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B·R·A·H·M·S™ CgA II KRYPTOR™ is an automated immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE™) technology for quantitative determination of Chromogranin A concentration in human serum.

B·R·A·H·M·S™ CgA II KRYPTOR™ is to be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

The B-R-A-H-M-S CgA II KRYPTOR assay is based on the formation of a complex comprised of a Chromogranin A (CgA) analyte "sandwiched" between two monoclonal mouse anti-CgA antibodies. One of the antibodies (537/H2) is directed at the epitope AA124–144 and labelled with DiSMP cryptate, the other antibody (541/E2) binds to AA280-301 and is labelled with Alexa Fluor®647.

The measurement principle is based on a non-radiative energy transfer from a donor (cryptate) to an acceptor (Alexa Fluor™647) when they are part of an immunocomplex (TRACE technology (Time-Resolved Amplified Cryptate Emission)).

The fluorescent signal is proportional to the concentration of the analyte to be measured.

With this principle B-R-A-H-M-S CgA II KRYPTOR is a homogenous one-step immunoassay for the quantification of CgA II in human serum. The linear direct measuring range of the assay is from 20-3,000 ng/mL, going up to 1,000,000 ng/mL with automated dilution. Results can be retrieved after a 29 min incubation time.

Here's an analysis of the acceptance criteria and study findings for the B.R.A.H.M.S CgA II KRYPTOR device, based on the provided FDA 510(k) summary:

Acceptance Criteria and Reported Device Performance

Note: The provided document primarily describes analytical performance criteria and clinical performance measures (sensitivity, specificity) rather than explicit "acceptance criteria" in a pass/fail format for clinical decision-making. However, the sensitivity and specificity values obtained from the clinical study serve as the reported device performance against which implicit clinical acceptance would be judged. The analytical performance metrics are generally presented as numerical results meeting industry standards (CLSI guidelines).

Study Details:

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

   • Clinical Study (for Sensitivity and Specificity): 153 adult GEP-NET patients (grade 1 and 2), with 459 total observations (likely reflecting multiple monitoring visits per patient). The study was described as a prospective study.
   • Clinical Cut-off Derivation: 102 patients with diagnosed well-differentiated G1 and G2 GEP-NETs. This was a retrospective, bicentric observational pilot study.
   • Reference Range Determination: 206 samples from self-declared healthy individuals. Data provenance is USA.
   • Analytical studies: Various sample sizes were used, often involving replicates of pooled or individual human serum samples. For example, LoQ used 420 total replicates from 7 different pools of human serum samples.
   • Provenance for analytical samples: Not explicitly stated but generally implied to be from human subjects, for instance, "human serum samples".

2. 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):

   • For the clinical study, tumor progression was classified by RECIST 1.1 criteria. This implies that experts (typically radiologists or oncologists) were involved in interpreting imaging (CT/MRI) according to these established criteria to determine the ground truth for tumor progression.
   • The document does not specify the direct number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, RECIST 1.1 is an internationally recognized standard for evaluating cancer treatment response based on imaging, implying adjudication by qualified personnel.

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

   • The ground truth for tumor progression in the clinical studies was established using RECIST 1.1 criteria based on standard imaging (CT/MRI).
   • The document does not explicitly state an adjudication method like "2+1" or "3+1" for discordant interpretations if multiple readers were involved in RECIST assessment. However, RECIST guidelines themselves are designed to standardize interpretation, and clinical trials often employ independent central review or consensus panels for definitive RECIST ratings, though this specific detail is not provided here.

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, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) for quantitative determination of Chromogranin A concentration in human serum, intended to be used in conjunction with other clinical methods as an aid in monitoring. It is not an AI-assisted imaging device or a device that directly aids human readers in interpreting images.

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

   • This is an IVD assay, which functions as a "standalone" measurement of a biomarker in serum. The results are generated by the automated instrument (B.R.A.H.M.S KRYPTOR compact PLUS analyzer) without direct human interpretation of the measurement itself. However, the device's output (CgA concentration) is explicitly stated to not be used for standalone diagnosis or monitoring but "in conjunction with other clinical methods." So while the analytical measurement is standalone, the clinical interpretation for decision-making is not.

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

   • For the clinical performance evaluation (sensitivity and specificity for tumor progression), the ground truth was imaging-based tumor assessment using RECIST 1.1 criteria. This is a form of expert assessment based on a standardized methodology, often relying on radiologists and oncologists to interpret imaging studies.

7. The sample size for the training set:

   • This document describes an IVD device submission, not a machine learning/AI device. Therefore, the concept of a "training set" for an algorithm in the typical AI sense does not directly apply. The development and validation of the assay itself would have involved numerous samples for optimization and establishment of analytical performance characteristics, but these are not referred to as a "training set" here.

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

   • As addressed above, the concept of a "training set" in the context of machine learning/AI is largely inapplicable here. The development of the assay's analytical characteristics (e.g., linearity, precision, detection limits) would be established through standard laboratory practices and reference materials, for which "ground truth" is defined by known concentrations or established analytical methods.

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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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