ARCHITECT STAT High Sensitivity Troponin-I

K191595 · Abbott Laboratories Diagnostics Division · MMI · Sep 13, 2019 · Clinical Chemistry

Device Facts

• Record ID: K191595
• Device Name: ARCHITECT STAT High Sensitivity Troponin-I
• Applicant: Abbott Laboratories Diagnostics Division
• Product Code: MMI · Clinical Chemistry
• Decision Date: Sep 13, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1215
• Device Class: Class 2

Indications for Use

The ARCHITECT STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnI) in human plasma (dipotassium [K2] EDTA) on the ARCHITECT i2000SR System. The ARCHITECT STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

Device Story

The ARCHITECT STAT High Sensitivity Troponin-I is a two-step chemiluminescent microparticle immunoassay (CMIA) performed on the ARCHITECT i2000SR System. It measures cardiac troponin I (cTnI) in human K2 EDTA plasma. The process involves: 1) binding cTnI in the sample to anti-troponin I coated paramagnetic microparticles; 2) adding anti-troponin I acridinium-labeled conjugate; 3) adding Pre-Trigger and Trigger solutions to initiate a chemiluminescent reaction. The system measures relative light units (RLUs), which are directly proportional to cTnI concentration, determined against a standard curve. Used in clinical laboratories, the assay provides quantitative results to clinicians to aid in diagnosing myocardial infarction. Results are interpreted alongside clinical signs, symptoms, and other diagnostic data (e.g., ECG, imaging) per universal MI definitions. The device benefits patients by providing high-sensitivity detection of cardiac injury, facilitating faster clinical decision-making in emergency settings.

Clinical Evidence

Multi-center prospective study of 1065 ED subjects with symptoms consistent with ACS. Adjudicated diagnosis by three cardiologists (10.89% MI prevalence). Performance evaluated at baseline, 2-4 hours, and 4-9 hours. Using overall 99th percentile (28 ng/L), sensitivity ranged 81.8-94.4% and specificity 81.0-92.0%. Using sex-specific cutoffs (17 ng/L female, 35 ng/L male), sensitivity ranged 78.8-95.8% and specificity 82.8-87.6%. AUC values ranged 0.9136-0.9479.

Technological Characteristics

Chemiluminescent microparticle immunoassay (CMIA). Reagents: anti-troponin I (mouse monoclonal) coated paramagnetic microparticles and anti-troponin I (mouse-human chimeric monoclonal) acridinium-labeled conjugate. Energy source: ARCHITECT i2000SR system optics. Measuring range: 3.5 to 5000.0 ng/L. Traceable to NIST SRM2921. Connectivity: ARCHITECT i2000SR system-integrated.

Indications for Use

Indicated for quantitative determination of cardiac troponin I (cTnI) in human K2 EDTA plasma to aid in the diagnosis of myocardial infarction (MI) in patients presenting with symptoms consistent with acute coronary syndrome.

Regulatory Classification

Identification

A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.

Predicate Devices

• Elecsys Troponin T Gen 5 STAT Immunoassay (K162895)

Submission Summary (Full Text)

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Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K191595

B Applicant

Abbott Laboratories Diagnostic Division

C Proprietary and Established Names

ARCHITECT STAT High Sensitivity Troponin-I

D Regulatory Information

| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| MMI | Class II | 21 CFR 862.1215 - Creatine Phosphokinase / Creatine Kinase Or Isoenzymes Test System | CH - Clinical Chemistry |

## II Submission/Device Overview:

A Purpose for Submission:

New Device

B Measurand:

Cardiac Troponin I (cTnI)

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C Type of Test:

Quantitative Immunoassay

III Intended Use/Indications for Use:

A Intended Use(s):

See Indications for Use below.

B Indication(s) for Use:

The ARCHITECT STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnI) in human plasma (dipotassium [K2] EDTA) on the ARCHITECT i2000SR System.

The ARCHITECT STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

C Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

For in vitro diagnostic use

D Special Instrument Requirements:

ARCHITECT i2000SR

IV Device/System Characteristics:

A Device Description:

The ARCHITECT STAT High Sensitivity Troponin-I reagent kit contains:

- Microparticles: 1 bottle (6.6 mL per 100 test bottle / 29.0 mL per 500 test bottle) Anti-troponin I (mouse, monoclonal) coated microparticles in TRIS buffer with protein (bovine) stabilizer. Minimum concentration: 0.035% solids. Preservative: ProClin 300.
- Conjugate: 1 bottle (5.9 mL per 100 test bottle / 28.5 mL per 500 test bottle). Anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and human IgG. Minimum concentration: 0.1 mg/L. Preservative: ProClin 300.

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## B Principle of Operation:

The ARCHITECT STAT High Sensitivity Troponin-I assay is a two-step immunoassay for the quantitative determination of cardiac troponin I (cTnI) in human plasma using chemiluminescent microparticle immunoassay (CMIA) technology with flexible assay protocols, referred to as Chemiflex.

1. Sample and anti-troponin I antibody-coated paramagnetic microparticles are combined. The cTnI present in the sample binds to the anti-troponin I coated microparticles.
2. After incubation and wash, anti-troponin I acridinium-labeled conjugate is added.
3. Following another wash cycle, Pre-Trigger and Trigger Solutions are added to the reaction mixture.
4. The resulting chemiluminescent reaction is measured as relative light units (RLUs). There is a direct relationship between the amount of cTnI in the sample and the RLUs detected by the ARCHITECT iSystem optics.

The cTnI concentration is read relative to a standard curve established with calibrators of known cTnI concentrations.

## V Substantial Equivalence Information:

### A Predicate Device Name(s):

Elecsys Troponin T Gen 5 STAT Immunoassay

### B Predicate 510(k) Number(s):

K162895

### C Comparison with Predicate(s):

| Device & Predicate Device(s): | K191595 | K162895 |
| --- | --- | --- |
| Device Trade Name | ARCHITECT STAT High Sensitivity Troponin-I | Roche cobas Elecsys Troponin T Gen 5 STAT |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | The assay is to be used as an aid in the diagnosis of myocardial infarction. | Same |
| General Device Characteristic Differences | | |
| Specific Analyte Detected | cTnI | cTnT |

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| Device & Predicate Device(s): | K191595 | K162895 |
| --- | --- | --- |
| Specimen Type | Plasma (dipotassium [K2] EDTA) | Plasma (lithium heparin) |
| 99th Percentile Cutoff / Expected Values from Apparently Healthy Individuals | Female: 17 ng/L (ng/L)
Male: 35 ng/L (ng/L)
Overall: 28 ng/L (ng/L) | Female: 14 ng/L
Male: 22 ng/L
Overall: 19 ng/L |

VI Standards/Guidance Documents Referenced:

Clinical and Laboratory Standards Institute (CLSI) EP05-A2: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline—Second Edition

CLSI EP06-A: Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline

CLSI EP07-A2: Interference Testing in Clinical Chemistry; Approved Guideline—Second Edition

CLSI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline—Second Edition

CLSI EP28-A3c: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline—Third Edition

VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:

A study was performed using 1 lot of the ARCHITECT STAT High Sensitivity Troponin-I reagent, 1 lot of the ARCHITECT STAT High Sensitivity Troponin-I Calibrators, and 1 lot of the ARCHITECT STAT High Sensitivity Troponin-I Controls. The study was performed to include K₂ EDTA plasma specimens within each of 4 concentration ranges (> 3.5 to 6 ng/L, 10 to 20 ng/L, 30 to 50 ng/L, and 150 to 200 ng/L). Data was collected within the 8 hour stability claim for patient samples. The study was performed over a minimum of 3 days. Each specimen was stored at room temperature and tested in duplicate, twice in one day, on each of 3 instruments (for a total of 12 replicates per sample) within 8 hours of collection. Within laboratory precision includes within-run and between-run variability. Reproducibility includes within-run, between-run, and between-instrument variance components.

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| Sample | n | Mean (ng/L) | Within-Run | | Between-Run | | Within-Laboratory | | Reproducibility | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Sample 3 | 12 | 5.3 | 0.12 | 2.2 | 0.23 | 4.2 | 0.25 | 4.8 | 0.25 | 4.8 |
| Sample 4 | 12 | 11.2 | 0.47 | 4.2 | 0.00 | 0.0 | 0.47 | 4.2 | 0.62 | 5.5 |
| Sample 5 | 12 | 17.5 | 0.50 | 2.9 | 0.23 | 1.3 | 0.55 | 3.1 | 0.81 | 4.6 |
| Sample 6 | 12 | 18.8 | 0.60 | 3.2 | 0.22 | 1.2 | 0.64 | 3.4 | 0.75 | 4.0 |
| Sample 7 | 12 | 34.6 | 0.84 | 2.4 | 0.00 | 0.0 | 0.84 | 2.4 | 1.10 | 3.2 |
| Sample 8 | 12 | 38.8 | 1.00 | 2.6 | 1.10 | 2.8 | 1.48 | 3.8 | 1.92 | 5.0 |
| Sample 9 | 12 | 45.0 | 1.52 | 3.4 | 1.42 | 3.2 | 2.08 | 4.6 | 3.16 | 7.0 |
| Sample 10 | 12 | 163.7 | 5.00 | 3.1 | 6.23 | 3.8 | 7.99 | 4.9 | 11.68 | 7.1 |
| Sample 11 | 12 | 167.5 | 6.82 | 4.1 | 2.82 | 1.7 | 7.38 | 4.4 | 11.09 | 6.6 |
| Sample 12 | 12 | 179.6 | 6.76 | 3.8 | 0.00 | 0.0 | 6.76 | 3.8 | 8.19 | 4.6 |

Samples 1 and 2 were below the LoQ and were not included in the above analysis.

The sponsor also provided between-lot variability (which was similar to the reproducibility estimates described above) and between-instrument variability (which was similar to the within-run estimates described above) using patient samples.

A second study was performed following the recommendations in the EP05-A2 guideline. Testing was conducted using 3 lots of the ARCHITECT STAT High Sensitivity Troponin-I reagent, 2 lots of the ARCHITECT STAT High Sensitivity Troponin-I Calibrators, and 1 lot of the ARCHITECT STAT High Sensitivity Troponin-I Controls and 2 instruments. Five controls were tested in duplicate, twice per day on 20 days. Within-laboratory variability contains within-run, between-run, and between day variability. Patient samples can only be stored for 8 hours at room temperature; therefore, 20-day precision studies were conducted with quality control materials. On each day of testing a new vial of quality control material from the same lot was used.

| Sample | Instrument | Reagent Lot | N | Mean (ng/L) | Within-Run | | Within-Laboratory (Total) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | | SD | %CV | SD | %CV |
| Low Control | 1 | 1 | 80 | 19.3 | 0.61 | 3.2 | 0.72 | 3.7 |
| | | 2 | 80 | 20.3 | 0.61 | 3.0 | 0.78 | 3.9 |
| | | 3 | 80 | 19.7 | 0.64 | 3.3 | 0.78 | 3.9 |
| | 2 | 1 | 80 | 20.4 | 0.84 | 4.1 | 0.85 | 4.1 |
| | | 2 | 80 | 20.2 | 0.64 | 3.2 | 0.83 | 4.1 |
| | | 3 | 80 | 20.0 | 0.66 | 3.3 | 0.87 | 4.3 |

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| Sample | Instrument | Reagent Lot | N | Mean (ng/L) | Within-Run | | Within-Laboratory (Total) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | | SD | %CV | SD | %CV |
| Medium Control | 1 | 1 | 80 | 190.7 | 4.21 | 2.2 | 5.54 | 2.9 |
| | | 2 | 80 | 195.0 | 3.57 | 1.8 | 4.13 | 2.1 |
| | | 3 | 80 | 191.2 | 4.27 | 2.2 | 4.49 | 2.3 |
| | 2 | 1 | 80 | 197.8 | 5.26 | 2.7 | 5.76 | 2.9 |
| | | 2 | 80 | 196.8 | 4.65 | 2.4 | 5.36 | 2.7 |
| | | 3 | 80 | 194.3 | 4.43 | 2.3 | 5.95 | 3.1 |
| Commercial Control Level Low | 1 | 1 | 80 | 43.3 | 1.27 | 2.9 | 1.46 | 3.4 |
| | | 2 | 80 | 46.1 | 1.48 | 3.2 | 1.57 | 3.4 |
| | | 3 | 80 | 45.4 | 1.27 | 2.8 | 1.51 | 3.3 |
| | 2 | 1 | 80 | 45.2 | 1.36 | 3.0 | 1.82 | 4.0 |
| | | 2 | 80 | 46.4 | 1.80 | 3.9 | 1.84 | 4.0 |
| | | 3 | 80 | 46.0 | 1.40 | 3.0 | 1.48 | 3.2 |
| Commercial Control Level 2 | 1 | 1 | 80 | 1198.0 | 31.13 | 2.6 | 33.80 | 2.8 |
| | | 2 | 80 | 1281.3 | 33.38 | 2.6 | 40.95 | 3.2 |
| | | 3 | 80 | 1267.1 | 27.57 | 2.2 | 31.72 | 2.5 |
| | 2 | 1 | 80 | 1260.1 | 38.34 | 3.0 | 42.33 | 3.4 |
| | | 2 | 80 | 1309.1 | 28.25 | 2.2 | 42.68 | 3.3 |
| | | 3 | 80 | 1309.6 | 35.68 | 2.7 | 43.81 | 3.3 |
| Commercial Control Level 3 | 1 | 1 | 80 | 2812.3 | 64.56 | 2.3 | 80.50 | 2.9 |
| | | 2 | 80 | 3023.0 | 83.52 | 2.8 | 93.82 | 3.1 |
| | | 3 | 80 | 3015.3 | 94.13 | 3.1 | 95.14 | 3.2 |
| | 2 | 1 | 80 | 2978.3 | 80.34 | 2.7 | 102.42 | 3.4 |
| | | 2 | 80 | 3103.9 | 83.93 | 2.7 | 96.25 | 3.1 |
| | | 3 | 80 | 3138.2 | 55.49 | 1.8 | 84.50 | 2.7 |

Below is the between-lot and between-instrument precision estimates for the five control materials. Overall variability contains within-run, between-run, between-day, between-lot, between-instrument, and instrument-lot interaction variance components.

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| | | | Between-Lot | | Between-Instrument | | Overall | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Sample | N | Mean (ng/L) | SD | %CV | SD | %CV | SD | %CV |
| Low Control | 480 | 20.0 | 0.39 | 1.9 | 0.44 | 2.2 | 1.07 | 5.3 |
| Medium Control | 480 | 194.3 | 1.97 | 1.0 | 3.15 | 1.6 | 6.67 | 3.4 |
| Commercial Control Level Low | 480 | 45.4 | 1.11 | 2.4 | 0.82 | 1.8 | 2.21 | 4.9 |
| Commercial Control Level 2 | 480 | 1270.9 | 37.01 | 2.9 | 32.33 | 2.5 | 63.97 | 5.0 |
| Commercial Control Level 3 | 480 | 3011.8 | 102.59 | 3.4 | 89.69 | 3.0 | 166.88 | 5.5 |

## 2. Linearity:

Linearity was evaluated following the recommendations in the CLSI EP06-A guideline with 10 samples ranging in concentrations from $< 10 \, \mathrm{ng/L}$ to $>5000 \, \mathrm{ng/L}$ . The high samples and the low samples were native and the intermediate samples were prepared by mixing high and low concentration samples. Four replicates were measured for each sample, and the mean of these replicates was used to calculate the reported results. There were three sets of linearity samples made. Deviation from linearity within the claimed range was never observed to be greater than $14.1\%$ .

The measuring range is 3.5 to $5000.0\mathrm{ng / L}$ with the upper end of the measuring range being defined by the upper linear range of the assay. See detection limits below for information supporting the lower end of the measuring range.

## Hook Effect

The sponsor demonstrated that there is no hook effect with the assay up to $500,000\mathrm{ng / L}$ .

## Dilution Recovery

The sponsor provided dilution studies which supported the measurement of samples above the measurement range diluted by a factor of 10.

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# 3. Analytical Specificity/Interference:

Endogenous interference studies were performed following the recommendations in the CLSI EP07-A2 guideline. Two sample pools were tested. One sample pool had 20-60 ng/L cTnI and the second sample pool had 700-2000 ng/L cTnI. These sample pools were spiked with potential interferents. Test results from samples spiked with the potential interferent were compared to test results from the control samples lacking the potential interferent. At the tested concentrations, these compounds caused <10% interference.

| Endogenous Substance | Highest Concentration Tested Without Significant Interference |
| --- | --- |
| Unconjugated Bilirubin | 20 mg/dL |
| Conjugated Bilirubin | 20 mg/dL |
| Hemoglobin | 500 mg/dL |
| Total Protein | 9.3 g/dL |
| Triglycerides | 3000 mg/dL |

# Human anti-mouse antibodies (HAMA) and rheumatoid factor (RF)

The sponsor provided studies that evaluated the effect of HAMA and RF on the function of their device. The sponsor included the following information in the labeling to address the results:

"Specimens from patients who have received preparations of mouse monoclonal antibodies for diagnosis or therapy may contain human anti-mouse antibodies (HAMA). Such specimens may show either falsely elevated or depressed values when tested with assay kits such as ARCHITECT STAT High Sensitivity Troponin-I or others that employ mouse monoclonal antibodies.

Heterophilic antibodies and rheumatoid factor (RF) in human plasma can react with reagent immunoglobulins, interfering with in vitro immunoassays. The presence of heterophilic antibodies or RF in a patient specimen may demonstrate anomalous values. Additional information may be required for diagnosis.

Although the ARCHITECT STAT High Sensitive Troponin-I assay is specifically designed to minimize the effects of HAMA, heterophilic antibodies, and RF, assay results that are not consistent with other clinical observations may require additional information for diagnosis."

The same protocol described above was used to evaluate potential interference from therapeutic drugs. The results are summarized below. At the tested concentrations, all drugs caused <10% interference.

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| Compound | Highest Concentration Tested Without Interference |
| --- | --- |
| Abciximab | 20 µg/mL |
| Acetaminophen | 250 µg/mL |
| Acetylsalicylic Acid | 1000 µg/mL |
| Adrenaline | 0.37 µg/mL |
| Allopurinol | 400 µg/mL |
| Ambroxol | 400 µg/mL |
| Ampicillin | 1000 µg/mL |
| Ascorbic Acid | 300 µg/mL |
| Atenolol | 10 µg/mL |
| Biotin | 290 ng/mL |
| Bivalirudin | 42 µg/mL |
| Caffeine | 100 µg/mL |
| Captopril | 50 µg/mL |
| Carvedilol | 150 µg/mL |
| Cefoxitin | 2500 µg/mL |
| Cinnarizine | 400 µg/mL |
| Clopidogrel | 75 µg/mL |
| Cocaine | 10 µg/mL |
| Cyclosporine | 5 µg/mL |
| Diclofenac | 50 µg/mL |
| Digoxin | 7.5 µg/mL |
| Dopamine | 900 µg/mL |
| Doxycycline | 50 µg/mL |
| Eptifibatide | 7 µg/mL |
| Erythromycin | 200 µg/mL |
| Fibrinogen | 100 mg/dL |
| Fondaparinux | 4 µg/mL |
| Furosemide | 400 µg/mL |
| Ibuprofen | 500 µg/mL |
| Levodopa | 20 µg/mL |
| Low MW Heparin | 5 U/mL |
| Methyldopa | 25 µg/mL |
| Methylprednisolone | 80 µg/mL |
| Metronidazole | 200 µg/mL |
| Nicotine | 2 mg/dL |
| Nifedipine | 60 µg/mL |
| Nitrofurantoin | 64 µg/mL |
| Nystatin | 7.5 µg/mL |
| Oxytetracycline | 5 µg/mL |
| Phenobarbital | 15 mg/dL |
| Phenylbutazone | 400 µg/mL |
| Phenytoin | 100 µg/mL |
| Primidone | 10 mg/dL |
| Propranolol | 5 µg/mL |
| Quinidine | 20 µg/mL |

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| Compound | Highest Concentration Tested Without Interference |
| --- | --- |
| Rifampicin | 60 μg/mL |
| Salicylic Acid | 600 μg/mL |
| Simvastatin | 20 μg/mL |
| Sodium Heparin | 8 U/mL |
| Streptokinase | 31.3 U/mL |
| Theophylline | 75 μg/mL |
| TPA | 2.3 μg/mL |
| Trimethoprim | 75 μg/mL |
| Verapamil | 160 μg/mL |
| Warfarin | 30 μg/mL |

Interference beyond ± 10% was observed at the concentrations shown below for the following drug.

| Potentially Interfering Substance | Interferent Level | | Analyte Level | % Interference |
| --- | --- | --- | --- | --- |
| | Therapeutic | High | | |
| Fibrinogen | NA | 1000 mg/dL | 15 ng/L | 11.6 |

## Cross-Reactivity

Potential cross-reactivity was evaluated following the recommendations in the CLSI guideline EP07-A2.

To evaluate cross reactivity, the substances shown in the following table were added to K₂EDTA plasma patient samples at two cTnI concentrations (~ 0 and ~ 40 ng/L). Test results from samples spiked with the cross-reactant were compared to test results from samples without cross-reactant added. Samples were measured using three lots. There was no observed cross-reactivity at the concentrations tested below.

| Potential Cross-Reacting Substance | Highest Concentration Tested (ng/mL) |
| --- | --- |
| Cardiac Troponin T | 1000 |
| Skeletal Troponin I | 1000 |
| Tropomyosin | 1000 |
| Actin | 1000 |
| Troponin C | 1000 |
| Myosin Light Chain | 1000 |
| Myoglobin | 1000 |
| CK-MB | 1000 |

The following interferences are also described in the labeling:

Specimens from individuals with elevated levels of fibrinogen may demonstrate falsely elevated values.

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Total protein at 12.4 g/dL decreases troponin values at 15 ng/L and 500 ng/L by -12.0% and -18.4%, respectively.

Potential interference has not been evaluated for substances other than those described in the SPECIFIC PERFORMANCE CHARACTERISTICS, Interference section of this package insert.

Troponin autoantibodies have been reported to be present in approximately 10% to 20% of patients presenting to the emergency department (ED) and may lead to falsely low troponin assay results and delay in treatment of acute coronary syndrome (ACS). Therefore, a test result that is inconsistent with the clinical picture and patient history should be interpreted with caution.

4. Assay Reportable Range:

3.5 to 5000.0 ng/L cTnI

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

The Abbott ARCHITECT STAT High Sensitivity Troponin-I is traceable to the National Institute of Standards and Technology (NIST) Standard Reference Material SRM2921. The sponsor's traceability scheme was reviewed and found acceptable.

6. Detection Limit:

Limit of Blank (LoB) Test Protocol

The LoB was determined as described in the CLSI EP17-A2 guideline. Testing was performed using two sets of 4 zero-analyte samples tested with 3 replicates on 5 runs over the course of 3 days. Testing was performed using 4 reagent lots and 5 instruments. 60 determinations were obtained for each reagent lot / instrument combination. LoB was calculated parametrically. The largest estimate across all reagent lot-instrument combinations tested was 0.9 ng/L.

Limit of Detection (LoD) Test Protocol

The LoD was determined following the recommendations in the CLSI EP17-A2 guideline. Testing was performed using three reagent lots and one instrument. For the three lots tested, seven to ten native low analyte K₂EDTA plasma samples were tested every day, respectively, with four replicates for each test, for three days.

The parametric approach described in EP17-A2 was followed to determine the LoD. The largest estimate across all reagent lot-instrument combinations tested was 1.7 ng/L.

Limit of Quantitation (LoQ) Protocol

The Limit of Quantitation (LoQ) was determined as the analyte level with a within-lab CV of less than or equal to 20% following the recommendations in the CLSI EP17-A2 guideline. Testing was completed two times a day (n=2) for at least 20 days for a total of 60 replicates

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with eight to 10 native K₂EDTA plasma pools measured on one instrument using three reagent lots. For each reagent lot-instrument combination, the within-laboratory precision for each sample, expressed as %CV, was plotted against the mean concentration obtained for each sample. LoQ was determined by this precision profile as the concentration where the %CV was less than 20%. The largest estimate across all reagent lot-instrument combinations tested was 2.3 ng/L.

The sponsor claims a LoB of 0.9 ng/L, and LoD of 1.7 ng/L, and an LoQ of 3.5 ng/L.

7. Assay Cut-Off:

See Expected Values/Reference Range Section below.

8. Carry-Over:

Potential sample carryover was evaluated using EDTA plasma.

Potential sample carryover was evaluated by comparing the results of an unprotected low sample to a protected low sample. The protected low sample was tested before the high sample, and the unprotected low sample was tested after the high sample. The low sample had a native cTnI concentration of ≤ 10 ng/L. The high sample had a recombinant cTnI concentration ≥ 500,000 ng/L. The carry-over observed was approximately 0.3 ng/L cTnI going from a high sample to a low sample.

B Comparison Studies:

1. Method Comparison with Predicate Device:

Not applicable.

2. Matrix Comparison:

Not applicable.

C Clinical Studies:

1. Clinical Sensitivity:

A multi-center prospective study was performed to assess the diagnostic accuracy of the ARCHITECT STAT High Sensitivity Troponin-I assay. Specimens were collected at 11 emergency departments (ED) from 1065 subjects presenting to the ED with symptoms consistent with acute coronary syndrome (ACS). All subject diagnoses were adjudicated by three board certified cardiologists based on the 2007 ACC/AHA/ESC guidelines for MI. Serial samples were collected from patients presenting to the emergency department. The number of patients adjudicated with an MI was 10.8% (116/1065). The sample collection times were at 0 – 2 hours from presentation to the ED and at the following time-point relative to the time from presentation: 2 – 4 hours and 4 – 9 hours. Investigators and adjudicators were blinded to the proposed device’s results. Adjudicators were also blinded to site diagnoses. All results presented below were based on the adjudicated diagnoses. Clinical

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performance was estimated at an overall cut-off (male and female combined 99th percentile upper reference limit (URL) cut-off) and male- and female-specific URL cut-offs, calculated as described in Expected values/Reference range (in Section E below).

The samples collected in the study were frozen and stored prior to analysis. Abbott provided additional information to confirm that the performance estimates in the labeling were not affected by the freezing of these clinical samples. The results are summarized below.

An analysis for both females and males was performed using the overall 99th percentile cutoff (28 ng/L). The results are summarized in the following table.

| Sex | Time Point | N | Sensitivity | | Specificity | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | % | 95% CI | % | 95% CI |
| Female | Baseline | 412 | 91.7 (22/24) | 73.0 - 99.0 | 92.0 (357/388) | 88.9 - 94.5 |
| | 2 - 4 Hours | 418 | 94.4 (17/18) | 72.7 - 99.9 | 89.3 (357/400) | 85.8 - 92.1 |
| | 4 - 9 Hours | 372 | 94.1 (16/17) | 71.3 - 99.9 | 87.0 (309/355) | 83.1 - 90.4 |
| Male | Baseline | 519 | 81.8 (54/66) | 70.4 - 90.2 | 81.5 (369/453) | 77.6 - 84.9 |
| | 2 - 4 Hours | 526 | 91.7 (55/60) | 81.6 - 97.2 | 83.5 (389/466) | 79.8 - 86.7 |
| | 4 - 9 Hours | 489 | 93.7 (59/63) | 84.5 - 98.2 | 81.0 (345/426) | 76.9 - 84.6 |
| Sex | Time Point | N | PPV | | NPV | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | % | 95% CI | % | 95% CI |
| Female | Baseline | 412 | 41.5 (22/53) | 28.1 - 55.9 | 99.4 (357/359) | 98.0 - 99.9 |
| | 2 - 4 Hours | 418 | 28.3 (17/60) | 17.5 - 41.4 | 99.7 (357/358) | 98.5 - 100.0 |
| | 4 - 9 Hours | 372 | 25.8 (16/62) | 15.5 - 38.5 | 99.7 (309/310) | 98.2 - 100.0 |
| Male | Baseline | 519 | 39.1 (54/138) | 30.9 - 47.8 | 96.9 (369/381) | 94.6 - 98.4 |
| | 2 - 4 Hours | 526 | 41.7 (55/132) | 33.2 - 50.6 | 98.7 (389/394) | 97.1 - 99.6 |

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| Sex | Time Point | N | PPV | | NPV | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | % | 95% CI | % | 95% CI |
| | 4 - 9 Hours | 489 | 42.1
(59/140) | 33.9 - 50.8 | 98.9
(345/349) | 97.1 - 99.7 |

The following limitation is in the labeling regarding the clinical performance of this device.

Using the established overall 99th percentile (28 ng/L), the lower end of the confidence interval (CI) for positive predictive value (PPV) for female subjects was as low as 15.5% and for male subjects was as low as 30.9% in the clinical validation study. Up to 84.5% and 69.1% of positive troponin results could come from females and males, respectively, without an MI.

The results using the sex-specific 99th percentile cutoffs (female 17 ng/L, male 35 ng/L) are summarized in the following tables.

| Cutoff
(ng/L) | Time Point | N | Sensitivity | | Specificity | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | % | 95% CI | % | 95% CI |
| 17
(Female only) | Baseline | 412 | 95.8
(23/24) | 78.9 - 99.9 | 87.6
(340/388) | 83.9 - 90.7 |
| | 2 - 4 Hours | 418 | 94.4
(17/18) | 72.7 - 99.9 | 85.3
(341/400) | 81.4 - 88.6 |
| | 4 - 9 Hours | 372 | 94.1
(16/17) | 71.3 - 99.9 | 82.8
(294/355) | 78.5 - 86.6 |
| 35
(Male only) | Baseline | 519 | 78.8
(52/66) | 67.0 - 87.9 | 84.5
(383/453) | 80.9 - 87.8 |
| | 2 - 4 Hours | 526 | 90.0
(54/60) | 79.5 - 96.2 | 86.1
(401/466) | 82.6 - 89.1 |
| | 4 - 9 Hours | 489 | 93.7
(59/63) | 84.5 - 98.2 | 84.3
(359/426) | 80.5 - 87.6 |

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| Cutoff (ng/L) | Time Point | N | PPV | | NPV | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | % | 95% CI | % | 95% CI |
| 17 (Female only) | Baseline | 412 | 32.4 (23/71) | 21.8 - 44.5 | 99.7 (340/341) | 98.4 - 100.0 |
| | 2 - 4 Hours | 418 | 22.4 (17/76) | 13.6 - 33.4 | 99.7 (341/342) | 98.4 - 100.0 |
| | 4 - 9 Hours | 372 | 20.8 (16/77) | 12.4 - 31.5 | 99.7 (294/295) | 98.1 - 100.0 |
| 35 (Male only) | Baseline | 519 | 42.6 (52/122) | 33.7 - 51.9 | 96.5 (383/397) | 94.2 - 98.1 |
| | 2 - 4 Hours | 526 | 45.4 (54/119) | 36.2 - 54.8 | 98.5 (401/407) | 96.8 - 99.5 |
| | 4 - 9 Hours | 489 | 46.8 (59/126) | 37.9 - 55.9 | 98.9 (359/363) | 97.2 - 99.7 |

The following limitations are in the labeling regarding the clinical performance of this device.

Using the established sex-specific 99th percentiles in the same study (female 17 ng/L, male 35 ng/L), the lower end of the CI for PPV for female subjects was as low as 12.4% and for male subjects was as low as 33.7%. Up to 87.6% and 66.3% of positive troponin results could come from females and males, respectively, without an MI.

2. Clinical Specificity:

See Clinical Sensitivity above (Section C).

D Clinical Cut-Off:

The cut-offs for this assay were determined based on the 99th percentile upper reference limit in apparently healthy adults. Please see Expected Values/Reference Range below (Section E) for the determination of the clinical cut-offs.

E Expected Values/Reference Range:

A reference range study was conducted based on guidance from CLSI EP28-A3c. Specimens were collected from 1531 apparently healthy individuals in a US population with the following levels of biomarkers:

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| Biomarker | Male | Female |
| --- | --- | --- |
| Cardiac BNP (pg/mL) | ≤ 25 | ≤ 40 |
| HbA1c (%) | ≤ 6 | |
| GFR (mL/min/1.73 m2) | ≥ 60 | |

Each specimen was stored frozen, thawed, and evaluated in replicates of one using the ARCHITECT STAT High Sensitivity Troponin-I assay. The 99th percentiles described in the following table for this population were determined using the robust statistical method described in CLSI EP28-A3c.

| Apparently Healthy Population | N | Age Range (years) | 99th Percentile (ng/L) | 90% CI (ng/L) |
| --- | --- | --- | --- | --- |
| Female | 765 | 21 - 75 | 17 | [14, 20] |
| Male | 766 | 21 - 73 | 35 | [27, 44] |
| Overall | 1531 | 21 - 75 | 28 | [22, 33] |

## VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

## IX Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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