 mg/dL. |
| Interfering Substances | Biases due to common additives (heparin, EDTA, fluoride, oxalate, iodoacetate) should be minimal. | Biases observed were less than 2 mg/dL. | (Not explicitly stated for automated method, implied similar) |
| Reagent Stability | Reagent performance should remain stable over claimed storage periods (combined working reagent). | Observed shifts in standard recovery were less than 1.8% over 3 months at 2-8℃ and 10 days at 18-25℃. | (Not explicitly stated for automated method specific reagent stability, but overall performance shown to be stable). |
| Calibration Stability | Calibration should remain stable over claimed period. | (Not explicitly stated for manual method) | Observed shifts in recoveries over 47 days without calibration were less than the greater of 2 mg/dL or 2%. |
Detailed Precision Tables:
Manual Method Precision:
| Specimen | n | mean | within run SD | total SD |
|---|---|---|---|---|
| Low serum control | 30 | 95.6 mg/dL | 0.89 mg/dL | 2.77 mg/dL |
| High serum control | 30 | 296.1 mg/dL | 2.78 mg/dL | 4.41 mg/dL |
| Low urine pool | 30 | 18.7 mg/dL | 0.75 mg/dL | 1.50 mg/dL |
| High urine pool | 30 | 274.2 mg/dL | 2.10 mg/dL | 6.95 mg/dL |
| Low CSF control | 30 | 59.8 mg/dL | 0.78 mg/dL | 2.9 mg/dL |
| High CSF control | 30 | 41.9 mg/dL | 1.11 mg/dL | 2.8 mg/dL |
Automated Method Precision (Hitachi 704):
| Specimen | n | mean | within run SD | total SD |
|---|---|---|---|---|
| Low serum control | 60 | 86.5 mg/dL | 0.68 mg/dL | 1.07 mg/dL |
| Mid. serum control | 60 | 294.0 mg/dL | 1.18 mg/dL | 2.09 mg/dL |
| High serum control | 60 | 577.5 mg/dL | 2.18 mg/dL | 5.39 mg/dL |
| Low urine pool | 60 | 23.5 mg/dL | 0.67 mg/dL | 0.77 mg/dL |
| High urine pool | 60 | 669.5 mg/dL | 2.41 mg/dL | 4.88 mg/dL |
| Low CSF control | 58 | 33.6 mg/dL | 1.02 mg/dL | 1.13 mg/dL |
| High CSF control | 59 | 57.2 mg/dL | 0.78 mg/dL | 1.26 mg/dL |
2. Sample Sizes Used for the Test Set and Data Provenance
The document describes several test sets for different aspects of performance:
- Linearity (Manual & Automated): "Linearity standards" were used. The exact number of points or replicates per point for these standards is not specified.
- Precision (Manual):
- Low serum control: n = 30 replicates
- High serum control: n = 30 replicates
- Low urine pool: n = 30 replicates
- High urine pool: n = 30 replicates
- Low CSF control: n = 30 replicates
- High CSF control: n = 30 replicates
- Precision (Automated):
- Low serum control: n = 60 replicates
- Mid. serum control: n = 60 replicates
- High serum control: n = 60 replicates
- Low urine pool: n = 60 replicates
- High urine pool: n = 60 replicates
- Low CSF control: n = 58 replicates
- High CSF control: n = 59 replicates
- Method Comparison (Manual):
- Serum and plasma: 80 mixed specimens
- Spiked urine specimens: 36 specimens
- CSF specimens: 37 specimens
- Method Comparison (Automated):
- Mixed serum and plasma specimens: 105 specimens
- Spiked urine specimens: 56 specimens
- CSF specimens: 40 specimens
- Interfering Substances: "Spiked and unspiked serum pools" were used. The number of pools or replicates is not specified.
- Reagent Stability: "Serum controls and linearity standards" were used. The number of samples/measurements is not specified.
- Calibration Stability: "Serum controls" were used. The number of samples/measurements is not specified.
Data Provenance: The document does not specify the country of origin of the data. Given the context of a 510(k) submission in the US, it is likely the studies were conducted in the US, but this is not explicitly stated. The data is retrospective in the sense that existing samples (control sera, urine pools, patient specimens) were likely used in a laboratory study, rather than being collected prospectively for the sole purpose of this study.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
This document describes a diagnostic reagent for quantitative measurement of glucose, not an imaging or diagnostic device that requires expert interpretation. Therefore, the concept of "experts used to establish the ground truth" in the sense of physicians or radiologists making diagnoses is not directly applicable.
Instead, the "ground truth" for this type of device is established by:
- Known concentrations: For linearity and control materials.
- Reference methods/predicate devices: The comparative methods used to determine equivalence (Sigma Glucose (HK) Reagent and BMD Glucose/HK Reagent) serve as the "ground truth" or reference for patient sample comparisons. These predicate devices are established diagnostic tools, and their results are accepted as clinically valid.
Qualifications: The qualifications of the personnel performing the laboratory tests (e.g., medical technologists, clinical chemists) would be relevant but are not detailed in this summary.
4. Adjudication Method for the Test Set
Adjudication methods (e.g., 2+1, 3+1) are typically used for studies involving human interpretation where discrepancies need to be resolved (e.g., in radiology studies). This is a laboratory reagent study for quantitative measurement. Therefore, an adjudication method for a "test set" in the traditional sense is not applicable. The data are numerical measurements; disagreements would typically be resolved through repeat testing, calibration verification, or troubleshooting laboratory procedures.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done.
MRMC studies are relevant for diagnostic devices that involve human interpretation (e.g., radiologists reading images). This device is a reagent for automated/manual biochemical measurement. There are no human "readers" involved in interpreting the output of this reagent in the way an MRMC study would assess. The comparison is between the new reagent's numerical output and that of established predicate reagents.
6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done
The performance presented is essentially standalone in the sense that it evaluates the reagent's analytical performance on its own, either manually or when integrated with an automated analyzer (Hitachi 704). There is no "human-in-the-loop performance" in the traditional sense of a human interpreting the device's output to make a diagnosis and then comparing that to the device acting alone. The device provides the measurement, and a human uses that measurement in a clinical context. The performance data is the "algorithm only" (reagent only) performance regarding its ability to accurately measure glucose.
7. The Type of Ground Truth Used
The ground truth used for this device can be categorized as:
- Reference Standards/Known Concentrations: For linearity assessments, precision studies (using control materials with established concentration ranges), and stability studies.
- Predicate Device/Reference Method: For method comparison studies, the results obtained from the established predicate devices (Sigma Glucose (HK) Reagent and BMD Glucose/HK Reagent) are used as the reference values against which the HiChem Glucose/HK Reagent's performance is compared. This is a common and accepted method for demonstrating substantial equivalence for in vitro diagnostic devices.
8. The Sample Size for the Training Set
This document does not specify a "training set." This is typical for a traditional analytical performance study of an in vitro diagnostic reagent. "Training sets" are most commonly associated with machine learning or AI models, where data is used to train an algorithm. For a biochemical reagent, its performance characteristics (linearity, precision, accuracy) are inherent to its chemical formulation and reaction principles, not derived from a data-driven training process. The studies described are validation studies, not training studies.
9. How the Ground Truth for the Training Set Was Established
As there is no "training set" in the context of an AI/ML algorithm, this question is not applicable. The 'truth' for the development of reagent performance would come from the biochemical principles of the hexokinase method itself and iterative optimization of the reagent formulation, which is not detailed in this summary.
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SUMMARY OF 510(K) SAFETY AND EFFECTIVENESS INFORMATION
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.
HiChem Glucose/HK Reagent (product no. 70007) is for the quantitative determination of glucose in serum, plasma, cerebrospinal fluid and urine. The most common causes of abnormal glucose levels are diabetes, liver disease, and certain endocrine disorders.
The HiChem Glucose/HK Reagent determines glucose by enzymatic phosphorylation using ATP in the presence of hexokinase. The extent of this reaction, and the quantity of glucose in the specimen, is determined through the measurement of the resulting glucose-o-phosphate by producing NADH in the presence of glucose-o-phosphate dehydrogenase.
The HiChem Glucose Reagent is intended to be used either as a manual procedure or on clinical analyzers which ean automate the required manipulations. The reagent is supplied as two liquid-stable components which are combined, either before or during use, in the approximate ratio of 1 part Glucose Enzyme Reagent and 8 parts Glucose Reagent Buffer. The Glucose Enzyme Reagent can also be used as a start reagent and combined with the Reagent Buffer following sample addition.
The HiChem Glucose/HK Reagent calibrated with the HiChem Chemistry Standard, product 70023 is substantially equivalent to the BMD Glucose/HK Reagent, product no. 704035 calibrator Serum and Diluent, product no. 620213, both manufactured by Boehringer Mannheim Corp., Indianapolis, IN. and the Sigma Glucose (HK) Reagent, procedure no. 16-UV calibrated with Glucose/Urea Nitrogen Standard, product no. 16-300, both manufactured by Sigma Diagnostics, St. Louis, MO. Substantial equivalence between the HiChem and the other calibrators for the purpose of calibrating uca nitrogen methods is also shown. All three reagent/calibrator pairs support the same intended use (with the exception of the specimen limitations for the Sigma reagent) and produce equivalent results with the same clinical purpose. In addition, they are all based on the same methodology which determines glucose through the measurement of NADH production. Finally, all reagents are sold in a generic format with their use on various instruments supported through procedure supplements (application sheets).
The effectiveness of the manual procedure is shown by the recovery of linearity standards, the precision of control recoveries, a comparison of servin and plasma recoveries to the Sigma Glucose (HK) Reagent, a comparison of urine and CSF recoveries to the BMD Glucose/HK Reagent and validation of the chemical additive and reconstituted stability claims.
The recovery of glucose using HiChem Glucose/HK Reagent as a manual method is linear to at least 500 mg/dL as shown by the recovery of linearity standards which span the claimed linear range. Regression statistics are shown below.
(HiChem Results) = 2.1 mg/dL + 0.9769 x (Standard Value), r = 0.9999, Sy.x = 2.6 mg/dL.
Precision, demonstrated by replicate assay of commercially available control sera and urine pools, is shown below.
| Specimen | n | mean | within run SD | total SD |
|---|---|---|---|---|
| Low serum control | 30 | 95.6 mg/dL | 0.89 mg/dL | 2.77 mg/dL |
| High serum control | 30 | 296.1 mg/dL | 2.78 mg/dL | 4.41 mg/dL |
| Low urine pool | 30 | 18.7 mg/dL | 0.75 mg/dL | 1.50 mg/dL |
| High urine pool | 30 | 274.2 mg/dL | 2.10 mg/dL | 6.95 mg/dL |
| Low CSF control | 30 | 59.8 mg/dL | 0.78 mg/dL | 2.9 mg/dL |
| High CSF control | 30 | 41.9 mg/dL | 1.11 mg/dL | 2.8 mg/dL |
Glucose recoveries of 80 mixed serum and plasma specimens are compared between the HiChem and Sigma reagents. Glucose recoveries of 36 spiked urine specimens and 37 CSF specimens are compared between the
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HiChem Glucose/HK Reagent and the BMD Glucose/HK Reagent used on the Hitachi 704. All reagents were calibrated with their recommended calibrators. Least squares regression statistics are shown below.
| Serum/Plasma Comparison(HiChem Results) = 0.2 mg/dL + 1.013 x (Sigma Results) | r = 0.999, | Sy.x = 2.3 mg/dL. |
|---|---|---|
| Urine Comparison(HiChem Results) = 4.1 mg/dL + 0.944 x (BMD Results) | r = 0.998, | Sy.x = 5.58 mg/dL. |
| CSF Comparison(HiChem Results) = 1.9 mg/dL + 0.972 x (BMD Results) | r = 0.997, | Sy.x = 1.8 mg/dL. |
The use of heparin, EDTA, fluoride, oxalate and iodoacetate are shown to be acceptable chemical additives by comparison of spiked and unspiked serum pools. In all cases, the biases observed were less than 2 mg/dL.
The stability of the combined working reagent over 3 months at 2-8℃ and 10 days at 18-25℃ are documented through the recovery of serum controls and linearity standards which span the claimed linear range of the method. In all cases, the observed shifts in standard recovery were less than 1.8%.
The effectiveness of the automated Hitachi 704 procedure is shown by the recovery of linearity standards, the precision of control recoveries, comparison of patient specimen recoveries to the BMD Glucose/HK Reagent and the recovery of serum controls over the claimed calibration stability period.
The recovery of glucose using HiChem Glucose/HK Reagent as an automated method is linear to at least 1000 mg/dL as shown by the recovery of linearity standards which span the claimed linear range. Regression statistics are shown below.
Sy.x = 2.7 mg/dL. (HiChem Results) = 1.4 mg/dL + 0.986 × (Standard Value), r = 1.0000,
Precision, demonstrated by replicate assay of commercially available control sera and urine pools, is shown below.
| Specimen | n | mean | within run SD | total SD |
|---|---|---|---|---|
| Low serum control | 60 | 86.5 mg/dL | 0.68 mg/dL | 1.07 mg/dL |
| Mid. serum control | 60 | 294.0 mg/dL | 1.18 mg/dL | 2.09 mg/dL |
| High serum control | 60 | 577.5 mg/dL | 2.18 mg/dL | 5.39 mg/dL |
| Low urine pool | 60 | 23.5 mg/dL | 0.67 mg/dL | 0.77 mg/dL |
| High urine pool | 60 | 669.5 mg/dL | 2.41 mg/dL | 4.88 mg/dL |
| Low CSF control | 58 | 33.6 mg/dL | 1.02 mg/dL | 1.13 mg/dL |
| High CSF control | 59 | 57.2 mg/dL | 0.78 mg/dL | 1.26 mg/dL |
Glucose recoveries of 105 mixed serum and plasma specimens, 56 spiked urine specimens and 40 CSF specimens, compared between the HiChem and BMD reagents using least squares regression, yield the following statistics.
| Serum/Plasma Comparison(HiChem Results) = -1.1 mg/dL + 1.004 × (BMD Results) | r = 0.999, | sy.x = 1.61 mg/dL |
|---|---|---|
| Urine Comparison(HiChem Results) = -1.4 mg/dL + 0.989 × (BMD Results) | r = 0.999, | sy.x = 3.3 mg/dL. |
| CSF Comparison(HiChem Results) = 0.1 mg/dL + 0.978 × (BMD Results) | r = 0.999, | sy.x = 1.1 mg/dL. |
The calibration stability claim of one month is documented through the recovery of serum controls which span from 43 to 570 mg/dL glucose. In all cases, the observed shifts in recoveries over 47 days without callbration are less than the greater of 2 mg/dL or 2%.
The HiChem Glucose/HK Reagent, calibrated with the HiChem Chemistry Standard, is shown to be safe and effective and substantially equivalent to the Sigma Glucose (FK) Reagent, procedure no. 16-UV, callingted with Sigma Glucose/Urea Nitrogen Standard, product no. 16-300 and the BMD Glucose/HK Reagent, product for. 857429, calibrated with Precical Calibrator Serum and Diluent, product no. 620213.
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Wynn Stocking Regulatory Affairs Manager
§ 862.1345 Glucose test system.
(a)
Identification. A glucose test system is a device intended to measure glucose quantitatively in blood and other body fluids. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.(b)
Classification. Class II (special controls). The device, when it is solely intended for use as a drink to test glucose tolerance, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.