(186 days)
The ARCHITECT Sirolimus assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of sirolimus in human whole blood on the ARCHITECT i System. The ARCHITECT Sirolimus assay is to be used as an aid in the management of renal transplant patients receiving sirolimus therapy.
The ARCHITECT Sirolimus Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of sirolimus in human whole blood.
The ARCHITECT Sirolimus Whole Blood Precipitation Reagent is for the extraction of sirolimus from samples (human whole blood patient specimens, controls, and ARCHITECT Sirolimus Calibrators) to be tested on the ARCHITECT i System.
The ARCHITECT Sirolimus assay is a delayed one-step immunoassay for the quantitative determination of sirolimus 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, heated, and centrifuged. The supernatant is decanted into a Transplant Pretreatment Tube, which is placedonto the ARCHITECT i System.
Sample, assay diluent, and anti-sirolimus coated paramagnetic microparticles are combined to create a reaction mixture. Sirolimus present in the sample binds to the anti-sirolimus coated microparticles. After a delay, sirolimus acridinium-labeled conjugate is added to the reaction mixture. The sirolimus acridinium-labeled conjucate competes for the available binding sites on the anti-sirolimus coated paramagnetic microparticles. Following an incubation, the microparticles are washed, and pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs),
An indirect relationship exists between the amount of sirolimus in the RLUs detected by the ARCHITECT i System optics.
The provided document describes the ARCHITECT Sirolimus Assay and its performance characteristics, primarily focusing on demonstrating substantial equivalence to a predicate device (ABBOTT IMx® Sirolimus Microparticle Enzyme Immunoassay) and LC/MS/MS as a reference method.
Here's an analysis of the acceptance criteria and study information:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state numerical acceptance criteria in a dedicated section with pre-defined thresholds. Instead, it presents the results of equivalence studies against a predicate device and a reference method, implying that the observed performance was deemed acceptable for demonstrating substantial equivalence. For performance characteristics like precision, linearity, and sensitivity, the results are presented, and implicit acceptance is given by stating the achieved values (e.g., "less than or equal to 10%").
Here's a table summarizing the reported device performance from the provided text:
| Performance Metric | Acceptance Criteria (Implicit from context) | Reported Device Performance (ARCHITECT Sirolimus Assay) |
|---|---|---|
| Equivalence to IMx Sirolimus (Predicate) | Correlation/Agreement with predicate | Intercept: 0.12 (-0.38 to 0.47) Slope: 1.05 (1.00 to 1.11) Correlation Coefficient: 0.94 |
| Equivalence to LC/MS/MS (Reference Method) | Correlation/Agreement with reference | Intercept: -0.37 (-0.89 to 0.12) Slope: 1.18 (1.11 to 1.27) Correlation Coefficient: 0.91 |
| Precision (Total %CV) | No explicit numerical criterion, but generally low %CV is desired. | ≤ 10% |
| Linearity (Mean % Recovery) | No explicit numerical criterion, but generally close to 100% is desired. | Within 10% of the expected result for diluted samples. |
| Functional Sensitivity | Reportable range is 2-30 ng/mL. Lower functional sensitivity desired. | 0.7 ng/mL (at 20% CV, upper 95% CI) |
| Analytical Sensitivity (Limit of Detection) | Reportable range is 2-30 ng/mL. Lower LOD desired. | 0.3 ng/mL (at 2 SD above Calibrator A) |
| Interference (Average Recovery) | Generally, recovery close to 100% (e.g., 90-110%) is desired. | 95 to 106% (for various interfering compounds) |
| Specificity (Cross-Reactivity) | Low cross-reactivity desired for related metabolites. | F2: 8.7% F3: 7.6% F4: 36.8% F5: 20.3% |
2. Sample Size Used for the Test Set and Data Provenance:
- Sample Size for Equivalence Studies:
- ARCHITECT Sirolimus vs. IMx Sirolimus: 168 observations (specimens).
- ARCHITECT Sirolimus vs. LC/MS/MS: 167 observations (specimens).
- Data Provenance: "human whole blood specimens from renal transplant patients receiving sirolimus therapy." The country of origin is not specified, but the context of an FDA 510(k) submission typically implies US-based or internationally accepted clinical study protocols. The data is retrospective in the sense that the patients were already receiving therapy and specimens were collected. It's not explicitly stated if it was a prospective collection for this specific study, but it's patient data.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:
This information is not provided in the document. For an immunoassay device like this, ground truth is typically established by comparing against a reference method (like LC/MS/MS) or a previously validated predicate device. Human expert interpretation of results is not usually the primary ground truth for quantitative laboratory assays.
4. Adjudication Method for the Test Set:
This information is not applicable and therefore not provided in the document. Adjudication methods (like 2+1, 3+1) are typically used in studies involving subjective human interpretation of images or clinical events, where multiple readers' assessments need to be reconciled to form a ground truth. For quantitative assays like the Sirolimus assay, the ground truth is based on the chemical measurement itself, often against a gold standard method.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study focuses on the impact of a device on human readers' performance (e.g., radiologists interpreting images using an AI tool). The ARCHITECT Sirolimus Assay is a standalone, quantitative in vitro diagnostic device, not one that assists human readers in making interpretations.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study:
Yes, the studies presented are standalone performance studies. The ARCHITECT Sirolimus Assay, as an immunoassay, works as an "algorithm only" (the automated measurement process produces a quantitative result) without human input during the core measurement process. The results reported (equivalence, precision, linearity, sensitivity, interference, specificity) directly reflect the performance of the device itself.
7. Type of Ground Truth Used:
- Predicate Device Comparison: The ABBOTT IMx® Sirolimus Microparticle Enzyme Immunoassay (K042411) was used as a reference for comparison. While not a "ground truth" in the strictest sense, it's a legally marketed and accepted assay that served as a benchmark for substantial equivalence.
- Reference Method Comparison: LC/MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry) was used as a more definitive "ground truth" or reference method for validating the assay's accuracy against a highly sensitive and specific analytical technique.
8. Sample Size for the Training Set:
The document does not provide specific information on the sample size used for the training set. Immunoassays are often developed and optimized using a variety of samples and reagents during the R&D phase, but a distinct "training set" in the machine learning sense is not typically explicitly defined or reported for this type of device in a 510(k) summary. The development process would involve iterative testing and refinement.
9. How the Ground Truth for the Training Set was Established:
As the document doesn't detail a specific "training set" or its ground truth, this information is not provided. For immunoassay development, ground truth for initial optimization would similarly be based on established reference methods (like LC/MS/MS) or careful spiking/dilution experiments with known concentrations of the analyte.
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510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
The assigned 510(k) number is: K070822
SEF 2 8 2007
Submitter Information
| Address: | Fujirebio Diagnostics, Inc.201 Great Valley ParkwayMalvern, PA 19355 |
|---|---|
| ---------- | ------------------------------------------------------------------------------ |
| Contact person: | Diana L. Dickson |
|---|---|
| (610) 240-3917 | |
| dicksond@fdi.com |
Summary preparation date: September 28, 2007
Name of Device
| Trade/Proprietary Name: | ARCHITECT Sirolimus Assay |
|---|---|
| ARCHITECT Sirolimus Calibrators |
NRP
DLJ
Common/Usual Name: Sirolimus Test Systems Calibrator
21 CFR 862.3840 Regulation Number: 21 CFR 862.3200
Requlatory Class: Class II
Product Code:
Predicate Device
ABBOTT IMx® Sirolimus Microparticle Enzyme Immunoassay (K042411)
Device Description
The ARCHITECT Sirolimus assay is a delayed one-step immunoassay for the quantitative determination of sirolimus 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, heated,
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and centrifuged. The supernatant is decanted into a Transplant Pretreatment Tube, which is placed onto the ARCHITECT i System.
Sample, assay diluent, and anti-sirolimus coated paramagnetic microparticles are combined to create a reaction mixture. Sirolimus present in the sample binds to the anti-sirolimus coated microparticles. After a delay, sirolimus acridinium-labeled conjugate is added to the reaction mixture. The sirolimus acridinium-labeled conjucate competes for the available binding sites on the anti-sirolimus coated paramagnetic microparticles. Following an incubation, the microparticles are washed, and pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs),
An indirect relationship exists between the amount of sirolimus in the RLUs detected by the ARCHITECT i System optics.
Reportable Range
The reportable range for the ARCHITECT Sirolimus assay is 2 ng/mL (minimum reportable value based on Functional Sensitivity) to 30 ng/mL.
Intended Use
Reagent Kit
The ARCHITECT Sirolimus assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of sirolimus in human whole blood on the ARCHITECT i System. The ARCHITECT Sirolimus assay is to be used as an aid in the management of renal transplant patients receiving sirolimus therapy.
Calibrator Kit
The ARCHITECT Sirolimus Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of sirolimus in human whole blood.
Whole Blood Precipitation Reagent
The ARCHITECT Sirolimus Whole Blood Precipitation Reagent is for the extraction of sirolimus from samples (human whole blood patient specimens, controls, and ARCHITECT Sirolimus Calibrators) to be tested on the ARCHITECT i System.
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Statement of Substantial Equivalence
The ARCHITECT Sirolimus assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of sirolimus in human whole blood on the ARCHITECT i System. The ARCHITECT Sirolimus assay is to be used as an aid in the management of renal transplant patients receiving sirolimus therapy.
The ARCHITECT Sirolimus assay is substantially equivalent to the IMx Sirolimus assay. Both of the devices are IVD products and are indicated for the quantitative determination of sirolimus in human whole blood and used as an aid in the management of renal transplant patients receiving sirolimus therapy.
A study was performed using human whole blood specimens from renal transplant patients receiving sirolimus therapy, where regression analysis was performed using the Passing-Bablok' method. Data from the study are summarized in the following table.
| ARCHITECT Sirolimus vs. IMx Sirolimus | |||
|---|---|---|---|
| Number ofObservations | Intercept(95% CIa) | Slope(95% CI) | CorrelationCoefficient |
| 168 | 0.12(-0.38 to 0.47) | 1.05(1.00 to 1.11) | 0.94 |
ª Confidence Interval Specimen Range (ARCHITECT): 2.1 ng/mL - 29.7 ng/mL Specimen Range (IMx): 1.8 ng/mL - 29.6 ng/mL
Additional testing of the above sample was completed with LC/MS/MS, where regression analysis was performed using the Passing-Bablok1 method. Data from the study are summarized in the following table.
| ARCHITECT Sirolimus vs. LC/MS/MS | |||
|---|---|---|---|
| Number ofObservations | Intercept(95% CI) | Slope(95% CI) | CorrelationCoefficient |
| 167 | -0.37(-0.89 to 0.12) | 1.18(1.11 to 1.27) | 0.91 |
Specimen Range (ARCHITECT): 2.1 nq/mL - 29.7 ng/mL Specimen Range (LC/MS/MS): 1.65 ng/mL - 29.1 ng/mL
' Passing H, Bablok W. A new biometrical procedure for testing the equality of measurements from two different analytical methods. J Clin Chem Clin Biochem 1983; 21(11)709-20.
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Image /page/3/Picture/1 description: The image shows the logo for "FUJIREBIO Diagnostics, Inc." The logo consists of a stylized graphic on the left, followed by the company name in bold, black letters. Below the company name, the words "Diagnostics, Inc" are written in a smaller, non-bold font. The graphic on the left appears to be a stylized representation of three overlapping shapes, with the left shape being solid black and the right shape being filled with vertical lines.
A comparison of the features of the ARCHITECT Sirolimus assay and the IMx Sirolimus assay are as follows:
| Similarities | ||
|---|---|---|
| ARCHITECT Sirolimus(Proposed Device) | IMx Sirolimus(Predicate Device)K042411 | |
| Device Type | In vitro diagnostic | In vitro diagnostic |
| Classification andProduct Code | Class II, NRP | Class II, NRP |
| Product Usage | Clinical and Hospital laboratories | Clinical and Hospital laboratories |
| Intended Use | Quantitative determination ofsirolimus in human whole blood asan aid in the management of renaltransplant patients receivingsirolimus therapy. | Quantitative determination ofsirolimus in human whole blood asan aid in the management of renaltransplant patients receivingsirolimus therapy. |
| Type of Specimen | Human Whole Blood | Human Whole Blood |
| Specimen CollectionMethod | EDTA Whole Blood CollectionTubes | EDTA Whole Blood CollectionTubes |
| Specimen PretreatmentStep | Manual extraction of sirolimus inhuman whole blood | Manual extraction of sirolimus inhuman whole blood |
| Calibrators | 6 Levels (0 - 30 ng/mL) | 6 Levels (0 - 30 ng/mL) |
| Calibrator Matrix | Processed human whole blood | Processed human whole blood |
| Antibody | Mouse monoclonal (anti -sirolimus) | Mouse monoclonal (anti -sirolimus) |
| Interpretation of Results | Calibrator CurveAn indirect relationship existsbetween the amount of sirolimus inthe sample and the light detectedby the instrument system | Calibrator CurveAn indirect relationship existsbetween the amount of sirolimus inthe sample and the light detectedby the instrument system |
| Differences | ||
|---|---|---|
| ARCHITECT Sirolimus(Proposed Device) | IMx Sirolimus(Predicate Device)K042411 | |
| Instrument System | ARCHITECT System | IMx System |
| Principle of Operation | Chemiluminscent MicroparticleImmunoassay (CMIA) | Microparticle EnzymeImmunoassay (MEIA) |
| Conjugate | Sirolimus-Acridinium Conjugate incitrate buffer | Sirolimus-alkaline phosphatase inTRIS buffer with protein stabilizers |
| Microparticles | Anti-sirolimus (mouse,monoclonal) coated paramagneticmicroparticles in MES buffer | Anti-sirolimus (mouse monoclonal)coated polystyrene latexmicroparticles in TRIS buffer |
| Precipitation Reagent | Zinc sulfate solution in DMSO andEthylene glycol | Zinc sulfate solution in methanoland Ethylene glycol |
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Performance Characteristics
Precision:
A study was performed with the ARCHITECT Sirolimus assay based on guidance from the Clinical and Laboratory Standards Institute, document (CLSI, formerly NCCLS) Protocol EP5-A2. Abbott Immunosuppressent-MCC (levels 1, 2) 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. Each reagent lot used a single calibration curve throughout the study.
The total precision %CV of the ARCHITECT Sirolimus assay was determined to be less than or equal to 10%.
Linearity:
A dilution linearity study was performed by diluting high concentration sirolimus whole blood specimens with the ARCHITECT Sirolimus Calibrator A. The concentration of sirolimus was determined for each dilution of sample and the mean percent (%) recovery was calculated.
The ARCHITECT Sirolimus assay was determined to have a mean recovery within 10% of the expected result for diluted samples.
Functional Sensitivity:
Whole blood specimens were spiked with sirolimus to achieve approximate concentrations from 0.1 to 5.3 ng/mL and tested in replicates of 10, twice a day, for five days. At the upper 95% confidence limit, the lowest ARCHITECT Sirolimus assay value exhibiting a 20% CV was calculated to be 0.7 ng/mL, which is below the reportable range of the ARCHITECT Sirolimus assay.
Analytical Sensitivity:
The limit of detection for the ARCHITECT Sirolimus assay, defined as the concentration at two standard deviations above the ARCHITECT Sirolimus Calibrator A (0.0 ng/mL) was calculated to be 0.3 ng/mL, which is below the reportable range of the ARCHITECT Sirolimus assay at 95% confidence (based on one study with n=24 runs, 10 replicates calibrator A and 4 replicates calibrator B per run).
Interference:
Whole blood specimens were supplemented with various drugs and potentially interfering compounds (triglycerides, hematocrit, bilirubin, total protein, cholesterol, uric acid, HAMA, and rheumatoid factor [RF]). The average recovery observed during the study ranged from 95 to 106%.
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Specificity:
Aliquots of whole blood specimens were augmented with sirolimus, targeting values ranging from 5 to 22 ng/mL. These five specimens were spiked with cross-reactant solution. Data from this study are summarized in the following table.
| Metabolite | AmountAdded(ng/mL) | Mean ExcessConcentrationDetected(ng/mL, n=5) | % CrossReactivity |
|---|---|---|---|
| F2 (41-0-demethyl-hydroxyl-sirolimus) | 10 | 0.87 | 8.7 |
| F3 (41-0-demethyl-hydroxylsirolimus; 7-0-demethylsirolimus) | 3 | 0.12 | 7.6 |
| F4 (11-hydroxy-sirolimus) | 10 | 3.7 | 36.8 |
| F5 (41-0-demethyl-sirolimus) | 10 | 2.0 | 20.3 |
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DEPARTMENT OF HEALTH & HUMAN SERVICES
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Food and Drug Administration 2098 Gaither Road Rockville MD 20850
SEP 2 8 2007
Fujirebio Diagnostics, Inc c/o Ms. Diana Dickson 201 Great Valley Parkway Malvern, PA 19355
Re: K070822
Trade/Device Name: ARCHITECT Sirolimus Assay Regulation Number: 21 CFR 862.3840 Regulation Name: Sirolimus test system Regulatory Class: Class II Product Code: NRP, JIT Dated: September 14, 2007 Received: September 17, 2007
Dear Ms. Dickson:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements af the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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Page 2 -
This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial your device of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0490. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its tolli the (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely vours.
Jean M. Coopes, M.S., D.V.M.
Yéan M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known): K070822
Device Name: ARCHITECT Sirolimus
Indications For Use:
Reagent Kit
The ARCHITECT Sirolimus assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of sirolimus in human whole blood on the ARCHITECT i System. The ARCHITECT Sirolimus assay is to be used as an aid in the management of renal transplant patients receiving sirolimus therapy.
Calibrator Kit
The ARCHITECT Sirolimus Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of sirolimus in human whole blood.
Whole Blood Precipitation Reagent
The ARCHITECT Sirolimus Whole Blood Precipitation Reagent is for the extraction of sirolimus from samples (human whole blood patient specimens, controls, and ARCHITECT Sirolimus Calibrators) to be tested on the ARCHITECT i System.
Sean Cooper
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Satety
510(k) 070822
Prescription Use ﺮﺍ (Part 21 CFR 801 Subpart D)
AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Page 1 of 1
§ 862.3840 Sirolimus test system.
(a)
Identification. A sirolimus test system is a device intended to quantitatively determine sirolimus concentrations in whole blood. Measurements are used as an aid in management of transplant patients receiving therapy with sirolimus.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Sirolimus Test Systems.” See § 862.1(d) for the availability of this guidance document.