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The Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay is an in vitro diagnostic test for the quantitative measurement of procalcitonin in human serum and plasma (lithium heparin, K2EDTA, and K3EDTA) using the Dimension® EXL™ integrated chemistry system with LOCI® Module.

The Dimension EXL LOCI® 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 Intensive Care Unit (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 percentage change in PCT levels 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 Dimension EXL LOCI BRAHMS PCT assay is a homogeneous sandwich chemiluminescent immunoassay based on LOCI technology. The LOCI reagents include two synthetic bead reagents and one biotinylated anti-procalcitonin (anti-PCT) monoclonal antibody. The first bead reagent (Sensibeads) is coated with streptavidin and contains photosensitizer dye. The second bead reagent (Chemibeads) is coated with two anti-PCT monoclonal antibodies and contains chemiluminescent dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-PCT-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the procalcitonin (PCT) concentration in the sample.

The provided document describes the performance characteristics of the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay and its equivalence to a predicate device.

Here's a breakdown of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

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

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Used in conjunction with other laboratory findings and clinical assessments, Elecsys B R A - H M S PCT 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 determine the change in PCT level 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 ICU or when obtained in the emergency department or other medical wards prior to ICU admission,

· to aid in decision making on antibiotic therapy, for inpatients in the emergency department 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),

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

The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles, biotinylated antibody and antibody labeled with ruthenium as well as an electrochemiluminescence detection system. Procalcitonin (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 performance evaluation of the Elecsys BRAHMS PCT device. Here's a breakdown of the acceptance criteria and study details based on the information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for all performance parameters in a singular table. However, it presents claims and then demonstrates performance against those claims, implying these are the acceptance criteria.

2. Sample Size and Data Provenance for Test Set

• Precision: Seven (7) human serum samples and two (2) QC samples.
• Sample Matrix Comparison: A minimum of 40 serum/plasma pairs per sample material (serum, Li-Heparin plasma, K2-EDTA plasma, K3-EDTA plasma).
• Endogenous Interferences: Spiked serum pools.
• Exogenous Interferences (Drugs): Two human serum samples, spiked.
• Analytical Specificity/Cross-reactivity: Native human serum samples, spiked.
• Reagent On-Board Stability: Eight (8) human serum (HS) sample pools.
• Calibration Stability: Fourteen (14) human serum samples.
• LoQ: Seven native human serum (HS) samples. Total of 150 measuring points collected (7 samples measured in five-fold determination for each of 5 days).
• Clinical Performance Evaluation (Method Comparison to Predicate): 496 native human clinical samples.
• Data Provenance: The document states "human serum" and "human clinical samples" without specifying the country of origin. The assays are for "in vitro quantitative determination" using patient samples, implying retrospective collection for these performance studies.

3. Number of Experts and Qualifications for Ground Truth

This information is not provided in the document. The studies primarily involve analytical performance and method comparison against a predicate device and established laboratory guidelines rather than clinical interpretation by experts for ground truth establishment.

4. Adjudication Method for Test Set

This information is not applicable as the studies are analytical and method comparison, not involving expert adjudication of diagnostic outcomes or images.

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

This information is not provided and is not applicable. This device is an in-vitro diagnostic (IVD) assay that quantitatively measures procalcitonin levels, not an AI-assisted diagnostic imaging device requiring human reader interaction.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

This is an IVD assay, meaning its performance is inherently standalone (algorithm only, or rather, assay-only). The results are quantitative measurements. Human interpretation comes after the device generates the PCT value, in conjunction with other clinical assessments, as indicated in the "Indications for Use." The data presented here (e.g., precision, interference, method comparison) reflects the standalone analytical performance of the assay.

7. Type of Ground Truth Used

• For precision, interference, stability, LoQ, and analytic specificity, the ground truth is based on known spiked concentrations or the reference value/measurement of the analyte in the samples.
• For the method comparison study, the "ground truth" for comparison is the results obtained from the legally marketed predicate device (Elecsys BRAHMS PCT cleared under K173927). This establishes substantial equivalence.

8. Sample Size for the Training Set

This information is not provided. The document describes performance evaluation (testing) of the device. It does not detail the development or training process for the assay's reagents or calibration, which would involve a "training set." For an immunoassay, the "training" equivalent would typically involve assay development and optimization using various known samples and controls, rather than a distinct "training set" as understood in machine learning. Calibration data also serves a role similar to training in defining the dose-response curve.

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

This information is not provided as the document does not discuss a "training set" in the context of this IVD device. For an immunoassay, ground truth for development (e.g., calibrators) is typically established through careful gravimetric or volumetric preparations, reference methods, and standardization to an international reference material where available (as indicated by "This method has been standardized against the BRAHMS PCT LIA assay" and "Traceability/ Standardization").

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

The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Used in conjunction with other laboratory findings and clinical assessments, Elecsys B.R.A.H.M.S.PCT 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 determine the change in PCT level 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 ICU or when obtained in the emergency department or other medical wards prior to ICU admission,

· to aid in decision making on antibiotic therapy, for inpatients in the emergency department 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),

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

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.

This document describes the Elecsys BRAHMS PCT assay, an in vitro diagnostic immunoassay for the quantitative determination of Procalcitonin (PCT) in human serum and plasma. The K173927 510(k) submission seeks substantial equivalence to the B.R.A.H.M.S. PCT sensitive KRYPTOR® (K171338) for updated Indications for Use.

Acceptance Criteria and Reported Device Performance

Study Information:

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

   • Sample Size: 2617 samples were used for the clinical performance evaluation (method comparison to predicate).
   • Data Provenance: Retrospective multicenter testing of PCT from available frozen samples of adult patients (>18 years of age) diagnosed with severe sepsis or septic shock. These patients were enrolled in the BRAHMS MOSES study from the Intensive Care Unit (ICU) or the emergency department, other wards, or directly from out of hospital and subsequently admitted to the ICU.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable. The ground truth for the comparative study was based on measurements obtained from the predicate device (B.R.A.H.M.S. PCT sensitive KRYPTOR®). Clinical diagnoses (severe sepsis or septic shock) were based on patient enrollment criteria for the BRAHMS MOSES study, which likely involved clinicians, but specific details on expert involvement in establishing ground truth for the test set's PCT values are not provided.

3. Adjudication method (e.g., 2+1, 3+1, none) for the test set: Not applicable. The study compares the candidate device's analytical results directly against the predicate device's analytical results. There is no mention of a human adjudication process for resolving discrepancies.

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: Not applicable. This is an analytical performance study comparing an immunoassay device to a predicate immunoassay device, not a human reader or AI-assisted diagnostic study.

5. If a standalone (i.e. algorithm only without human-in-the loop performance) was done: Yes, the entire performance evaluation described is a standalone evaluation of the Elecsys BRAHMS PCT assay, an automated immunoassay device, without human-in-the-loop performance influencing the assay results themselves. The results are intended to be used in conjunction with other laboratory findings and clinical assessments.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.): The "ground truth" for the method comparison study was the results obtained from the legally marketed predicate device, the B.R.A.H.M.S. PCT sensitive KRYPTOR®. For the clinical context, patients were diagnosed with severe sepsis or septic shock based on the BRAHMS MOSES study criteria, implying clinical and outcomes data were involved in the original classification of these patients.

7. The sample size for the training set: Not applicable. This is an in vitro diagnostic immunoassay, not a machine learning algorithm that typically requires a discrete training set for model development. The assay itself is a chemical and electrochemiluminescence process.

8. How the ground truth for the training set was established: Not applicable, as there is no specific "training set" in the context of an immunoassay for which ground truth would be established in the same way as for a machine learning model. The assay's analytical characteristics and calibration are established through standard laboratory and calibration procedures, which involve reference materials and calibrators. The assay is standardized against the BRAHMS PCT LIA assay.

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The LIAISON® B.R.A.H.M.S PCT® II GEN assay uses chemiluminescence immunoassay (CLIA) technology for the in vitro quantitative determination of Procalcitonin in human serum and lithium heparin plasma specimens. Used in conjunction with other laboratory findings and clinical assessments, LIAISON® B.R.A.H.M.S.PCT® II GEN 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 sepsic 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 (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,

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

The LIAISON® Control B.R.A.H.M.S PCT® II GEN (level 1 and level 2) are intended for use as assayed quality control samples to monitor the performance and reliability of the LIAISON® BRAHMS PCT® II GEN assay. The performance characteristics of LIAISON® BRAHMS PCT® II GEN controls have not been established with any other assay or instrument platform different from the LIAISON® Analyzer.

The LIAISON® B.R.A.H.M.S PCT® II GEN Verifiers (four levels) are assayed quality control materials intended in the quantitative verification of calibration and reportable range of the LIAISON® BRAHMS PCT® II GEN assay. The performance characteristics of LIAISON® BRAHMS PCT® II GEN calibration verifiers have not been established in connection with any other assay or instrument platforms different from the LIAISON® Analyzer.

The method for the quantitative determination of PCT is a sandwich chemiluminescence immunoassav. A specific monoclonal antibody is coated on the magnetic particles (solid phase); another monoclonal antibody (specific for a different epitope of the procalcitonin molecule) is linked to an isoluminol derivative (isoluminol-antibody conjugate).

During the first incubation, PCT present in calibrators, samples or controls binds to the antibody conjugate. Then the solid phase is added to the reaction. A sandwich is formed only in the presence of PCT molecules that bridge both antibodies. After the second incubation, the unbound material is removed with a wash cycle.

Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminolantibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of PCT concentration present in calibrators, samples or controls.

Here's a breakdown of the acceptance criteria and study details for the LIAISON® BRAHMS PCT® II GEN assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

*   The origin of these samples (e.g., country) and whether they were retrospective or prospective is **not explicitly stated** in the provided text.

• Precision (Internal 20-day): 10 frozen serum panel samples, 2 levels of kit controls, and 4 levels of verifiers.
  • The origin of the serum samples is not explicitly stated, but they were prepared by DiaSorin S.p.A.
• Precision (Multi-Site): 10 frozen serum panel samples, 2 lots of kit controls (2 levels each), and 2 lots of verifiers (4 levels each).
  • The origin of the serum samples is not explicitly stated, but they were prepared by DiaSorin S.p.A.
• Sample Equivalence: 40 matched patient samples (serum and lithium heparin collection tubes). These were "spiked or diluted" to span the assay range.
  • The origin of these samples is not explicitly stated.

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

This device is an in vitro diagnostic (IVD) assay that measures a specific analyte (Procalcitonin) quantitatively. For such devices, "ground truth" is typically established by comparing the device's measurements against a recognized reference method or by using samples with known, carefully characterized concentrations of the analyte.

The document states:

• Method Comparison: "A quantitative method comparison study was performed... following CLSI EP09-A2." This implies comparison against a predicate device (VIDAS® B-R-A-H·M·S PCT™ (K162827)), which serves as the reference method.
• Analytical Performance (LoB, LoD, LoQ): "Following the method from CLSI EP17-A2." This refers to standard statistical methods for determining these analytical characteristics, not expert consensus on individual case diagnoses.
• Precision: Standard statistical methods for assessing reproducibility.

Therefore, for this type of device, the "ground truth" is established by:

• Reference measurement methods: The predicate device itself acts as the comparative reference.
• Analytical standards/spiked samples: For LoB, LoD, LoQ, and precision, samples with known or precisely defined analyte concentrations (e.g., purified calibrators, spiked samples, control materials) are used.

Thus, this document does not indicate the use of human "experts" to establish a diagnostic ground truth for individual cases in the way one might for an imaging AI device (e.g., radiologists reviewing images). The ground truth here is analytical and comparative to a well-established predicate.

4. Adjudication Method for the Test Set

Not applicable in the context of an IVD assay measuring an analyte. The comparative method is against an established reference method (the predicate device) or analytical standards, not through human adjudication of diagnostic interpretations.

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

No, an MRMC study was not done. This is an in vitro diagnostic device, not an imaging AI device that would assist human readers in interpretation. Its performance is measured analytically and comparatively against a predicate device.

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

Yes, the studies presented are all standalone. The LIAISON® BRAHMS PCT® II GEN assay is an automated chemiluminescence immunoassay device. The results presented (LoB, LoD, LoQ, method comparison, precision, stability) reflect the direct output of the assay system without human interpretation or intervention in the measurement process itself. The indication for use states it is "Used in conjunction with other laboratory findings and clinical assessments," implying that clinicians will interpret the results, but the performance data presented is for the device operating independently.

7. The Type of Ground Truth Used

The ground truth used in the studies is primarily:

• Reference Method Comparison: The measurements obtained from the FDA-cleared predicate device (VIDAS® B-R-A-H·M·S PCT™) for the method comparison studies.
• Known Concentrations/Analytical Standards: For LoB, LoD, LoQ, accuracy, and precision, samples with known, manufactured, or precisely characterized concentrations of Procalcitonin (e.g., calibrators, controls, characterized panel samples) are used.

It is not pathology, outcomes data, or expert diagnostic consensus on patient cases for the performance studies presented here.

8. The Sample Size for the Training Set

The provided document describes performance verification studies for a medical device (an IVD assay). It does not pertain to an AI/Machine Learning device that undergoes "training." Therefore, there is no training set in the context of AI models. The device operates based on established chemical and immunological principles, not learned patterns from data.

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

As there is no training set for this type of device, this question is not applicable.

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The Lumipulse G B•R•A•H•M•S PCT is a Chemiluminescent Enzyme Immunoassay (CLEIA) for the quantitative determination of PCT (procalcitonin) in human serum and plasma (sodium heparin, sodium citrate or dipotassium EDTA) on the LUMIPULSE G System.

Used in conjunction with other laboratory findings and clinical assessments, Lumipulse G B.R.A.H.M.S PCT 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 (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.

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

Lumipulse G B.R.A.H.M.S PCT Calibrators set

Lumipulse G B R A H M S PCT Calibrators set is for in vitro diagnostic use in the calibration of Lumipulse G B.R.A.H.M.S.PCT on the LUMIPULSE G System.

Lumipulse G B+R•A•H•M•S PCT is an assay system, including a set of immunoassay reagents, for the quantitative measurement of PCT in specimens based on CLEIA technology by a two-step sandwich immunoassay method on the LUMIPULSE G1200 System.

Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges: | IRC 235058. The Lumipulse G B•R•A•H•M•S PCT Immunoreaction Cartridges consists of 3 x 14 tests. Each kit contains the following:

1.) Antibody-Coated Particle Solution (Liquid when used, 250 µL/Immunoreaction Cartridge) Contains 150 µg/mL anti-PCT monoclonal antibody (mouse) and anti-calcitonin monoclonal antibody (mouse) coated particles, protein stabilizers (bovine and mouse) and chemical stabilizers in 0.15 M sodium chloride/Tris buffer. This solution contains gelatin and turns into gel at 15°C or lower. Preservative: sodium azide.

2.) Enzyme-Labeled Antibody Solution (Liquid, 350 µL/Immunoreaction Cartridge) Contains 0.25 µg/mL alkaline phosphatase (ALP: calf)-labeled anti-katacalcin monoclonal antibody (mouse), protein stabilizers (bovine, calf and mouse) and chemical stabilizers in 0.1 M sodium chloride/MES buffer. Preservative: sodium azide.

Lumipulse G B+R+A+H+M+S PCT Calibrators set |CAL SET 234150, Lyophilized, 2 x 2 Concentrations

Each calibrator kit contains one bottle each of Calibrators 1 - 2, and Reconstituting Solution. The calibrator kit is packaged separately.

CAL 1 0 ng/mL PCT calibrator (2 x 0.5 mL/vial)

CAL 2 100 ng/mL PCT calibrator (2 x 0.5 mL/vial)

Contains procalcitonin in 0.15 M sodium chloride in Tris buffer with protein stabilizer (bovine). Preservative: ProClin 300.

RS Reconstituting Solution: Liquid, 1 x 10 mL Preservative: sodium azide.

These calibrators are lyophilized and have to be prepared by adding exactly 0.5 mL of Reconstituting Solution to each Iyophilized calibrator.

The provided document describes the Lumipulse G B.R.A.H.M.S PCT Immunoreaction Cartridges and its associated calibrator set. This is an in-vitro diagnostic device, not an AI/ML medical device. Therefore, the questions related to AI/ML device acceptance criteria, performance studies (sample sizes, expert usage, adjudication, MRMC studies, standalone performance), and ground truth establishment are not applicable.

However, based on the provided text, the device's analytical performance and comparison studies can be summarized as follows:

1. A table of acceptance criteria and the reported device performance (for Analytical Performance):

The document refers to CLSI protocols for acceptance criteria, specifically for precision, linearity, and analytical specificity. The acceptance criteria themselves are generally implied by meeting the guidelines or by specific thresholds mentioned in conjunction with the results.

2. Sample sizes used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective):

• Precision (20-day): n=80 for each sample (Control Levels 1-3, Panels 1-8). Data generated at Fujirebio Diagnostics, Inc. (FDI).
• Precision (Lot-to-Lot Reproducibility): n=120 for each sample (Control Levels 1-3, Panels 1-6).
• Precision (Site-to-Site Reproducibility): n=120 for each panel (Control Levels 1-3, Panels 1-6). Performed at "several sites" (implied, typical for site-to-site reproducibility; specific sites or countries not mentioned).
• Linearity/Reportable Range: High and low sample pools created using patient serum samples. Number of samples not specified, but the study was "consistent with the guidelines in the CLSI Protocol EP6-A."
• Detection Limit (LoB/LoD/LoQ): Seven low-level specimens were tested over 3 days using two LUMIPULSE G1200 Systems and two Lumipulse G PCT lots, giving 120 determinations per panel for LoD. Number of unique samples for LoQ not specified, but involved "modeling analysis."
• Analytical Specificity (Interference): Human serum specimen pools (approximately 0.25 and 2.0 ng/mL PCT) supplemented with potentially interfering compounds. Number of individual samples not specified.
• Analytical Specificity (Cross-Reactivity): Human serum specimens (approximately 0.1, 0.25, 0.5, 2.0 and 80 ng/mL PCT) supplemented with potentially cross-reacting compounds. Number of individual samples not specified.
• Method Comparison: n=207 lithium heparin specimens.
• Expected Values/Reference Range: Population of 213 self-reported healthy individuals.

Data Provenance: The document does not explicitly state the country of origin for all patient samples or whether studies were retrospective or prospective, beyond "human serum," "patient serum samples," or "self-reported healthy individuals." The precision studies were conducted at "FDI" (Fujirebio Diagnostics, Inc. in Malvern, PA, USA) and "across several sites."

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience):

Not applicable. This is an immunoassay device for quantitative determination of Procalcitonin (PCT), where the "ground truth" is measured analytically by the device itself or compared to a predicate device. It does not involve human interpretation of images or other subjective data that would require expert consensus for ground truth.

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

Not applicable. As described above, this device is a quantitative immunoassay and does not involve human adjudication methods for its analytical performance or comparison studies.

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 an in-vitro diagnostic device, not an AI/ML device, and does not involve human readers interpreting cases.

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

Not applicable. This is an in-vitro diagnostic device, not an AI/ML device. The performance data presented are for the analytical device itself.

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

For the analytical performance studies (precision, linearity, detection limits, specificity), the "ground truth" is typically defined by reference materials, spiked samples with known concentrations, or established analytical methods. For method comparison, the predicate device (B.R.A.H.M.S PCT sensitive KRYPTOR®) serves as the comparator. For establishing expected values, the measured PCT levels in a population of "self-reported healthy individuals" are used.

8. The sample size for the training set:

Not applicable in the context of AI/ML. For analytical performance, the samples used in the various studies (e.g., 20-day precision, lot-to-lot, site-to-site, linearity, detection limits, interference, cross-reactivity) are referred to as test samples or panels to evaluate the device's accuracy and reliability. There is no concept of a "training set" in the AI/ML sense for this type of IVD device.

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

Not applicable, as there is no "training set" in the AI/ML sense. The analytical performance is established through rigorous testing against reference materials and predicate devices following CLSI guidelines.

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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.

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.

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.

• 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.

Ask a specific question about this device

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.
Used in conjunction with other laboratory findings and clinical assessments, B·R·A·H·M·S PCT sensitive KRYPTOR® 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 determine the change in PCT level 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 ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
• to aid in decision making on antibiotic therapy, for inpatients or patients in the emergency department 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),
• to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The B·R·A·H·M·S KRYPTOR® compact PLUS analyzer is a fully automated system. The B-R-A-H-M-S KRYPTOR® compact PLUS analyzer is a closed system and can only operate utilizing special reagents provided by B.R.A.H.M.S GmbH.
The B·R·A·H·M·S PCT sensitive KRYPTOR® is a homogeneous sandwich immunoassay for detection of PCT in human serum or plasma. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal that is emitted from an immunocomplex with time delay.

The provided text describes a 510(k) premarket notification for the B·R·A·H·M·S PCT sensitive KRYPTOR® device, which measures procalcitonin levels. The submission seeks clearance for expanded indications for use based on comparisons to predicate devices and meta-analyses of clinical studies.

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

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a tabular format with corresponding performance results for each expanded indication in a single place. Instead, it details various analytical and clinical performance characteristics from previous submissions (DEN150009 and K070310) and new meta-analyses to support the expanded claims.

However, we can infer acceptance criteria from the context of a 510(k) submission, which generally requires demonstrating substantial equivalence to a legally marketed predicate device. This often involves showing comparable analytical performance and equivalent safety and effectiveness for the intended use. For the expanded indications, the performance is demonstrated through meta-analyses of existing clinical trial data.

Inferred "Acceptance Criteria" (based on regulatory expectations for an IVD and expanded claims) and Reported Device Performance:

• %CV values for repeatability ranged from 0.58% to 12.31%.
• Total Reproducibility %CV ranged from 2.57% to 14.88%.

(The table provides detailed SD and %CV for various components like repeatability, between-operator, between-day, between-calibration, between-run, and between-lot for 12 different samples (P10-P16, QC1, QC2, HG1-HG3) with N=56 for most samples and N=54 for HG3.) |
| Linearity/Assay Reportable Range | From DEN150009 (Page 16):

• Direct measuring range: 0.02 µg/L - 50 µg/L
• Measuring range with automatic dilution: 0.02 µg/mL - 5000 µg/L |
  | Detection Limit (LoB, LoD, LoQ) | From DEN150009 (Page 17):
• LoB and LoD determined (same as predicate).
• LOQ (lowest reported concentration level with bias ≤ 5%, % CV ≤ 15%, TE ≤ 30%) = 0.075 µg/L.
• TE ≤ 20% at 0.25 µg/L (bias ≤ 5%, precision CV ≤ 10%)
• TE ≤ 30% at 0.10 µg/L (bias ≤ 5%, precision CV ≤ 15%)
  Performance at key cutoffs (table on Page 17):
• 0.10 µg/L: %CV 10.33, %BIAS 2.07, %TE 19.11
• 0.23 µg/L: %CV 5.04, %BIAS 1.85, %TE 10.17
• 0.27 µg/L: %CV 6.71, %BIAS 0.76, %TE 11.83 |
  | Analytical Specificity/Interference | From DEN150009; supplementary interference studies performed for lower cut-offs (Page 17-18):
• No interference up to specified concentrations for numerous endogenous substances (e.g., Hemoglobin 500 mg/dL, Triglycerides 22.5 mg/mL, Bilirubin 20mg/dL), cross-reacting substances (e.g., Human calcitonin 3.9 ng/mL), and drugs (e.g., Cefotaxim 90 mg/dL, Heparin 8000 IU/L, common asthma/COPD drugs like Budesonide, Albuterol, etc.). |
  | Method Comparison (vs. Predicate) | Qualitative Agreement with VIDAS B·R·A·H·M·S PCT (PCT) on 203 samples (Page 19):
• At 0.10 µg/L: Positive Agreement 86.5%, Negative Agreement 86.8%, Overall Agreement 86.7%, Kappa 0.7309.
• At 0.25 µg/L: Positive Agreement 96.4%, Negative Agreement 98.0%, Overall Agreement 97.5%, Kappa 0.9380.
• At 0.50 µg/L: Positive Agreement 95.6%, Negative Agreement 100.0%, Overall Agreement 99.0%, Kappa 0.9710.
• At 2.00 µg/L: Positive Agreement 79.2%, Negative Agreement 100.0%, Overall Agreement 97.5%, Kappa 0.8702. |
  | Clinical Performance (supporting expanded claims via Meta-analyses) |
  | Aid in decision-making on antibiotic therapy for LRTI (reduce antibiotic use without negative outcomes) | Patient-level meta-analysis (13 RCTs, N=3142 total patients) for LRTI (Page 21):
• 19.2% reduction in relative antibiotic initiation.
• 38% reduction in overall antibiotic exposure (inpatients).
• 51% reduction in overall antibiotic exposure (ED/outpatients).
• 2.9 day reduction in antibiotic duration.
• 3.6 day reduction in total antibiotic exposure.
• No negative effects in regards to mortality, complications, or length of stay.
  Summary table (Page 21):
• Antibiotic initiation: 88.4% (standard) vs. 71.4% (PCT guided)
• Duration of antibiotics: 10 days (standard) vs. 7 days (PCT guided)
• Total exposure of antibiotics: 9 days (standard) vs. 5 days (PCT guided)
• 30-day mortality: 7.4% (standard) vs. 6.7% (PCT guided)
• Complications: 21.1% (standard) vs. 18.0% (PCT guided) |
  | Aid in decision-making on antibiotic discontinuation for sepsis (reduce antibiotic use without negative outcomes) | Patient-level meta-analysis for Sepsis (5 RCTs, N=598 sepsis patients) (Page 22):
• 1.5 day reduction in antibiotic duration.
• 3.2 day reduction in total antibiotic exposure.
• 23% reduction in overall antibiotic exposure.
• No negative effects in regards to mortality, hospital length of stay, or ICU length of stay.
  Summary table (Page 22):
• Total exposure of antibiotics: 12 days (standard) vs. 8 days (PCT guided)
• 30-day mortality: 23.8% (standard) vs. 19.9% (PCT guided) |

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

• Analytical Performance Test Set (Method Comparison):

  • Sample Size: 203 frozen banked samples.
  • Data Provenance: Retrospective. Samples were from the "ProRESP trial bank of consecutive patients with clinically suspected COPD, acute bronchitis and CAP," analyzed for concordance with a predicate device.
  • Country of Origin: Not explicitly stated but the publication referenced, "Schuetz P, et al. Clin Biochem. 2010," suggests European origin (Switzerland is common for Müller and Schuetz research groups).

• Clinical Performance Test Set (Meta-analyses for expanded indications):

  • LRTI Antibiotic Decision Making:
    • Study-level Meta-analysis: 11 Randomized Controlled Trials (RCTs), 4090 patients.
    • Patient-level Meta-analysis: 13 RCTs, 3142 patients.
    • Data Provenance: Retrospective, aggregated from previously published RCTs.
    • Country of Origin: Not specified, but given the list of publications, these would be multi-national clinical trials.
  • Sepsis Antibiotic Discontinuation:
    • Study-level Meta-analysis: 10 RCTs, 3489 patients.
    • Patient-level Meta-analysis: 5 RCTs, 598 patients (after excluding non-sepsis patients).
    • Data Provenance: Retrospective, aggregated from previously published RCTs.
    • Country of Origin: Not specified, but likely multi-national.

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

• Analytical Performance (Method Comparison): The "ground truth" here is the measurement by the predicate device (VIDAS B·R·A·H·M·S PCT). No human experts were involved in establishing the ground truth for this direct measurement comparison.

• Clinical Performance (Meta-analyses): For PCT-guided therapy trials, the ground truth for patient outcomes (e.g., diagnosis of LRTI, sepsis, mortality, complications, length of stay, antibiotic duration) would have been established by the clinical teams and investigators involved in each of the original RCTs. The document does not specify the number or qualifications of these individual experts for the initial studies, as it relies on published, peer-reviewed clinical trial data as its basis. The meta-analyses themselves are statistical syntheses of these existing ground truths.

4. Adjudication Method for the Test Set

• Analytical Performance: Not applicable for a quantitative assay method comparison. Results are compared directly between two devices.

• Clinical Performance: For the individual RCTs that form the basis of the meta-analyses, adjudication methods for clinical endpoints would have been defined in their original protocols. The meta-analyses themselves don't involve a separate adjudication process beyond the data synthesis. The text states "Each meta-analysis used random-effects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs) and 95% confidence intervals as appropriate," which describes the statistical method, not human adjudication.

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

This is an In Vitro Diagnostic (IVD) device (a blood test for procalcitonin), not an imaging AI device. Therefore, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study, which is typically relevant for evaluating medical imaging interpretation (human readers with/without AI assistance), was not conducted. The "comparative effectiveness" demonstrated here is about the utility of the PCT biomarker (measured by the device) in guiding clinical decisions (like antibiotic therapy) when compared to standard care, based on clinical trial outcomes.

6. Standalone Performance

The device is an in vitro diagnostic (IVD) that provides a quantitative measurement of PCT. Its "standalone performance" is implicitly covered by the analytical performance studies (precision, linearity, detection limit, interference). It's not an "algorithm only" device in the sense of an AI interpreting medical images; it's a lab instrument that measures an analyte. Its performance is the accurate measurement of PCT levels.

The "standalone" statement regarding its clinical use (Page 6) is a warning/precaution: "B·R·A·H·M·S PCT sensitive KRYPTOR® is not indicated to be used as a stand-alone diagnostic assay and should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence." This clarifies that the clinical decision-making should not solely rely on PCT even if the device itself accurately measures PCT.

7. Type of Ground Truth Used

• Analytical Performance: The ground truth for the method comparison was the quantitative result provided by a legally marketed predicate device (VIDAS B·R·A·H·M·S PCT).
• Clinical Performance: The ground truth for the expanded indications was based on outcomes data and clinical diagnoses established in prospective, randomized controlled trials. These outcomes include antibiotic initiation and duration, total antibiotic exposure, 30-day mortality, complications, and length of hospital/ICU stay.

8. Sample Size for the Training Set

The document does not directly mention a "training set" in the context of machine learning or AI algorithm development, as this is an IVD device measuring a biomarker. The analytical performance data (precision, linearity, detection limits, interference) are part of its fundamental characterization, not typically referred to as a "training set."

For the meta-analyses, the "training" analogous to that for an AI would be the collective body of clinical evidence from the published RCTs. The data from various studies (Ns provided in point 2) are "pooled" or combined within the meta-analysis framework. It's not a single "training set" for a new algorithm, but rather a synthesis of existing clinical evidence to support a new clinical claim for an established diagnostic test.

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

Since there isn't a "training set" for a machine-learning algorithm in this context, the question translates to: How were the original clinical trial data (which underpin the meta-analyses) established?

The clinical data used in the meta-analyses (serving as the "evidence base" for the expanded indications) were derived from multi-center, prospective, randomized controlled clinical trials (RCTs). In these trials, patient outcomes (e.g., diagnosis, mortality, antibiotic use) were carefully collected and documented by the individual study investigators according to their original study protocols. This type of data from well-designed RCTs is considered high-quality evidence in medical research. The meta-analyses then systematically combined and statistically analyzed the results from these individual studies, effectively using their established "ground truths."

Ask a specific question about this device

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.

Used in conjunction with other laboratory findings and clinical assessments, VIDAS® B•R•A•H•M•S PCT™ 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 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.

The provided text describes the non-clinical and clinical studies conducted for the clearance of the VIDAS® B·R·A·H·M·S PCT™ device.

1. Table of Acceptance Criteria and Reported Device Performance

The document provides analytical performance (non-clinical) results rather than specific acceptance criteria thresholds the device must meet in a table. However, it reports the performance of the device against common analytical metrics. For clinical performance, it summarizes the findings of meta-analyses.

Analytical Performance (Non-Clinical)

Clinical Performance (Summary of Meta-Analyses Findings)

The clinical studies involved meta-analyses of existing Randomized Control Trials (RCTs) rather than new primary clinical trials with specific acceptance criteria in the format of sensitivity/specificity/accuracy for the device itself. Instead, the meta-analyses aimed to demonstrate the clinical utility of PCT-guided therapy.

For Decision Making on Antibiotic Therapy for LRTI:

• Antibiotic initiation: 19.2% reduction in relative antibiotic initiation for all patients.
• Overall antibiotic exposure: 38% reduction for inpatients, 51% reduction for ER patients.
• Antibiotic duration: 2.9 days reduction (patient-level meta-analysis), 1.25 days reduction (study-level meta-analysis).
• Total antibiotic exposure: 3.6 days reduction (patient-level meta-analysis), 2.79 days reduction (study-level meta-analysis).
• Negative effects (mortality, complications, length of stay): No negative effects observed.
• Ranked patient outcomes: Statistically significant improvement in PCT-guided management vs. standard management.

For Decision Making on Antibiotic Discontinuation for Septic Patients:

• Antibiotic duration: 1.5 days reduction.
• Total antibiotic exposure: 3.2 days reduction.
• Overall antibiotic exposure: 23% reduction.
• Negative effects (mortality, hospital/ICU length of stay): No negative effects observed.

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

• Analytical (Non-Clinical) Test Set:

  • Limits of Detection & Quantitation: The sample size is not explicitly stated as a number of individual samples, but rather as determinations on the VIDAS® and VIDAS®3 instruments.
  • Precision Study: Panel of 11 human samples. Each sample was tested in duplicate in 2 runs per day over 20 days using 3 VIDAS® and 3 VIDAS®3 instruments (N=240 values for each sample) at 3 sites. Two reagent lots were used (10 days of tests, 6 calibrations per lot).
  • Interference Study: Not specified how many samples, but multiple drugs and substances were tested at specified concentrations.
  • Data Provenance: Not explicitly stated, but generally, such analytical studies are conducted in a laboratory setting, likely within the manufacturer's R&D or a contract research organization.

• Clinical Test Set:

  • Decision making on antibiotic therapy for LRTI:
    • Study-level meta-analysis: 11 Randomized Control Trials (RCTs), 4090 patients.
    • Patient-level meta-analysis: 13 RCTs, 3142 patients.
  • Decision making on antibiotic discontinuation for septic patients:
    • Study-level meta-analysis: 10 RCTs, 3489 patients.
    • Patient-level meta-analysis: 5 RCTs, 598 patients.
  • Data Provenance for Clinical Studies: The data comes from retrospective meta-analyses of previously published Randomized Control Trials (RCTs). The countries of origin for these RCTs are not specified in the provided text.

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

• Analytical (Non-Clinical) Test Set: Ground truth for analytical performance (LoB, LoD, LoQ, precision, interference) is established through standardized laboratory reference methods and certified control materials, following CLSI guidelines. This typically does not involve human experts establishing ground truth in the same way clinical ground truth is established.
• Clinical Test Set (Meta-Analyses): The "ground truth" in these meta-analyses refers to the patient outcomes (e.g., antibiotic exposure, mortality, complications, length of stay) as reported in the original RCTs. These outcomes would have been objectively measured or determined by the clinicians and researchers involved in those original studies, based on their clinical assessments, laboratory findings, and established diagnostic criteria. No specific number or qualification of experts for "establishing ground truth" for the meta-analysis itself is mentioned, as the meta-analysis aggregates existing validated data.

4. Adjudication Method for the Test Set

• Analytical (Non-Clinical) Test Set: Adjudication is not typically applicable for these types of analytical tests as they rely on quantitative measurements against reference standards and statistical analysis.
• Clinical Test Set (Meta-Analyses): The meta-analyses involve combining and contrasting data from multiple sources. Each original RCT would have had its own methods for clinical assessment and outcome determination, which might have included adjudication by a panel of clinicians. However, the provided document does not describe an adjudication method for the meta-analysis itself beyond the systematic review and pooling of data.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. The device is an in vitro diagnostic (IVD) test that measures procalcitonin levels, not an imaging device or AI-driven diagnostic that would involve human readers interpreting cases with and without AI assistance. The clinical studies performed were meta-analyses of PCT-guided therapy vs. standard care, focusing on patient outcomes and antibiotic usage, not on human reader performance.

6. Standalone Performance Study

Yes, the analytical (non-clinical) tests demonstrate the standalone performance of the algorithm/device. The "Limits of detection and quantitation," "Precision," and "Study of drugs and other potentially interfering substances" sections describe the device's inherent performance characteristics independent of human interpretation or intervention beyond performing the assay itself. This is the algorithm only without human-in-the-loop performance for an IVD device.

7. Type of Ground Truth Used

• Analytical (Non-Clinical) Studies: The ground truth is based on:
  • Established analytical methods and reference materials for measuring procalcitonin concentration.
  • Statistical methods (e.g., CLSI guidelines) for determining LoB, LoD, LoQ, and precision.
  • Controlled interference studies with known concentrations of drugs and substances.
• Clinical Studies (Meta-Analyses): The ground truth is based on:
  • Outcomes Data from previously published Randomized Control Trials (RCTs), including antibiotic administration duration, total antibiotic exposure, mortality, hospital length of stay, and ICU length of stay.
  • Clinical assessments and diagnoses made in the original RCTs for patient admission with suspected sepsis/LRTI and severe sepsis/septic shock.

8. Sample Size for the Training Set

The document describes premarket notification for a diagnostic test, not a machine learning or AI algorithm in the typical sense that requires a training set for model development. The VIDAS® B·R·A·H·M·S PCT™ is an ELFA (Enzyme-Linked Fluorescent Assay) technique. Therefore, the concept of a "training set" for a machine learning model is not applicable here. The assay relies on a biochemical reaction and fluorescent detection.

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

As explained in point 8, the concept of a "training set" for model development is not relevant to this type of diagnostic assay. The ground truth for calibrating the assay and establishing its analytical performance relies on established laboratory standards, controls, and reference methods as part of its development and validation process.

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