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.

The ARCHITECT Tacrolimus Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of tacrolimus in human whole blood.

The ARCHITECT Tacrolimus Whole Blood Precipitation Reagent is for the extraction of tacrolimus from samples (human whole blood patient specimens, controls, and ARCHITECT Tacrolimus Calibrators) to be tested on the ARCHITECT i System.

Device Description

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 centrifyged. The supernatant is decanted into a Transplant Pretreatment Tube, which is placed onto the ARCHITECT i 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 an incubation, the microparticles are washed, and pretrigger 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 tacrolimus in the RLUs detected by the ARCHITECT i System optics.

AI/ML Overview

Here's a summary of the acceptance criteria and the study details for the ARCHITECT Tacrolimus assay, based on the provided 510(k) summary:

Acceptance Criteria and Device Performance

This document primarily describes performance characteristics rather than explicit acceptance criteria with defined pass/fail thresholds against which the reported performance is compared. However, the reported performance values implicitly define the level of performance deemed acceptable by the manufacturer for substantial equivalence.

Acceptance Criterion	Reported Device Performance
Precision	Total precision %CV ≤ 10%
Linearity	Mean recovery within 10% of expected result for diluted samples
Functional Sensitivity	Lowest ARCHITECT Tacrolimus assay value exhibiting a 20% CV was 0.8 ng/mL (at the upper 95% confidence limit)
Analytical Sensitivity (Limit of Detection)	0.3 ng/mL at 95% confidence (calculated at two standard deviations above ARCHITECT Tacrolimus Calibrator A)
Interference	Average recovery observed during the study ranged from 95% to 105% (with various drugs and potentially interfering compounds)
Method Comparison (vs. Predicate Device IMx Tacrolimus II)	Intercept (95% CI): 0.37 (0.00 to 0.68) Slope (95% CI): 0.81 (0.75 to 0.88) Correlation Coefficient: 0.90
Method Comparison (vs. LC/MS/MS)	Intercept (95% CI): 0.22 (0.02 to 0.48) Slope (95% CI): 1.07 (1.01 to 1.12) Correlation Coefficient: 0.92
Specificity (Cross-Reactivity)	M-I: <1.5 ng/mL excess detected (NA % Cross Reactivity) M-II: 9.4 ng/mL excess detected (94% Cross Reactivity) M-III: 4.5 ng/mL excess detected (45% Cross Reactivity) M-IV: <1.5 ng/mL excess detected (NA % Cross Reactivity)

Study Details

Sample size used for the test set and the data provenance:
- Method Comparison (vs. IMx Tacrolimus II):
  - Number of Observations: 124 human whole blood specimens.
  - Provenance: From renal and liver transplant patients receiving tacrolimus therapy (retrospective/prospective not explicitly stated, but the "patients receiving tacrolimus therapy" suggests real-world clinical samples). Country of origin is not specified.
- Method Comparison (vs. LC/MS/MS):
  - Number of Observations: 125 human whole blood specimens.
  - Provenance: The text states "Additional testing of the above sample was completed with LC/MS/MS," implying these were likely the same or a very similar set of clinical samples as used for the IMx comparison. Country of origin not specified.
- Precision: Not explicitly stated as a "test set" and rather uses "Abbott Immunosuppressent-MCC (levels 1, 2, and 3) and five whole blood panels".
- Linearity: Not explicitly stated as a "test set" sample size beyond "high concentration tacrolimus whole blood specimens."
- Functional Sensitivity: Not explicitly stated as a "test set" sample size beyond "Whole blood specimens were spiked with tacrolimus."
- Analytical Sensitivity: n=24 runs, 10 replicates for calibrator A, 4 replicates for calibrator B.
- Interference: "Whole blood specimens were supplemented with various drugs and potentially interfering compounds." Specific sample size not given.
- Specificity: "Aliquots of whole blood specimens" augmented with tacrolimus, 5 specimens spiked with cross-reactant solution for each metabolite.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not mention the use of human experts to establish ground truth. Instead, it compares the device's performance against a predicate device (IMx Tacrolimus II assay) and a reference method (LC/MS/MS).
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable as the ground truth was established by comparison to other analytical methods (IMx and LC/MS/MS), not by expert adjudication of cases.
If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- Not applicable. This is an in vitro diagnostic (IVD) device for quantitative determination of a drug in whole blood, not an imaging device requiring human reader interpretation or AI assistance.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, the performance characteristics (Precision, Linearity, Functional Sensitivity, Analytical Sensitivity, Interference, Specificity) and method comparison studies (against IMx and LC/MS/MS) describe the standalone performance of the ARCHITECT Tacrolimus assay system itself, without human interpretation in the results generation. The human interaction is limited to the manual pretreatment step and placing the sample on the system.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Reference Method Comparison: The ground truth for the method comparison studies was established by:
  - Comparison to an existing, legally marketed predicate device: ABBOTT IMx® Tacrolimus II Microparticle Enzyme Immunoassay.
  - Comparison to a gold standard analytical method: LC/MS/MS (Liquid Chromatography-Tandem Mass Spectrometry).
- For other performance characteristics (Precision, Linearity, Functional Sensitivity, Analytical Sensitivity, Interference, Specificity), the ground truth was implicitly defined by the known concentrations in spiked or controlled samples, or by established analytical methods for assessing these parameters.
The sample size for the training set:
- The document does not explicitly mention a "training set" in the context of machine learning or AI models. This device is an immunoassay (CMIA), which typically relies on established chemical and biological reactions and calibration curves rather than an AI model requiring a distinct training phase with a labeled dataset in the same way an imaging AI might. The development and validation of the assay reagents and protocols would involve extensive internal testing and optimization, but this is not typically referred to as a "training set" in the context of this device type.
How the ground truth for the training set was established:
- As there's no explicit "training set" for an AI/machine learning model described, this question is not fully applicable. However, for the development of the assay, the "ground truth" (i.e., accurate tacrolimus concentrations) would have been established through highly analytical methods such as LC/MS/MS or gravimetric preparation of standards to develop and validate the calibrators and control materials used throughout the assay's development.

Summary

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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:

Submitter Information

AUG - 1 2007

Fujirebio Diagnostics, Inc. Address: 201 Great Valley Parkway Malvern, PA 19355
Diana L. Dickson Contact person: (610) 240-3917 dicksond@fdi.com

Summary preparation date: March 23, 2007

Name of Device

Trade/Proprietary Name: ARCHITECT Tacrolimus Assay ARCHITECT Tacrolimus Calibrators
MLM DLJ
Common/Usual Name: Tacrolimus Test Systems Calibrator
Regulation Number: 21 CFR 862.1678 21 CFR 862.3200

Requlatory Class: Class II

Product Code:

Predicate Device

ABBOTT IMx® Tacrolimus II Microparticle Enzyme Immunoassay (P97000)'

Device Description

1 note: tacrolimus test systems have been reclassified into Class II since the predicate was approved

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An indirect relationship exists between the amount of tacrolimus in the RLUs detected by the ARCHITECT i System optics.

Intended Use

Reagent Kit

Calibrator Kit

The ARCHITECT Tacrolimus Calibrators are for the ARCHITECT i System when used for the quantitative determination of tacrolimus in human whole blood.

Whole Blood Precipitation Reagent

The ARCHITECT Tacrolimus Whole Blood Precipitation Reagent is for the extraction of sirolimus from samples (human whole blood patient specimens, controls, and ARCHITECT Tacrolimus Calibrators) to be tested on the ARCHITECT i System.

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Statement of Substantial Equivalence

The ARCHITECT Tacrolimus assay is substantially equivalent to the IMx Tacrolimus II assay. Both of the devices are IVD products and are indicated for the quantitative determination of tacrolimus in human whole blood and used as an aid in the management of liver and kidney allograft patients receiving tacrolimus therapy.

A study was performed using human whole blood specimens from renal and liver transplant patients receiving tacrolimus therapy, where regression analysis was performed using the Passing-Bablok2 method. Data from the study are summarized in the following table.

ARCHITECT Tacrolimus vs. IMx Tacrolimus II
Number ofObservations	Intercept(95% CIa)	Slope(95% CI)	CorrelationCoefficient
124	0.37(0.00 to 0.68)	0.81(0.75 to 0.88)	0.90

a Confidence Interval Specimen Range (ARCHITECT): 2.2 ng/mL to 14.8 ng/mL Specimen Range (IMx): 2.1 nq/mL to 15.9 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 Tacrolimus vs. LC/MS/MS
Number ofObservations	Intercept(95% Cl)	Slope(95% CI)	CorrelationCoefficient
125	0.22(0.02 to 0.48)	1.07(1.01 to 1.12)	0.92

Specimen Range (ARCHITECT): 2.1 ng/mL to 14.8 ng/mL Specimen Range (LC/MS/MS): 1.78 ng/mL to 19.20 ng/mL

2 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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A comparison of the features of the ARCHITECT Tacrolimus assay and the IMx Tacrolimus II assay are as follows:

Similarities
	ARCHITECT Tacrolimus(Proposed Device)	IMx Tacrolimus II(Predicate Device)P9700071
Device Type	In vitro diagnostic	In vitro diagnostic
Classification andProduct Code	Class II, MLM	Class II, MLM
Product Usage	Clinical and Hospital laboratories	Clinical and Hospital laboratories
Intended Use	Quantitative determination oftacrolimus in human whole bloodas an aid in the management ofliver and kidney allograft patientsreceiving tacrolimus therapy.	Quantitative determination oftacrolimus in human whole bloodas an aid in the management ofliver and kidney allograft patientsreceiving tacrolimus 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 tacrolimus inhuman whole blood	Manual extraction of tacrolimus 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 -tacrolimus)	Mouse monoclonal (anti -tacrolimus)
Interpretation of Results	Calibrator CurveAn indirect relationship existsbetween the amount of tacrolimusin the sample and the lightdetected by the instrument system	Calibrator CurveAn indirect relationship existsbetween the amount of tacrolimusin the sample and the lightdetected by the instrument system

Differences
	ARCHITECT Tacrolimus(Proposed Device)	IMx Tacrolimus II(Predicate Device)P9700071
Instrument System	ARCHITECT System	IMx System
Principle of Operation	Chemiluminscent MicroparticleImmunoassay (CMIA)	Microparticle EnzymeImmunoassay (MEIA)
Conjugate	Tacrolimus-Acridinium Conjugatein citrate buffer with proteinstabilizers	Tacrolimus-alkaline phosphatasein TRIS buffer with proteinstabilizers
Microparticles	Anti-tacrolimus (mouse,monoclonal) coated paramagneticmicroparticles in EDTA buffer	Anti-tacrolimus (mousemonoclonal) coated polystyrenelatex microparticles in TRIS buffer
Precipitation Reagent	Zinc sulfate solution in methanoland ethylene glycol.	Zinc sulfate solution in methanoland Ethylene glycol

1 note: tacrolimus test systems have been reclassified into Class II since the predicate was approved

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Performance Characteristics

Precision:

A study was performed with the ARCHITECT Tacrolimus 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 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. Each reagent lot used a single calibration curve throughout the study.

The total precision %CV of the ARCHITECT Tacrolimus assay was determined to be less than or equal to 10%.

Linearity:

A dilution linearity study was performed by diluting high concentration tacrolimus whole blood specimens with the ARCHITECT Tacrolimus Calibrator A. The concentration of Tacrolimus was determined for each dilution of sample and the mean percent (%) recovery was calculated.

The ARCHITECT Tacrolimus 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 tacrolimus to achieve approximate concentrations from 0.2 to 4.4 ng/mL and tested in replicates of 10, twice a day, for five days. At the upper 95% confidence limit, the lowest ARCHITECT Tacrolimus assay value exhibiting a 20% CV was calculated to be 0.8 ng/mL.

Analytical Sensitivity:

The limit of detection for the ARCHITECT Tacrolimus assay, defined as the concentration at two standard deviations above the ARCHITECT Tacrolimus Calibrator A (0.0 ng/mL) was calculated to be 0.3 ng/mL at the 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 105%.

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Specificity:

Aliquots of whole blood specimens were augmented with tacrolimus, targeting values ranging Alliquette of 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)	% CrossReactivitya
M-I (13-O-demethyl-tacrolimus)	10	<1.5	NAb
M-II (31-O-demethyl-tacrolimus)	10	9.4	94
M-III (15-O-demethyl-tacrolimus)	10	4.5	45
M-IV (12hydroxytacrolimus)	10	<1.5	NAb

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Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Fujirebio Diagnostics, Inc Ms. Diana Dickson 201 Great Valley Parkway Malvern, PA 19355

AUG - 1 2007

Re: K070820 Trade/Device Name: ARCHITECT Tacrolimus Assay Regulation Number: 21 CFR 862.1687 Regulation Name: Tacrolimus test system (special controls) Regulatory Class: Class II Product Code: MLM, JIT Dated: July 18, 2007 Received: July 19, 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 of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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Page 2 -

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (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 toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Jean M. Cooper, M.S., D.V.M.

Jean 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

K070820 510(k) Number (if known):

Device Name: _________________________________________________________________________________________________________________________________________________________________

Indications For Use:

Reagent Kit

Calibrator Kit

The ARCHITECT Tacrolimus Calibrators are for the calibration of the ARCHITECT i System when used for the quantitative determination of tacrolimus in human whole blood.

Whole Blood Precipitation Reagent

Prescription Use V

AND/OR

Over-The-Counter Use

(Part 21 CFR 801 Subpart D)

(21 CFR 807 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)

Division Signal-Unit

Office of In Vitro Diegnostic Device Evaluation and Safe

510(k) L070820

Page 1 of

Regulation Number and Section

§ 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.