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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.
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."

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The B.R.A.H.M.S PCT sensitive KRYPTOR® is designed for automated detection of PCT (procalcitonin) in human serum or plasma (EDTA, heparin) samples by the immunofluorescent B·R·A·H·M·S PCT sensitive KRYPTOR® assay.

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 ICU admission for progression to severe sepsis and septic shock.

The B-R-A-H-M-S PCT sensitive KRYPTOR® assay is a homogeneous sandwich immunoassay for detection of PCT in human serum or plasma. The BrR.A.H.M.S KRYPTOR® analyzer is a fully automated system. The B·R·A·H·M·S KRYPTOR® analyzer is a closed system and can only operate utilizing special reagents provided by B.R.A.H.M.S Aktiengesellschaft. 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 basis of the TRACE® technology is a non-radiative energy transfer from a donor [a cage-like structure with a europium ion in the center (cryptate)] to an acceptor (XL 665). The proximity of donor (cryptate) and acceptor (XL 665) in a formed immunocomplex and the spectral overlap between donor emission and acceptor absorption spectra on the one hand intensifies the fluorescent signal and on the other hand extends the life span of the acceptor signal, allowing for the measurement of temporally delayed fluorescence.

After the sample to be measured has been excited with a nitrogen laser at 337 nm, the donor (cryptate) emits a long-life fluorescent signal in the milli-second range at 620 nm, while the acceptor (XL 665) generates a short-life signal in the range of nanoseconds at 665 nm. When both components are bound in an immunocomplex, both the signal amplification and the prolonged life span of the acceptor signal occur at 665 nm, and the life is in the microsecond range. This delayed acceptor signal is proportional to the concentration of the analyte to be measured.

The specific fluorescence which is proportional to the antigen concentration is obtained through a double selection: spectral (separation depending on wave-length) and temporal (time resolved measurement). This enables an exclusive measurement of the signal emitted by the immunological complex and the ratio between the two wave-lengths (665/620) allows a real-time correction of the variations in optic transmission from the medium.

Here's a summary of the acceptance criteria and the study details for the B·R·A·H·M·S PCT sensitive KRYPTOR® Test System, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

8. Sample Size for the Training Set

• Not explicitly provided/applicable in the same way: For in vitro diagnostic assays, especially those based on established immunofluorescence technology like TRACE®, the concept of a "training set" for an algorithm in the machine learning sense is not directly applicable. The assay formulation, antibody selection, and calibration are developed through R&D, not typically "trained" on a large dataset in the way an AI algorithm would be. The document describes the device's components and underlying technology rather than a data-driven training process.

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

• Not explicitly provided/applicable: As mentioned above, the assay's development isn't described in terms of a "training set" and "ground truth" in an AI/machine learning context. The "ground truth" in assay development is typically established through rigorous analytical verification and validation against known standards, spiked samples, and comparison with reference methods or clinically characterized samples during the research and development phases of the assay itself. The given document focuses on the validation of the finalized device.

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