FDA 510(k) Search - By Innolitics (SaMD and AI Experts)

The ARCHITECT B R A H M S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem.

Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT BR A-H-M-S PCT assay is intended for use as an:

· Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.

· Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.

· Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.

· Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The ARCHITECT B R A H M S PCT Calibrators are for the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.

The ARCHITECT B-R-A-H-M-S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.

Device Description

The ARCHITECT B.R.A.H.M.S PCT assay reagents are available in 100 or 500 test kits. The kit components include PCT Microparticles coated with Rat monoclonal anti-PCT and PCT Conjugate with Mouse monoclonal anti-PCT acridinium-labeled conjugate. Both contain Bovine serum albumin and preservatives. The ARCHITECT B.R.A.H.M.S PCT Calibrators kit consists of 6 bottles, with Calibrator A containing normal human plasma and Calibrators B-F containing recombinant human PCT in phosphate buffer. The ARCHITECT B.R.A.H.M.S PCT Controls kit consists of 2 x 3 bottles at three target concentrations of recombinant PCT in phosphate buffer. The assay is a two-step immunoassay using chemiluminescent microparticle immunoassay (CMIA) technology.

AI/ML Overview

The ARCHITECT B.R.A.H.M.S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem. It is intended to aid in the risk assessment of critically ill patients for progression to severe sepsis and septic shock, aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock, and aid in decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) or sepsis.

Here's an analysis of the acceptance criteria and study proving the device meets these criteria:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a tabulated format for all performance characteristics. Instead, it describes validated performance characteristics. I will compile a table based on the provided performance summaries and their implied acceptance as suitable for the intended use.

Performance Characteristic	Acceptance Criteria (Implied)	Reported Device Performance
Reproducibility/Precision	Meets CLSI EP05-A3 guidelines for internal precision.	Internal Precision: Within-laboratory (total) %CVs:

Low control: 2.5% to 2.8%
Medium control: 2.1% to 2.5%
High control: 3.5% to 3.8%
Panel 1: 2.5%
Panel 3: 2.1%
Panel 5: 2.2% to 2.3% |
| | Meets CLSI EP15-A3 guidelines for multi-site precision. | Multi-Site Precision:
Within-laboratory %CVs (individual sites): 1.5% to 4.0% for concentrations > 0.1 ng/mL; SD ≤ 0.005 ng/mL for concentrations ≤ 0.1 ng/mL.
Total precision %CVs (pooled data): 2.3% to 4.0% for concentrations > 0.1 ng/mL; SD ≤ 0.005 ng/mL for concentrations ≤ 0.1 ng/mL. |
| Linearity/Assay Reportable Range | Meets CLSI EP06-A for linearity across the intended range. Bias acceptance criteria met for auto-dilution. | Linearity: Linear in the range of 0.01 to 106.80 ng/mL.
Dilution Tests: 1:10 auto-dilution protocol meets 10% bias acceptance criteria from 20.5 ng/mL to 1000 ng/mL.
Analytical Measuring Range: 0.02 to 100.00 ng/mL.
Extended Measuring Range (with auto-dilution): Up to 1000.00 ng/mL. |
| Reagent Stability | Sufficient shelf-life for intended use. | Reagent Shelf Life: 9 months for intended storage (2-8°C).
Transport Stability: Can be shipped at ambient or refrigerated conditions. |
| Calibrator Stability | Sufficient shelf-life for intended use. | Calibrator Shelf Life: 9 months for frozen conditions (-10°C or colder), including 3 freeze/thaw cycles. |
| Control Stability | Sufficient shelf-life for intended use. | Control Shelf Life: 9 months for frozen conditions (-10°C or colder).
In Use Storage: 30 days post-thaw at 2-8°C. |
| Detection Limit | Meets CLSI EP17-A2 for detection capabilities. | LoB: 0.0004 ng/mL
LoD: 0.0018 ng/mL
LoQ: 0.0077 ng/mL |
| Analytical Specificity/Cross Reactivity | No significant interference from tested substances. | No interference seen with up to:
10 ng/mL Human Katacalcin
2 ng/mL Human Calcitonin
10 µg/mL Human α-CGRP
10 µg/mL Human β-CGRP |
| Interfering Substances (Endogenous) | Less than 5% interference from tested endogenous substances. | Interferent levels not affecting test performance:
Hemoglobin: ≤ 500 mg/dL (1.9% interference)
Triglycerides: ≤ 3000 mg/dL (0.9% interference)
Unconjugated Bilirubin: ≤ 20 mg/dL (2.8% interference)
Conjugated Bilirubin: ≤ 30 mg/dL (3.9% interference)
Total Protein: ≤ 12 g/dL (4.8% interference) |
| Interfering Substances (Exogenous) | No significant interference from tested substances. | No interference seen with up to listed concentrations for: Imipenem, Cefotaxime, Vancomycin, Dopamine, Noradrenaline, Dobutamine, Heparin, Furosemide.
HAMA Effect: No interference seen with up to 3600 ng/mL.
RF Effect: No interference seen with up to 2000 IU/mL. |
| High Dose Hook Effect | No hook effect within the tested range. | Free of hook effects up to 10,000 ng/mL PCT. |
| Specimen Stability | Samples remain stable for specified storage conditions and times. | On Board Stability: Stable for up to 3 hours.
Room Temperature (15-30°C): Stable for up to 24 hours (plasma/serum harvested); ≤ 8 hours (on cells/clot/separator gel); ≤ 24 hours (off cells/clot/separator gel).
Refrigerated (2-8°C): Stable for up to 48 hours.
Freeze-Thaw Cycles: Up to 3 cycles (EDTA plasma, no-additive serum, SST serum); 1 cycle (lithium heparin plasma).
Frozen Short Term (-10°C or colder): Up to 15 days.
Frozen Long Term (-70°C): 18 months. |
| Matrix Comparison | Different matrix types are equivalent within defined bias. | Minimal bias between K2EDTA plasma (base tube) and other types:
Lithium heparin plasma: +2% bias
Serum: -4% bias
SST: -6% bias
All four tube types considered equivalent. |
| Method Comparison | Strong correlation with the predicate device. | Correlation coefficient (r): 0.99 (between ARCHITECT B.R.A.H.M.S PCT and B.R.A.H.M.S PCT sensitive KRYPTOR®).
Slope: 1.00; Intercept: -0.02. |
| Clinical Performance (28-day mortality) | Significant association between ΔPCT and 28-day mortality. Prognostic accuracy demonstrated. Ability to differentiate risk groups. | MOSES Study:
Binary test result (ΔPCT > 80% or ≤ 80%) significantly associated with 28-day cumulative mortality (p=0.001).
Adjusted for ICU vs. non-ICU: p=0.017.
Relative mortality ratios (ΔPCT positive vs. negative) ranged from 1.49 to 3.38 across subgroups.
Kaplan-Meier curves showed lower survival probability for ΔPCT positive.
Hazard ratio for ΔPCT ≤ 80% vs. > 80% was 1.99 (p=0.002) for Day 0 to Day 4 change, indicating a ~2-fold higher mortality risk.
ΔPCT remains a prognostic parameter even when adjusted for other mortality predictors in Cox multi-regression models.
Clinical Concordance: >96% total agreement with predicate at 0.5 µg/L and 2.0 µg/L decision points. |

2. Sample Size Used for the Test Set and Data Provenance:

Analytical Performance Studies (Precision, Linearity, Detection Limit, Specificity, Interference, Hook Effect, Reagent/Calibrator/Control Stability):
- Precision (Internal): 320 replicates (80 per sample-reagent-calibrator lot combination) for controls and plasma panels.
- Precision (Multi-Site): 25 replicates per sample per site over 5 days.
- Linearity: 3 unique EDTA plasma High pools, each diluted to 10 levels.
- Dilution Tests: 5 specimens evaluated by three methods (neat, manual, auto-dilution) in replicates of five for concentrations between Cal E and Cal F; 5 specimens evaluated by manual and auto-dilution in replicates of five for concentrations between Cal F and 1000 ng/mL.
- Detection Limit (LoB): 288 replicates (4 blank plasma lots, 6 replicates each, on 2 instruments with 2 reagent lots per instrument for 3 days).
- Detection Limit (LoD): 400 replicates (1 blank plasma lot spiked to 4 levels, 5 replicates each, for 5 days on 2 instruments with 3 reagent lots and 2 calibrator lots).
- Detection Limit (LoQ): 1000 replicates (2 blank plasma lots spiked to 5 levels, 5 replicates each, for 5 days on 2 instruments with 3 reagent lots and 2 calibrator lots).
- Analytical Specificity/Cross Reactivity: Samples tested in replicates of seven in a single run.
- Interfering Substances (Endogenous): 3 plasma-based panels, each tested in replicates of eight across three runs.
- Interfering Substances (Exogenous): 8 potential drug interferents, spiked into 3 plasma panels, run in replicates of eight. HAMA stock solutions spiked into 3 plasma panels, run in replicates of eight. RF stock solution spiked into 3 plasma panels, run in replicates of eight.
- High Dose Hook Effect: 7 spiked samples and Cal F tested in 18 replicates each.
- Specimen Stability: Fresh samples from 53 patients for 4 tube types.
- Matrix Comparison: Matched set specimens from patients (number not specified but assumed to be sufficient per CLSI EP09-A3).
- Method Comparison: 142 human K2EDTA plasma specimens.
- Reference Range Study: n=446 normal healthy donor K2EDTA plasma individuals.
- Data Provenance: Primarily conducted at the Thermo Fisher internal laboratory. Multi-site precision involved two external CLIA certified laboratories and the Thermo Fisher internal laboratory. Clinical samples for linearity were from multiple donors; for specimen stability and matrix comparison, samples were prospectively collected from two hospital sites in Switzerland. The clinical study (MOSES) involved 13 investigational sites in the United States. The method comparison study used human K2EDTA plasma specimens. All samples appear to be retrospective clinical samples or laboratory-prepared panels.
Clinical Studies (MOSES Study):
- Sample Size: 858 adult patients initially, analyzed population of 598 subjects.
- Data Provenance: Prospective clinical trial conducted across 13 investigational sites in the United States.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

This device is an in-vitro diagnostic (IVD) assay that measures a biomarker (PCT) quantitatively. The "ground truth" for analytical performance tests is typically established through reference methods, certified standards, and rigorous statistical analysis according to CLSI guidelines, rather than expert interpretation of images or clinical cases. For the clinical study, the ground truth for mortality was the outcome data (28-day all-cause mortality). No information is provided about experts establishing ground truth for the test set in the traditional sense of consensus reading for subjective data.

4. Adjudication Method for the Test Set:

Not applicable in the typical sense for quantitative biomarker assays. The clinical ground truth (28-day mortality) is an objective outcome, not requiring adjudication. Analytical studies rely on quantitative measurements against defined standards and statistical methods.

5. 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 a standalone quantitative diagnostic assay for a biomarker (PCT), not a device that assists human readers in interpreting medical images or clinical cases.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done:

Yes, the device is explicitly a standalone assay. It quantitatively determines PCT levels. Although the indications for use state "Used in conjunction with other laboratory findings and clinical assessments," the performance data presented is for the assay's output itself, not for human-in-the-loop interpretation of the assay's results. The hazard ratios and mortality predictions are based solely on the PCT values generated by the device.

7. The Type of Ground Truth Used:

Analytical Performance: Various types of ground truth relevant to analytical testing were used:
- Reference standards/gravimetric dilutions: For linearity, detection limits, and calibrator/control value assignment.
- Known concentrations: For spike-recovery and interference studies.
- Predicate device results: For method comparison (B.R.A.H.M.S PCT sensitive KRYPTOR®).
Clinical Performance (MOSES Study):
- Outcomes Data: 28-day all-cause mortality was the primary outcome for the clinical study. This is objective, hard outcome data.

8. The Sample Size for the Training Set:

The document describes performance studies, not a machine learning model that requires a distinct "training set." The analytical studies and clinical validation study (MOSES study) collectively serve as the evidence base demonstrating the device's performance and suitability for its intended use. The samples used in these studies, as detailed in point 2, were used for validation and verification, not for training a model in the AI/ML sense.

9. How the Ground Truth for the Training Set Was Established:

Not applicable, as there isn't a "training set" in the context of an AI/ML model for this device. The ground truth for the various performance evaluation samples was established through established laboratory methods, reference standards, and objective clinical outcomes as described in point 7.

Summary

Regulation Number and Section

§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.

(a)
Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.
(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.
(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.
(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.
(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.
(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.
(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (
e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.