(151 days)
The ADVIA Centaur® Intact Parathyroid Hormone (PTH) assay is for in vitro diagnostic use in the quantitative determination of intact parathyroid hormone (PTH) in human serum and plasma using the ADVIA Centaur XP system. This assay is intended to be used to aid in the differential diagnosis of hyperparathyroidism, or disorders of calcium metabolism. This assay can be used intra-operatively.
The ADVIA Centaur® Intact Parathyroid Hormone (PTH) assay is a chemiluminescence sandwich immunoassay. It consists of a Lite Reagent containing acridinium ester-labeled mouse monoclonal anti-human PTH antibody and a Solid Phase Reagent containing biotinylated mouse monoclonal anti-human PTH antibody bound to streptavidin-coated paramagnetic particles. The assay also includes Low and High Calibrators which are reconstituted synthetic peptide in buffered saline with human EDTA plasma, surfactants, and preservatives.
Here's a breakdown of the acceptance criteria and study information for the ADVIA Centaur Intact Parathyroid Hormone (PTH) Assay, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally not explicitly stated as quantitative thresholds in this type of 510(k) summary for all tests (e.g., "must achieve X% recovery"). Instead, the document demonstrates that the device meets performance expectations through studies that align with recognized standards. Where explicit criteria or comparative results are given, they are listed below.
| Performance Characteristic | Acceptance Criteria (Implied/Explicit) | Reported Device Performance |
|---|---|---|
| Precision | Demonstrated precision according to CLSI EP5-A2 (within-run and within-lab CVs at various concentrations). The CV values are presented as meeting acceptable laboratory practice. | Repeatability (Within-Run) CV: Range from 0.81% to 5.16%Within-Lab (Total Precision) CV: Range from 1.62% to 6.78% (See Table in section 10.1 for detailed values at different concentrations). |
| Linearity | Demonstrated linearity across the assay range with acceptable deviation from linear fit, according to CLSI EP06-A. Explicit: Bias from the linear fit estimate was <10%. | Linear Range: 6.3 to 2000 pg/mLDeviation from Linear Fit: Ranged from -4% to 4% (See Table in section 10.2). |
| Dilution Recovery | Demonstrated acceptable recovery percentages for diluted high-concentration samples. | Recovery (%): 101.6%, 104.2%, 102.6% for three different spiked concentrations. Mean recovery of 102.8%. |
| Method Comparison | Demonstrated good correlation with the predicate device across the assay range using patient samples, according to CLSI EP9-A3. | Regression Equation: ADVIA Centaur PTH = 1.02(iPTH) – 2.18 pg/mLCorrelation Coefficient (r): 0.99 (indicating strong correlation). |
| Matrix Comparison | No significant difference between various tube types (serum, SST, EDTA, lithium heparin, sodium heparin) compared to dipotassium EDTA plasma, according to CLSI EP9-A3. | Correlation Coefficients (r): 0.996 to 0.998 for various matrix comparisons against Dipotassium EDTA plasma. Regression equations showed close to 1.0 slope and small intercepts (e.g., Serum = 0.99 EDTA – 1.85). |
| Reference Intervals | Established interval based on healthy donors consistent with clinical utility, according to CLSI EP28-A3c. The ranges are presented as acceptable for diagnostic aid. | EDTA Plasma: 18.4 - 80.1 pg/mL (95% CI)Serum: 18.5 – 88.0 pg/mL (95% CI) |
| Detection Limit | Established LoB, LoD, and LoQ according to CLSI EP17-A2. The values are presented as meeting analytical sensitivity requirements. Explicit: LoQ defined as lowest concentration at a total CV of 20%. | LoB: 1.5 pg/mLLoD: 3.2 pg/mLLoQ: 4.6 pg/mL |
| Interference | No significant interference (< 10% effect) from common endogenous substances and drugs at specified concentrations, according to CLSI EP07-A2. | Endogenous Substances & Drugs: All tested substances showed interference < 10% (range -7.5% to 6.9%).HAMA: Difference from expected values ranged from -11.5% to 3.2% (for 60 pg/mL PTH) and -3.8% to 2.4% (for 340 pg/mL PTH). |
| Cross-Reactivity | Minimal cross-reactivity with structurally similar compounds, presented as acceptable for specificity. | Most cross-reactants showed < 0.001% cross-reactivity. Significant cross-reactivity observed with PTH (7-84) at 37.36% in normal patient samples and 17.5033% in blank. |
| High-Dose Hook Effect | No paradoxical decrease in RLU up to a specified high concentration, confirming reliable measurement at high PTH levels. | Patient samples with intact PTH levels as high as 100,000 pg/mL are reported as > 2000 pg/mL (no hook effect within this range). |
| Intra-Operative Use (Clinical Study) | Miami Criterion: A 50% or greater drop in PTH level from baseline to 10 minutes post-excision. The device should show high agreement with a clinical PTH test cleared by the FDA for intra-operative use. | Positive Agreement: 100% (29/29 successful surgeries)Overall Agreement: 96.7% (29/30). One discrepant sample explained by the local device failing to meet the 50% drop at 10 min, while the ADVIA Centaur PTH assay did. |
2. Sample Size Used for the Test Set and Data Provenance
- Precision: Six EDTA plasma samples and three levels of controls.
- Linearity: 11 serially diluted samples.
- Dilution Recovery: 3 spiked samples (low sample pool spiked to ~3,000, ~6,000, and ~9,000 pg/mL).
- Method Comparison: 349 EDTA plasma patient samples.
- Matrix Comparison: 56 matched specimens drawn in different tube types (serum red top, SST, EDTA, lithium heparin, and sodium heparin).
- Reference Intervals: 142 paired serum and EDTA plasma samples from apparently healthy donors.
- Detection Limit: Not explicitly stated beyond "CLSI protocol EP17-A2," which typically involves multiple replicates of blank and low-concentration samples.
- Interference: Two EDTA sample pools (at ~75 pg/mL and ~600 pg/mL PTH) for endogenous substances/drugs. Six human plasma samples for HAMA.
- Cross-Reactivity: One normal human EDTA plasma sample and blank assay diluent for each test compound.
- High-Dose Hook Effect: Patient samples as high as 100,000 pg/mL.
- Intra-Operative Clinical Study: Sets of specimens from 30 subjects.
Data Provenance (Country of origin / Retrospective or Prospective):
The document does not explicitly state the country of origin for the samples used in the performance or clinical studies. The method comparison and clinical study are likely prospective in nature (collecting new data for the device evaluation), given the testing against a predicate or a comparator device. The reference interval study is explicitly from "apparently healthy donors," implying a prospective collection or at least a specific selection criteria. The other studies typically involve controlled laboratory conditions or spiked samples rather than broad patient cohorts for provenance purposes.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
For this type of in vitro diagnostic (IVD) assay, "ground truth" is typically established by reference methods, established predicate devices, or pathology results, rather than by individual human experts evaluating diagnostic images or clinical cases.
- For the analytical performance studies (Precision, Linearity, etc.): Ground truth is established by the known concentrations of calibrators, controls, spiked samples, or by comparison to a legally marketed predicate device (ADVIA Centaur iPTH assay) which is itself a validated IVD. No specific number or qualification of experts is mentioned for establishing these analytical "ground truths."
- For the Clinical Study (Intra-operative use): The "ground truth" for surgical success was defined by the Miami Criterion (50% or greater drop in PTH level). The comparison was made against "the assays used by participating surgeons/sites (comparator devices)." This implies that the 'truth' was the outcome determined by the established clinical practice and the results of a clinically used (FDA-cleared) PTH assay at the sites. No external experts were used to establish this ground truth, but rather comparison to existing clinical standards.
4. Adjudication Method for the Test Set
Not applicable in the conventional sense of image or case adjudication. For the clinical study, the "Miami Criterion" served as the objective rule for determining surgical success, which was then compared between the investigational and comparator devices. There was no explicit adjudication process by multiple human readers for a single "ground truth" determination.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size
No, an MRMC comparative effectiveness study, as typically understood for imaging devices involving multiple human readers, was not conducted. This is an IVD assay, not an imaging device. The clinical study focused on the agreement of the device's quantitative output with existing clinical practice based on a well-defined criterion (Miami Criterion), not on how human readers' diagnostic accuracy improves with or without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, this entire submission revolves around the standalone performance of the ADVIA Centaur Intact Parathyroid Hormone (PTH) Assay. It's an automated in vitro diagnostic device, designed to produce quantitative results independently for clinical interpretation. The clinical study for intra-operative use also evaluated the device's ability to meet the Miami Criterion, comparing its raw output to that of other clinical devices, not its assistance to a human in a diagnostic workflow.
7. The Type of Ground Truth Used
- Analytical Studies (Precision, Linearity, Dilution Recovery, Detection Limit): Ground truth is based on known concentrations of standards and controls, or scientifically established principles of measurement procedure performance.
- Method Comparison & Matrix Comparison: Ground truth is the results obtained from a legally marketed predicate device (ADVIA Centaur Intact Parathyroid Hormone (iPTH) assay) or a comparison against a "gold standard" or accepted methodology.
- Reference Intervals: Ground truth is derived from results obtained from apparently healthy donors which define a normal range.
- Clinical Study (Intra-operative): Ground truth for surgical success was the Miami Criterion (a predefined clinical outcome threshold based on PTH levels), as determined by a separate, FDA-cleared clinical PTH test device used at the sites.
8. The Sample Size for the Training Set
This document does not specify a "training set" in the context of an AI/ML algorithm. This is a traditional IVD immunoassay. Therefore, there's no machine learning model that requires a distinct training dataset for its development that would be reported in this manner. The development and optimization of the assay reagents and parameters would be internal to the manufacturer's R&D process.
9. How the Ground Truth for the Training Set Was Established
As explained above, there is no "training set" or "ground truth for the training set" in the context of AI/ML for this device. The development of the assay's reagents and methodologies would be based on biochemical principles, antigen-antibody interactions, and optimization studies performed by the manufacturer, rather than by training a model on labeled data.
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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
May 23, 2017
SIEMENS HEALTHCARE DIAGNOSTICS INC. DARIUS DARUWALA SENIOR SPECIALIST, REGULATORY AFFAIRS 511 BENEDICT AVENUE TARRYTOWN NY 10591
Re: K163658
Trade/Device Name: ADVIA Centaur Intact Parathyroid Hormone (PTH) Assay Regulation Number: 21 CFR 862.1545 Regulation Name: Parathyroid hormone test system Regulatory Class: II Product Code: CEW Dated: April 24, 2017 Received: April 25, 2017
Dear Darius Daruwala:
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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
Kellie B. Kelm -S
for Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K163658
Device Name
ADVIA Centaur® Intact Parathyroid Hormone (PTH) Assay
Indications for Use (Describe)
The ADVIA Centaur® Intact Parathyroid Hormone (PTH) assay is for in vitro diagnostic use in the quantitative determination of intact parathyroid hormone (PTH) in human serum and plasma using the ADVIA Centaur XP system. This assay is intended to be used to aid in the differential diagnosis of hyperparathyroidism, or disorders of calcium metabolism. This assay can be used intra-operatively.
Type of Use (Select one or both, as applicable)
| Prescription Use (Part 21 CFR 801 Subpart D) |
|---|
| Over-The-Counter Use (21 CFR 801 Subpart C) |
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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.
The assigned 510(k) Number is: K163658
Date Prepared 1.
May 22, 2017
Applicant Information 2.
| Contact: | Darius DaruwalaRegulatory Affairs Senior Specialist |
|---|---|
| Address: | Siemens Healthcare Diagnostics Inc511 Benedict AvenueTarrytown, NY 10591-5097 |
| Phone: | 914-524-2812 |
| Fax: | 914-524-3579 |
| Email: | darius.daruwala@siemens.com |
Regulatory Information 3.
Table 1. Regulatory Information for ADVIA Centaur PTH Assay
| Trade Name | ADVIA Centaur® Intact Parathyroid Hormone (PTH) |
|---|---|
| Model Numbers | 10699154 (1-pack); 10699155 (5-pack) |
| Common Name | Immunoassay, intact parathyroid hormone |
| Classification Name | Parathyroid Hormone Test System |
| FDA Classification | Class II |
| Review Panel | Clinical Chemistry (75) |
| Product Code | CEW |
| Regulation Number | 862.1545 |
Predicate Device Information 4.
ADVIA Centaur Intact Parathyroid Hormone (iPTH)
Predicate Device Name: ADVIA Centaur Intact Parathyroid Hormone (iPTH)
510(k) Number: K133601
Intended Use / Indications for Use 5.
ADVIA Centaur Intact Parathyroid Hormone (PTH)
The ADVIA Centaur Intact Parathyroid Hormone (PTH) reagent is for in vitro diagnostic use in the quantitative determination of intact parathyroid hormone (PTH) in human serum and plasma using the ADVIA Centaur XP system.
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510(k) Summary of Safety and Effectiveness
This assay is intended to be used to aid in the differential diagnosis of hyperparathyroidism, hypoparathyroidism, or disorders of calcium metabolism. This assay can be used intraoperatively.
Device Description 6.
| Table 2. Summary of Ingredients of the ADVIA Centaur PTH Assay Components | ||
|---|---|---|
| Component | Volume | Ingredients |
|---|---|---|
| ADVIA Centaur PTH Primary Reagent ReadyPack (included in assay kit) | ||
| ADVIA Centaur PTH LiteReagent | 10.0 mL/pack | Acridinium ester-labeled mouse monoclonalanti-human PTH antibody (~0.6 mg/L) inbuffered saline with mouse gamma globulin,bovine serum albumin, and preservatives |
| ADVIA Centaur PTHSolid Phase Reagent | 20.0 mL/pack | Biotinylated mouse monoclonal anti-humanPTH antibody bound to streptavidin-coatedparamagnetic particles (~0.4 g/L) in bufferedsaline with bovine gamma globulin, bovineserum albumin, and preservatives |
| ADVIA Centaur PTH Calibrator (included in assay kit) | ||
| ADVIA Centaur PTH Lowand High Calibrators | 1.0 mL/vial | After reconstitution, low or high levels of intactPTH synthetic peptide in buffered saline withhuman EDTA plasma (10%), surfactants, andpreservatives |
Purpose of the Submission 7.
The purpose of this submission is a premarket notification for a new device: ADVIA Centaur Intact Parathyroid Hormone (PTH) assay.
8. Comparison of Candidate Device and Predicate Device
| Item | ADVIA Centaur Intact ParathyroidHormone (PTH) Assay(Candidate Device) | ADVIA Centaur Intact ParathyroidHormone (iPTH) Assay(Predicate Device) |
|---|---|---|
| Intended Use | For in vitro diagnostic use in thequantitative determination of intactparathyroid hormone (PTH) in humanserum and plasma using the ADVIACentaur XP system. | For in vitro diagnostic use in thequantitative determination of intactparathyroid hormone (iPTH) inEDTA plasma or serum using theADVIA Centaur systems. |
| Indications for Use | This assay is intended to be used toaid in the differential diagnosis ofhyperparathyroidism,hypoparathyroidism, or disorders ofcalcium metabolism. This assay can beused intra-operatively. | This assay is intended to be used toaid in the differential diagnosis ofhyperparathyroidism andhypoparathyroidism. |
| Measurement | Quantitative | Same |
Table 3. Comparison of ADVIA Centaur PTH Assay to Predicate
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| ltem | ADVIA Centaur Intact ParathyroidHormone (PTH) Assay(Candidate Device) | ADVIA Centaur Intact ParathyroidHormone (iPTH) Assay(Predicate Device) |
|---|---|---|
| Methodology | Chemiluminescence | Same |
| Assay Protocol | Sandwich immunoassay | Same |
| Traceability/Standardization | Internal standards. Values have beenassigned to correlate to the Predicatedevice. | Same |
| Specimen Type | Human serum and plasma | Same |
| Sample Volume | 50 uL | 200 µL |
| Measuring Range | 6.3 to 2000 pg/mL | 6.3 — 1900 pg/mL |
| Calibration | 2-point calibration | Same |
| Detection Antibody | Mouse monoclonal antibodyconjugated to Acridium Ester in theLite Reagent | Goat polyclonal antibodyconjugated to Acridium Ester in theLite Reagent |
| Capture Antibody | Biotinylated mouse monoclonal anti-human PTH antibody withstreptavidin-coated paramagneticparticles pre-formed in Solid PhaseReagent | Biotinylated goat polyclonal anti-human PTH antibody withstreptavidin-coated paramagneticparticles pre-formed in Solid PhaseReagent |
| Expected Values | 18.4 - 80.1 pg/mL (plasma)18.5 – 88.0 pg/mL (serum) | 13.8 - 85.0 pg/mL (plasma)12.4 - 76.8 pg/mL (serum) |
Standard/Guidance Document References 9.
The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:
- Evaluation of Precision of Quantitative Measurement Procedures; Approved S Guideline - Third Edition (CLSI EP05-A3, 2014; Recognition Number 7-251)
- S Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach: Approved Guideline (CLSI EP06-A, 2003; Recognition Number 7-193)
- Interference Testing in Clinical Chemistry: Approved Guideline Second Edition S (CLSI EP07-A2, 2005; Recognition Number 7-127)
- S Measurement Procedure Comparison And Bias Estimation Using Patient Samples --Third Edition (CLSI EP9-A3, 2013; Recognition Number 7-245)
- Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures: S Approved Guideline -- Second Edition (CLSI EP17-A2, 2013; Recognition Number 7-233)
- S Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition (CLSI EP28-A3c - formerly C28-A3c, 2010; Recognition Number 7-224)
- S Medical devices – Application of risk management to medical devices (ANSI/AAMI/ISO 14971:2007/(R)2010; Recognition Number 5-70)
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10. Performance Characteristics: ADVIA Centaur PTH
10.1 Precision
A 20-day precision study was performed according to CLSI EP5-A2. Six EDTA plasma samples and three levels of controls were tested.
| Sample | Mean | Repeatability(Within-Run) | Within-Lab(Total Precision) | |||||
|---|---|---|---|---|---|---|---|---|
| (pg/mL) | (pmol/L) | SD(pg/mL) | SD(pmol/L) | % CV | SD(pg/mL) | SD(pmol/L) | % CV | |
| Sample 1 | 16.9 | 1.79 | 0.9 | 0.09 | 5.16 | 1.1 | 0.12 | 6.78 |
| Sample 2 | 50.3 | 5.34 | 1.4 | 0.15 | 2.78 | 2.3 | 0.24 | 4.57 |
| Sample 3 | 146.4 | 15.52 | 1.9 | 0.20 | 1.30 | 2.9 | 0.30 | 1.95 |
| Sample 4 | 409.2 | 43.37 | 6.8 | 0.72 | 1.67 | 16.9 | 1.79 | 4.13 |
| Sample 5 | 596.3 | 63.20 | 7.3 | 0.78 | 1.23 | 9.7 | 1.02 | 1.62 |
| Sample 6 | 1080.4 | 114.52 | 11.8 | 1.25 | 1.09 | 25.1 | 2.66 | 2.32 |
| ADVIA Centaur PTH Quality Controls | ||||||||
| Control 1 | 41.6 | 4.41 | 0.4 | 0.04 | 0.91 | 1.4 | 0.15 | 3.36 |
| Control 2 | 235.9 | 25.00 | 1.9 | 0.20 | 0.81 | 4.4 | 0.46 | 1.85 |
| Control 3 | 874.0 | 92.64 | 8.0 | 0.85 | 0.92 | 18.4 | 1.96 | 2.11 |
10.2 Linearity
A linearity study was performed according to CLSI EP06-A using 11 serially diluted samples spanning the assay range. The mean was taken from each sample tested in triplicate. As presented below, the bias from the linear fit estimate was <10%. The assay is linear from 6.3 to 2000 pg/mL.
| Sample | Expected Dose (pg/mL) | Observed Dose (pg/mL) | Recovery (Observed vs Expected) | Weighted Linear Fit Estimate | Deviation from Linear Fit |
|---|---|---|---|---|---|
| A | 2.7 | 2.7 | 100% | 2.6 | 3% |
| B | 3.8 | 3.5 | 92% | 3.7 | -4% |
| C | 7.1 | 6.6 | 93% | 6.8 | -4% |
| D | 20.3 | 19.2 | 95% | 19.5 | -1% |
| E | 73.3 | 68.9 | 94% | 70.2 | -2% |
| F | 143.9 | 137.0 | 95% | 137.8 | -1% |
| G | 285.1 | 264.3 | 93% | 273.0 | -3% |
| H | 567.5 | 529.9 | 93% | 543.4 | -3% |
| I | 850.0 | 819.8 | 96% | 813.9 | 1% |
| J | 1132.4 | 1089.9 | 96% | 1084.3 | 1% |
| K | 2262.1 | 2262.1 | 100% | 2166.0 | 4% |
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10.3 Dilution Recovery
A low sample pool (~ 22 pq/mL PTH) was spiked with a commercially available synthetic PTH peptide to reach levels of approximately 3,000 pg/mL (318 pmol/L), 6,000 pg/mL (636 pmol/L) and 9,000 pg/mL (954 pmol/L). Each sample was diluted 1:5 with ADVIA Centaur Multi-Diluent 13 on-board the ADVIA Centaur XP system. All samples were run in triplicate.
| Sample | Observed Mean(pg/mL) | Expected(pg/mL) | Observed Mean(pmol/L) | Expected(pmol/L) | Recovery(%) |
|---|---|---|---|---|---|
| 1 | 3068.8 | 3020.9 | 325.3 | 320.2 | 101.6 |
| 2 | 6270.8 | 6019.8 | 664.7 | 638.1 | 104.2 |
| 3 | 9253.2 | 9018.7 | 980.8 | 956.0 | 102.6 |
| Mean | 102.8 |
10.4 Method Comparison
Method Comparison studies were done with 349 EDTA plasma patient samples distributed over the assay range to demonstrate equivalence to the Predicate (ADVIA Centaur iPTH). The ADVIA Centaur PTH assay shows good correlation in sample results compared to the Predicate. The regression equation from the analysis is presented below.
ADVIA Centaur PTH = 1.02(iPTH) – 2.18 pg/mL (r = 0.99)
10.5 Matrix Comparison
The ADVIA Centaur PTH assay was evaluated using different specimen matrices and tube collection types. A specimen collection study was performed using 56 matched specimens drawn in different tube types including serum red top, serum separator tube (SST), EDTA, lithium heparin, and sodium heparin, on two reagent lots. No significant difference between tube types was observed. The following results were obtained:
| Comparisona | Regression Equation | r |
|---|---|---|
| Serum vs. Dipotassium EDTA plasma | Serum = 0.99 EDTA – 1.85 | 0.996 |
| Serum separator tube vs. Dipotassium EDTA plasma | Serum separator tube = 1.03 EDTA + 0.20 | 0.996 |
| Lithium Heparin vs. Dipotassium EDTA plasma | Lithium Heparin = 0.99 EDTA + 1.95 | 0.998 |
| Sodium Heparin vs. Dipotassium EDTA plasma | Sodium Heparin = 1.00 EDTA + 1.03 | 0.997 |
I his study was performed using Becon Dickinson tubes. Siements that laboratories evaluate performance when using other manufacturers' tubes.
10.6 Reference Intervals
Reference intervals for the ADVIA Centaur PTH assay were established according to CLSI EP28-A3c. A total of one hundred forty-two (142) paired serum and EDTA plasma samples from apparently healthy donors were analyzed. Based on a 95% confidence interval, the following reference intervals were established.
| SampleType | Lower Limit(95% Cl) | Upper Limit(95% CI) |
|---|---|---|
| EDTA Plasma | 18.4 pg/mL | 80.1 pg/mL |
| Serum | 18.5 pg/mL | 88.0 pg/mL |
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10.7 Detection Limit
The limit of blank (LoB). limit of detection (LoD). and the limit of quantitation (LoQ) were determined as described in CLSI protocol EP17-A2. The LoB is defined as the highest measurement result that is likely to be observed for a blank sample. The LoD is defined as the lowest concentration of PTH that can be detected with 95% probability. The LoQ is defined as the lowest concentration of PTH that can be detected at a total CV of 20%.
The ADVIA Centaur PTH assay has a LoB of 1.5 pg/mL, a LoD of 3.2 pg/mL, and a LoQ of 4.6 pg/mL.
10.8 Interference
Interference studies were performed according to CLSI EP07-A2. Two EDTA sample pools were tested. One sample pool had approximately 75 pg/mL PTH. The second sample pool had approximately 600 pg/mL PTH. These sample pools were spiked with potential interferents. There was no indication of interference (< 10% effect) up to the interferent levels claimed. Results are presented below.
| Endogenous Substance | Endogenous SubstanceConcentration | Interference(%) |
|---|---|---|
| Hemoglobin | 500 mg/dL | -4.5 |
| Triglycerides | 3275 mg/dL | -0.4 |
| Bilirubin (unconjugated) | 60 mg/dL | -2.2 |
| Bilirubin (conjugated) | 60 mg/dL | 5.9 |
| Biotin | 1000 ng/mL | 6.9 |
| Cholesterol | 500 mg/dL | -6.5 |
| Total Protein (high) | 12 g/dL | -4.2 |
| Total Protein (low) | 6 g/dL | -7.5 |
| IgG | 6 g/dL | 1.3 |
| Calcitrol | 360 pg/mL | 2.5 |
| Furosemide | 181 µmol/L | -2.6 |
| Caffeine | 308 µmol/L | 2.3 |
| Aliskiren | 200 µg/mL | 5.3 |
| Enalaprilat | 0.86 µmol/L | -2.6 |
| Epoetin alfa | 15 mU/L | -1.2 |
| Fosrenol | 20 ng/mL | 3.4 |
Six human plasma samples containing human anti-mouse antibodies (HAMA) were tested at 2 PTH concentrations. Samples at a PTH concentration of 60 pg/mL (6.36 pmol/L) demonstrated a difference of -11.5% to 3.2% from the expected values. Samples at a PTH concentration of 340 pg/mL (36.04 pmol/L) demonstrated a difference of -3.8% to 2.4% from the expected values.
10.9 Cross-Reactivity
Cross reactivity was evaluated in the ADVIA Centaur iPTH immunoassay using a normal human EDTA plasma sample and blank assay diluent for each test compound. An aliquot of
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510(k) Summary of Safety and Effectiveness
each sample was spiked with test compound so that the final test sample contained the compound at the required concentration. A second aliquot of the base pool is spiked with just the diluent to serve as a control sample. Multiple replicates of the test and control samples are processed. Cross-reactivity was calculated as the % difference between the mean test and control sample results, with respect to the test compound concentration. Results are presented below.
| Cross-Reactant(Conc.) | Normal Patient (pg/mL) | Blank (MD13) (pg/mL) | ||
|---|---|---|---|---|
| Calcitonin(100,000 pg/mL) | Test | 30.39 | Test | 0.34 |
| Control | 30.33 | Control | 0.00 | |
| %XR | 0.0001% | %XR | 0.0003% | |
| Beta-CrossLaps(10,000 pg/mL) | Test | 30.40 | Test | 0.00 |
| Control | 31.15 | Control | 0.00 | |
| %XR | -0.0075% | %XR | 0.0000% | |
| Osteocalcin(50,000 pg/mL) | Test | 30.56 | Test | 0.00 |
| Control | 30.71 | Control | 0.00 | |
| %XR | -0.0003% | %XR | 0.0000% | |
| PTH (1-34)(12,000 pg/mL) | Test | 30.87 | Test | 0.00 |
| Control | 30.79 | Control | 0.00 | |
| %XR | 0.0007% | %XR | 0.0000% | |
| PTH (39-68)(100,000 pg/mL) | Test | 30.66 | Test | 0.00 |
| Control | 30.69 | Control | 0.00 | |
| %XR | 0.0000% | %XR | 0.0000% | |
| PTH (53-84)(100,000 pg/mL) | Test | 29.81 | Test | 0.00 |
| Control | 30.74 | Control | 0.00 | |
| %XR | -0.0009% | %XR | 0.0000% | |
| PTH (44-68)(100,000 pg/mL) | Test | 30.57 | Test | 0.00 |
| Control | 30.24 | Control | 0.00 | |
| %XR | 0.0003% | %XR | 0.0000% | |
| PTH (39-84)(100,000 pg/mL) | Test | 30.24 | Test | 0.00 |
| Control | 29.82 | Control | 0.00 | |
| %XR | 0.0004% | %XR | 0.0000% | |
| PTH-RP (1-34)(100,000 pg/mL) | Test | 30.13 | Test | 0.00 |
| Control | 29.95 | Control | 0.00 | |
| %XR | 0.0002% | %XR | 0.0000% | |
| PTH (7-84)(300 pg/mL) | Test | 141.94 | Test | 52.51 |
| Control | 29.85 | Control | 0.00 | |
| %XR | 37.36% | %XR | 17.5033% |
10.10 High-Dose Hook Effect
Patient samples with high intact PTH levels can cause a paradoxical decrease in the RLUs (high-dose hook effect). In this assay, patient samples with intact PTH levels as high as 100,000 pg/mL (10,600 pmol/L) are reported as > 2000 pg/mL (> 212 pmol/L).
10.11 Stability
The onboard stability of the ADVIA Centaur PTH reagents is 28 days with a calibration interval of 21 days. Unopened reagents and calibrators are stable until the date printed on the box label when stored at 2-8°C.
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10.12 Clinical Study
A clinical study was performed to confirm the effectiveness of the ADVIA Centaur® Intact Parathyroid Hormone (PTH) assay for Intra-operative (IO) use. Sets of specimens from 30 subjects that qualified for the primary endpoints (described below), that met the inclusion criteria, and which were not excluded based on exclusion criteria, were analyzed using the ADVIA Centaur PTH assay on the Centaur XP system.
The following Inclusion/exclusion criteria were used:
Inclusion Criteria
- Patients undergoing parathyroid surgery with intra-operative parathyroid (PTH) . testing.
- Patients who have available preoperative calcium and PTH measurements .
- Patients who have baseline PTH and PTH monitored on the day of surgery on a . clinical PTH test device cleared by the FDA for use intra-operatively.
Exclusion Criteria
- Patients who do not meet inclusion criteria.
- Specimens for which handling and storage quidelines aren't followed.
- Specimens which do not have sufficient quantity available for testing.
- Specimens from pediatric subjects (<21 years old.)
Specimens underwent testing in single replicates on both the ADVIA Centaur XP PTH assay and the comparator (hospital) assays.
For this clinical study, the 'Miami' criterion was utilized to determine 'success'.
Miami Criterion: A successful surgery is defined to be a 50% or greater drop in PTH level from the greater of the pre-incision or pre-excision baseline values to the 10 minute post-excision test result after the last parathyroid gland excision.
The analyses were based on agreement between the ADVIA Centaur PTH Assay (investigational device) and the assays used by participating surgeons/sites (comparator devices), utilizing the same criteria of a successful surgery for each. Concordance between the surgeon's assays and PTH is presented in the table below.
| PTH Assay Used DuringSurgery | |||
|---|---|---|---|
| Successful | Unsuccessful | ||
| ADVIA CentaurPTH | Successful | 29 | 1* |
| Unsuccessful | 0 | 0 |
The above table displays success based on the Miami criteria for the first 30 set of patient samples that have a 10 minute post-excision draw.
Primary Endpoint Positive Agreement = 29/29 = 100%
Primary Endpoint Overall Agreement = 29/30 = 96.7%
- Note that for one subject, local PTH device did not reach 50% drop from baseline until a blood draw after the 10 minute draw, therefore by the Miami criterion for the surgery is defined as a failure'. That subject's specimens yielded only a 48% drop in PTH values by 10 minutes post-excision with the assay used during surgery, but a 55% drop with the ADVA
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Centaur PTH assay run onsite. This was the only set of patient samples that were discrepant based on the Miami criterion definition of success.
Conclusions 11.
Based on the results of comparative testing, the new ADVIA Centaur Intact Parathyroid Hormone (PTH) assay is substantially equivalent in principle and performance to the currently-marketed predicate device, the ADVIA Centaur Intact Parathyroid Hormone (iPTH) assay, cleared under 510(k) K133601.
§ 862.1545 Parathyroid hormone test system.
(a)
Identification. A parathyroid hormone test system is a device intended to measure the levels of parathyroid hormone in serum and plasma. Measurements of parathyroid hormone levels are used in the differential diagnosis of hypercalcemia (abnormally high levels of calcium in the blood) and hypocalcemia (abnormally low levels of calcium in the blood) resulting from disorders of calcium metabolism.(b)
Classification. Class II.