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The IDS Cortisol assay is an in vitro diagnostic device intended for the quantitative determination of cortisol in human serum and plasma on the IDS system. Results are to be used in conjunction with other clinical and laboratory data to assist clinicians in the diagnosis and treatment of disorders of the adrenal gland.

The IDS Cortisol assay consists of a reagent cartridge. The reagent cartridge contains multiple reagents:

• MPE1:Magnetic particles coated rat anti-mouse monoclonal antibody in a phosphate buffer with Proclin as preservative.
• CONJ: Cortisol coupled with an acridinium ester derivative in = phosphate buffer with Proclin as a preservative.
• mAb: Mouse anti-cortisol monoclonal antibody in phosphate buffer with Proclin as a preservative .;
• BUF: HEPES buffer containing Proclin as preservative .

This document describes the analytical performance of the IDS Cortisol assay, an in vitro diagnostic device, and demonstrates its substantial equivalence to a predicate device (Roche Elecsys Cortisol II). The acceptance criteria and the study proving the device meets these criteria are detailed below.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for this in vitro diagnostic device are primarily based on demonstrating analytical performance that is comparable to, or meets specified standards relative to, established laboratory methods and a predicate device.

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

• Precision Testing:
  • Per sample/concentration level (for one representative lot on one system): N=80 replicates.
  • Combined (3 lots on 3 systems): N=240 replicates per sample/concentration level.
  • Provenance: Not explicitly stated, but clinical laboratory studies typically use samples from diverse patient populations to cover the measurement range. The study mentions "human serum samples" and "low level samples."
• Linearity Testing:
  • A high human serum sample and a low human serum sample were used, along with 12 evenly spaced dilutions.
  • Provenance: "high patient sample with a low patient sample."
• Detection Limit Testing (LoB, LoD, LoQ):
  • 60 blank replicates and 13 low-level samples.
  • Provenance: Not explicitly stated, but based on typical laboratory practices.
• Analytical Specificity (Interference):
  • Human serum samples with low and high cortisol concentrations.
  • For Rheumatoid Factor, a serum sample with low Cortisol and high Rheumatoid Factor was diluted 1:2 and 1:4. Each was assayed in duplicate.
  • For cross-reactivity, serum samples spiked with cross-reactants and unspiked controls were assayed in 26 replicates each.
• Method Comparison (vs. Predicate Device):
  • N: 194 samples.
  • Provenance: Samples were "selected to represent a wide range of Cortisol concentrations" (0.64 to 44.66 ug/dL), implying patient samples. Country of origin not specified, but usually derived from laboratory settings.
• Matrix Comparison:
  • N: 45 samples (36 native, 9 spiked or diluted) per matrix type.
  • Provenance: "human samples" to cover the range of 0.89 to 42.38 ug/dL.
• Expected Values/Reference Range:
  • N: 307 apparently healthy donors.
  • Provenance: "serum samples collected from 307 apparently healthy donors" from 21 to 65 years of age. Details imply a prospective collection for this specific study, but geographical location not explicitly stated beyond "local population" for general reference ranges.

All studies mentioned state they followed CLSI (Clinical and Laboratory Standards Institute) guidelines, which implies these were prospective analytical performance studies conducted under controlled laboratory conditions.

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

For an in vitro diagnostic (IVD) device like the IDS Cortisol assay, "ground truth" for the test set is established through reference methods or highly accurate comparative assays, not typically by human expert consensus or adjudicated readings. The nature of this device is a quantitative immunoassay meant to measure a biomarker.

• Ground Truth Establishment for Analytical Performance:

  • Traceability: The IDS Cortisol assay is traceable to the LC-MS/MS Candidate Reference Measurement Procedure (cRMP) Total Serum Cortisol. This is a highly accurate chemical analytical method, considered a "higher-order" reference method. The ground truth in this context is the quantitative value determined by this cRMP, often involving specialized laboratories and expert analytical chemists.
  • Method Comparison: The test device's performance is compared against the Roche Elecsys Cortisol II (K152227), a previously cleared and marketed predicate device. The values obtained from the predicate device serve as the comparative "truth" for demonstrating substantial equivalence.
  • Precision, Linearity, Detection Limits, Analytical Specificity, Matrix Comparison: These performance characteristics are evaluated against pre-defined statistical criteria (e.g., CV thresholds, R² values, bias limits) using controlled samples, calibrators, and reference materials. The "truth" is the known concentration or behavior of these materials, verified through standard laboratory practices and reference methods.

• Number of Experts & Qualifications: Not applicable in the context of human expert adjudication for image interpretation. The "experts" would be the skilled laboratory personnel and analytical chemists performing the LC-MS/MS and predicate device measurements, as well as those defining the CLSI protocols for analytical testing.

4. Adjudication Method for the Test Set

Not applicable. This is an in vitro quantitative diagnostic device, not an imaging device requiring human-in-the-loop reading and adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

Not applicable. This is an in vitro quantitative diagnostic device, not an imaging device requiring human readers or MRMC studies.

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

Yes, the entire analytical performance evaluation (precision, linearity, detection limits, interference, method comparison, and matrix comparison) represents the standalone performance of the IDS Cortisol assay as an algorithm (chemical reaction + instrument measurement and calculation) without human-in-the-loop intervention for result generation. The human role is in operating the instrument and interpreting the results, but the measurement itself is automated.

7. The Type of Ground Truth Used

The primary ground truth used for this quantitative in vitro diagnostic device is:

• Reference Measurement Procedure: The IDS Cortisol assay is traceable to the LC-MS/MS Candidate Reference Measurement Procedure (cRMP) Total Serum Cortisol, which represents a highly accurate and standardized method for determining cortisol concentrations. This is a form of outcomes data in the sense of a definitive analytical outcome.
• Predicate Device Comparison: The values generated by the Roche Elecsys Cortisol II assay serve as a comparative ground truth for demonstrating substantial equivalence.
• Known Concentrations of Reference Materials/Spiked Samples: For analytical performance studies like precision, linearity, and detection limit, the ground truth is often established by using precisely prepared calibrators or samples with known, verified concentrations of the analyte.

8. The Sample Size for the Training Set

This document describes the analytical validation of a commercial diagnostic kit, not a machine learning algorithm that typically undergoes distinct "training" datasets. Therefore, there isn't a "training set" in the sense of data used to iteratively optimize an AI model.

The "development" or "design" of the assay (reagents, methodology) would have involved extensive R&D and internal testing, which could be considered analogous to a training phase in a broader sense, but no specific sample size for such a phase is provided in this regulatory submission. The data presented are for the validation of the final device.

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

As noted in point 8, there isn't a distinct "training set" in the context of an AI/ML algorithm as described in this document. The "ground truth" for the development of the assay itself would have been established through a combination of:

• Biochemical principles: Understanding the cortisol molecule and its interactions with antibodies.
• Standard laboratory methods: Using established analytical techniques (like spectrophotometry, chromatography, or existing cortisol assays) to characterize reagents and ensure proper reaction kinetics.
• Reference materials: Utilizing internationally recognized reference materials and calibrators for initial assay calibration and optimization.
• Iterative development and testing: Repeated internal testing with various concentrations of cortisol in different matrices to optimize assay components (antibodies, conjugates, buffers) and instrument parameters to achieve desired performance characteristics (sensitivity, specificity, dynamic range). This iterative process involves comparing results against known concentrations or a "gold standard" method (like LC-MS/MS) during development.

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Immunoassay for the in vitro quantitative determination of cortisol in human serum, and plasma. The determination of cortisol is used for the recognition and treatment of functional disorders of the adrenal gland. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Cortisol II CalSet is used for calibrating the quantitative Elecsys Cortisol II assay on the Elecsys and cobas e immunoassay analyzers.

The Elecsys Cortisol II assay makes use of a competition test principle using a monoclonal antibody which is specifically directed against cortisol. Endogenous cortisol which has been liberated from binding proteins with danazol competes with exogenous cortisol derivative in the test which has been labeled with ruthenium complex for the binding sites on the biotinylated antibody.

Results are determined via a calibration curve which is instrument specifically generated by 2point calibration and a master curve provided via reagent barcode.

The reagent working solutions include:

• rackpack (kit placed on instrument) .
  • Streptavidin coated microparticles, ş
  • Reagent 1 (Anti-cortisol-Ab~biotin) and ş
  • Reagent 2 (Cortisol-peptide~Ru(bpy)2+3). ş

The Cortisol II CalSet is a lyophilized human serum with added cortisol in two concentration ranges.

The CalSet includes:

• Cal 1 (approximately 12.5 nmol/L cortisol in a human serum matrix) .
• Cal 2 (approximately 1000 nmol/L cortisol in a human serum matrix) .

The provided document describes the Elecsys Cortisol II immunoassay and its associated calibrator, Cortisol II CalSet. It details various non-clinical performance evaluations and one clinical performance evaluation.

Here's an analysis of the acceptance criteria and the studies that prove the device meets them:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state acceptance criteria in a dedicated table for each technical performance study. Instead, it presents the results of these studies and implies that these results demonstrate the device's performance is acceptable and supports substantial equivalence to the predicate device. For analytical specificity and method comparison, the document includes tables comparing some key characteristics with the predicate device. For other studies like precision, linearity, and sensitivity, it reports the performance without directly listing a pre-defined acceptance criterion.

However, I can extract the reported performance directly from the document for key metrics.

2. Sample sizes used for the test set and the data provenance

• Precision (Human Serum)
  • Test Set Sample Size: 5 human serum samples (native, diluted, spiked) and 2 controls (PC Universal).
  • Data Provenance: Not explicitly stated, but implies laboratory testing internal to the manufacturer (Roche Diagnostics).
• Limit of Blank (LoB)
  • Test Set Sample Size: 5 blank samples. A total of n = 60 LoB measurements were made.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Limit of Detection (LoD)
  • Test Set Sample Size: 5 low-level human serum samples (diluted). A total of n = 60 LoD measurements were made.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Limit of Quantitation (LoQ)
  • Test Set Sample Size: 9 human serum samples.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Linearity (Serum and Plasma)
  • Test Set Sample Size: 19 concentrations (thereof 17 dilutions) prepared from a high analyte serum/plasma sample. Each assayed in 3-fold determination within a single run.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Analytical Specificity (Serum/Plasma)
  • Test Set Sample Size: Two human serum sample pools.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Endogenous Interferences
  • Test Set Sample Size: Three human serum samples (low, mid, high cortisol concentrations) for each interfering substance.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• HASA Effect
  • Test Set Sample Size: Two serum samples with cortisol concentrations of 173 and 789 nmol/L. Aliquots spiked with DASA and diluted in 10% increments.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Exogenous Interferences - Drugs
  • Test Set Sample Size: Two human serum samples (native, diluted, spiked) for 16 pharmaceutical compounds; each tested in 3-fold determination.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Exogenous Interferences - Anticoagulants
  • Test Set Sample Size: Minimum of 48 serum/plasma pairs per sample material (Serum, Li-Heparin, K2-EDTA-, K3-EDTA-plasma primary tubes and Li-Heparin Plasma Gel Separation Tubes). Each tested in duplicate.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Method Comparison 1: Elecsys Cortisol II vs. LC-MS (Reference Method)
  • Test Set Sample Size: 208 human serum samples (all native single donors).
  • Data Provenance: UZ Gent, Lab voor Klinische Biologie (Gent, Belgium); implies prospective collection for the study or a well-characterized archive.
• Method Comparison 2: Elecsys Cortisol II vs. Cortisol I (K070788)
  • Test Set Sample Size: 536 human serum samples (all native single donors).
  • Data Provenance: UZ Gent, LMU Großhadern, Uni Klinik Leipzig and Labor Limbach; implies prospective collection for the study or a well-characterized archive from multiple European sites.
• Reagent Stability (Onboard and After First Opening)
  • Test Set Sample Size: 5 human serum samples (native, diluted, spiked) and 2 controls.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Reagent Stability (Real-time, ongoing)
  • Test Set Sample Size: PreciControl Universal (Level 1 and 2) and human serum samples. Data for time-points at 0, 13, 16, 19 months (MP lot) and 0, 7, 16, 19 months (P2 and P3 lot)
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Sample Stability (2-8°C, Room Temperature, -15 to -25°C)
  • Test Set Sample Size: Twelve human serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma samples (all single donors, native, spiked, diluted) for each study.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Calibration Stability (Lot and On-board)
  • Test Set Sample Size: Five human serum samples (native, diluted, spiked) and two control samples.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Calibrator studies (Reconstitution, Stability)
  • Test Set Sample Size: Not explicitly stated beyond "two sets of Cortisol II CalSet" for reconstitution, and "on-test and reference materials" for stability. PreciControl Universal used to assess CalSet stability.
  • Data Provenance: Not explicitly stated, implies internal laboratory testing.
• Clinical Performance Evaluation (Reference Range)
  • Test Set Sample Size: 296 individuals for 6-10 am sample collection, 300 individuals for 4-8 pm sample collection.
  • Data Provenance: Three sites in the United States (one site in St Louis, Missouri for evaluation). These are prospective clinical samples.
• Training Set Sample Size: The document does not specify a separate "training set" for the Elecsys Cortisol II device. Immunoassays are not typically "trained" in the machine-learning sense with a distinct training dataset. Instead, they are developed, optimized, and then validated with performance studies. The "value assignment" for calibrators, and the master curves are part of the setup, but not a "training set" in the context of AI.

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

This information is not applicable or explicitly stated in the document for this type of medical device (an in-vitro diagnostic immunoassay). For immunoassays, ground truth (or reference values) is typically established through:

• Reference methods: Like LC-MS (Liquid Chromatography-Mass Spectrometry) as used in Method Comparison 1. These are highly accurate analytical techniques, not dependent on expert interpretation.
• Spiking studies/Dilution linearity: Known concentrations are added to samples, which serves as the "ground truth" for evaluating recovery and linearity.
• Clinical context: For reference ranges, the "truth" is derived statistically from a population of healthy individuals.
• Previous assay values: For comparative studies, the predicate device's results are used as a comparison point.

There are no mentions of human experts establishing "ground truth" in terms of interpreting clinical findings or images.

4. Adjudication method for the test set

Not applicable. This is not a device where human interpretation or adjudication is used to establish "ground truth" for the test results. The device measures a biomarker concentration.

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 document describes an immunoassay and calibrator, not an AI device that assists human readers in interpreting cases. There is no mention of human readers or AI assistance.

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

This refers to an immunoassay, which is by nature a standalone analytical system. The Elecsys Cortisol II assay determines the quantitative concentration of cortisol in human serum and plasma directly. There is no human-in-the-loop performance component in the measurement process itself, although clinical interpretation of the results by a healthcare professional is expected.

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

The types of "ground truth" or reference standards used in the studies include:

• Reference Method LC-MS: For Method Comparison 1, the Elecsys Cortisol II was compared against LC-MS, which serves as a highly accurate reference method for cortisol quantification.
• Predicate Device: For Method Comparison 2, the Elecsys Cortisol II was compared against the predicate Elecsys Cortisol (K070788) assay.
• Known Spiked/Diluted Concentrations: For studies like linearity, analytical specificity, and interference, known amounts of analyte or interfering substances were added to samples, establishing controlled "ground truth" for evaluation.
• Statistical Normative Data: For establishing the reference ranges, the results from a large cohort of self-reported healthy individuals were used to statistically define normal limits.
• Assigned Values: For calibrator and control stability, "assigned values" from independent measurements (e.g., using multiple analyzers and lots) were used as the reference.

8. The sample size for the training set

The document does not specify a "training set" in the context of machine learning for this immunoassay. Immunoassays typically involve development and optimization phases for reagent formulation, antibody selection, and instrument parameters, which could be seen as analogous to "training" in a broad sense, but not with a distinct training data set size as in AI/ML validation studies. Instead, the assay relies on a master curve (provided via reagent barcode) and 2-point calibration.

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

As there is no distinct "training set" in the AI/ML sense, this question is not directly applicable. However, for the reference values that define the assay's performance and calibration, the following methods are mentioned:

• Master curve: Provided via reagent barcode for quantitative determination.
• Calibration: Results are determined via a calibration curve that is instrument specifically generated by 2-point calibration.
• Traceability: The Elecsys Cortisol II assay has been standardized against the IRMM (Institute for Reference Materials and Measurements)/IFCC 451 panel (ID GC/MS, isotope dilution-gas chromatography/mass spectrometry), which serves as a highly accurate reference.
• Calibrator Value Assignment: For the Cortisol II CalSet, target values are chosen for the best fit with the Master Calibration Curve and Rodbard curve parameters. Calibrators are run in duplicate on multiple analyzers (at least 3 cobas e 411 and at least 3 cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers) with all available reagent lots. The assigned value is the mean over at least six runs on at least three analyzers.

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