(79 days)
The Nichols Advantage Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay (or simply: Nichols Advantage® H-hCG Assay) is intended for use with the Nichols Advantage® Specialty System for the quantitative measurement of hyperglycosylated human chorionic gonadotropin (H-hCG), a placental hormone in human serum, or for the qualitative determination of H-hCG in urine as an aid in the detection of pregnancy. These diagnoses should be made with appropriate additional clinical evidence. Clinical considerations and professional judgment should be applied to any test device result as with this Nichols H-hCG chemiluminescent immunoassay.
The Nichols Advantage® H-hCG Assay is used in conjunction with two H-hCG calibrators which are used to calibrate the assay and are provided separately to the reagent cartridge. The control is used for the monitoring of the accuracy and precision of the Nichols Advantage H-hCG Assay and successful calibration is confirmed using three H-hCG controls also provided separately to the calibrators and reagent cartridge.
The Nichols Advantage Hyperglycosylated Human Chorionic Gonadotropin Assay (i.e., Nichols Advantage® H-hCG Assay) is a two-step, two-site immunochemiluminometric assay for use with the Nichols Advantage® Specialty System, for the measurement of H-hCG as an aid in the detection of pregnancy. This new Nichols Advantage® H-hCG Assay Jas with the predicate of the Diagnostic Products Corporation (= DPC) termed: the DPC IMMULITE® hCG Immunoassay (K990222; cleared 2/26/99)] is a two-step, two-site immunochemiluminometric assay for use with the Nichols Advantage® Specialty System.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided 510(k) summary:
Acceptance Criteria and Device Performance for Nichols Advantage® H-hCG Assay
1. Table of Acceptance Criteria and the Reported Device Performance
| Feature / Metric | Acceptance Criteria (Target) | Reported Device Performance (Nichols Advantage H-hCG Assay) |
|---|---|---|
| Precision/Reproducibility | ||
| Total (Average CV) | No more than 2% higher than the predicate IMMULITE 2000 hCG Assay (Predicate was up to 7.22% C.V.) | 6.7% C.V. (This meets the implicit criteria as 6.7% is less than 7.22%) |
| Within-Run (CV) | Not greater than 5% at a dose > 10 ng/mL Serum | Not greater than 5% at a dose > 10 ng/mL Serum |
| Total (CV) (at >10 ng/mL Serum) | Not greater than 10% at a dose > 10 ng/mL Serum | Not greater than 10% |
| Linearity/Reportable Range | Linear regression correlation for critical values with predicate (r > 0.9, P < 0.05) | r = 0.935, P < 0.001 for values ranging from 0.2 to 27 ng/mL (NID) vs. ~4 to ~760 mIU/mL (DPC). Y(DPC's) = + 28.32X(NID's) -5.36. (Acceptable) |
| Detection Limit (Analytical Sensitivity) | No greater than 110% of the IMMULITE hCG 2000 analytical sensitivity (1.0 mIU/mL) | 0.2 ng/mL (estimated LOD), Critical cut-off for pregnancy determination was 1.0 ng/mL (This implies it's at least as sensitive as the predicate. The direct cross-comparison value is not explicitly stated in % but the 1.0 ng/mL serum threshold is used for positive reporting which aligns with the overall sensitivity objective.) |
| Analytical Specificity / Cross-Reactivity | No detectable cross-reactivity against 5 mIU TSH/mL, 80 IU LH/mL, 20 IU FSH/mL, 25 ng hPL/dL and 10 ng hGH/mL. Specific cross-reactivity for different hCG isoforms as tested. | 0.0% for FSH (10000 ng/mL), 0.1% for LH (10000 ng/mL), 0.0% for TSH (10000 ng/mL). Specific minor cross-reactivities for non-nicked and nicked hCG isoforms (e.g., 4.5% for non-nicked hCG, 5.4% for nicked hCG). |
| Assay Cut-off | Establish a clear decision threshold for pregnancy detection. | 1.0 ng/mL (both in serum and urine) for Positive. Less than 1.0 ng/mL for Negative. |
| Recovery | N/A (listed as 100% - 112% for predicate) | 89% - 110% (Compared to predicate, this is within a similar range and considered acceptable). |
| Parallelism | N/A (listed as 91% to 98% for predicate) | 86% - 115% (Compared to predicate, this is within a similar range and considered acceptable). |
| High Dose Hook Effect Level | None up to 2,000,000 mIU/mL (predicate) | Greater than 31,000 ng/mL (This is considered adequate as samples up to this level will read > dynamic range). |
| Method Comparison (Serum) | ||
| Concordance | Achieve high concordance with predicate (e.g., >95%) | 99.1% |
| % Agreement Positive | Achieve high positive agreement with predicate (e.g., >95%) | 100.0% |
| % Agreement Negative | Achieve high negative agreement with predicate (e.g., >95%) | 96.8% |
| Method Comparison (Urine) | ||
| Concordance | Achieve high concordance with predicate (e.g., >95%) | 97.2% |
| % Agreement Positive | Achieve high positive agreement with predicate (e.g., >95%) | 99.0% |
| % Agreement Negative | Achieve high negative agreement with predicate (e.g., >85-90%) | 89.6% |
2. Sample sizes used for the test set and the data provenance
- Precision/Reproducibility: Patient or patient pool samples were evaluated. An "accelerated format of the NCCLS EP-5 protocol" was used, involving two replicates of each specimen run on each of four assays per day over a 10-day period, yielding 80 data points.
- Linearity/Assay Reportable Range:
- n = 61 "apparently pregnant and health female subjects" reporting 0-2 weeks of gestation.
- Detection Limit/Assay Cut-off (Non-pregnant subjects): n = 81 "non-pregnant apparently health female subjects."
- Method Comparison (Serum): n = 659 total samples (479 pregnant, 180 non-pregnant).
- Method Comparison (Urine): n = 777 total samples (632 pregnant, 145 non-pregnant).
- Expected Values/Reference Range (Cut-off establishment):
- n = 178 serum samples (apparently healthy and non-pregnant adult women, age 17-64).
- n = 85 random urine samples (apparently healthy and non-pregnant adult women, age 17-71).
- Both groups were "ambulatory, free-living, southern California community-dwelling."
- Expected Values (Pregnant women): n = 357 first trimester serum samples from "apparently healthy pregnant women" (categorized by gestational weeks/LMP).
- Data Provenance: The document explicitly states that samples for establishing expected values/reference ranges were from "southern California community-dwelling adult women." For other studies, data provenance is not explicitly stated but is implied to be clinical samples from similar populations as tested by the predicate device. The samples for determining cross-reactivity of various hCG forms were provided by Columbia University or Sigma Chemical Co. All clinical data presented appears to be retrospective, derived from collected clinical samples.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The document does not explicitly state that experts were used to establish the ground truth for the test set. Instead, the ground truth for pregnancy status (pregnant vs. non-pregnant) relies on:
- Clinical reporting: "apparently pregnant and health female subjects [i.e., those reporting 0 to 2 weeks of gestation]" and "apparently healthy pregnant women."
- Comparison to a predicate device: The DPC IMMULITE® hCG Immunoassay (K990222) is used as the reference standard for method comparison, implying its results are the accepted ground truth for hCG levels and pregnancy status.
- Lack of specific mention: There is no mention of radiologists, pathologists, or other clinical experts adjudicating cases for ground truth.
4. Adjudication method (for the test set)
There is no explicit mention of an adjudication method (like 2+1, 3+1, none) for establishing ground truth from multiple experts. The ground truth appears to be based on:
- Self-reported gestational status.
- Comparison with a well-established predicate device, implying its results serve as a form of reference standard.
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
No MRMC comparative effectiveness study was done or mentioned. This device is an immunoassay (laboratory test system), not an AI-assisted diagnostic imaging or clinical decision support system that would involve human "readers" or AI assistance. The comparison is between two laboratory assay methods.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the device operates as a standalone algorithm/system without human-in-the-loop performance influencing the assay results. The Nichols Advantage® H-hCG Assay itself is a laboratory instrument that quantitatively measures H-hCG. Interpretation of results (e.g., positive for pregnancy) is based on defined cut-off values (e.g., >= 1.0 ng/mL), which are determined by the assay and not subject to real-time human interpretation for each primary result. Clinical considerations and professional judgment are applied after the objective result is obtained, suggesting the assay itself is standalone.
7. The type of ground truth used
The primary ground truth used is a combination of:
- Clinical status (self-reported/historical): "apparently pregnant" or "non-pregnant" status of individuals.
- Predicate device results: The DPC IMMULITE® hCG Immunoassay results serve as a comparative ground truth/reference standard for establishing correlation and agreement. For linearity, the DPC values were used to correlate with the NID values.
- Derived cut-off values: For the "detection limit" studies, the ground truth was derived from statistical analysis of H-hCG levels in known non-pregnant individuals.
8. The sample size for the training set
The document does not explicitly differentiate between "training" and "test" sets in the context of machine learning. For an immunoassay, the concept of a training set is typically represented by the samples and data used to develop the assay, establish its calibration, and set initial performance parameters. The document focuses on the validation or performance characteristic studies. For the purposes of this request, if we consider "training" analogous to the data used to define the assay's operational parameters and reference ranges, then:
- For establishing reference ranges/expected values: n=178 serum samples (non-pregnant) and n=85 urine samples (non-pregnant) were used to determine the decision threshold. n=357 first trimester serum samples (pregnant) were used to establish expected values by gestational week.
9. How the ground truth for the training set was established
For the data used to establish assay parameters and reference ranges:
- The ground truth (pregnant or non-pregnant status) was established based on the clinical status of the subjects (e.g., "apparently healthy and non-pregnant adult women," "pregnant women"). This likely involves a combination of medical history, last menstrual period, and potentially other clinical assessments not detailed in the summary.
- Analytical measures: The "ground truth" for linearity and method comparison was provided by the predicate device's quantitative results, allowing for a direct comparison and correlation study. The predicate device's established performance served as the benchmark.
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510(k) Summary of Safety and Effectiveness 12.0
This summary of 510(k) safety and effectiveness is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
510(k) Number: K042676
12.1. Name of Submitter, Contact Person and Date Summary Prepared:
Nichols Institute Diagnostics 1311 Calle Batido San Clemente, CA 92673 Phone: 949-940-7358 Fax: 949-940-7313
Contact Person: Xie Qiyi, MD., MPH Date Prepared: 7/21/2004
12.2. Device Name
| Trade/Proprietary Name: | Nichols Advantage® Hyperglycosylated Human ChorionicGonadotropin (H-hCG) Assay |
|---|---|
| Common/Usual Name: | Nichols Advantage® H-hCG Assay |
| Classification Name: | System, Test, Human Chorionic Gonadotropin (hCG) |
12.3. Predicate Device
Substantial equivalence is claimed to the DPC's IMMULITE® hCG Immunoassay (K990222; Cleared 2/26/99).
12.4. Device Description
The Nichols Advantage Hyperglycosylated Human Chorionic Gonadotropin Assay (i.e., Nichols Advantage® H-hCG Assay) is a two-step, two-site immunochemiluminometric assay for use with the Nichols Advantage® Specialty System, for the measurement of H-hCG as an aid in the detection of pregnancy. This new Nichols Advantage® H-hCG Assay Jas with the predicate of the Diagnostic Products Corporation (= DPC) termed: the DPC IMMULITE® hCG Immunoassay (K990222; cleared 2/26/99)] is a two-step, two-site immunochemiluminometric assay for use with the Nichols Advantage® Specialty System.
12.5. Intended Use
The Nichols Advantage Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay (or simply: Nichols Advantage H-hCG Assay) is intended for use with the Nichols Advantage® Specialty System for the quantitative measurement of hyperglycosylated human chorionic gonadotropin (H-hCG), a placental hormone in human serum, or for the qualitative determination of H-hCG in urine as an aid in the detection of pregnancy. These diagnoses should be made with appropriate additional clinical evidence. Clinical considerations and professional judgment should
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be applied to any test device result, particularly when preliminary positive results are obtained, as with this Nichols H-hCG chemiluminescent immunoassay.
The Nichols Advantage® H-hCG Assay is used in conjunction with two H-hCG calibrators which are used to calibrate the assay and are provided separately to the reagent cartridge. The control is used for the monitoring of the accuracy and precision of the Nichols Advantage HhCG Assay and successful calibration is confirmed using three H-hCG controls also provided separately to the calibrators and reagent cartridge.
Comparison to predicate device 12.6.
The Nichols Advantage® Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay is substantially equivalent to other laboratory based products in commercial distribution for similar use. Most notably, it is substantially equivalent to the DPC IMMULITE hCG Immunoassay. The following tables compare the Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay with the predicate device, the DPC IMMULITE hCG Immunoassay.
| Comparison Summary with Predicate Device | ||
|---|---|---|
| Similarities | ||
| Feature | Nichols Advantage H-hCG New Assay | DPC IMMULITE 2000 hCG Predicate Immunoassay |
| Antibody Recognition | Specific antibodies that bind isoforms of hCG | Specific antibodies that bind isoforms of hCG |
| Sample Type | Assay utilizes human serum or urine as test samples | Assay utilizes human serum or urine as test samples |
| Analysis Technology | Utilizes chemiluminescent technology for quantitation with assay incubated to 37°C. | Utilizes chemiluminescent technology for quantitation with assay incubated to 37°C. |
| Sensitivity | Sensitivity & critical detection limit sufficient to utilizes human serum or urine for hCG isoforms in determination of pregnancy | Sensitivity & critical detection limit sufficient to utilizes human serum or urine for hCG isoforms in determination of pregnancy |
| Interferences - serum | High limits for interference from serum a) protein, b) bilirubin, c) triglycerides, and d) free serum hemoglobin | High limits for interference from serum a) protein, b) bilirubin, c) triglycerides, and d) free serum hemoglobin |
| Interferences - urine | High limits for interference from urine glucose via severe diabetes | High limits for interference from urine glucose via severe diabetes |
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| Differences | ||
|---|---|---|
| Feature | Nichols AdvantageH-hCG New Assay* | DPC IMMULITE 2000 hCGPredicate Immunoassay |
| AntibodyRecognition | Monoclonal antibodies thatrecognize H-hCG* | Monoclonal antibodies thatrecognize hCG |
| Sample Volume | 15 microliters | 5 microliters |
| Reporting Unit | ng/ml* [for H-hCG, based onMass units of ng per ml serum] | mIU/ml [for hCG, basedon milli-International Units] |
- The Nichols Advantage Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay reports values in ng/ml. The correlation for the reporting units of the predicate device compared to NID is expressed by Y(DPC's) = -5.36 + 28.32X(NID's) with correlation factor r=0.935, P-Value < 0.001.(page 109)
12.7. Test Principle
Both Assays utilize Competition Assays and Immunometric Assays with chemiluminescence for detection and quantitation. A summary of a technological comparison of each method's test principles is presented in the following Table of Technology Comparisons:
| New DeviceNichols AdvantageH-hCG Assay | Predicate DeviceDPC IMMULITE hCG Assay | |
|---|---|---|
| ITEM | ||
| Test Principle | Immunochemiluminometric sandwichassay using biotinylated and acridiniumester-labeled mouse monoclonal anti-H-hCG antibodies coated on magneticparticles for capture and detection | Immunochemilumin assay usingmonoclonal antibody coatedpolystyrene bead for capture andsubsequent detection. |
| Sample Dilution | Operator selectable, sample-specificon-board dilutions | None described in directionalinsert |
| Tracer | Acridinium ester-labeled mousemonoclonal anti-H-hCG antibody | Alkaline phosphatase conjugatedto poly- clonal ovine (sic)anti-hCG antibody |
| Antigen Used inStandards | H-hCG derived from JEG-3 cell linecalibrated vs. C5 [Columbia University& NIH, Bethesda, MD] | WHO 3rd IS 75/573 |
| Separation System | Streptavidin-coated magnetic particles | Anti-hCG beta subunit-coatedpolystyrene bead |
| Incubation | Number of Incubations: TwoIncubation Period 1: 30 minutesIncubation Temperature: 37°CIncubation Period 2: 10 minutes | Number of Incubations: TwoIncubation Period 1: 30 minutesIncubation Temperature: 37°CIncubation Period:2: 5 min. |
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12.8. Performance Characteristics:
12.8.1. Analytical performance --
12.8.1.a. Precision/Reproducibility:
The patient or patient pool samples were evaluated by an accelerated format of the NCCLS EP-5 protocol; two replicates of each specimen run on each of four assays per day over a 10 day period. This format yields 80 data points, which will be analyzed according to the NCCLS EP-5 algorithm statistic. The Nichols Advantage® H-hCG Assay average CV for the total precision shall be no more than 2% higher than the corresponding CV of the predicate IMMULITE 2000 hCG Assay. The Nichols H-hCG Assay average total inter-assay precision was 6.7% C.V; the Acceptable Criteria was considered a high of: 7.22% C.V.
12.8.1.b. Linearity/assay reportable range:
A linear correlation comparison study of critical values for pregnancy determination using this new Nichols H-hCG Assay (X) was carried out versus the cleared (K990222, 5/27/99) predicate DPC Immulite 2000 hCG Assay (Y) for n = 61 apparently pregnant and health female subjects [i.e., those reporting 0 to 2 weeks of gestation]. Analysis of the resulting data gave a linear regression correlation equation that was acceptable for values ranging from 0.2 to 27 ng/mL for H-hCG by Nichols versus values of ~4 to ~760 mIU/mL by DPC Assay. Thus this Nichols H-hCG Assay yielded values in ng/ml that correlated well [i.e., gave correlation factor r= 0.935 (and P-Value < 0.001 )] with the DPC values, allowing for unit conversion from the predicate DPC units [i.e., mIU1. The NID assay gave ng units of H-hCG by way of a Linear Regression: Y(DPC's) = + 28.32X(NID's) -5.36 and yielded an acceptable determined correlation factor: r = 0.935, and P-value < 0.001 (using n = 61 critical pregnancy patient determination).
12.8.1.c. Traceability (controls, calibrators, or method):
The Nichols Advantage H-hCG assay is designed specifically to detect the present of Hyperglycosylated Human Chorionic Gonadotropin in both serum and urine. The Nichols Advantage H-hCG assay utilizes the monoclonal antibodies developed at Columbia University specific against to the isoforms of H-hCG. One of the antibodies (B152 obtained from Columbia University directed against H-hCG) is biotin labeled (US Patent #:5395938) and used as a capture antibody. The other antibody, H-hCG non-specific (B207 also obtained from Columbia University) is labeled with acridinium ester (ACR, US Patent #:5284952) and used for detection. Where B152 used as capture antibody is specific to the carbohydrate isoforms (H-hCG), the B207 antibody is against general hCG ß for detection. During assay, the serum or urine sample is added to a cuvette well within the Nichols Advantage Specialty System followed by the biotinylated-B152 anti-H-hCG antibodies and streptavidin-coated magnetic particles (Dynabeads®) obtained from Dynal Biotech. See Cross-Reactivity section below.
12.8.1.d. Detection limit:
In a detection limit study using H-hCG Nichols Advantage assay, N=81, non-pregnant apparently health female subjects, the detection levels of H-hCG for all subjects were under 0.3 ng/ml, and 95% of non pregnant subjects were below the detection level (0.2 ng/ml). None of the samples exceed a level of 1.0 H-hCG ng/ml in serum among normal non-pregnant subjects. The analytical sensitivity calculated from the Nichols Advantage® H-hCG Assay was no greater than 110% of the analytical sensitivity of the IMMULITE hGC 2000 analytical sensitivity, which had an accepted hCG analytical sensitivity of 1.0 mlU/mL. Therefore, Positive results from serum should only be reported out for serum H-hCG results equal to or greater than 1.0 ng/ml serum with the numerical. Positive results from urinary analysis may only be reported as Qualitatively Positive if the
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analytical results are equal or greater than 1.0 ng/ml urine, but without the numeric results being posted (i.e., a qualitative result of Positive without any numerical value assigned).
12.8.1.e. Analytical Specificity:
For analytical specificity, this Nichols H-hCG Assay was evaluated for cross-reactivity (CR) against 5 mIU TSH/mL, 80 IU LH/mL, 20 IU FSH/mL, 25 ng hPL/dL and 10 ng hGH/mL. No detectable cross-reactivity was observed. This assay was tested for cross-reactivity with various forms of hCG provided by Columbia University or from Sigma Chemical Co., and the results shown in the table below were obtained:
| Source | h CG Hormone | Lot No. | Concentration | Cross-reactivity (%) |
|---|---|---|---|---|
| Sigma (P/N C6322) | hCG, recombinant | 081K10-098 | 2000 IU/mL | < 1 |
| Columbia University | Non-nicked hCG* | -814 | 10.6 uM | 4.5 |
| Non-nicked Free Beta hCG | -931 | 2.1 uM | 1.0 | |
| Nicked hCG** | -813 | 137 nM | 5.4 | |
| Nicked Free Beta hCG*** | -841 | 20 nM | 1.5 |
- Non-nicked hCG (regular hCG,MW
36kDa) contains o-subunit with 92 and ß-subunits with 145 amino acid residue polypeptide; Non-nicked. ** Nicked hCG (MW36.5kDa) contains a-subunit with 92 and ß-subunits with 145 amino acid residue polypeptide and with ß-subunit polypeptide nicked/cut at B47-48, B43-44 or B44-45; ***Nicked, Free Beta hCG (MW~36.5kDa) contains only B-subunits polypeptide nicked/cut at b47-48, b43-44 or b44-45; these isoforms of hCG were obtained from Columbia University isolated from human body fluids.
12.8.1.f. Assay cut-off:
The minimum detectable concentration (MDC), or analytical sensitivity, of the Nichols Advantage® H-hCG Assay was determined using n = 81 non-pregnant apparently health female subjects. In this study, the detection levels of H-hCG for all subjects were under 0.3 ng/ml, and 95% of non-pregnant subjects were below the detection level (0.2 ng/ml), as summarized above in Section 1.d and the table below. None of the samples exceed a level of 1.0 H-hCG ng/ml in serum among normal non-pregnant subjects. This table depicts the Nichols Advantage® H-hCG Assay results:
| Nichols Advantage® H-hCG Assay | |
|---|---|
| Result | Interpretation |
| Greater than or equal to 1.0 ng/mL both in serum and urine | Positive for pregnancy |
| Less than 1.0ng/mL both in serum and urine | Negative for pregnancy |
INTERPRETATION OF RESULTS
The analytical sensitivity (Limit Of Detection, LOD) was determined by reading the +2SD response from n=20 replicate measurements of the zero standard from the stored master curve from several runs and systems. The analytical sensitivity for this assay was estimated to be at or below 0.2 ng/mL, while the Critical cut-off for pregnancy determination was found to be 1.0 ng/mL. Each laboratory should determine their own lower limit of detection based on their facilities' procedures. The relative sensitivity between the Nichols Advantage H-hCG Assay with the DPC Immulite predicate assay was found to be 100.0% in serum and 99.0% in urine.
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Again, we note that Positive results from serum should only be reported out for serum H-hCG results equal to or greater than 1.0 ng/ml serum with the numerical. Positive results from urinary analysis may only be reported as Qualitatively Positive if the analytical results are equal or greater than 1.0 ng/ml urine, but without the numeric results being posted (i.e., a qualitative result of Positive without any numerical value assigned).
12.8.1.g. Reproducibility
The Within-Run and Total imprecision of the Nichols Advantage H-hCG assay was calculated using the NCCLS EP5-A method (Evaluation of Precision Performance of Clinical Chemistry Devices: Approved Guideline). Serum pools and controls were tested in duplicate in two runs per day over 6 days. At a dose greater than 10 ng H-hCG/mL the Within-Run imprecision was not greater than 5% and the Total imprecision was not greater than 10%. The study was performed on five Nichols Advantage Specialty Systems.
12.8.1.h. High Dose Hook Effect Level
The high dose hook effect for the Nichols Advantage H-hCG Assay was determined to be greater than 31,000 ng/mL. Samples containing H-hCG values up to 31,000 ng/mL will read greater than the dynamic range.
12.8.2. Comparison studies:
12.8.2.a. Method and Matrix Comparisons with Predicate Device
The Nichols Advantage H-hCG assay was compared to the DPC IMMULITE 2000 hCG assay. A total of 1436 sample points were collected, including serum of pregnant (n=479, 18 trimester n=378, 204 trimester n=101) and non-pregnant (n=180); urine of pregnant (n=632, 18 trimester n=374, 2nd trimester n=258) and non-pregnant (n= 145) for the comparison. All the samples were assayed by both procedures following the manufacturers' directions and without modifications. Using the positive cut-off value for detection of pregnancy by the Nichols Advantage H-hCG assay (H-hCG >1.0 ng/ml) determined by the conversion of DPC's international units from mIU/ml to the NID's units of ng H-hCG/ml serum, the relative sensitivity between the Nichols Advantage H-hCG assay with the DPC predicate device was 100.0% in serum and 99.0% in urine.
| METHOD COMPARISON (SERUM)DPC vs. NID | METHOD COMPARISON (URINE)DPC vs. NID | ||||||
|---|---|---|---|---|---|---|---|
| 'n =659 | 'n =777 | ||||||
| DPC | DPC | ||||||
| NID | Positive | Negative | Total | NID | Positive | Negative | Total |
| Positive | 473 | 6 | 479 | Positive | 616 | 16 | 632 |
| Negative | 0 | 180 | 180 | Negative | 6 | 139 | 145 |
| Total | 473 | 186 | 659 | Total | 622 | 155 | 777 |
| 95% CI | 95% CI | ||||||
| Concordance | 99.1% | 98.4% | -100% | Concordance | 97.2% | 97.93% | -98.4% |
| Percentage agreementpositive | 100.0% | 99.1% | -100% | Percentage agreementpositive | 99.0% | 97.9% | -99.6% |
| Percentage Agreementnegative | 96.8% | 93.4% | -98.6% | Percentage Agreementnegative | 89.6% | 83.9% | -93.6% |
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Note: For n = 61 data pairs (from 357) with specific gestation equal or less than 2 weeks, results by both methods gave correlation readings of: Y/DPC] = - 5.36 + 28.32 X/NID/ and showed correlation value of r= 0.935, & P-Value < 0.001 as shown in graph 2 below:
GRAPH 1: Expected H-hCG values determined from serum during the 1st trimester of pregnancy
Image /page/6/Figure/2 description: The image is a scatter plot titled "Readings from NID Advantage by gestational weeks (N=380)". The x-axis is labeled "GESTATIONAL WEEK" and ranges from 0 to 14. The y-axis is labeled "ADV (Log) ng/ml" and ranges from 1 to 10000. There is a curve plotted on the scatter plot that increases from week 1 to week 6, and then decreases from week 6 to week 14.
GRAPH 2: Method of comparison (quantitative serum results):
Image /page/6/Figure/4 description: The image is a scatter plot titled "DPC hCG vs NID H-hCG In Frist 2 Gestation Weeks (n=61)". The x-axis is labeled "NID Reading (H-hCG ng/ml)" and ranges from 0 to 30. The y-axis is labeled "DPC Reading (hCG mIU/ml)" and ranges from 0 to 800. A regression line is plotted with the equation Y(DPC) = -5.36 + 28.32X(NID). The values for S, R-Sq, and R-Sq(adj) are 64.0722, 87.4%, and 87.2% respectively.
12.8.3. Expected values/Reference range: 12.8.3.a. DECISION THRESHOLD
Nichols Institute Diagnostics recommends that each laboratory establish its own expected values for the population they serve. To establish an expected reference range, the levels of HhCG were respectively determined in serum samples (n=178) and random urine samples (n=85) apparently healthy and non-pregnant, ambulatory, free-living, southern California community-dwelling adult women who donated serum ranged in age from 17 to 64; those who donated urine ranged in age from 17 to 71. Decision threshold (cut-off point) for this Nichols H-hCG assay was assigned as: Negative/Quantitative for less than 1.0 ng H-hCG/mL in serum anNegative/Qualitative for less than 1.0 ng H-hCG/ml in urine [See Summary Table below].
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INTERPRETATION OF RESULTS SUMMARY TABLE
| Nichols Advantage® H-hCG Assay | |
|---|---|
| Result | Interpretation |
| Greater than or equal to 1.0 ng/mLboth in serum and urine | Positive for pregnancy |
| Less than 1.0ng/mL both inserum and urine | Negative for pregnancy |
Again, we note that Positive and Numerical results from serum samples should only be reported out for serum H-hCG results equal to or greater than 1.0 ng/ml serum. Positive results from urinary analysis may only be reported as Qualitatively Positive results only if the analytical results are equal or greater than 1.0 ng/ml urine, but without any numeric results being posted (i.e., a qualitative result of Positive without any numerical value assigned).
12.8.3.b. EXPECTED VALUES
Based on its relationship to hCG (see Method Comparison), the similar pattern of reference ranges as follows are expected. In a study using H-hCG Nichols Advantage assay. n-81. non-pregmant apparently health female subjects, the detection levels of H-hCG are all under 0.3 ng/ml, and 95% of non-pregnant subjects were below the detection level (0.2ng/ml), and none of the samples exceed the level of 1ng/ml in serum among normal non pregnant subjects. Based on n=61 women in the gestational period of 0-2 weeks, the decision threshold (cut-off point) for non-pregnant using this Nichols H-hCG assay was determined to be less than 1.0 ng H-hCG/mL in serum and Jess than 1.0 ng H-hCG/mg creatinine in urine [See Summary Table above], and a "pregnant" result would be at or above these levels.
In summary, a total of 357 first trimester serum samples from apparently healthy pregnant women were tested by using Nichols Advantage H-hCG Assay. The observed results were summarized below (in ng/ml) by gestational weeks (GES-WK) and by gestational age since last menstrual period (LMP). These readings are considered as the guideline only and each laboratory should establish its own reference ranges. Again, we note that Positive and Numerical results from serum samples should only be reported out for serum H-hCG results equal to or greater than 1.0 ng/ml serum. Positive results from urinary analysis may only be reported as Qualitatively Positive results only if the analytical results are equal or greater than 1.0 ng/ml urine, but without any numeric results being posted (i.e., a qualitative result of Positive without any numerical value assigned).
| GES-WK. | LMP | N | MEDIAN | CENTRAL. 95% ± 2SD |
|---|---|---|---|---|
| >0-2 | 2-4 | 37 | 2.9 | 2.7-13.3 |
| 2-3 | 4-5 | 55 | 14.5 | 11.8-28.9 |
| 3-4 | 5-6 | 90 | 73.6 | 57.4-149.5 |
| 4-5 | 6-7 | 73 | 230.1 | 114.6-435.8 |
| 5-6 | 7-8 | 47 | 490.1 | 369.8-650.4 |
| 6-7 | 8-9 | 31 | 585.0 | 514.9-1054.3 |
| 7-12 | 9-14 | 24 | 101.7 | 42.2-297.9 |
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12.8.3.c. PARALLELISM
Samples with varying concentrations of H-hCG were either manually diluted with Sample Diluent before placing onto the system, or diluted on-board the system. The results demonstrate linearity across the dynamic range of this Nichols Advantage H-hCG immunochemiluminescent assay.
| Serum No. | Dilution | Observed (ng/mL) | Expected (ng/mL) | % Recovery |
|---|---|---|---|---|
| 1 | Undiluted | 12.2 | ||
| 1 | 1:2 | 6.7 | 6.1 | 110 |
| 1 | 1:4 | 3.3 | 3.1 | 106 |
| 2 | Undiluted | 70.1 | ||
| 2 | 1:2 | 35.2 | 35.1 | 100 |
| 2 | 1:4 | 19.1 | 17.5 | 109 |
| 2 | 1:8 | 9.0 | 8.8 | 102 |
| 3 | Undiluted | 135.6 | ||
| 3 | 1:2 | 69.5 | 67.8 | 103 |
| 3 | 1:4 | 37.1 | 33.9 | 109 |
| 3 | 1:8 | 19.6 | 17.0 | 115 |
12.8.3.d. RECOVERY
Three sets of a high and a low/normal serum samples were mixed in 2:1, 1:1 and 1:2 ratios and assayed. The recoveries were determined from the undiluted results. The results demonstrate recovery of H-hCG in patients' samples between 89 and 110%.
| Serum Sample | Observed(ng/mL) | Expected(ng/mL) | % Recovery |
|---|---|---|---|
| Sample A | 135.6 | ||
| 2 : 1 | 86.6 | 97.0 | 89 |
| 1 : 1 | 75.2 | 77.7 | 97 |
| 1 : 2 | 55.6 | 58.4 | 95 |
| Sample B | 19.8 | ||
| Sample C | 154.4 | ||
| 2 : 1 | 103.0 | 106.5 | 97 |
| 1 : 1 | 74.1 | 82.6 | 90 |
| 1 : 2 | 55.7 | 58.6 | 95 |
| Sample D | 10.7 | ||
| Sample E | 82.9 | ||
| 2 : 1 | 60.2 | 59.1 | 102 |
| 1 : 1 | 44.8 | 47.3 | 95 |
| 1 : 2 | 33.9 | 35.4 | 96 |
| Sample F | 11.6 |
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12.9. Performance Characteristics - Summary
| FEATURE | DPC IMMULITE hCGImmunoassay* | Nichols Advantage H-hCGAssay* |
|---|---|---|
| Within-Run | Not greater than 7% at dose greater than6.5 mIU/mL Serum | Not greater than 5% at a dose greater than10 ng/mL Serum |
| Total | Not greater than 8% at dose greater than6.5 mIU/mL Serum | Not greater than 10% at a dose greater than10 ng/mL Serum |
| Recovery | 100% - 112% | 89% - 110% |
| Parallelism | 91% to 98% | 86% - 115% |
| High DoseHook Effect | None up to 2,000,000 mIU/mL | None up to 31,000 ng/mL |
| Cross-Reactivity | DPC IMMULITE hCGImmunoassay* | Nichols Advantage H-hCG Assay* |
| Cross-Reactant | Quantity Spiked(ng/mL)Cross-Reactivity | Quantity Spiked(ng/mL)Cross-Reactivity |
| FSH | 26.8ND | 100000.0% |
| LH | 16.5ND | 100000.1% |
| TSH | 860ND | 100000.0% |
Table of Methods Comparisons - for Recovery, Hook Dose & Cross-Reactivity*
- Table 22a shows the performance characteristics in parallel between DPC and NID assays where DPC's readings were in mIU/ml and NID readings were in ng/ml except cross reactivity results in ng/ml as substances were spiked.
** FSH Unit/Mass conversion factor: LH Unit/Mass conversion factor: TSH Unit/Mass conversion factor:
2735 IU/mg 10,000 IU/mg 6.5 IU/mg
Table of Methods Comparisons -
for Both Serum & Urine re: Positives & Negatives **
| Method Comparison** | |
|---|---|
| Serum Sample Size: | 659 (pregnant and non pregnant) |
| Range of Results: | DPC IMMULITE hCG Immunoassy: < 1 mIU hCG/mL to365,224 mIU hCG/mL, serum.Nichols Advantage H-hCG Assay: < 1 ng H-hCG/mL to3616 ng H-hCG/mL, serum. |
| Concordance: | 99.1% |
| Percent Agreement Positive: | 100% |
| Percent Agreement Negative: | 96.8% |
| Urine Sample Size: | 777(pregnant and non pregnant) |
| Range of Results: | DPC IMMULITE hCG Immunoassy: < 1 mIU hCG/mL to493,194 mIU hCG/mL, urine.Nichols Advantage H-hCG Assay: < 1 ng H-hCG/ml to 1,689ng H-hCG/ml, urine. |
| Concordance: | 97.2% |
| Percent Agreement Positive: | 99.0% |
| Percent Agreement Negative: | 89.7% |
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12.10. Conclusions
Based upon the information provided, the Nichols Advantage® H-hCG Assay [quantitative with serum and qualitative with urine] has been found to be substantially equivalent or SE to the DPC predicate device.
:
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/11/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized caduceus symbol, which is a staff with two snakes coiled around it, topped by a single wing. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the caduceus.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
DEC 17 2004
Nichols Institute Diagnostics c/o Alfredo Quattrone, Ph.D. California Department of Health Food and Drug Branch 1500 Capitol Avenue Mailstop 7602 Sacramento, CA 95814
Re: K042676
Trade/Device Name: Nichols Advantage® Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay Regulation Number: 21 CFR 862.1155 Regulation Name: Human Chorionic gonadotropin (HCG) test system Regulatory Class: Class II Product Code: DHA, JIT, JJX Dated: October 22, 2004 Received: October 26, 2004
Dear Dr. Quattrone:
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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Page 2 -
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 (301) 594-3084. 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 (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Sincerely yours,
Sincerely yours,
Cornelia B. Parks
Cornelia B. Rooks, MA Acting 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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INDICATIONS FOR USE
K042676 510(k) Number:
Device Name:
Nichols Advantage® Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay
Indications For Use Statement: The Nichols Advantage Hyperglycosylated Human Chorionic Gonadotropin (H-hCG) Assay (or simply: Nichols Advantage® H-hCG Assay) is intended for use with the Nichols Advantage Specialty System for the quantitative measurement of hyperglycosylated human chorionic gonadotropin (H-hCG), a placental hormone in human serum, or for the qualitative determination of H-hCG in urine as an aid in the detection of pregnancy. These diagnoses should be made with appropriate additional clinical evidence. Clinical considerations and professional judgment should be applied to any test device result as with this Nichols H-hCG chemiluminescent immunoassay.
The Nichols Advantage® H-hCG Assay is used in conjunction with two H-hCG calibrators which are used to calibrate the assay and are provided separately to the reagent cartridge. The control is used for the monitoring of the accuracy and precision of the Nichols Advantage H-hCG Assay and successful calibration is confirmed using three H-hCG controls also provided separately to the calibrators and reagent cartridge,
Prescription Use (Part 21 CFR 801 Subpart D)
AND/OR Over-The-Counter use _________________________________________________________________________________________________________________________________________________________
(21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices.(OIDE)
Carol C. Benson
Division Sign-Off
§ 862.1155 Human chorionic gonadotropin (HCG) test system.
(a)
Human chorionic gonadotropin (HCG) test system intended for the early detection of pregnancy —(1)Identification. A human chorionic gonadotropin (HCG) test system is a device intended for the early detection of pregnancy is intended to measure HCG, a placental hormone, in plasma or urine.(2)
Classification. Class II.(b)
Human chorionic gonadotropin (HCG) test system intended for any uses other than early detection of pregnancy —(1)Identification. A human chorionic goadotropin (HCG) test system is a device intended for any uses other than early detection of pregnancy (such as an aid in the diagnosis, prognosis, and management of treatment of persons with certain tumors or carcinomas) is intended to measure HCG, a placental hormone, in plasma or urine.(2)
Classification. Class III.(3)
Date PMA or notice of completion of a PDP is required. As of the enactment date of the amendments, May 28, 1976, an approval under section 515 of the act is required before the device described in paragraph (b)(1) may be commercially distributed. See § 862.3.