(217 days)
The IDS-iSYS Ostase® BAP assay is an in vitro diagnostic device intended for the quantitative determination of bone-specific alkaline phosphatase (BAP), an indicator of osteoblastic activity, in human serum on the IDS system. Results are to be used in conjunction with other clinical and laboratory data to aid the clinician in the management of postmenopausal osteoporosis and Paget's disease.
The IDS-iSYS Ostase® BAP assay consists of one reagent cartridge and one set of calibrators (CAL A & CAL B).
The reagent cartridge contains multiple reagents:
- MPM1 (Magnetic particles coated with streptavidin in a phosphate buffer with sodium azide as preservative);
- Ab-BIOT Monoclonal anti-BAP labelled with biotin, in buffer containing horse serum with bovine and mouse proteins and sodium azide as a preservative (<0.1 %)
- -SUBS (p-nitrophenyl phosphate in a stabilising buffer containing preservatives).
Calibrators A and B are buffered bovine protein matrix containing human BAP with sodium azide as preservative (<0.1 %).
The provided document is a 510(k) Premarket Notification from the FDA for a medical device called "IDS-iSYS Ostase® BAP." This document is primarily concerned with demonstrating the substantial equivalence of the new device to a predicate device, rather than focusing on the acceptance criteria and study proving performance for an AI/ML-based medical device.
Therefore, the requested information regarding AI/ML-specific acceptance criteria and validation studies (like sample size for test set, data provenance, number of experts for ground truth, adjudication methods, MRMC studies, standalone performance, training set details) is not present in this document because it describes an in vitro diagnostic (IVD) test for quantitative determination of bone-specific alkaline phosphatase, not an AI/ML-driven imaging or diagnostic algorithm.
However, I can extract the relevant performance characteristics that are analogous to "acceptance criteria" for this type of IVD device and the study data proving it meets those.
Device Description
The IDS-iSYS Ostase® BAP assay is an in vitro diagnostic device intended for the quantitative determination of bone-specific alkaline phosphatase (BAP), an indicator of osteoblastic activity, in human serum on the IDS system. Results are to be used in conjunction with other clinical and laboratory data to aid the clinician in the management of postmenopausal osteoporosis and Paget's disease.
1. Table of Acceptance Criteria (Performance Characteristics) and Reported Device Performance
For an in vitro diagnostic device, "acceptance criteria" are typically defined by various analytical performance characteristics that demonstrate the device's accuracy, precision, and reliability for its intended use. While explicit acceptance ranges are not always presented as a separate "criteria" table in a 510(k), the studies conducted implicitly aim to demonstrate performance within acceptable ranges for IVDs. The comparison to the predicate device and adherence to CLSI guidelines are key for demonstrating substantial equivalence.
Here's a table summarizing the analytical performance characteristics and the reported device performance, which serve as the "proof" that the device meets the implied acceptance criteria for an IVD:
| Performance Characteristic | Acceptance Criteria (Implied / Comparator) | Reported Device Performance (IDS-iSYS Ostase® BAP) |
|---|---|---|
| Precision | Typically aims for low %CV (Coefficient of Variation) within and between runs, indicating reproducibility. Compared to predicate: - Predicate Within Run: 2.6% to 6.5% (7.4 to 79.5 μg/L) - Predicate Between Run: 2% to 6.4% (8.4 to 81.1 µg/L) | Repeatability (Within Run): From 1.7% to 2.8% in the concentration range 6.2 to 59.8 µg/L (N=80 data points for each sample, for one representative lot). From 1.7% to 2.8% for combined 3 lots across samples 1-10 (6.2-59.8 μg/L). Within Laboratory (Between Run/Total Precision): From 3.0% to 7.6% in the concentration range 6.2 to 59.8 µg/L (N=80 data points for each sample, for one representative lot). From 3.0% to 7.2% for combined 3 lots across samples 1-10 (6.2-59.8 μg/L). Overall, shows robust precision comparable or improved relative to the predicate. |
| Linearity / Reportable Range | The assay should demonstrate linearity across its claimed measuring range. Expected a high correlation coefficient (R²) close to 1.0. - Predicate Range: 0.7 – 90 µg/L. | Linear Range: 0.9 to 78.5 µg/L. Measuring (Reportable) Range: 3 to 70 µg/L. Regression: Observed = 0.98 x (Expected) - 0.9 ng/mL. Regression coefficient R²: 1.00. The high R² demonstrates excellent linearity across the range. |
| Detection Limits (LoB, LoD, LoQ) | Low values for LoB (Limit of Blank), LoD (Limit of Detection), and LoQ (Limit of Quantitation) are desirable to demonstrate the ability to detect very low concentrations of the analyte. - Predicate: LoD 0.7 µg/L. Other values N/A. | LoB (Limit of Blank): 0.3 µg/L LoD (Limit of Detection): 0.4 µg/L LoQ (Limit of Quantitation): 0.5 µg/L Demonstrates improved or comparable sensitivity to the predicate. |
| Analytical Specificity (Interference) | Bias due to common interfering substances should be non-significant, typically defined as <10% bias between test and control samples. | Non-significant interference (<10% bias) observed for: Acetaminophen, Alendronate, Bilirubin (Conjugated & Unconjugated), Biotin, Calcium Chloride, Cholesterol, Estradiol, Etidronate, Haemoglobin, HAMA, Ibuprofen, Pamidronate, Progesterone, PTH 1-34, PTH 1-84, Raloxifene, Red Blood Cells, Rheumatoid Factor (RF), Risedronate, Salicylic Acid (Asprin), Salmon Calcitonin, Total Protein, Triglycerides, 25-hydroxyvitamin D. Tested at specified high concentrations (e.g., Bilirubin 40 mg/dL, Biotin 400 ng/mL, Haemoglobin 300 mg/dL etc.). |
| Analytical Specificity (Cross-Reactivity) | Low percent cross-reactivity with structurally similar substances is desired to ensure specificity to BAP. | Low cross-reactivity observed for: - Liver ALP (745 µg/L spiked): 0.1% - Placental ALP (90 U/L spiked): 0.5% - Intestinal ALP (500 µg/L spiked): Undetectable Demonstrates high specificity to BAP. |
| Method Comparison | Strong correlation and agreement with the legally marketed predicate device (Ostase® BAP EIA) is required for substantial equivalence. A slope close to 1.0 and an intercept close to 0, with a high correlation coefficient (r) close to 1.0, are expected. - Predicate comparison to Tandem-R Ostase: slope 1.02, intercept 0.28, r = 0.97. | Comparison against Ostase® BAP EIA: - N: 150 samples - Slope: 0.99 (95% CI: 0.97 to 1.02) - Intercept: 0.17 µg/L (95% CI: -0.1 to 0.5) - Correlation Coefficient (r): 0.99 These results demonstrate excellent agreement and strong correlation, supporting substantial equivalence. |
| Stability | The device should maintain its performance over a defined shelf life. | Shelf Life: 12 months, determined based on real-time studies. |
| Expected Values / Reference Range | Established ranges for different populations. Consistency with established clinical understanding. | Population-specific BAP Concentrations (µg/L) for IDS-iSYS Ostase® BAP: - Males (N=140): Mean 13.7, Median 13.0, Observed Range 7.9 to 23.5 - Pre-menopausal (N=140): Mean 11.5, Median 11.1, Observed Range 5.9 to 20.5 - Post-menopausal (N=139): Mean 15.7, Median 14.3, Observed Range 7.9 to 34.2 These values are consistent with the general understanding of BAP levels in these populations, though laboratories are advised to establish their own ranges. |
Study Details (Based on the Provided Document)
As this is an IVD device, not an AI/ML system, many of the AI/ML-specific questions are not applicable. However, I will address what is implied or directly stated in the context of an IVD submission.
2. Sample Size Used for the Test Set and Data Provenance:
- Precision/Reproducibility:
- 10 native serum samples.
- Each sample assayed 80 replicates (in duplicate, twice per day for 20 days) on one system (representative lot) and 240 replicates (combined from 3 lots, 3 systems).
- Data provenance not explicitly stated (e.g., country of origin, retrospective/prospective), but implied to be laboratory-based analytical studies.
- Linearity:
- Not specified how many serum samples (a high and a low human serum sample were used to create 11 dilutions, but the N for testing these dilutions is not given).
- Detection Limits (LoB, LoD, LoQ):
- LoB: 60 replicates of blank per kit lot (total 180 over 3 lots).
- LoD & LoQ: 10 low BAP concentration samples tested per kit lot (details on number of replicates not fully clear, mentions tested in duplicate for 5 days per lot).
- Analytical Specificity (Interference/Cross-Reactivity):
- For interference: Two serum samples at two different BAP concentrations were spiked with potential interferents. For each condition, 26 replicate assays were performed for spiked and control samples.
- For cross-reactivity: Not explicitly stated, but substances were spiked into serum samples and measured.
- Method Comparison:
- N = 150 samples.
- Samples were "selected to represent a wide range of BAP concentrations [3.0 to 67.6 ug/L]".
- Data provenance not explicitly stated (e.g., country of origin, retrospective/prospective).
- Expected Values/Reference Range:
- N = 419 apparently healthy donors from the United States.
- 140 males (35 to 75 years of age)
- 140 pre-menopausal women (35 to 45 years of age)
- 139 post-menopausal women (55 to 75 years of age).
- This is a prospective collection of reference interval data.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
- Not applicable in the AI/ML sense. For IVD tests measuring a biomarker like BAP, the "ground truth" is typically the quantitative value obtained from a reference method or the assigned values of traceable calibrator materials. No human expert "adjudication" or "ground truth labeling" of the BAP level in a sample is described as a part of establishing test set ground truth; rather, it’s about the measured BAP concentration.
- The calibrators for the new device are traceable to the predicate device via internal standards that were value-assigned using the predicate assay procedure. This method of traceability establishes the "truth" for calibration.
4. Adjudication Method for the Test Set:
- Not applicable. As above, for an IVD, the measurement itself is the "truth" within the context of the assay's analytical performance. No human adjudication is involved in determining the concentration of BAP in a blood sample for these types of studies.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done:
- No. MRMC studies are specific to image-based diagnostic aids where multiple human readers' performance is evaluated and compared with and without AI assistance. This document describes an in vitro diagnostic assay that quantifies a substance in human serum, not an imaging device.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:
- Yes, in essence. For an IVD, the "standalone" performance is the analytical performance of the assay itself – its precision, linearity, detection limits, specificity, and comparison to a predicate device. The performance characteristics described in Section 1 (Precision, Linearity, Detection Limits, Analytical Specificity, Method Comparison) represent the standalone performance of the IDS-iSYS Ostase® BAP assay. It is designed to provide a quantitative result without direct human "interpretation" of the assay's output in the way an AI would assist a radiologist.
7. The Type of Ground Truth Used:
- Analytical Ground Truth (for analytical performance): For precision, linearity, detection limits, and specificity, the "ground truth" refers to:
- The known properties of control materials or spiked samples.
- The measured values from samples used in reproducibility studies.
- The established values/performance of the predicate device (for comparison studies).
- Reference Intervals (for clinical context): For expected values, the "ground truth" is derived from a defined cohort of apparently healthy individuals, and ranges are statistically determined (e.g., 2.5th to 97.5th percentile).
8. The Sample Size for the Training Set:
- Not applicable (in the AI/ML sense). This device is an IVD assay, not an AI/ML model that requires training on a vast dataset. The "training" for an IVD involves assay development, reagent optimization, and establishing manufacturing controls, not statistical model training based on patient data.
- The calibrators for the device are value-assigned using a method traceable to the predicate device. This process involves testing calibrators in multiple runs (minimum 20 assay runs on one system) to determine their assigned values. This could be considered analogous to "training" the assay system to accurately report concentrations based on known standards.
9. How the Ground Truth for the Training Set Was Established:
- Not applicable (in the AI/ML sense). However, for an IVD, the "ground truth" for calibrator and control materials is established through:
- Traceability: The IDS-iSYS Ostase® BAP kit calibrators are value assigned against in-house secondary standards (IRs). These IRs are themselves value assigned against the predicate device (Ostase® BAP EIA assay) using the predicate assay procedure. This establishes traceability to a previously cleared, legally marketed device.
- Verification: The assigned kit calibrator values are then verified by running the assay on three different IDS systems and analyzing internal quality control (IQC) samples of known values across the range of the assay.
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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
September 30, 2020
Immunodiagnostic Systems Ltd. Mick Henderson RA Manager 10 Didcot Way, Boldon Business Park Boldon, Tyne and Wear NE35 9PD United Kingdom
Re: K200475
Trade/Device Name: IDS-iSYS Ostase® BAP Regulation Number: 21 CFR 862.1050 Regulation Name: Alkaline phosphatase or isoenzymes test system Regulatory Class: Class II Product Code: CIN Dated: August 27, 2020 Received: August 31, 2020
Dear Mick Henderson:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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
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542 of the Act); 21 CFR 1000-1050.
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 Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-
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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Marianela Perez- Torres, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K200475
Device Name IDS-iSYS Ostase® BAP
Indications for Use (Describe)
The IDS-iSYS Ostase® BAP assay is an in vitro diagnostic device intended for the quantitative determination of bonespecific alkaline phosphatase (BAP), an indicator of osteoblastic activity, in human serum on the IDS system. Results are to be used in conjunction with other clinical and laboratory data to aid the clinician in the management of postmenopausal osteoporosis and Paget's disease.
| 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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Image /page/3/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, connected font, with a red circle above the "i". Below the letters, the words "immunodiagnosticsystems" are written in a smaller, red font. A registered trademark symbol is located to the right of the logo.
510(k) SUMMARY
| 510k Number | K200475 |
|---|---|
| Introduction | According to the requirements of 21CFR807.92, the followinginformation provides sufficient detail to understand the basis for adetermination of substantial equivalence. |
| Submitter | Immunodiagnostic Systems Limited10 Didcot WayBoldon Business ParkBoldonTyne and WearNE35 9PDUnited Kingdom |
| Contact Person: Mick HendersonPhone: +44 191 5190660Fax: +44 191 5190760Email: mick.henderson@idsplc.com | |
| Secondary Contact: Alexandra BennettPhone: +44 191 5190660Fax: +44 191 5190760Email: alexandra.bennett@idsplc.comDate prepared: 28 September 2020 | |
| Device Name | Proprietary names: IDS-iSYS Ostase® BAP |
| Common names: As above | |
| Classification: 21CFR862.1050 Alkaline phosphatase orisoenzymes test system. | |
| Class II | |
| Product Code: CIN |
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Image /page/4/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters 'ids' in a stylized, interconnected design, with a small red circle above the 'i'. Below the main logo, the words 'immunodiagnosticsystems' are written in a smaller, sans-serif font, with the first word in red and the second in gray. The 'R' in a circle indicates that the logo is a registered trademark.
- Predicate Device The IDS-iSYS Ostase® BAP is substantially equivalent to other products in commercial distribution intended for similar use. We claim equivalency to the currently marketed Tandem-MP Ostase Immunoenzymetric Assay (K972666), commercially known as Ostase® BAP EIA.
Device Description The IDS-iSYS Ostase® BAP assay consists of one reagent cartridge and one set of calibrators (CAL A & CAL B).
The reagent cartridge contains multiple reagents:
- MPM1 (Magnetic particles coated with streptavidin in a phosphate buffer with sodium azide as preservative);
- Ab-BIOT Monoclonal anti-BAP labelled with biotin, in buffer containing horse serum with bovine and mouse proteins and sodium azide as a preservative (<0.1 %)
- -SUBS (p-nitrophenyl phosphate in a stabilising buffer containing preservatives).
Calibrators A and B are buffered bovine protein matrix containing human BAP with sodium azide as preservative (<0.1 %).
- Indications for Use The IDS-iSYS Ostase® BAP assay is an in vitro diagnostic device intended for the quantitative determination of bone-specific alkaline phosphatase (BAP), an indicator of osteoblastic activity, in human serum on the IDS system. Results are to be used in conjunction with other clinical and laboratory data to aid the clinician in the management of postmenopausal osteoporosis and Paget's disease.
- Conditions for use: For in vitro diagnostic use only. Rx Only
Special instrument Requirements:
IDS System (K091849)
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Image /page/5/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters 'ids' in a stylized, gray font, with a red circle above the 'i'. Below the letters, the words 'immunodiagnosticsystems' are written in a smaller, red font. A circled 'R' trademark symbol is located in the upper right corner of the logo.
Comparison Tables
Similarities compared to the chosen (FDA cleared; marketed) predicate device (K972666)
Assay
| AssayPerformance | Predicate DeviceTandem-MP OstaseImmunoenzymetric Assay(K972666), commerciallyknown as Ostase® BAP EIA | Candidate DeviceIDS-iSYS Ostase® BAP(K200475) |
|---|---|---|
| Intended Use | For quantitative determination ofBone Alkaline Phosphataseconcentration | For quantitative determination ofBone Alkaline Phosphataseconcentration |
| Analyte | Bone Alkaline Phosphatase | Bone Alkaline Phosphatase |
| SampleVolume | 50 μL | 50 μL |
| Sample Type | Human Serum | Human Serum |
| Specificity,Interferingsubstances &CrossReactivity | Interfering SubstancesAcetaminophen 20 mg/dLAlendronate 5 mg/dLAsprin 50 mg/dLBilirubin –unconjugated 40 mg/dLCalcitonin – salmon 112 IU/dLCalcium 20 mg/dLIbuprofen 40 mg/dLPamidronate 18 mg/dLProgesterone 25 mg/dL | Interfering SubstancesAcetaminophen SameAlendronate SameAsprin SameBilirubin –unconjugated SameCalcitonin - salmon SameCalcium SameIbuprofen SamePamidronate SameProgesterone Same |
| Performance | Predicate DeviceTandem-MP OstaseImmunoenzymetric Assay(K972666), commercially knownas Ostase® BAP EIA | Candidate DeviceIDS-iSYS Ostase® BAP(K200475) |
| Indicationsfor Use | The Ostase® BAP EIA Assay is anin vitro device indicated for thequantitative measurement of bone-specific alkaline phosphatase(BAP), an indicator of osteoblasticactivity, in human serum. Thisdevice is intended to be used as anaid in the management ofpostmenopausal osteoporosis andPaget's disease. | The IDS-iSYS Ostase® BAPassay is an in vitro diagnosticdevice intended for thequantitative determination ofbone-specific alkaline phosphatase(BAP), an indicator of osteoblasticactivity, in human serum on theIDS system. Results are to be usedin conjunction with other clinicaland laboratory data to aid theclinician in the management ofpostmenopausal osteoporosis andPaget's disease |
| Method ofdetection(Testmethodology) | Manual | Automated |
| Kit reagentcomponents | Conjugate (1 x 14 mL)anti-BAP(mouse monoclonal IgG)with biotin in a bovine/horse proteinmatrix with 0.09% sodium azideMicroplates (1 x 96 wells)Streptavidin coated plastic wellstripsZero Calibrator (1 x 14 mL)A bovine protein matrix containingno detectable concentration of BAPand 0.09% sodium azideCalibrators (1-5) (5 x 1 mL)A bovine protein matrix containingapproximately 7, 15, 30, 60 and 90ug human BAP/L and 0.09%sodium azide | Reagent CartridgeMPM1 (1 x 2.6 mL)Magnetic particles coated withstreptavidin in a Phosphate bufferwith sodium azide as preservative(<0.09%)Ab-BIOT (1 x 10.5 mL)Monoclonal anti-BAP labelledwith biotin, in buffer containinghorse serum with bovine andmouse proteins and sodium azideas a preservative (<0.09%) |
| Low Control (1 x 1 mL)A bovine protein matrix containingapproximately 11 ug human BAP/Land 0.09% sodium azide | SUBS (1 x 40 mL)p-nitrophenyl phosphate in astabilizing buffer containingpreservatives | |
| High Control (1 x 1 mL)A bovine protein matrix containingapproximately 45 ug human BAP/Land 0.09% sodium azide | Calibrators (1 each of 2concentrations levels – 2.5ml perbottle).A buffered bovine protein matrixcontaining human BAP withsodium azide as preservative(<0.09%) | |
| Wash Concentrate (1 x 50 mL)Phosphate buffered salinecontaining Tween | ||
| Substrate (1 x 20 mL)p-nitrophenyl phosphate in astabilizing buffer containingpreservatives | ||
| Quench Reagent (1 x 14ml)1 N Sodium hydroxide | ||
| Range of assay | 0.7 – 90 μg/L | 3 – 70 μg/L |
| Sensitivity | LoB N/ALoD 0.7 µg/LLoQ N/A | LoB 0.3 µg/LLoD 0.4 µg/LLoQ 0.5 µg/L |
| Expectedvalues | MalesMean 12.3 µg/LMedian 11.6 µg/L95th percentile 20.1 µg/LPre-MenopausalMean 8.7 µg/LMedian 8.5 µg/L95th percentile 14.3 µg/LPost-MenopausalMean 13.2 µg/LMedian 12.5 µg/L95th percentile 22.4 µg/L | MalesMean 13.7 µg/LMedian 13 µg/LRange 7.9 to 23.5 μg/LPre-MenopausalMean 11.5 µg/LMedian 11.1 µg/LRange 5.9 to 20.5 μg/LPost-MenopausalMean 15.7 µg/LMedian 14.3 µg/LRange 7.9 to 34.2 μg/L |
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Image /page/6/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, gray font, with a red circle above the "i". Below the letters, the words "immunodiagnosticsystems" are written in a smaller, red font. A registered trademark symbol is located to the right of the "s" in "ids".
Differences compared to the chosen (FDA cleared; marketed) predicate device (K972666)
Assay
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Image /page/7/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, gray font, with a red circle above the "i". Below the letters, the words "immunodiagnostic systems" are written in a smaller, red font. The logo is simple and modern, with a focus on the company's name and area of expertise.
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Image /page/8/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, sans-serif font, with a red circle above the "i". Below the letters, the words "immunodiagnostic systems" are written in a smaller, sans-serif font.
| Precision | Within Run Precision n =202.6% to 6.5% in the concentrationrange 7.4 to 79.5 μg/LBetween Run Precision n = 202% to 6.4% in the concentrationrange 8.4 to 81.1 µg/L | Repeatability n =801.7% to 2.8% in the concentrationrange 6.2 to 59.8 µg/LWithin Laboratory n = 803.0% to 7.6% in the concentrationrange 6.2 to 59.8 µg/L | ||
|---|---|---|---|---|
| Specificity,InterferingsubstancesAndCrossReactivity | Interfering Substances | Interfering Substances | ||
| Bilirubin –conjugatedBiotinCholesterolEstradiolEtidronateHaemoglobinHAMAPTH 1-34PTH 1-84RaloxifeneRed Blood CellsRheumatoid Factor(Rf)RisedronateTotal ProteinTriglycerides25-hydroxyvitamin D | Bilirubin –20 mg/dLconjugatedNo ClaimBiotinNo ClaimCholesterol400 ng/dLEstradiol105 mg/dLEtidronate500 mg/dLHaemoglobinNo ClaimHAMANo ClaimPTH 1-34No ClaimPTH 1-84No ClaimRaloxifeneNo ClaimRed Blood CellsNo ClaimRheumatoid Factor(Rf)No ClaimRisedronateNo ClaimTotal Protein14 g/dLTriglycerides2000 mg/dL25-hydroxyvitamin D80,500 IU/dL | Bilirubin –40 mg/dLconjugatedBiotin400 ng/mLCholesterol340 mg/dLEstradiol400 µg/mLEtidronate90 mg/dLHaemoglobin300 mg/dLHAMA4000 ng/mLPTH 1-3420 µg/dLPTH 1-8411.8 µg/dLRaloxifene20 µg/mLRed Blood Cells0.3%Rheumatoid Factor(Rf)1200 IU/mLRisedronate50 µg/dLTotal Protein12 g/dLTriglycerides667 mg/dL25-hydroxyvitamin D125 ng/mL | ||
| Cross ReactivityIntestinal ALP100U/L yields a result of 1.0 µg/LLiver ALP100 U/L yields a result of 6.2µg/LPlacental ALPNon detectable | Cross ReactivityIntestinal ALPSpiked 745 µg/L yields 0.1%Liver ALPSpiked 90 U/L yields 0.5%Placental ALPNon detectable | |||
| Methodcomparison | Against Tandem-R Ostase(K961573)n = 136$Ostase® BAP EIA =1.02 x (Tandem-R Ostase) +0.28 µg/L$Correlation coefficient (r) = 0.97 | Against Ostase® BAP EIA:n = 150$IDS-iSYS Ostase® BAP =0.99 x (Ostase® BAP EIA) +0.17µg/L$Correlation coefficient (r) = 0.99 |
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Image /page/9/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, connected font, with a red dot above the "i". Below the letters, the words "immunodiagnosticsystems" are written in a smaller, red font. The logo is simple and modern, with a focus on the company's name and area of expertise.
| Linearity | No Claim | Observed = |
|---|---|---|
| 0.98 x (Expected) -0.9 µg/L | ||
| Regression coefficient R2: 1.00 |
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Image /page/10/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, connected font, with a red circle above the "i". Below the letters, the words "immunodiagnosticsystems" are written in a smaller, sans-serif font. A registered trademark symbol is located to the right of the "s" in "ids".
Performance Characteristics (if/when applicable):
-
- Analytical performance:
a. Precision/Reproducibility:
Precision was evaluated in accordance with a modified protocol based on CLSI EP-5A3, "Evaluation of Precision Performance of Quantitative Measurement Methods". Ten (10) native serum samples were assayed using three reagent lots in duplicate, twice per day for 20 days (n= 80 replicates per sample) on three systems.
| Mean | Repeatability | Within Laboratory | ||||
|---|---|---|---|---|---|---|
| Sample | N | Conc.(µg/L) | SD (µg/L) | %CV | SD (µg/L) | %CV |
| Sample 1 | 80 | 6.1 | 0.2 | 2.5% | 0.2 | 2.8% |
| Sample 2 | 80 | 8.4 | 0.1 | 1.6% | 0.2 | 2.8% |
| Sample 3 | 80 | 11.4 | 0.2 | 2.0% | 0.4 | 3.9% |
| Sample 4 | 80 | 12.1 | 0.3 | 2.2% | 0.5 | 4.5% |
| Sample 5 | 80 | 18.0 | 0.4 | 2.4% | 0.8 | 4.5% |
| Sample 6 | 80 | 19.8 | 0.5 | 2.5% | 0.9 | 4.6% |
| Sample 7 | 80 | 45.1 | 1.2 | 2.7% | 1.6 | 3.5% |
| Sample 8 | 80 | 52.4 | 1.0 | 1.9% | 1.9 | 3.5% |
| Sample 9 | 80 | 54.3 | 0.9 | 1.7% | 1.6 | 2.9% |
| Sample 10 | 80 | 58.6 | 1.1 | 1.8% | 1.5 | 2.5% |
Results from one representative reagent lot (Lot #3):
Results for the combined 3 lots:
| Sample | N | Mean Conc. (µg/L) | Repeatability SD (µg/L) | %CV | Within Laboratory SD (µg/L) | %CV |
|---|---|---|---|---|---|---|
| Sample 1 | 240 | 6.2 | 0.2 | 2.8% | 0.4 | 5.9% |
| Sample 2 | 240 | 8.7 | 0.1 | 1.7% | 0.5 | 6.2% |
| Sample 3 | 240 | 11.7 | 0.3 | 2.5% | 0.8 | 6.6% |
| Sample 4 | 240 | 12.5 | 0.3 | 2.4% | 0.9 | 7.1% |
| Sample 5 | 240 | 18.4 | 0.4 | 2.4% | 1.3 | 6.8% |
| Sample 6 | 240 | 20.6 | 0.5 | 2.5% | 1.5 | 7.2% |
| Sample 7 | 240 | 45.5 | 1.0 | 2.3% | 1.4 | 3.0% |
| Sample 8 | 240 | 53.2 | 1.1 | 2.1% | 1.8 | 3.4% |
| Sample 9 | 240 | 54.7 | 0.9 | 1.7% | 2.1 | 3.9% |
| Sample 10 | 240 | 59.8 | 1.1 | 1.9% | 2.3 | 3.8% |
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Image /page/11/Picture/0 description: The image shows the logo for Immunodiagnostic Systems (IDS). The logo features the letters "ids" in a stylized, sans-serif font, with the "i" having a red circular dot above it. Below the letters, the words "immunodiagnosticsystems" are written in a smaller, red font. The logo has a registered trademark symbol in the upper right corner.
b. Linearity/assay reportable range:
A linearity study was conducted based on CLSI EP6-A for the candidate device. A high human serum sample and a low human serum sample were used to create 11 evenly spaced dilutions by mixing the high and low sample to cover the assay measuring range as indicated below:
| Sample | Dilution | Dilution Factor (%) |
|---|---|---|
| 1: | Low (L) | 0 |
| 2: | 0.90L + 0.10H | 10 |
| 3: | 0.80L + 0.20H | 20 |
| 4: | 0.70L + 0.30H | 30 |
| 5: | 0.60L + 0.40H | 40 |
| 6: | 0.50L + 0.50H | 50 |
| 7: | 0.40L + 0.60H | 60 |
| 8: | 0.30L + 0.70H | 70 |
| 9: | 0.20L + 0.80H | 80 |
| 10: | 0.10L + 0.90H | 90 |
| 11: | High (H) | 100 |
Results:
Observed = 0.98 x (Expected) -0.9 ng/mL Regression coefficient R2: 1.00
The IDS-iSYS Ostase® BAP assay linear range was determined as 0.9 to 78.5 µg/L, with a measuring (reportable) range of 3 to 70 µg/L.
c. Traceability, Stability, Expected values (controls, calibrators, or methods):
Calibrator traceability and value assignment
The IDS-iSYS Ostase® BAP kit calibrators are value assigned against in house secondary standard (IRs) using an internal OC procedure. The IR's are value assigned against the predicate device (Ostase® BAP EIA assay) using the predicate assay procedure. Therefore, the kit calibrators are traceable to the predicate device via the secondary standards.
Calibrator Value Assignment and Verification Method
For kit calibrator value assignment, the kit calibrators are tested as unknowns in a minimum of 20 assay runs on one IDS-iSYS system. The secondary standards (IRs) are assayed in each of the runs, and the values of the Kit Calibrators are assigned with direct reference to the secondary standards (IRs). The assigned kit calibrator values are then verified following the IDS QC procedure; by running the assay on three different IDS systems and analyzing IQCs of known values across the range of the assay.
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Stability
Full kit stability was performed in which the kit calibrators were tested in combination with all kit combination reagents.
The stability based on real time studies determined a shelf life of 12 months.
d. Detection limit:
The limit of blank (LoB). limit of detection (LoD) and limit of quantitation (LoO) were determined with guidance from CLSI EP17-A, "Protocols for Determination of Limits of Detection and Limits of Quantitation" in three (3) kit lots.
Each LoB sample was measured in duplicate, for a total of five assays in a five-day period, generating a total of 60 replicates per kit lot. Each kit lot was tested on a different instrument. Analyse-It software was used to calculate the LoB.
The LoD was determined using ten (10) samples with very low BAP concentrations. Each LoD sample was measured in duplicate, for a total of five assays in a five-day period per kit lot. Each kit lot was tested on a different instrument. Analyse-It software was used to calculate the LoD.
The LoQ was calculated using ten (10) samples with low BAP concentration. Each LoQ sample was measured in duplicate, for a total of five assays in a five-day period. Each kit lot was tested on a different instrument. Analyse-It software was used to calculate the predicted LoQ. The claim limit for each kit lot is the actual closest value to the Analyse-It's precited value.
The limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) were determined with guidance from CLSI EP17-A, "Protocols for Determination of Limits of Detection and Limits of Quantitation" using 60 replicates of blank and 10 low level samples.
| Sensitivity | BAP Concentration (µg/L) |
|---|---|
| LoB (Limit of Blank) | 0.3 |
| LoD (Limit of Detection) | 0.4 |
| LoQ (Limit of Quantitation) | 0.5 |
e. Analytical specificity:
Interference and cross-reactivity studies were performed in accordance with the CLSI EP07-A3 Interference.
To determine potential interference, two serum samples at two different concentrations of BAP were spiked with the potential interferent. Control samples (blank) were spiked with a volume of Phosphate Buffer saline (PBS) (0 ng/mL) or relevant diluent equal to that of the spiked interferent. The mean of 26 replicate assays, for both spiked and control samples,
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were then compared. The differences observed between the mean spiked and control sample values were examined and assessed according to acceptance criteria.
For Rheumatoid factor (Rf) or total cholesterol, the interference was tested by recovery of BAP from a high serum pool spiked into a serum sample with known Rf levels or cholesterol levels. % Interference was calculated using below formula:
% Interference = (mean spiked concentration - mean un-spiked concentration) x 100 mean un-spiked concentration
% Recovery was calculated using the formula below:
Recovery value = Observed mean spiked value - Observed mean unspiked value
% Recovery = (Recovery value / Expected Recovery value (Analyte added)) x 100
The following compounds were tested and found not to interfere significantly with the test, based on the predefined acceptance criteria of non-significant interference of <10% bias between the test and control samples:
| Potential Interfering Substance | Highest concentration tested that demonstrated no significant interference |
|---|---|
| Acetaminophen | 20 mg/dL |
| Alendronate | 5 mg/dL |
| Bilirubin (Conjugated) | 40 mg/dL |
| Bilirubin (Unconjugated) | 40 mg/dL |
| Biotin | 400 ng/mL |
| Calcium Chloride | 20 mg/dL |
| Cholesterol | 325 mg/dL |
| Estradiol | 400 µg/mL |
| Etidronate | 90 mg/dL |
| Haemoglobin | 300 mg/dL |
| HAMA | 4000 ng/mL |
| Ibuprofen | 40 mg/dL |
| Pamidronate | 18 mg/dL |
| Progesterone | 25 mg/dL |
| PTH 1-34 | 20 µg/dL |
| PTH 1-84 | 11.8 µg/dL |
| Raloxifene | 20 µg/mL |
| Red Blood Cells | 0.3% |
| Rheumatoid Factor (RF) | 1200 IU/mL |
| Risedronate | 50 µg/mL |
| Salicylic Acid (Asprin) | 50 mg/dL |
| Salmon Calcitonin | 112 IU/dL |
| Total Protein | 12 g/dL |
| Triglycerides | 667 mg/dL |
| 25-hydroxyvitamin D | 125 ng/mL |
Cross-reactivity testing was performed on Liver, Placental and Intestinal derived ALP.
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the indicated substances were spiked into serum samples and measured with the IDS-iSY S Ostase® BAP, following the CLSI EP7-A2. The percent cross-reactivity was calculated using below formula:
% cross reactivity =
(Mean concentration of spiked sample - mean concentration of un-spiked sample) x100% Spike concentration
The substances with structures similar to bone alkaline phosphatase (BAP) were spiked into serum samples and measured with the IDS Ostase® BAP, following the CLSI EP7-A2. The exogenous substances were tested at the concentration listed below and determined to have the following percent cross-reactivity:
| Cross-Reactant | Spiked Concentration | % Cross Reactivity |
|---|---|---|
| Liver ALP | 745 µg/L | 0.1% |
| Placental ALP | 90 U/L | 0.5% |
| Intestinal ALP | 500 µg/L | Undetectable |
f. Assay cut-off: Not applicable
2. Comparison studies:
The IDS-iSYS Ostase® BAP assay was compared against the IDS Ostase® BAP EIA assay, following CLSI EP-9A2 "Method Comparison and Bias Estimation Using Patient A total of 150 samples, selected to represent a wide range of BAP Samples". concentrations [3.0 to 67.6 ug/L], was assayed by each method. Passing-Bablok regression analysis was performed on the comparative data:
| N | Slope | 95% CI | Intercept (µg/L) | 95% CI | Corr. Coefficient(r) |
|---|---|---|---|---|---|
| 150 | 0.99 | 0.97 to 1.02 | 0.17 | -0.1 to 0.5 | 0.99 |
3. Expected values/Reference range:
The BAP concentration was measured in serum samples collected from 419 apparently healthy donors from the United States using the IDS Ostase® BAP assay. The study population included 140 males (35 to 75 years of age), 140 pre-menopausal women (35 to 45 years of age) and 139 post-menopausal women (55 to 75 years of age). The observed ranges (2.5th to 97.5th percentile) were established, according to CLSI guideline C28-A3c, "How to Define and Determine Reference Intervals in the Clinical Laboratory" are summarized in the below table:
| Population | N | Age (years) | BAP Concentration (μg/L) |
|---|---|---|---|
| ------------ | --- | ------------- | -------------------------- |
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| Median | Min.-Max | Mean | Median | SD | Observed Range | ||
|---|---|---|---|---|---|---|---|
| Males | 140 | 49 | 35 to 75 | 13.7 | 13.0 | 4.1 | 7.9 to 23.5 |
| Pre-menopausal | 140 | 39 | 35 to 45 | 11.5 | 11.1 | 3.9 | 5.9 to 20.5 |
| Post-menopausal | 139 | 58 | 55 to 75 | 15.7 | 14.3 | 6.7 | 7.9 to 34.2 |
The above ranges should be considered as guidelines only; it is recommended that each laboratory establish its own expected range based upon its own patient population.
Conclusion:
The IDS-iSYS Ostase® BAP assay data presented and provided are complete and supports the basis for substantial equivalence to the predicate device.
§ 862.1050 Alkaline phosphatase or isoenzymes test system.
(a)
Identification. An alkaline phosphatase or isoenzymes test system is a device intended to measure alkaline phosphatase or its isoenzymes (a group of enzymes with similar biological activity) in serum or plasma. Measurements of alkaline phosphatase or its isoenzymes are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.(b)
Classification. Class II.