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For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of thyrotropin (TSH) in serum. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.

For in vitro diagnostic use with the IMMULITE® 2000 Systems Analyzers — for the quantitative measurement of non-protein-bound thyroxine (free T4) in serum and heparinized plasma. Measurements of free thyroxine are used in the diagnosis and treatment of thyroid disease.

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The provided text describes a 510(k) submission for the IMMULITE 2000 Third Generation TSH and IMMULITE 2000 Free T4 assays. The submission primarily focuses on adding pediatric reference intervals to the device's labeling and asserts that no modifications to the device's design or manufacturing processes are required, thus the predicate devices and subject devices are the same. This means that no new device performance studies were conducted for this specific submission, as the changes are limited to labeling updates based on existing assay capabilities and establishing new reference intervals for a specific population.

Therefore, the requested information regarding acceptance criteria and device performance for a new device study is largely not applicable in the context of this 510(k) summary, as it explicitly states that additional analytical performance data is not needed. The document emphasizes that existing performance characteristics continue to apply.

However, I can extract information related to the establishment of the pediatric reference intervals, which is a form of study performed to define normative values for a specific population for the device.

1. Table of Acceptance Criteria and Reported Device Performance

Since this submission is about establishing new reference intervals for an already approved device and not evaluating the device's analytical performance against new acceptance criteria, the "acceptance criteria" here refer to the statistical methodology used for defining these reference intervals. The "reported device performance" is the established reference interval.

Note: The primary "acceptance criteria" for this submission are that the methods used for establishing the reference intervals conform to CLSI EP28-A3c guidance and that the established pediatric reference intervals fall within the existing analytical measuring capability of the assay.

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

IMMULITE 2000 Free T4:

• Sample Size: A total of 426 patients were analyzed:
  • Infants (01 – 23 months): 81
  • Children (02 – 12 years): 197
  • Adolescents (13 – 20 years): 148
• Data Provenance: The document does not specify the country of origin of the data. It is prospective testing, as it states "Data from a total of [N] patients... tested with the IMMULITE 2000 Free T4 assay were analyzed to establish the reference intervals."

IMMULITE 2000 Third Generation TSH:

• Sample Size: A total of 433 patients were analyzed:
  • Infants (01 – 23 months): 90
  • Children (02 – 12 years): 195
  • Adolescents (13 – 20 years): 148
• Data Provenance: The document does not specify the country of origin of the data. Similar to Free T4, this appears to be prospective testing based on the phrasing "Data from a total of [N] patients... tested with the IMMULITE 2000 Third Generation TSH assay were analyzed to establish the reference intervals."

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

For reference interval studies, the "ground truth" is typically defined by statistical methods applied to a population defined as "healthy" or "normal" for the analyte in question, rather than through expert consensus on individual cases. The document states that the reference intervals were established per the CLSI EP28-A3c guideline: "Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory." This guideline outlines statistical procedures for determining reference intervals. Therefore, independent experts for case-by-case ground truth establishment are not typically involved in this type of study. The expertise lies in the clinical chemists or statisticians who apply the CLSI guideline.

4. Adjudication method for the test set

Not applicable. Reference interval studies do not typically involve adjudication of individual cases in the way diagnostic accuracy studies do. The process involves identifying a healthy reference population and then statistically determining the range of values for that population.

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 submission is for an in-vitro diagnostic (IVD) assay (a lab test), not an AI-based diagnostic imaging or interpretive device that would involve human readers or AI assistance in that context.

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

Not applicable. This is an IVD assay, which generates quantitative results. The device itself is the "standalone" component in the sense that it performs the measurement. The establishment of reference intervals is for interpreting these quantitative results within a specific population.

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

The "ground truth" for the pediatric reference interval studies relies on the selection of a "healthy" pediatric population (presumably free from known thyroid or pituitary disorders) from whom samples were collected and tested. The reference intervals are then statistically derived from the measurements of these healthy individuals, following CLSI EP28-A3c guidelines. This is a statistical definition of "normal range" within a defined population rather than a case-specific ground truth like pathology or expert consensus for individual diagnoses. The assumption is that the participants in these groups represented a healthy pediatric population for thyroid function.

8. The sample size for the training set

Not applicable in the typical sense of machine learning. The data described (426 for Free T4, 433 for TSH) is used to establish the reference intervals (similar to a development/validation set in traditional statistics), rather than "training" an algorithm that would then be separately tested. The entire dataset is used to directly calculate the intervals.

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

Not applicable as a "training set." The "ground truth" for the reference interval establishment relies on the statistical methodology (Robust Symmetric, Non-Parametric) applied to a population described as healthy, as per CLSI EP28-A3c. The selection criteria for this "healthy" pediatric population are implied to be part of the study design to appropriately define the "normal" range.

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The IMMULITE® Free T4 Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Free T4 assay on the IMMULITE 2000 systems.

The IMMULITE® IGF-1 Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE IGF-1 assay on the IMMULITE 2000 systems.

The IMMULITE® Prolactin Calibration Verification Material (CVM) is for in vitro diagnostic use in the verification of calibration of the IMMULITE Prolactin assay on the IMMULITE 2000 systems.

The IMMULITE® 2000 Free T4 Calibration Verification Material (CVM) contains one set of four vials each ImL. CVMIcontains a lyophilized processed human serum matrix with 1.58% sodium azide and preservative and CVM2, CVM3, and CVM4 contain various levels of lyophilized Free T4 in a processed human serum matrix with 1.58% sodium azide and preservative. CVMs are supplied frozen in a lyophilized form.

The IMMULITE® 2000 IGF-I Calibration Verification Material (CVM) contains one set of four vials, 2mL (CVM1) each. CVM1 contains a processed bovine protein/buffer matrix with preservatives. CVM2, CVM3, and CVM4 contain various levels of IGF-I in a processed bovine protein/buffer matrix with preservatives. The CVMs are supplied frozen in a liquid form.

IMMULITE® 2000 Prolactin Calibration Verification Material (CVM) contains one set of four vials, 3 mL each. CVM1 contains a lyophilized equine serum/buffer matrix with preservative. CVM2, CVM3, and CVM4 contain various levels of lyophilized prolactin in an equine serum/buffer matrix with preservative CVMs are supplied frozen in a lyophilized form.

Here's a breakdown of the acceptance criteria and study information for each of the three IMMULITE® 2000 Calibration Verification Materials (CVMs) mentioned in the provided text.

IMMULITE® 2000 Free T4 Calibration Verification Material

1. Table of Acceptance Criteria and Reported Device Performance

Note: The reported performance "Guideline ±2SD Range" is derived from the established Target Mean and Standard Deviation, and suggests the expected range within which the CVMs should perform. The exact demonstration of conformity to the ±10% or ±15% acceptance criteria based on this study is not explicitly stated as a pass/fail within this summary, but the derived ranges imply performance within expected limits.

2. Sample Size and Data Provenance for Test Set

• Sample Size:
  • 27 replicates for each CVM level (9 runs and 3 replicates per run).
  • 5 different reagent kit lots.
  • 9 IMMULITE 2000 systems.
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). Implied to be internal, prospective testing by the manufacturer.

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

Not applicable for this type of device (calibration verification material). The "ground truth" refers to the assigned dose values and established statistically derived ranges.

4. Adjudication Method for Test Set

Not applicable for this type of device. The evaluation is based on quantitative measurements against predefined statistical criteria.

5. MRMC Comparative Effectiveness Study

No. This is not a comparative effectiveness study involving human readers.

6. Standalone Performance Study (Algorithm Only)

Not applicable. This is a physical calibration verification material, not an algorithm. Performance is demonstrated through stability and value assignment studies in conjunction with the IMMULITE 2000 systems.

7. Type of Ground Truth Used

• Assigned Reference Calibrators: The CVMs are value assigned using assigned reference calibrators.
• Internal Material Gravimetrically Prepared: The CVMs are traceable to an internal material which has been gravimetrically prepared.
• Statistical Derivation: Target Mean and ± 2 Standard Deviation (SD) are used to establish Guideline Ranges.

8. Sample Size for Training Set

No explicit "training set" in the context of machine learning. The "Value Assignment" process is analogous to establishing the ground truth/reference for the CVMs. This involved:

• 6 levels of Total Free T4 calibrators (used internally, not commercialized).
• 6 levels of commercially available controls.
• 30 normal patient samples.

9. How Ground Truth for Training Set was Established

The ground truth (value assignment) for the CVMs was established using:

• Assigned reference calibrators.
• CVM dose values generated using curves from these assigned reference calibrators.
• CVM values calculated from recovered values for each run on each instrument independently and then averaged across all systems.
• Quality control performed by calculating recovery of patient samples, spiked patient samples, and controls using the assigned CVM values.

IMMULITE® 2000 IGF-I Calibration Verification Material

1. Table of Acceptance Criteria and Reported Device Performance

Note: The reported performance "Guideline ±2SD Range" is derived from the established Target Mean and Standard Deviation, and suggests the expected range within which the CVMs should perform. The exact demonstration of conformity to the ±10% acceptance criteria based on this study is not explicitly stated as a pass/fail within this summary, but the derived ranges imply performance within expected limits.

2. Sample Size and Data Provenance for Test Set

• Sample Size:
  • 27 replicates for each CVM level (9 runs and 3 replicates per run).
  • 7 IMMULITE 2000 systems.
  • 3 different reagent kit lots.
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). Implied to be internal, prospective testing by the manufacturer.

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

Not applicable for this type of device (calibration verification material). The "ground truth" refers to the assigned dose values and established statistically derived ranges.

4. Adjudication Method for Test Set

Not applicable for this type of device. The evaluation is based on quantitative measurements against predefined statistical criteria.

5. MRMC Comparative Effectiveness Study

No. This is not a comparative effectiveness study involving human readers.

6. Standalone Performance Study (Algorithm Only)

Not applicable. This is a physical calibration verification material, not an algorithm. Performance is demonstrated through stability and value assignment studies in conjunction with the IMMULITE 2000 systems.

7. Type of Ground Truth Used

• Assigned Reference Calibrators: The CVMs are value assigned using assigned reference calibrators.
• Internal Material Gravimetrically Prepared: The CVMs are traceable to an internal material which has been gravimetrically prepared.
• Statistical Derivation: Target Mean and ± 2 Standard Deviation (SD) are used to establish Guideline Ranges.

8. Sample Size for Training Set

No explicit "training set" in the context of machine learning. The "Value Assignment" process is analogous to establishing the ground truth/reference for the CVMs. This involved:

• 6 levels of IGF-I calibrators (used internally, not commercialized).
• 2 levels of commercially available controls.
• 60 samples (10 spiked samples and 50 normal patient samples).

9. How Ground Truth for Training Set was Established

The ground truth (value assignment) for the CVMs was established using:

• Assigned reference calibrators.
• CVM dose values generated using curves from these assigned reference calibrators.
• CVM values calculated from recovered values for each run on each instrument independently and then averaged across all systems.
• Quality control performed by calculating recovery of patient samples and controls using the assigned CVM values, ensuring controls fall within their target ranges.

IMMULITE® 2000 Prolactin Calibration Verification Material

1. Table of Acceptance Criteria and Reported Device Performance

Note: The reported performance "Guideline ±2SD Range" is derived from the established Target Mean and Standard Deviation, and suggests the expected range within which the CVMs should perform. The exact demonstration of conformity to the ±10% acceptance criteria based on this study is not explicitly stated as a pass/fail within this summary, but the derived ranges imply performance within expected limits. LPRCVM4 requires dilution for its target value to be within the reportable range of the assay.

2. Sample Size and Data Provenance for Test Set

• Sample Size:
  • 27 replicates for each CVM level (9 runs and 3 replicates per run).
  • 8 IMMULITE 2000 systems.
  • 4 different reagent kit lots.
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). Implied to be internal, prospective testing by the manufacturer.

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

Not applicable for this type of device (calibration verification material). The "ground truth" refers to the assigned dose values and established statistically derived ranges.

4. Adjudication Method for Test Set

Not applicable for this type of device. The evaluation is based on quantitative measurements against predefined statistical criteria.

5. MRMC Comparative Effectiveness Study

No. This is not a comparative effectiveness study involving human readers.

6. Standalone Performance Study (Algorithm Only)

Not applicable. This is a physical calibration verification material, not an algorithm. Performance is demonstrated through stability and value assignment studies in conjunction with the IMMULITE 2000 systems.

7. Type of Ground Truth Used

• Assigned Reference Calibrators: The CVMs are value assigned using assigned reference calibrators.
• 3rd IS 84/500: The CVMs are traceable to this international standard.
• Statistical Derivation: Target Mean and ± 2 Standard Deviation (SD) are used to establish Guideline Ranges.

8. Sample Size for Training Set

No explicit "training set" in the context of machine learning. The "Value Assignment" process is analogous to establishing the ground truth/reference for the CVMs. This involved:

• 8 levels of Prolactin calibrators (used internally, not commercialized).
• 6 levels of commercially available controls.
• 30 samples (10 normal patients and 20 spiked normal patient samples).

9. How Ground Truth for Training Set was Established

The ground truth (value assignment) for the CVMs was established using:

• Assigned reference calibrators.
• CVM dose values generated using curves from these assigned reference calibrators.
• CVM values calculated from recovered values for each run on each instrument independently and then averaged across all systems.
• Quality control performed by calculating recovery of patient samples and controls using the assigned CVM values.

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The IMMULITE® 2000 Free Thyroxine Assay is for in vitro diagnostic use with the IMMULITE 2000 Systems Analyzers - for the quantitative measurement of nonprotein-bound thyroxine (free T4) in serum and heparinized plasma, as an aid in the clinical assessment of thyroid status.

The IMMULITE 2000 Free T4 is a solid-phase, enzyme-labeled chemiluminescent competitive immunoassay. The solid phase (bead) is coated with monoclonal murine anti-T4 antibody. The liquid phase consists of alkaline phosphatase (bovine calf intestine) conjugated to T4. The patient sample and the reagent are incubated together with the coated bead for 30 minutes. During this time, free T4 in the sample competes with enzyme coniugated T4 in the buffer for a limited number of antibody binding sites on the bead. Unbound patient sample and enzyme conjugate are then removed by centrifugal washes. Finally, the chemiluminescent substrate is added to the reaction tube containing the bead and the signal is generated in proportion to the bound enzyme. The IMMULITE 2000 Free T4 procedure is a direct or single test assay, in the sense that its results are not calculated as a function of total T4, but interpolated from a (stored) standard curve calibrated in terms of free T4 concentrations.

Here's a breakdown of the acceptance criteria and study information for the IMMULITE® 2000 Free T4 assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Note on Acceptance Criteria: For many analytical performance characteristics (like linearity, precision, sensitivity, and interference), the "acceptance criteria" are implied by adherence to CLSI guidelines and demonstrating performance comparable to or better than established methods/predicate devices. Specific numerical thresholds for acceptance, beyond what is reported as achieved, are not explicitly stated. The primary acceptance criterion for the overall device's substantial equivalence is its performance relative to the predicate device in terms of accuracy/correlation and other analytical characteristics.

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

• Accuracy/Correlation (Method Comparison):
  • Sample Size: 282 samples
  • Data Provenance: Not explicitly stated, but based on a "Method Comparison" against a predicate device, it implies prospective testing of patient or control samples using both devices. The origin country is not specified.
• Precision:
  • Sample Size: Six different material/sample pools (Pool 05-09 and Control). For each, two aliquots were assayed in two runs per day on 20 different days. This amounts to 80 measurements per material (2 aliquots * 2 runs/day * 20 days).
  • Data Provenance: Not explicitly stated, but typically generated in a controlled laboratory setting (e.g., at Siemens Healthcare Diagnostics).
• Linearity/Recovery:
  • Sample Size: 9 samples (calibrators and mixed calibrators). Five replicates of each sample were assayed.
  • Data Provenance: Laboratory generated.
• Interference (Endogenous & Cross-Reactivity):
  • Sample Size: Not specified for how many samples or replicates were tested for each interferent, but implies a series of controlled experiments.
  • Data Provenance: Laboratory generated.
• Limit of Blank (LoB) & Limit of Detection (LoD):
  • Sample Size: Not explicitly stated, but guided by CLSI EP17-A.
  • Data Provenance: Laboratory generated.

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

• This device is an in vitro diagnostic (IVD) assay for quantitative measurement of Free T4, not an imaging or diagnostic AI tool that requires expert interpretation of images/data for ground truth.
• The "ground truth" for the test set (e.g., the true Free T4 concentration for method comparison, linearity, or precision) would be established by:
  • Using reference materials with known concentrations.
  • Performance of the predicate device (ADVIA Centaur FrT4) for comparison studies.
  • Validated analytical methods as performed by laboratory professionals.
• Therefore, the concept of "number of experts used to establish ground truth" as it applies to subjective interpretation (like radiology reads) is not directly relevant here. Instead, it relies on the analytical accuracy and precision of established methods and technical expertise in laboratory testing and calibration.

4. Adjudication Method for the Test Set

• Not applicable as this is an IVD assay, not an AI diagnostic tool requiring subjective interpretation and adjudication. The "ground truth" for method comparison is the measurement by the predicate device (ADVIA Centaur FrT4).

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

• No, an MRMC comparative effectiveness study was not done. This is an in vitro diagnostic assay measuring a biochemical marker, not a system that relies on human readers interpreting medical cases.

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

• Yes, the performance presented (e.g., precision, linearity, sensitivity, method comparison) is standalone performance of the IMMULITE 2000 Free T4 assay system (analyzer, reagents, and calibration software) without human-in-the-loop interpretation beyond standard laboratory procedures for running the assay and reviewing results. The "algorithm" here refers to the immunoassay chemistry and the instrument's computational processing of chemiluminescent signals to produce a quantitative result.

7. The Type of Ground Truth Used

The ground truth for the various performance studies can be categorized as:

• Predicate Device Measurements: For the accuracy/correlation (method comparison) study, the measurements from the ADVIA Centaur FrT4 assay served as the comparative 'ground truth'.
• Known Concentrations/Reference Materials: For linearity/recovery, limit of blank, and limit of detection, the ground truth was established using calibrators, known dilutions, or samples expected to contain no analyte, where the "true" concentrations are precisely defined.
• Statistical Definitions: Functional sensitivity is defined by a specific statistical criterion (20% CV), rather than an external "ground truth" measurement.

8. The Sample Size for the Training Set

• This document describes the validation of an immunoassay kit for an existing instrument platform (IMMULITE 2000). It is not an AI/machine learning device in the sense of requiring a "training set" of data for algorithm development. The assay's "learning" or calibration involves using specific calibrator materials with known concentrations to generate a standard curve, which is distinct from an AI training set. Therefore, this concept is not applicable here.

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

• As stated above, the concept of a "training set" for an AI algorithm is not applicable to this immunoassay device. The assay is calibrated using calibrators with precisely known concentrations of Free T4. The "ground truth" for these calibrators would be established through highly accurate reference methods or certified reference materials.

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