(321 days)
Abbott ARCHITECT Tacrolimus Assay K070820
Not Found
No
The summary describes a standard immunoassay technology (ECLIA) and its performance characteristics. There is no mention of AI, ML, or any related concepts in the device description, intended use, or performance studies. The results are determined via a calibration curve, which is a traditional method, not indicative of AI/ML.
No
This device is an immunoassay for the in vitro quantitative determination of tacrolimus, used as an aid in managing transplant patients. It is a diagnostic tool, not a therapeutic device that directly treats a condition.
Yes
The device is an immunoassay for the in vitro quantitative determination of tacrolimus, which is used as an aid in the management of liver and kidney transplant patients. This directly indicates its use for diagnostic purposes.
No
The device is an immunoassay that requires physical reagents and a specific hardware analyzer (cobas e immunoassay analyzers) to perform the test and generate results. It is not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The "Intended Use / Indications for Use" section explicitly states "Immunoassay for the in vitro quantitative determination of tacrolimus in EDTA human whole blood." The term "in vitro" is a key indicator of an IVD.
- Purpose: The assay is used "as an aid in the management of liver and kidney transplant patients receiving tacrolimus therapy." This indicates the test is performed on a biological sample (blood) outside of the body to provide information for medical decision-making.
- Device Description: The description details a laboratory-based assay using a specific technology (electrochemiluminescence immunoassay) and requiring sample preparation (pretreatment, centrifugation). This is typical of an IVD.
- Performance Studies: The document describes extensive performance evaluations including precision, accuracy, linearity, analytical specificity, and method comparison against a predicate device and a reference method (LC-MS/MS). These are standard studies for demonstrating the performance of an IVD.
- Predicate Device: The mention of a "Predicate Device(s)" with a K number (K070820; Abbott ARCHITECT Tacrolimus Assay) indicates that this device is being compared to a previously cleared IVD, which is a common pathway for regulatory clearance of new IVDs.
All of these points strongly support the classification of this device as an In Vitro Diagnostic.
N/A
Intended Use / Indications for Use
Immunoassay for the in vitro quantitative determination of tacrolimus in EDTA human whole blood. The assay is used as an aid in the management of liver and kidney transplant patients receiving tacrolimus therapy.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
Product codes (comma separated list FDA assigned to the subject device)
MLM
Device Description
The Elecsys Tacrolimus immunoassay uses the principle of electrochemiluminescence for detection and measurement. Before testing with the Elecsys Tacrolimus assay, the specimen, calibrators and controls are pretreated with the Elecsys ISD Pretreatment Reagent. The reagent lyses the cells, extracts Tacrolimus and precipitates virtually all of the blood proteins. The pretreated samples are centrifuged, and an aliquot of the resulting supernatant containing Tacrolimus is then assayed using the Elecsys Tacrolimus assay.
Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
Not Found
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Not Found
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Precision:
A seven-member panel consisting of four pooled patient and single donor spiked human whole blood samples and three controls (PreciControl ISD Level 1, 2 and 3) were measured. The protocol consisted of testing the samples in single determination in four separate aliquots (divided in two runs per day) for 21 operating days. The measurements were performed on the cobas e 411 with one reagent lot, performing rack pack calibration according to instruction for use.
All results met the pre-defined acceptance criteria for repeatability and intermediate precision.
Limit of Blank (LoB):
LoB was determined as the 95th percentile of the measurement of blank samples. The distribution of values for five analyte-free whole blood samples was determined with one reagent lot on two cobas e 411 analyzers with six runs distributed over a period of 5 days. The sample was measured in one-fold determination in each run. In summary, 30 measuring points were collected per instrument, for a total of 60 measured values.
Acceptance criterion: LoB 3 ng/mL .
Based on data, the recovery (accuracy) meets the specifications.
Linearity:
The linearity of the Tacrolimus assay was assessed on the cobas e 411 immunoassay analyzer; three dilution series were prepared from three different spiked human whole blood samples. Each dilution series included 22 dilutions. Each sample was measured 4-fold within one run and the measured concentrations were plotted against the expected sample concentration. A separate extraction was performed with the ISD Sample Pretreatment reagent for each sample measurement. The linearity data was determined in accordance with CLSI EP6-A. In a first step, a linearity check was performed with a first order (linear) regression and then with higher order models (quadratic and cubic).
Acceptance criterion:
- 2 ng/mL .
Linearity was confirmed in the range from 0.75 to 30 ng/mL.
Dilution:
To demonstrate the Tacrolimus assay dilution study, three ISD-free human whole blood samples were spiked separately with a known concentration of gravimetrically weight tacrolimus. These samples were used to prepare a dilution series of nine respective dilutions. Each sample was measured in duplicates (n=2). The dilution factor for samples outside the measuring range is 1:3. The samples prepared above were diluted with the Elecsys Diluent Universal prior to the manual pre-treatment procedure. Testing was performed on two cobas e 411 analyzers. The percent recoveries were calculated between the expected and the measured concentrations.
Analytical Specificity:
The specificity was determined using the cross-reactant compound. Each cross-reactant compound was spiked into two human whole blood samples (analyte-free and slightly elevated analyte level). Testing was performed with one reagent lot in one run. The spiked samples were evaluated at four dilutions.
Endogenous Interferences:
The effect on quantitation of analyte in the presence of endogenous interfering substances using the Tacrolimus was determined on the cobas e 411 immunoassay analyzer for the following 10 interfering substances Intralipid, Biotin, Bilirubin, Rheumatic Factor, Human Serum Albumin, IgG, Cholesterol, HASA, Uric Acid and Hematocrit using three spiked human whole blood samples (one low and one high concentration) to prepare dilution series of 10 dilutions that were tested with one reagent lot.
For Hemotocrit interfering substance the following protocol was followed:
ISD-free human EDTA blood is split into two equal volume fractions. A sample is taken to measure the initial hematocrit using a hematocrit centrifuge. Cellular constituents of each fraction are separated from the plasma either by centrifugation at approximately 1000 g for about 15 minutes or overnight sedimentation in the fridge. Blood plasma of the two fractions is then blended in a way that hematocrit concentrations of 15 % resp. 65 % are achieved. Afterwards the samples are homogenized for at least 30 min on a roller mixer at room temperature. After homogenization the two sample preparations are spiked with equal amounts of analyte (USP or other suitable reference material) to reach desired concentrations and again homogenized overnight on a roller mixer at 2-8 °C. Thereafter the two stocks (15% and 65% hematocrit) are blended in a way to obtain 11 hematocrit dilutions ranging from 15% to 65%, roller mixed for at least 30 minutes at room temperature and then measured. The recovery for every single sample was calculated based on the mean result of the respective first 10 replicates.
Acceptance criterion:
- LoO to 3 to 30 ng/mL must be
§ 862.1678 Tacrolimus test system.
(a)
Identification. A tacrolimus test system is a device intended to quantitatively determine tacrolimus concentrations as an aid in the management of transplant patients receiving therapy with this drug. This generic type of device includes immunoassays and chromatographic assays for tacrolimus.(b)
Classification. Class II (special controls). The special control is “Class II Special Controls Guidance Document: Cyclosporine and Tacrolimus Assays; Guidance for Industry and FDA.” See § 862.1(d) for the availability of this guidance document.
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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.
November 6, 2018
Roche Diagnostics Khoa Tran Regulatory Affairs Principal 9115 Hague Road Indianapolis, IN 46250
Re: K173857
Trade/Device Name: Elecsys Tacrolimus Regulation Number: 21 CFR 862.1678 Regulation Name: Tacrolimus test system Regulatory Class: Class II Product Code: MLM Dated: October 23, 2018 Received: October 24, 2018
Dear Khoa Tran:
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 mav, 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 avare 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 statutes and regulations administered by other Federal agencies. You must comply with all the Act's
1
requirements, including, but not limited to: registration and listing (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/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (OS) 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 531-542 of the Act); 21 CFR 1000-1050.
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 comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). 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 (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely.
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) K173857
Device Name Elecsys Tacrolimus
Indications for Use (Describe)
Immunoassay for the in vitro quantitative determination of tacrolimus in EDTA human whole blood. The assay is used as an aid in the management of liver and kidney transplant patients receiving tacrolimus therapy.
The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.
| 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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3
510(k) Summary
K173857
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
| Submitter Name | Roche Diagnostics | |
|---|---|---|
| Address | 9115 Hague Road | |
| Indianapolis, IN, 46250 | ||
| Contact | Khoa Tran | |
| Phone: (317) -521-3409 | ||
| FAX: (317) 521-2324 | ||
| Email: khoa.tran@roche.com | ||
| Date Prepared | November 5th, 2018 | |
| Proprietary Name | Elecsys Tacrolimus | |
| Common Name | Tacrolimus assay | |
| Classification Name | Tacrolimus Test System | |
| Product Codes | MLM, 21 CFR 862.1678 | |
| Predicate Devices | Abbott ARCHITECT Tacrolimus Assay K070820 | |
| Establishment Registration | Roche Diagnostics GmbH in Mannheim, Germany, is 9610126 | |
| Roche Diagnostics GmbH in Penzberg, Germany, is 9610529 | ||
| Roche Diagnostics in the United States is 1823260 |
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1. DEVICE DESCRIPTION
The Elecsys Tacrolimus immunoassay uses the principle of electrochemiluminescence for detection and measurement. Before testing with the Elecsys Tacrolimus assay, the specimen, calibrators and controls are pretreated with the Elecsys ISD Pretreatment Reagent. The reagent lyses the cells, extracts Tacrolimus and precipitates virtually all of the blood proteins. The pretreated samples are centrifuged, and an aliquot of the resulting supernatant containing Tacrolimus is then assayed using the Elecsys Tacrolimus assay.
Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode.
1.1. Reagents
The reagent working solution includes:
- M Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL: . Streptavidin-coated microparticles 0.72 mg/mL; preservative
- R1 Anti-Tacrolimus-S-Ab~biotin (gray cap), 1 bottle, 10 mL: . Biotinylated monoclonal anti-tacrolimus-antibody (sheep) 15 ug/L: phosphate buffer 100 mmo1/L, pH 7.8; preservative
- R2 Tacrolimus~Ru(bpy) (black cap), 1 bottle, 8 mL: Tacrolimus-derivative labeled . with ruthenium complex 4 µg /L; citrate buffer 10 mmol/L, pH 3.3; preservative
ISD Sample Pretreatment reagent 1.2.
ISD Sample Pretreatment is labeled as ISD Sample PT and it includes:
- . 1 bottle containing 30 mL
Contents: zinc sulfate solution in methanol and ethylene glycol
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2. INDICATIONS FOR USE
Immunoassay for the in vitro quantitative determination of tacrolimus in EDTA human whole blood. The assay is used as an aid in the management of liver and kidney transplant patients receiving tacrolimus therapy.
The electrochemiluminescence immunoassay “ECLIA” is intended for use on Elecsys and cobas e immunoassay analyzers.
TECHNOLOGICAL CHARACTERISTICS 3.
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device: | |
| Abbott ARCHITECT Tacrolimus (K070820) | Candidate Device: | |
| Elecsys Tacrolimus | ||
| General Assay Features | ||
| Intended Use/ | ||
| Indications for | ||
| Use | The ARCHITECT Tacrolimus assay is a | |
| chemiluminescent microparticle immunoassay | ||
| (CMIA) for the quantitative determination of | ||
| tacrolimus in human whole blood on the | ||
| ARCHITECT i System. The ARCHITECT | ||
| Tacrolimus assay is to be used as an aid in the | ||
| management of liver and kidney allograft patients | ||
| receiving tacrolimus therapy | Immunoassay for the in vitro quantitative | |
| determination of tacrolimus in human whole | ||
| blood. The assay is used as an aid in the | ||
| management of liver and kidney transplant | ||
| patients receiving tacrolimus therapy. | ||
| The electrochemiluminescence immunoassay | ||
| "ECLIA" is intended for use on Elecsys and | ||
| cobas e immunoassay analyzers. | ||
| Test Principle | The ARCHITECT Tacrolimus assay is a delayed | |
| one-step immunoassay for the quantitative | ||
| determination of tacrolimus in human whole | ||
| blood using CMIA technology with flexible assay | ||
| protocols, referred to as Chemiflex. Prior to the | ||
| initiation of the automated ARCHITECT | ||
| sequence, a manual pretreatment step is | ||
| performed in which the whole blood sample is | ||
| extracted with a precipitation reagent and | ||
| centrifuged. The supernatant is decanted into a | ||
| Transplant Pretreatment Tube, which is placed | ||
| onto the ARCHITECT System Sample, assay | ||
| diluent, and anti-tacrolimus coated paramagnetic | ||
| microparticles are combined to create a reaction | ||
| mixture. Tacrolimus present in the sample binds | ||
| to the anti-tacrolimus coated microparticles. After | ||
| a delay, tacrolimus acridinium-labeled conjugate | ||
| is added to the reaction mixture. The tacrolimus | ||
| on the acridinium-labeled conjugate competes for | ||
| the available binding sites on the microparticles. | ||
| Following incubation, the microparticles are | The Elecsys Tacrolimus immunoassay uses the | |
| principle of electrochemiluminescence for | ||
| detection and measurement. Before testing with | ||
| the Elecsys Tacrolimus assay, the specimen, | ||
| calibrators and controls are pretreated with the | ||
| Elecsys ISD Pretreatment Reagent. The reagent | ||
| lyses the cells, extracts Tacrolimus and | ||
| precipitates most of the blood proteins. The | ||
| pretreated samples are centrifuged, and an aliquot | ||
| of the resulting supernatant containing | ||
| Tacrolimus is then assayed using the Elecsys | ||
| Tacrolimus reagent. | ||
| Competition principle. Total duration of assay: | ||
| 18 minutes. | ||
| 1st incubation: 35 $ μ $ L of pretreated sample is | ||
| incubated with a Tacrolimus-specific | ||
| biotinylated antibody and a ruthenium | ||
| complex (Tris(2,2'-bipyridyl)ruthenium(II)- | ||
| complex (Ru(bpy) ) labeled Tacrolimus- | ||
| derivative. Depending on the concentration | ||
| of the analyte in the sample and the |
Table 1: Assay Comparison
6
| Assay Comparison | ||
|---|---|---|
| Feature | Predicate Device: | |
| Abbott ARCHITECT Tacrolimus (K070820) | Candidate Device: | |
| Elecsys Tacrolimus | ||
| added to the reaction mixture. The resulting | ||
| chemiluminescent reaction is measured as | ||
| relative light units (RLUs). An indirect | ||
| relationship exists between the amount of | ||
| tacrolimus in the sample and the RLUs detected | ||
| by the ARCHITECT' System optics. | formation of the respective immune | |
| complex, the labeled antibody binding site | ||
| is occupied in part with sample analyte and | ||
| in part with ruthenylated hapten 2nd incubation: After addition of | ||
| streptavidin-coated microparticles the entire | ||
| complex becomes bound to the solid phase | ||
| via interaction of biotin and streptavidin. | ||
| Assay Comparison | ||
| Feature | Predicate Device: | |
| Abbott ARCHITECT Tacrolimus (K070820) | Candidate Device: | |
| Elecsys Tacrolimus | ||
| The reaction mixture is aspirated into the | ||
| measuring cell where the microparticles are | ||
| magnetically captured onto the surface of | ||
| the electrode. Application of a voltage to the | ||
| electrode then induces chemiluminescent | ||
| emission which is measured by a | ||
| photomultiplier. | ||
| Results are determined via a calibration curve | ||
| which is instrument-specifically generated by | ||
| 2-point calibration and a master curve provided | ||
| via the reagent barcode. | ||
| Sample Matrix | Human Whole Blood | Same |
| Sample | ||
| Preparation | Manual Pretreatment | Same |
| Reagent | Liquid Ready-to-Use (Antibody coati | |
| microparticle reagent, Tacrolimus conjugate | ||
| reagent, and Assay diluent) | Liquid Ready-to-Use (Streptavidin-coated | |
| microparticle reagent, biotinylated anti- | ||
| Tacrolimus antibody reagent, tacrolimus | ||
| conjugated reagent). | ||
| Assay Range | 2.0 to 30.0 ng/mL | 0.75 to 30.0 ng/mL |
| Detection | ||
| Protocol | Chemiluminescent Microparticle immunoassay | |
| (CMIA) | Electrochemiluminescent Immunoassay (ECLIA) | |
| Applications | Did not specified | 18-minute application |
| Instrument | ||
| Platform | ARCHITECT i System | cobas e 411 |
| Sample Type | Human Whole Blood | Same |
| Reagents | Competition principle | Competition principle. |
| Total duration of assay: 18 minutes | ||
| Calibration | ||
| Interval | Once an ARCHITECT Tacrolimus calibration is | |
| accepted and stored, all subsequent samples may | ||
| be tested without further calibration unless: | ||
| A reagent kit with a new lot number is used.Controls are out of range. | Calibration must be performed once per reagent | |
| lot using fresh reagent (i.e. not more than | ||
| 24 hours since the reagent kit was registered on | ||
| the analyzer). Renewed calibration is | ||
| recommended as follows: | ||
| After 1 month (28 days) when using the | ||
| same reagent lot.After 7 days (when using the same reagent | ||
| kit on the analyzer).As required: e.g. quality control findings | ||
| outside the defined limits | ||
| Traceability / | ||
| Standardization | The ARCHITECT Tacrolimus Calibrators are | |
| traceable to an internal reference standard | ||
| gravimetrically prepared and confirmed via | ||
| HPLC. Calibrators' values must be within ±1 % | ||
| of the reference calibrator value. | This method has been standardized against | |
| reference standards traceable to tacrolimus | ||
| reference material (USP = United States | ||
| Pharmacopeia) by weight. |
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| Assay Comparison | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Feature | Predicate Device: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abbott ARCHITECT Tacrolimus (K070820) | Candidate Device: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Elecsys Tacrolimus | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Reagent | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Stability | Unopened: 2-8°C - Up to the stated expiration date. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| After Opening at 2-8°C - 30 days | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| On the Analyzers – 30 days | Unopened: 2-8°C - Up to the stated expiration date. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| After Opening at 2-8°C - 84 days | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| On the Analyzers – 56 days | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Measuring | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Range | 2 -30 ng/mL | 0.75 - 30 ng/mL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Precision | Within-run (results from two instruments) | cobas e 411: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Within-run (will be labeled Intermediate precision) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sample Mean (ng/mL) SD CV (%) Level 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 3.0 0.1 3.7 Instrument 2 2.9 0.2 5.8 Level 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 7.8 0.2 2.4 Instrument 2 8.5 0.2 2.7 Level 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 14.5 0.4 2.5 Instrument 2 15.7 0.5 2.9 Panel 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 5.5 0.2 3.6 Instrument 2 5.9 0.2 4.0 Panel 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 14.0 0.5 3.5 Instrument 2 15.3 0.6 4.1 Panel 3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 4.8 0.2 4.4 Instrument 2 4.9 0.2 5.0 Panel 4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 10.1 0.2 2.4 Instrument 2 11.2 0.5 4.1 Panel 5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Instrument 1 21.2 0.7 3.3 Instrument 2 22.4 0.8 3.6 | Sample Mean (ng/mL) SD CV (%) HSP 1 1.28 0.182 14.2 HSP 2 9.14 0.513 5.6 HSP 3 18.5 0.600 3.3 HPS 4 27.07 0.882 3.3 PC ISD1 2.49 0.213 8.6 PC ISD2 10.2 0.383 3.7 PC ISD 3 19.6 0.571 2.9 HSP = Human Sample Pool | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PC = PreciControl | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abbott Immunosuppressant-MCC (levels 1, 2 and 3) and five whole blood panels were assayed, using two lots of reagents, on two instruments, in replicates of two at two separate times per day for 20 days. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Analytical | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sensitivity | Limit of detection ≤ 1.5 ng/mL | Limit of Blank (LoB): = 0.3 ng/mL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limit of Detection (LoD): = 0.5 ng/mL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limit of Quantitation (LoQ): = 0.75 ng/mL |
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| Assay Comparison | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Feature | Abbott ARCHITECT Tacrolimus (K070820) | Predicate Device: | Candidate Device: | ||||||
| Elecsys Tacrolimus | |||||||||
| Analytical | |||||||||
| Specificity | Cross reactant | ||||||||
| (Metabolite) | |||||||||
| M I | Amount Added | ||||||||
| (ng/mL) | |||||||||
| 10 | % Cross- | ||||||||
| reactivity | |||||||||
| 8 | Cross reactant | ||||||||
| (Metabolite) | Maximum | ||||||||
| Concentration | |||||||||
| of Metabolite | |||||||||
| Added (ng/mL) | % Cross- | ||||||||
| reactivity | |||||||||
| (13-O-demethyl) | |||||||||
| M II | 10 | 94 | M I | ||||||
| (13-O-demethyl) | 50 | l | |||||||
| (31-O-demethyl) | |||||||||
| M III | 10 | 45 | M II | ||||||
| (31-O-demethyl) | 50 | 71 | |||||||
| (15-O-demethyl) | |||||||||
| M IV | |||||||||
| (12-O-hydroxy) | 10 | 9 | M III | ||||||
| (15-O-demethyl) | 50 | 3 | |||||||
| M V | N/A | N/A* | M IV | ||||||
| (12-O-hydroxy) | 50 | l | |||||||
| M VI | N/A* | N/A* | M V | 6.6 | 52 | ||||
| M VII | N/A* | N/A* | M VI | 50 | l | ||||
| M III | N/A* | N/A* | M VII | 50 | 0 | ||||
| *Not available | M VIII | 50 | 4 | ||||||
| Linearity | 2 to 30 ng/mL | 0.75-30 ng/mL | |||||||
| Limitations | The assay is unaffected by: | ||||||||
| Albumin 12 mg/dL | |||||||||
| ● | |||||||||
| Bilirubin ≤ 40.0 mg/dL | |||||||||
| ● | |||||||||
| Cholesterol 500 mg/dL | |||||||||
| HAMA 215 ng/mL | |||||||||
| ● | |||||||||
| Triglycerides 800 mg/dL | |||||||||
| Uric Acid 20 mg/dL | Hematocrit ≤ 25%, ≥ 55 % | ||||||||
| Rheumatoid Factor 245 IU | The assay is unaffected by: | ||||||||
| Albumin ≤ 12.0 g/dL | |||||||||
| ● | |||||||||
| ● | |||||||||
| HASA 3.5 – 12 ng/mL | CV ≤ 5 % | CV ≤ 6 % | |||||||
| > 12 – 30 ng/mL | CV ≤ 6 % | CV ≤ 7 % |
5.1.1. -Specifications
All results met the pre-defined acceptance criteria for repeatability and intermediate precision.
Limit of Blank (LoB) 5.2.
LoB of the Tacrolimus assay has been determined according to CLSI EP17-A2. The Limit of Blank was determined as the 95th percentile of the measurement of blank samples. The distribution of values for five analyte-free whole blood samples was determined with one reagent lot on two cobas e 411 analyzers with six runs distributed over a period of 5 days. The sample was measured in one-fold determination in each run. In summary, 30 measuring points were collected per instrument, for a total of 60 measured values.
Acceptance criterion: LoB ≤ 0.3 ng/mL
Limit of Detection (LoD) 5.3.
LoD of the Tacrolimus assay has been determined according to CLSI EP17-A2. The LoD was determined as the lowest amount of analyte in a sample that can be detected with a 95% probability. The distribution of values for five spiked human whole blood samples with low analyte has been determined with one reagent lot on two cobas e 411 analyzers with six runs distributed over a period of 5 days. Samples were measured in one-fold determination in each run. In summary, 30 measuring points were collected per instrument, for a total of 60 measured values. The sum of standard deviations (SD total) of the five samples was calculated. The LoD was determined according to the following EP17-A2 calculation: LoD = LoB + 1.653 x SDtotal (of low analyte samples).
Acceptance criterion: LoD ≤ 0.5 ng/mL
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Limit of Quantitation (LoQ) 5.4.
LoO of the Tacrolimus assay has been determined according to CLSI EP17-A2. The LoO was determined as the lowest concentration of analyte which can be quantified with a total error of no more than 25%. The distribution of values for 14 spiked human whole blood samples each diluted to concentrations which covered the range between LoB and 2x LoO has been determined with three reagent lot on two cobas e 411 analyzers with six runs distributed over six days. Each run was calibrated separately using a two-point calibration. Samples were extracted separately and measured in one-fold determination in each run. In summary, a total of 84 measuring points were collected per instrument, for a total of 168 measured values per lot. A separate extraction was performed with the ISD Sample Pretreatment reagent for each sample measurement. The total error (TE) was calculated based on the following equation:
$$TE = \sqrt{\mathbf{s}^2 + \mathbf{bias}^2}$$
Since the % CV and % bias are a function of the concentration, LoQ was calculated individually for each member of the Low level sample set.
The LoQ samples are sorted according to the concentration of their measured mean value. LoQ is defined as the mean value of that sample which is the first that fulfills specifications for TErel and for which no sample with lower concentration exists that exceeds this specification.
A graphic is generated that plots the measured mean values of the LoQ samples (x) against the relative total error (TErel) (y).
Acceptance criterion: 25% total error at LoQ ≤ 0.75 ng/mL
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Recovery (Accuracy) 5.5.
The measure of accuracy study included the ISD free and patient samples. ISD-free human blood is spiked with known concentration of tacrolimus (USP or other suitable reference material). Each level will be spiked independently (no dilution series). The patient derived samples (from patients taking Tacrolimus) were measured prior spiking, to evaluate the 'endogenous' concentration. The samples were then divided into at least four aliquots. Each of this aliquot is spiked with a defined concentration of analyte (5 ng/mL, 15 ng/mL and 20 ng/mL ) to obtain at least four different 'spiking' levels for each patient sample. Each level will be spiked independently (no dilution series). The samples were measured on cobas e 411.
Acceptance criterion:
- $\n\leq \pm 0.3\n$ ng/mL for samples LoQ to 3 ng/mL .
- $\n\pm 10\n$% for samples > 3 ng/mL .
Based on data, the recovery (accuracy) meets the specifications.
Linearity 5.6.
The linearity of the Tacrolimus assay was assessed on the cobas e 411 immunoassay analyzer; three dilution series were prepared from three different spiked human whole blood samples. Each dilution series included 22 dilutions. Each sample was measured 4-fold within one run and the measured concentrations were plotted against the expected sample concentration. A separate extraction was performed with the ISD Sample Pretreatment reagent for each sample measurement. The linearity data was determined in accordance with CLSI EP6-A. In a first step, a linearity check was performed with a first order (linear) regression and then with higher order models (quadratic and cubic).
Acceptance criterion:
- 2 ng/mL .
Linearity was confirmed in the range from 0.75 to 30 ng/mL.
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5.7. Dilution
To demonstrate the Tacrolimus assay dilution study, three ISD-free human whole blood samples were spiked separately with a known concentration of gravimetrically weight tacrolimus. These samples were used to prepare a dilution series of nine respective dilutions. Each sample was measured in duplicates (n=2).
The dilution factor for samples outside the measuring range is 1:3. The samples prepared above were diluted with the Elecsys Diluent Universal prior to the manual pre-treatment procedure.
Testing was performed on two cobas e 411 analyzers. The percent recoveries were calculated between the expected and the measured concentrations.
Analytical Specificity 5.8.
The specificity was determined using the cross-reactant compound. Each cross-reactant compound was spiked into two human whole blood samples (analyte-free and slightly elevated analyte level). Testing was performed with one reagent lot in one run. The spiked samples were evaluated at four dilutions.
Endogenous Interferences 5.9.
The effect on quantitation of analyte in the presence of endogenous interfering substances using the Tacrolimus was determined on the cobas e 411 immunoassay analyzer for the following 10 interfering substances Intralipid, Biotin, Bilirubin, Rheumatic Factor, Human Serum Albumin, IgG, Cholesterol, HASA, Uric Acid and Hematocrit using three spiked human whole blood samples (one low and one high concentration) to prepare dilution series of 10 dilutions that were tested with one reagent lot.
For each interfering substance the following protocol was followed:
One low and one high analyte containing sample were divided into two aliquots each. One aliquot was spiked with the interfering substance up to a concentration given in the table below (sample b) while the other was treated without interferent to mimic the dilution effect (sample a).
The recovery for each sample was calculated by comparison to the reference sample.
15
For Hemotocrit interfering substance the following protocol was followed:
ISD-free human EDTA blood is split into two equal volume fractions. A sample is taken to measure the initial hematocrit using a hematocrit centrifuge. Cellular constituents of each fraction are separated from the plasma either by centrifugation at approximately 1000 g for about 15 minutes or overnight sedimentation in the fridge. Blood plasma of the two fractions is then blended in a way that hematocrit concentrations of 15 % resp. 65 % are achieved. Afterwards the samples are homogenized for at least 30 min on a roller mixer at room temperature. After homogenization the two sample preparations are spiked with equal amounts of analyte (USP or other suitable reference material) to reach desired concentrations and again homogenized overnight on a roller mixer at 2-8 °C.
Thereafter the two stocks (15% and 65% hematocrit) are blended in a way to obtain 11 hematocrit dilutions ranging from 15% to 65%, roller mixed for at least 30 minutes at room temperature and then measured. The recovery for every single sample was calculated based on the mean result of the respective first 10 replicates. Acceptance criterion:
- LoO to 3 to 30 ng/mL must be $\n\leq \pm 10\n$% recovery to the reference .
5.10. Exogenous Interferences — Drugs
The effect on quantitation of analyte in the presence of drugs was determined by using 16 common and 25 additional pharmaceutical compounds were spiked into each two spiked human tacrolimus containing human whole blood samples. The spiked samples (single donor samples spiked with 3 ng/mL and 10 ng/mL tacrolimus) were evaluated at drug concentrations greater than the daily dose and tested for interference by the Elecsys Tacrolimus assay on cobas e 411 immunoassay analyzer. Acceptance criterion is recovery within $\n\pm 10\n$% of initial value. All drugs met the predetermined criterion except for Itraconazole. The Itraconazole (INN international non-proprietary name) recovery was found to interfere at 10 ug/mL (114%) .
16
5.11. Biotin interference
Biotin interference was tested up to 1,200 ng/mL in whole blood samples at low and high concentrations of Tacrolimus. Mean concentration of Biotin dilution sample divided by mean corresponding sample without Biotin. The results are summarized in the table below:
| % Bias for samples containing various concentrations of biotin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Samples | Biotin Concentration (ng/mL) | ||||||||
| (ng/mL) | 100 | 200 | 250 | 300 | 350 | 400 | 600 | 1000 | 1200 |
| 2.28 | +5.1% | +11.2% | +20.2% | +27.4% | +30.8% | +41.7% | +87.8% | +165.6% | +203.7% |
| 18.1 | +1.8% | +6.1% | +8.6% | +12.4% | +14.7% | +17.8% | +34.4% | +76.5% | +93.3% |
The labeling states:
Specimens with biotin concentrations up to 100 ng/mL demonstrated $\n\leq 10\n$% bias in results. Biotin concentrations greater than 100 ng/mL led to higher positive bias Tacrolimus results. Some studies have shown that serum concentrations of biotin can reach up to 355 ng/mL within the first hour after biotin ingestion for subjects consuming supplements of 20 mg biotin per day and up to 1160 ng/mL for subjects after a single dose of 300 mg biotin.
Do not test samples from patients who are taking biotin.
Reagent Stability 6.1.
To test reagent stability, the reagent stability was performed in three different studies.
Study 1: Reagent Stability after First Opening (2-8ºC) 6.1.1.
Reagent stability after first opening for the Elecsys Tacrolimus assay was determined on a cobas e 411 immunoassay analyzer by comparing the reagent stability for four kits of the same lot. All reagent kits were opened on day 0. One kit was placed on the analyzer and calibrated and reference values for the samples tested were determined. The other three kits were stored at 2 to 8°C. After 36, 64 and 92 days, one of the stored kits was placed on the analyzer and calibrated, and the original test samples were measured. Samples tested include five human whole blood samples (pooled patient samples and single donor samples spiked with tacrolimus) and three controls. Acceptance criterion for recovery was compared to day 0 value.
17
Study 2: On-board Reagent Stability 6.1.2.
On-board reagent stability for the Tacrolimus assay was tested on one cobas e 411 immunoassay analyzer. A fresh kit was placed on the analyzer and calibrated. Reference values for the samples tested were determined. After measurement, the kit was closed and kept at 20°C $\n\pm 3\n$°C for 9 weeks (64 days) to simulate on-board conditions. Measurements were repeated every week for nine weeks (64 days). The kit was placed on the analyzer again utilizing the calibration curve from seven days earlier for determinations of stability, and the original test samples were measured. The recovery was compared to the measurements from day one. Samples were tested with one reagent lot in one run per day on one cobas e 411 analyzer in duplicate. Samples tested included five human whole blood samples (pooled patient samples and single donor samples spiked with tacrolimus) and three controls (PreciControl ISD). Acceptance criterion for recovery was compared to day 1 value.
6.1.3. Study 3: Shelf Life Stability
In the real-time stability study, the Tacrolimus assay material was stored at 2 to 8°C. The stored assay reagents were tested at time point T=0 and at specified intervals over the shelf life of the device up to the planned shelf life plus one month. Testing was performed using PreciControl ISD 1, 2 and 3 (stored at -20°C). For the production lots 171852, 172226 and 173556 data for the time-points at 0, 8, 10 and 16 months were tested in duplicates.
The average on-test recovery was calculated as percent recovery compared to the reference value (Assigned value for PreciControl ISD 1, 2 and 3).
The acceptance criterion for PreciControl ISD 1 is recovery of 75 – 125% of the reference value.
The acceptance criterion for PreciControl ISD 2 and 3 are recovery of 80 – 120% of the reference value.
6.2. Sample Stability
The sample stability was performed with six different studies and they are:
- Study 1. Sample stability before pre-treatment at room temperature (15 to 25°C) .
- Study 2. Sample stability before pre-treatment at 2 to 8°C .
18
- Study 3. Sample stability before pre-treatment at -20°C .
- Study 4. Stability through freeze/thaw cycles .
- Study 5. Sample stability after pre-treatment on-board in Hitachi sample cups .
- Study 6. Sample stability after pre-treatment at room temperature in closed Hitachi . sample cups
The stability claims to be tested are:
- . 5 days storage at room temperature before pretreatment
- 7 days storage before pretreatment at 2-8°C .
- . 1 time freeze/thaw before pretreatment
- 4 hours storage at room temperature after pretreatment in closed tube .
- . 30 minutes on the analyzer after pretreatment
- . 1 month storage before pretreatment at -15°C to -25°C
The percent recovery was calculated based on reference T0 (fresh sample) values.
The data collected in house supported the short stability claims. Literature reference is use to support 1 month stability claim.
CLINICAL PERFORMANCE EVALUATION 7.
Reproducibility 7.1.
Reproducibility was evaluated by testing human sample pools and PreciControl materials with the Elecsys Tacrolimus assay on the e 411 analyzer at three sites. Testing was conducted in accordance with requirements within CLSI EP5-A2 and EP15-A2. Table 3 below provides the summary of the clinical reproducibility study.
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| | | | Repeatability | | | Between Day | | | Between Lot | | Between Site | | System
Reproducibility | | |
|-----------|----|-----------------|---------------|-----------------------------|------|-------------|------|------|-------------|------|--------------|------|-----------------------------|------|--|
| Sample | N | Mean
(ng/mL) | SD | UCL of SD
1-sided
95% | % CV | SD | % CV | SD | % CV | SD | % CV | SD | UCL of SD
1-sided
95% | % CV | |
| HSP 01 | 90 | 2.67 | 0.19 | 0.23 | 7.3 | 0.18 | 6.8 | 0.00 | 0.0 | 0.21 | 7.8 | 0.34 | 0.53 | 12.6 | |
| HSP 02 | 90 | 6.23 | 0.52 | 0.61 | 8.3 | 0.28 | 4.4 | 0.00 | 0.0 | 0.25 | 4.0 | 0.64 | 0.78 | 10.2 | |
| HSP 03 | 90 | 11.38 | 0.69 | 0.81 | 6.1 | 0.55 | 4.8 | 0.00 | 0.0 | 0.44 | 3.9 | 0.99 | 1.26 | 8.7 | |
| HSP 04 | 90 | 20.66 | 0.74 | 0.87 | 3.6 | 0.86 | 4.2 | 0.00 | 0.0 | 0.63 | 3.0 | 1.30 | 1.75 | 6.3 | |
| HSP 05 | 90 | 27.76 | 1.19 | 1.40 | 4.3 | 2.09 | 7.5 | 0.00 | 0.0 | 1.52 | 5.5 | 2.85 | 4.09 | 10.2 | |
| HSP 06 | 90 | 34.85 | 1.27 | 1.49 | 3.6 | 2.19 | 6.3 | 0.00 | 0.0 | 1.05 | 3.0 | 2.74 | 3.54 | 7.9 | |
| PC ISD_L1 | 90 | 2.11 | 0.12 | 0.14 | 5.5 | 0.15 | 7.0 | 0.00 | 0.0 | 0.18 | 8.3 | 0.26 | 0.45 | 12.1 | |
| PC ISD_L2 | 90 | 9.49 | 0.28 | 0.33 | 3.0 | 0.51 | 5.4 | 0.00 | 0.0 | 0.37 | 3.9 | 0.69 | 0.99 | 7.3 | |
| PC ISD_L3 | 90 | 15.83 | 0.39 | 0.46 | 2.5 | 0.85 | 5.3 | 0.00 | 0.0 | 0.19 | 1.2 | 0.95 | 1.18 | 6.0 | |
Table 2: Reproducibility
Note: SD of zero due to variance contributed by particular component was below stated significant figure.
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7.2. Method Comparison
Clinical test results for enrolled subjects were obtained using the Elecsys Tacrolimus Immunoassay and two comparative methods: Abbott ARCHITECT Tacrolimus, and LC-MS/MS, in order to validate performance of the Elecsys Tacrolimus Immunoassay. Table 4 below provides the summary of the clinical method comparison study.
| Abbott ARCHITECT Tacrolimus vs. Elecsys Tacrolimus | ||||
|---|---|---|---|---|
| Total # of samples | Slope (95% CI) | |||
| (Deming) | Intercept (95% CI) | |||
| (Deming) | Correlation (r) | |||
| Combined 553 | 0.99 (0.98, 1.01) | 0.06 (-0.07, 0.18) | 0.99 | |
| Kidney 346 | 1.01 (0.98, 1.03) | 0.04 (-0.17, 0.24) | 0.99 | |
| Liver 207 | 0.97 (0.95, 0.99) | 0.13 (-0.01, 0.27) | 0.99 | |
| Elecsys Tacrolimus vs. LC-MS/MS | ||||
| Total # of samples | Slope (95% CI) | |||
| (Deming) | Intercept (95% CI) | |||
| (Deming) | Correlation (r) | |||
| Combined 554 | 0.92 (0.90, 0.95) | -0.01(-0.16, 0.14) | 0.96 | |
| Kidney 344 | 0.93 (0.90, 0.96) | 0.04 (-0.19, 0.27) | 0.97 | |
| Liver 210 | 0.91 (0.87, 0.95) | -0.05 (-0.25, 0.16) | 0.95 |
Summary of Clinical Method Comparison Table 3:
CONCLUSIONS 8.
The information provided in this Premarket Notification [510(k)] will support a determination of substantial equivalence for the Elecsys Tacrolimus Assay.