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The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in vitro diagnostic use in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin, and sodium heparin) using the Atellica® IM Analyzer.

The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in:

· The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

• 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 percent change in PCT level over time.

· Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) – 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.

• · Decision-making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The Atellica IM BRAHMS PCT assay is a 2-site sandwich immunoassay using direct chemiluminescent technology that uses 3 mouse monoclonal antibodies specific for PCT. The first antibody, in the Lite Reagent, is a mouse monoclonal anti-PCT antibody labeled with acridinium ester. The second and third antibodies, in the ancillary reagent, are mouse monoclonal anti-PCT antibodies labeled with fluorescein. The immunocomplex formed with PCT is captured with mouse monoclonal anti-fluorescein antibody coupled to paramagnetic particles in the Solid Phase.

A direct relationship exists between the amount of PCT present in the patient sample and the amount of relative light units (RLUs) detected by the system.

The provided text describes the Siemens Healthcare Diagnostics Atellica IM B.R.A.H.M.S Procalcitonin (PCT) assay, an in vitro diagnostic device. The study presented focuses on the analytical and clinical performance of this assay, comparing it to a predicate device and evaluating its utility in specific clinical scenarios related to sepsis and respiratory tract infections.

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

Acceptance Criteria and Reported Device Performance

The acceptance criteria for this device are implicitly derived from the performance goals demonstrated in the analytical and clinical studies. Since this is a 510(k) submission, the primary goal is to show substantial equivalence to a legally marketed predicate device (B.R.A.H.M.S PCT sensitive KRYPTOR). The performance characteristics are presented as meeting industry standards (CLSI guidelines) and showing comparable results to the predicate.

Here's a table summarizing the analytical performance with implicit acceptance criteria (typically, these would be defined before the study in a protocol, often as a deviation tolerance from the predicate or a specific measure):

Detailed Study Information:

1. Sample sizes used for the test set and the data provenance:

   • Analytical Performance:
     • Precision: 5 contrived human serum samples, 80 replicates per sample.
     • Linearity: 9 samples (prepared from high and low human serum pools).
     • Dilution Recovery: 5 human serum samples.
     • Detection Limits (LoD): 360 determinations (160 blank, 200 low-level replicates).
     • Endogenous/Therapeutic Drug/Cross-Reactivity Interference: Not specified beyond "serum pools" and "serum and plasma."
     • Heterophile Interference: HAMA and RF positive patient samples + control samples.
     • Method Comparison: 623 native human serum samples with assigned values from the predicate device.
     • Matrix Comparison: 51 matched specimen sets in 4 tube types (Serum, EDTA plasma, Lithium Heparin Plasma, Sodium Heparin Plasma).
     • Expected Values/Reference Interval: 144 serum samples from normal subjects.
   • Clinical Studies:
     • 28-day Mortality: 858 adult patients (>18 years) diagnosed with severe sepsis or septic shock admitted to ICU. The analysis population comprised 598 subjects.
     • Antibiotic Therapy/Discontinuation Support: Systematic literature reviews and meta-analyses:
       • Study-level meta-analysis (Initiation/Discontinuation): 11 RCTs (4090 patients) published 2004-2016.
       • Patient-level meta-analysis (Initiation): 13 RCTs (3142 patients) published 2004-2011.
       • Patient-level meta-analysis (Discontinuation): 5 RCTs (598 patients) published 2008-2010.
   • Data Provenance:
     • Analytical Data: In-house or contracted lab studies (implied to be prospective given the detailed methodology descriptions).
     • Clinical Data: "Banked specimens that were collected from subjects... and included as part of the intention-to-diagnose population from the BRAHMS MOSES study (DEN150009)." This indicates retrospective use of previously collected clinical trial data. The original MOSES study subjects were recruited across 13 investigational sites in the US. The meta-analyses for antibiotic guidance consolidated data from previously published RCTs.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • For the analytical test sets, ground truth is established by standard laboratory methods and reference materials (e.g., recombinant PCT, serum pools), not human experts.
   • For the clinical study, the ground truth for patient outcomes (e.g., severe sepsis/septic shock diagnosis, 28-day all-cause mortality, need for ICU care) was presumably established by the clinical assessments and medical records from the original BRAHMS MOSES study that provided the banked specimens. The document does not specify the number or qualifications of clinicians/experts who established these initial diagnoses and outcomes for the MOSES study, but it's implied to be standard clinical practice within a multi-site clinical trial.
   • For the meta-analyses, the "ground truth" for antibiotic management decisions and patient outcomes (mortality, LOS, etc.) derived from the various RCTs where those decisions and outcomes were prospectively recorded by the clinical teams involved in those trials.

3. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

   • For the analytical studies, the "ground truth" values are quantitative measurements or characteristics of samples, typically not subject to human adjudication in the same way as, for example, image interpretation. Internal laboratory quality control and statistical methods (e.g., regression analysis, CV calculations) serve as "adjudication."
   • For the clinical study, the data were obtained from previously collected "banked specimens" and "clinical assessments" from the BRAHMS MOSES study. The document does not describe a new adjudication process for this particular 510(k) submission's analysis of this retrospective data. The rigor of the original MOSES study's data collection and endpoint ascertainment would be relevant but is not detailed here.
   • The meta-analyses relied on data from published RCTs; any adjudication would have occurred within the original trials.

4. 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:

   • No. This device is an in vitro diagnostic (IVD) assay that measures a biomarker (Procalcitonin) in human specimens. It is not an AI-assisted diagnostic imaging or pathology device that requires human "readers." Therefore, an MRMC study is not applicable and was not performed.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • Yes, implicitly. The performance characteristics (precision, linearity, detection limits, interference, method comparison) are "standalone" results of the assay itself, demonstrating its analytical performance when run on the Atellica IM Analyzer. The clinical studies demonstrate the performance of the assay's results when used in conjunction with "other laboratory findings and clinical assessments," but the assay itself generates the PCT value independently of human interpretation of that specific run.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

   • Analytical Studies: "Ground truth" for analytical studies is typically established by meticulously prepared reference materials, spike-in methods, and comparison to a well-validated predicate device using a large sample size of native patient samples.
   • Clinical Studies:
     • For the 28-day mortality prediction, the ground truth was outcomes data (survival status at 28 days) derived from a pre-existing clinical study (BRAHMS MOSES study).
     • For antibiotic guidance, the insights were derived from meta-analyses of published Randomized Controlled Trials (RCTs). The "ground truth" here is the aggregated, prospectively collected patient outcomes (antibiotic use, duration, mortality, complications, LOS) from these trials where patients were managed either by standard care or PCT-guided protocols.

7. The sample size for the training set:

   • This document describes a 510(k) premarket notification for an IVD assay, not an AI/ML device that typically requires a distinct "training set." The performance studies for an IVD device like this are primarily for validation and demonstrate clinical and analytical performance. There is no explicit "training set" in the context of machine learning.
   • However, if one were to consider the development of the assay's methodologies, the calibration and control materials (e.g., PCT MCM) would be used for standardization and quality control, which could be seen as analogous to internal "training" or optimization data during product development, but no specific sample size for this is detailed as "training set."

8. How the ground truth for the training set was established:

   • As noted above, the concept of a "training set" with ground truth establishment in the ML sense is not directly applicable to this type of IVD device submission. The assay is a chemical measurement system. Its "truth" is established via analytical validation showing its accuracy, precision, and comparability to reference methods/predicate devices.

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