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For in-vitro diagnostic use only.

For the quantitative measurement of procalcitonin (PCT) in human serum and plasma (lithium heparin and EDTA) using the VITROS 3600 Immunodiagnostic System.

Used in conjunction with other laboratory findings and clinical assessments, the VITROS B R A PA - M S PCT test is intended for use as follows:

· to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,

· to 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,

· to aid in 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,

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

The VITROS B·R·A·H·M·S PCT test is performed using the VITROS B·R·A·H·M·S PCT Reagent Pack and the VITROS B·R·A·H·M·S PCT Calibrators on the VITROS Systems.

Reagent Pack Contents
1 reagent pack containing:

• 100 coated wells (rat monoclonal anti-procalcitonin antibody, 1.0 µg/mL) ●
• 10.20 mL assay reagent (buffer containing bovine gamma globulin, bovine serum ● albumin and antimicrobial agent)
• . 13.10 mL conjugate reagent (HRP-conjugated mouse monoclonal procalcitonin antibody. 1.65 ug/mL in buffer with bovine serum albumin and antimicrobial agent)

Calibrator Contents

• . 3 sets of VITROS B•R•A•H•M•S PCT Calibrators 1 and 2, 1.0 mL, procalcitonin in buffer with antimicrobial agent, nominal values 0.080 and 75.0 ng/mL (ug/L)
• . Lot calibration card
• Protocol card ●
  • 16 calibrator bar code labels (8 for each calibrator) ●

The provided text is a 510(k) Summary for the VITROS B·R·A·H·M·S PCT Reagent Pack and Calibrators, intended for quantitative measurement of procalcitonin (PCT). This document describes the device's performance characteristics and clinical studies to establish substantial equivalence to a predicate device.

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

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a 510(k) summary for an in vitro diagnostic device, the "acceptance criteria" are implied by the comparison to the predicate device and established analytical performance metrics. The key criterion is demonstrating substantial equivalence to the predicate device, B·R·A·H·M·S PCT sensitive KRYPTOR (K171338), especially at critical clinical decision points.

2. Sample Sizes and Data Provenance

• Test Set (Method Comparison with Predicate):

  • Sample Size: 266 patient samples were used for the regression analysis comparing the VITROS B·R·A·H·M·S PCT test to the B·R·A·H·M·S PCT sensitive KRYPTOR assay. 246 samples were within the measuring range.
  • Data Provenance: Not explicitly stated for analytical studies, but for the clinical performance study, samples were "retrospective samples from a study of 858 adult patients diagnosed with severe sepsis or septic shock recruited across 13 investigational sites in the United States." The original MOSES Study (DEN150009) collected samples from patients admitted to ICU from emergency departments, other wards, or directly from out of the hospital. EDTA samples were used.

• Test Set (Clinical Concordance):

  • Sample Size: 2168 samples (evaluating concordance at various PCT decision points).
  • Data Provenance: "serial sample sets obtained from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study collection, a well-characterized sample collection in 13 sites across the United States." This indicates a prospective collection used retrospectively for this specific device's evaluation.

• Test Set (28-Day Mortality Prediction):

  • Sample Size: 858 adult patients in the study, with an analysis population of 598 subjects.
  • Data Provenance: Retrospective samples from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study collection in 13 sites across the United States.

3. Number of Experts and Qualifications for Ground Truth

• For an in vitro diagnostic device measuring an analyte (procalcitonin), the "ground truth" for analytical studies is typically established by reference methods or gravimetric preparation with known concentrations. Experts are not typically involved in establishing ground truth for analytical performance like precision, linearity, LoD/LoQ, and interference.
• For clinical studies (concordance and mortality prediction), the primary "ground truth" for the device's performance against clinical decision points is the predicate device's measurement (B.R.A.H.M.S PCT sensitive KRYPTOR assay). Physician discretion and clinical assessments were used for patient diagnosis and mortality outcomes in the MOSES study, which provided the samples. While physicians made clinical diagnoses, they were not experts establishing a "ground truth score" for the device; rather, clinical outcomes (mortality, diagnosis of sepsis/septic shock) were endpoints. No individual "experts" were formally used to establish a ground truth for the test set, but rather the clinical outcomes and the predicate device's results served as the reference.

4. Adjudication Method

• Not applicable in the context of this 510(k) summary for an in vitro diagnostic device assessing an analyte level. Adjudication methods like 2+1 or 3+1 are typically used for subjective evaluations (e.g., imaging interpretation) where expert consensus is needed to determine the correct ground truth for a given case. Here, the ground truth for analytical performance is quantitative, and for clinical performance, it is the predicate device's measurement and observed clinical outcomes (e.g., 28-day mortality).

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• No, an MRMC comparative effectiveness study was not performed. This device is an in vitro diagnostic assay, not an AI-assisted diagnostic tool for human readers. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply.

6. Standalone Performance Study

• Yes, the performance described is a standalone performance study of the VITROS B·R·A·H·M·S PCT Reagent Pack and Calibrators. The "algorithm only" in this context refers to the assay's ability to quantitatively measure PCT levels. All analytical performance studies (precision, linearity, detection limits, analytical specificity, matrix comparison, high-dose hook, sample auto-dilution, carry-over) were conducted to demonstrate the standalone performance of the VITROS B·R·A·H·M·S PCT test. The clinical concordance with the predicate device also serves as a standalone performance benchmark.

7. Type of Ground Truth Used

• Analytical Ground Truth: For analytical performance studies (precision, linearity, LoD/LoQ, interference, matrix equivalence, high dose hook, carry over), the ground truth was established by:
  • Reference calibrators: Traceable to in-house reference calibrators, which were value-assigned to correlate to B·R·A·H·M·S PCT sensitive KRYPTOR.
  • Known concentrations: Prepared by gravimetric spiking with recombinant PCT.
  • Validated analytical methods: Following CLSI guidelines (e.g., EP05-A3 for precision, EP17-A2 for detection limits, EP06-A for linearity, EP07-A3 for interference).
• Clinical Ground Truth:
  • Predicate device results: For clinical concordance, the measurements from the B·R·A·H·M·S PCT sensitive KRYPTOR assay were considered the reference for comparison.
  • Outcomes data: For the 28-day mortality prediction claim, the vital status (mortality) of patients at Day 28 was the ground truth. This outcome data was collected during the original MOSES study.

8. Sample Size for the Training Set

• This 510(k) document describes a traditional in vitro diagnostic device clearance, not an AI/ML software submission that often explicitly details "training sets."
• However, the device's calibration is "traceable to in-house reference calibrators, which have been value-assigned to correlate to B·R·A·H·M·S PCT sensitive KRYPTOR." The development of these in-house reference calibrators and the assay itself would have involved some form of "training" or optimization using an internal dataset, but its size and specific characteristics are not provided in this regulatory summary.
• The clinical study samples from the MOSES study were used for validation (evaluation) of the device's clinical performance, not as a training set for the assay's underlying methodology.

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

• As noted above, a formal "training set" in the AI/ML sense is not described. The ground truth for the development of the assay (e.g., for calibrator assignment) would have been established through a combination of:
  • Reference materials: Highly characterized procalcitonin standards.
  • Defined analytical methods: Using established laboratory practices and potentially comparing to existing, well-regarded PCT assays during the R&D phase to create the "in-house reference calibrators."
  • Value assignment: A process where the concentration of an analyte in a calibrator is accurately determined. This often involves multiple measurements using reference methods or by gravimetric preparation.

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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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VIDAS® B·R·A·H·M·S PCT " (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.

VIDAS® B·R·A·H·M·S PCT™ (PCT) is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

VIDAS® B·R·A·H·M·S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments 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.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intension for progression to severe sepss and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

PCT levels on the first day of ICU admission above 2.0 ng/mL are associated with a higher risk for progression to severe sepsis and/or septic shock than PCT levels below 0.5 ng/mL.

A PCT level that declines 80%.

The combination of the first PCT level (≤2.0 ng/mL or > 2.0 ng/mL) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important adout the mortality risk.

The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA).

The Solid Phase Receptacle (SPR®), serves as the solid phase as well as the pipetting device. Reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips.

All of the assay steps are performed automatically by the instrument. The sample is transferred into the wells containing anti-procalcitonin antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the SPR® several times. This operation enables the antigen to bind with the immunoglobulins fixed to the interior wall of the SPR® and the conjugate to form a sandwich. Unbound compounds are eliminated during washing steps.

Two detection steps are performed successively. During each step, the substrate (4-Methylumbelliferyl phosphate) is cycled in and out of the SPR®. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone) the fluorescence of which is measured at 450 nm. The intensity of the fluorescence is proportional to the concentration of antigen present in the sample.

At the end of the assay, results are automatically calculated by the instrument in relation to two calibration curves corresponding to the two detection steps. A fluorescence threshold value determines the calibration curve to be used for each sample. The results are then printed out.

This document describes the VIDAS® B·R·A·H·M·S PCT™ (PCT), an automated test for determining human procalcitonin levels in serum or plasma, used to aid in the risk assessment of critically ill patients for progression to severe sepsis and septic shock, and to assess the cumulative 28-day risk of all-cause mortality in patients diagnosed with severe sepsis or septic shock.

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

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly define "acceptance criteria" for clinical performance in a comparative table with reported values. Instead, it provides clinical study results demonstrating the device's prognostic accuracy. Analytical performance is reported against established guidelines.

Here's a summary of the analytical performance:

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

• Sample Size (Clinical Study): 858 adult patients were recruited across 13 investigational sites. The "per protocol population" used for the analysis comprised 598 patients.
• Data Provenance: The study was conducted at 13 investigational sites in the US. The study is prospective, as patients were recruited and followed for 28 days to assess mortality.

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

• The document does not specify the number of experts used or their qualifications for establishing the ground truth related to patient diagnosis of severe sepsis or septic shock, or the 28-day all-cause mortality outcome. These are assumed to be standard clinical diagnoses and outcome tracking in a hospital setting.

4. Adjudication Method for the Test Set:

• The document does not specify an explicit adjudication method for clinical diagnoses or outcomes. It implies that diagnoses of severe sepsis/septic shock and 28-day mortality were determined based on standard clinical practice at the participating sites.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Improvement with AI vs. Without AI Assistance:

• No, this is not an MRMC study. This is a clinical study evaluating the prognostic utility of a biomarker (PCT) measured by an automated in-vitro diagnostic device. It does not involve human readers interpreting cases or AI assistance in interpretation. The device provides a quantitative measurement, which clinicians then use in conjunction with other findings.

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

• Yes, in essence, the analytical performance studies are "standalone" algorithm-only performance. The device automatically measures procalcitonin levels. The clinical study then evaluates how these quantitative results, particularly the change in PCT levels (ΔPCT), correlate with patient outcomes (28-day mortality), independent of human interpretation of the PCT value itself, though still in the context of clinical assessment.

7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.):

• Outcomes Data and Clinical Diagnosis:
  • Clinical Diagnosis of severe sepsis or septic shock: This served as the inclusion criteria for the patient cohort. While the method for establishing this initial diagnosis is not detailed, it would typically be based on established clinical criteria.
  • Cumulative 28-day all-cause mortality: This was the primary outcome measured and served as the ground truth for evaluating the prognostic accuracy of the PCT values and ΔPCT.

8. The Sample Size for the Training Set:

• The document does not specify a separate training set size for the clinical performance evaluation. The 598 patients in the per-protocol population appear to be a single cohort used for the performance assessment. For analytical performance (e.g., LoB, LoD, LoQ, Precision), specific numbers of replicates and samples are provided (e.g., 240 values for each of 9 samples for precision).

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

• As a separate "training set" for clinical performance is not explicitly mentioned for this 510(k) submission, the method for establishing ground truth for a training set is not provided. For the clinical study that assessed prognostic accuracy, the ground truth was the 28-day all-cause mortality outcome, as observed and recorded for the enrolled patients. The diagnoses of severe sepsis or septic shock were clinical diagnoses used for patient enrollment.

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Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 and K3 EDTA, Li-Heparin).

The Elecsys BRAHMS PCT assay is intended for use to determine the change of PCT over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the Intensive Care Unit (ICU) or when obtained in the emergency department or other medical wards prior to ICU admission. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids 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. The percent change in PCT level over time aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

A PCT level that declines ≤ 80 % from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80 %.

The combination of the first PCT level (≤ 2.0 ng/mL or > 2.0 ng/mL) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important additional information about the mortality risk.

The PCT level on Day 1 (the day after severe septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles and an electrochemiluminescence detection system. PCT in the sample reacts with these labeled antibodies to form a sandwich complex. This complex binds to streptavidin coated magnetic microparticles, which are magnetically captured onto an electrode. Application of voltage to the electrode induces chemiluminescence which is measured by a photomultiplier tube. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode. An optional Procalcitonin CalCheck product is also available.

The provided text describes the Elecsys BRAHMS PCT assay, an immunoassay for the quantitative determination of procalcitonin (PCT) in human serum and plasma, intended to aid in assessing the 28-day risk of all-cause mortality for patients with severe sepsis or septic shock. The document outlines the performance characteristics and a clinical study conducted to support its indications for use.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a table of acceptance criteria with numerical targets for clinical performance endpoints (e.g., specific sensitivity, specificity, or predictive values that the device needed to meet to be considered "accepted"). Instead, it presents the results of the clinical study and infers substantial equivalence to a predicate.

However, the non-clinical performance evaluation sections (analytical sensitivity, precision, linearity, etc.) implicitly have acceptance criteria, as the reported performance values are deemed satisfactory to demonstrate substantial equivalence. The document states: "The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys BRAHMS PCT test system. The data supports a safe, effective device which performs as well as or better than the predicate device." This strongly suggests that the reported values met internal or regulatory expectations for substantial equivalence.

Here's a table summarizing the reported device performance from the provided text, derived from the non-clinical and clinical performance evaluations:

• HS1: 5.03% CV @ 0.079 ng/mL
• HS2: 1.71% CV @ 0.442 ng/mL
• HS3: 2.35% CV @ 1.49 ng/mL
• HS4: 1.38% CV @ 27.5 ng/mL
• HS5: 2.23% CV @ 71.4 ng/mL
• HS6: 1.35% CV @ 88.1 ng/mL
• PC1: 1.91% CV @ 0.456 ng/mL
• PC2: 1.83% CV @ 9.07 ng/mL
  Intermediate Precision:
• HS1: 6.44% CV @ 0.079 ng/mL
• HS2: 3.14% CV @ 0.442 ng/mL
• HS3: 3.40% CV @ 1.49 ng/mL
• HS4: 3.24% CV @ 27.5 ng/mL
• HS5: 3.66% CV @ 71.4 ng/mL
• HS6: 3.18% CV @ 88.1 ng/mL
• PC1: 3.21% CV @ 0.456 ng/mL
• PC2: 3.35% CV @ 9.07 ng/mL |
  | Limit of Blank (LoB) | Determined as the 95th percentile of blank-sample measurements. | 0.015 ng/mL |
  | Limit of Detection (LoD) | Smallest amount of analyte detectable with 95% probability. | 0.02 ng/mL |
  | Limit of Quantitation (LoQ) | Lowest concentration quantifiable with intermediate precision ≤ 20%. | 0.06 ng/mL |
  | Measuring Range | Needs to cover clinically relevant range. | 0.02 – 100 ng/mL |
  | Hook Effect | No hook effect within tested concentration. | No hook effect up to 1000 ng/mL |
  | Interferences | Recovery within ± 15% of initial value for endogenous and exogenous substances. | Unaffected by icterus ( 80% or ≤ 80%) significantly associated with 28-day cumulative mortality (Two-sided Fisher's Exact Test p-value = 0.002). Adjusted for ICU vs. non-ICU: p-value = 0.020. |
  | Prognostic Accuracy (Day 0-4 interval) | Sensitivity and Specificity values demonstrating utility in risk assessment. | ICU Patients:
• Sensitivity: 73.4% (62.9-83.8)
• Specificity: 35.0% (28.2-41.8)
  Non-ICU Patients:
• Sensitivity: 72.3% (55.9-88.6)
• Specificity: 44.4% (38.4-50.3) |
  | Hazard Ratio for 28-day all-cause mortality (ΔPCT) | Hazard Ratio (HR) significantly > 1.0 for positive ΔPCT (≤ 80%). | Univariate Model (Per-Protocol):
• ΔPCT4.0 (≤ 80% vs. > 80%): HR = 1.80 (1.15-2.82); p=0.011
• ΔPCT4.1 (≤ 80% vs. > 80%): HR = 1.61 (1.04-2.49); p=0.034 |

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

• Test Set Sample Size:

  • Method Comparison: 2617 samples were used to compare the Elecsys BRAHMS PCT assay with the predicate device (BRAHMS PCT sensitive KRYPTOR®).
  • Clinical Performance Evaluation: 858 adult patients were enrolled. The "per protocol analysis population" was 598 subjects.
  • Reference Range: 282 self-reported healthy individuals.

• Data Provenance:

  • Clinical Performance Evaluation: The clinical trial was a prospective study conducted across 13 investigational sites in the US. This indicates prospective data from multiple US sites.
  • Reference Range: Implied to be from healthy individuals, likely domestic (US) given the submission context.
  • Non-Clinical Studies: The text does not explicitly state the country of origin for all non-clinical samples or specific data provenance for each analytical study, but it implies internal testing by Roche Diagnostics, which has sites in Germany and the United States (as per Establishment Registration).

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

The document describes a clinical study for an in vitro diagnostic (IVD) device that measures a biomarker (PCT) to aid in risk assessment for mortality. For IVD devices, "ground truth" for clinical performance is typically defined by the clinical outcome itself, not by expert consensus on interpreting images or other subjective data.

• For the clinical performance study: The ground truth was cumulative 28-day all-cause mortality. This is an objective clinical outcome. It does not involve expert interpretation or adjudication in the way that, for example, a radiology AI model might. The diagnosis of "severe sepsis or septic shock" would have been established by clinicians based on recognized medical criteria at each investigational site. The "experts" in this context would be the attending clinicians who managed the patients and determined their clinical status and outcomes, but their role was in providing the clinical data, not in acting as a ground truth panel for the PCT assay results themselves.

• For the reference range study: The ground truth was "self-reported healthy individuals," which implies a general population considered free from disease, not requiring expert adjudication of individual cases.

4. Adjudication Method for the Test Set

As mentioned above, the primary clinical endpoint was objective (28-day all-cause mortality). There is no indication of an "adjudication method" in the sense of a panel of experts reviewing the outcome or interpreting the device's results. Outcomes like mortality are typically recorded facts. The diagnosis of severe sepsis or septic shock would have been made by the local clinicians at each site.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC comparative effectiveness study was not done. This type of study is typically associated with imaging devices where multiple human readers interpret cases and their performance is compared with and without AI assistance. The Elecsys BRAHMS PCT assay is an in vitro diagnostic (blood test) device quantifying a biomarker, not an imaging device.

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

Yes, the very nature of an in vitro diagnostic (IVD) test like the Elecsys BRAHMS PCT assay is that it operates as a standalone algorithm/device. It quantitatively measures PCT levels from a human specimen. The "algorithm" in this context is the immunochemical reaction and the analyzer's detection system, which then calculates a numerical PCT value. The clinical performance study evaluates this standalone measurement in relation to a clinical outcome (mortality risk) and how its results can be integrated into clinical decision-making by human clinicians, but the device itself functions independently to produce the PCT value.

7. The Type of Ground Truth Used

• Clinical Performance Evaluation: The ground truth was outcomes data, specifically cumulative 28-day all-cause mortality for patients diagnosed with severe sepsis or septic shock.
• Reference Range: The ground truth was based on a population of self-reported healthy individuals.
• Non-Clinical Studies (e.g., Linearity, Dilution): Ground truth would be the known concentration of spiked PCT or reference materials.

8. 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. For an IVD assay like this, "training" usually refers to the development and optimization process (e.g., optimizing reagent concentrations, reaction times), rather than a distinct dataset used for machine learning. The clinical performance data presented serves as a validation dataset to demonstrate the assay's utility when used according to its indications.

If "training set" refers to the data used to initially establish the assay's performance characteristics or calibrate it, then:

• Calibrator Value Assignment: The calibrators are run in duplicate on at least six cobas e 411 analyzers and least three cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers with "all Elecsys BRAHMS PCT reagent lots available."
• PreciControl Value Assignment: Controls are run in duplicate on at least six analyzers of the master analyzer platform and compared to a master calibration curve.

However, these are more akin to standardization and quality control procedures rather than a machine learning training set for an "algorithm."

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

Since an explicit "training set" for an AI/ML algorithm is not described, the concept of establishing its ground truth isn't directly applicable in that sense.

For the assay's development and analytical performance:

• Calibrators: Recombinant PCT in a human serum matrix (PCT CalSet). Their assigned values are determined through multiple runs on multiple analyzers using a Master Calibration Curve and must meet pre-defined acceptance criteria for associated controls (PreciControl PCT).
• Controls: Recombinant PCT in human plasma (PreciControl PCT). Their assigned values are read from the master calibration curve and must meet pre-defined acceptance criteria.
• Analytical Specificity/Interference: Ground truth is established by spiking known concentrations of interferents into known PCT samples.

In essence, the "ground truth" for the analytical performance characteristics is established by using controlled, manufactured materials with known properties or by challenging the assay with known substances at defined concentrations.

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The B·R·A·H·M·S PCT sensitive KRYPTOR is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.

The B.R.A.H.M.S.PCT sensitive KRYPTOR is intended to be performed on the B·R·A·H·M·S KRYPTOR analyzer family.

The B R A H M S PCT sensitive KRYPTOR is intended for use in conjunction with other laboratory findings and clinical assessments to 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.

The B·R·A·M·S PCT sensitive KRYPTOR is also intended for use to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of allcause mortality in conjunction with other laboratory findings and clinical assessments 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.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids 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. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

PCT level on the first day of ICU admission above 2.0 µg/L is associated with a higher risk for progression to severe sepsis and/or septic shock than a PCT level below 0.5 ug/L.

A PCT level that declines ≤ 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80%.

The combination of the PCT level (≤ 2.0 ug/L or > 2.0 µg/L) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important additional information about the mortality risk.

The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

The B·R·A·H·M·S PCT sensitive KRYPTOR is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma. It contains reagents including Cryptate Conjugate, XL665 Conjugate, and Diluent. Additional required materials include Calibrator, Controls, and KRYPTOR Consumables (Solutions 1, 2, 3, 4, BUFFER, Reaction plates, Dilution plates). The assay is a homogeneous sandwich immunoassay performed on the B·R·A·H·M·S KRYPTOR compact PLUS analyzer, a fully automated system. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal emitted from an immunocomplex with time delay. The system is a closed system and can only operate utilizing specially made reagent kits from B.R. A. H. M.S. The B.R.A.H-M-S KRYPTOR compact PLUS analyzer user interface displays the significant processes within the system to the user. An on-line 'Change in Procalcitonin Calculator' is also available as a web-based software application to aid in the interpretation of results.

B.R.A.H.M.S PCT sensitive KRYPTOR Device Performance Summary

This document describes the acceptance criteria and the supporting study for the B.R.A.H.M.S PCT sensitive KRYPTOR device, which aids in assessing the cumulative 28-day risk of all-cause mortality in patients with severe sepsis or septic shock.

1. Acceptance Criteria and Reported Device Performance

The device's performance regarding prognostic accuracy for 28-day all-cause mortality is evaluated based on the change in PCT levels over time. The primary acceptance criteria for the clinical claim are based on the association between the percent change in PCT level and 28-day all-cause mortality risk.

Table 1: Acceptance Criteria and Reported Device Performance for 28-Day Mortality Risk

Note: The table above primarily focuses on the clinical claim of assessing 28-day mortality risk. Other analytical performance characteristics were evaluated against established CLSI guidelines, which implicitly define acceptance criteria for precision, linearity, stability, etc.

2. Sample Size and Data Provenance for the Test Set

The clinical study (MOSES study - ClinicalTrials.gov Identifier: NCT01523717) evaluated the device's performance.

• Test Set Sample Size: The analysis population for the clinical study consisted of 598 subjects.
• Data Provenance: The data was collected from a prospective clinical trial across 13 investigational sites in the US.

3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)

The ground truth for the clinical study was 28-day all-cause mortality. This is an objective outcome, and therefore, no human experts were required to establish the ground truth for the test set.

4. Adjudication Method (Test Set)

Given that the primary ground truth for the clinical study was 28-day all-cause mortality, which is a definitive clinical outcome, no adjudication method was necessary for the test set.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was mentioned in the provided text. The device is an in vitro diagnostic assay, and the study focused on the performance of the assay itself in predicting mortality, rather than assessing human reader improvement with or without AI assistance.

6. Standalone (Algorithm Only) Performance

The clinical study evaluated the performance of the B.R.A.H.M.S PCT sensitive KRYPTOR assay in assessing 28-day mortality risk. This is inherently a standalone (algorithm only) performance evaluation, as it measures the quantitative change in PCT levels and correlates it with an outcome, without direct human intervention in the measurement interpretation for the purpose of the study's primary endpoint. The Change in Procalcitonin Calculator is a web-based tool provided as an aid for interpretation, but the assay results themselves are generated by the automated instrument.

7. Type of Ground Truth Used

The ground truth used for the clinical study was outcomes data, specifically cumulative 28-day all-cause mortality. This is a definitive patient outcome.

8. Sample Size for the Training Set

The provided document does not specify a separate training set sample size for the clinical study used to validate the mortality risk claim. The study (MOSES study) is described as a "prospective clinical trial... of 858 adult patients," with an "analysis population of 598 subjects." It is an observational study that evaluated the association between PCT change and mortality, rather than training an algorithm on a specific dataset. Therefore, the clinical claim was validated on the 598 subjects from the MOSES study, which may be considered the validation or test set rather than a training set for an AI model. For the analytical performance characteristics (precision, linearity, etc.), specific sample sizes were used for each analytical study, as detailed in section L.1.

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

As mentioned in point 8, the document does not describe a separate training set for an algorithm that predicts mortality. The clinical study was an observational study that validated the prognostic utility of PCT changes. The ground truth for the outcomes measured in this study (28-day all-cause mortality) was established through patient follow-up and recorded vital status (i.e., objective outcomes data).

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