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For in vitro diagnostic use with the IMMULITE® 2000 Analyzer -- for the quantitative measurement of allergen-specific IgE in human serum, as an aid in the clinical diagnosis of IgE-mediated allergic disorders. The test results are to be used in conjunction with clinical findings and other laboratory tests.

IMMULITE® 2000 3gAllergy™ Specific IgE is a solid-phase, two-step, chemiluminescent immunoassay that exploits liquid phase kinetics in a bead format. It represents a significant advance over conventional methods relying on allergens attached to a solid-phase support, such as a paper disk. The allergens are covalently bound to a soluble polymer matrix, which in turn is labeled with a ligand. The use of an amino acid co-polymer amplifies the amount of allergen that the matrix can support. Incubation Cycles: 2 × 30 minutes.

The Siemens Healthcare Diagnostics Inc. IMMULITE® 2000 3gAllergy™ Specific IgE Assay is intended for the quantitative measurement of allergen-specific IgE in human serum, to aid in the clinical diagnosis of IgE-mediated allergic disorders.

1. Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria for precision, linearity, or clinical performance in numerical terms for the new allergens to be cleared. However, the study results are presented to demonstrate acceptable analytical performance and comparability to clinical data.

Precision:
Precision was evaluated by calculating the intra-assay (Within-Run) and inter-assay (Total) percent coefficients of variation (%CV) for positive samples. The reported CVs are generally low, with within-run CVs mostly below 5% (with some exceptions like Positive #4 for Lime at 9.15%) and total CVs mostly below 6% (with some exceptions like Positive #4 for Lime at 11.47%). The document states that "acceptable analytical performance including precision" was demonstrated, implying these values met internal or regulatory expectations.

Linearity:
Linearity was assessed by comparing observed to expected data from 2-fold serial dilutions. The regression equations show slopes very close to 1 and intercepts close to 0, with 95% confidence intervals for both slope and intercept generally containing 1 and 0 respectively. This indicates good linearity across the tested range. The document states "acceptable analytical performance including linearity" was demonstrated.

Specificity (Inhibition Studies):
Specificity was confirmed through competitive inhibition testing. The acceptance criterion was explicitly stated as achieving a target % inhibition of 50% for the highest inhibitor concentration tested. The reported performance is that this target was met for all tested allergens.
Additional inhibition studies for cross-reactivity used a criterion of results being below 9.9% for specific allergens when tested with unrelated allergen extracts. The reported performance states that results were below 9.9% for Asparagus, Blueberry, Cauliflower, and Perch when tested with unrelated extracts, and for Apricot, Chili Pepper, Chub Mackerel, Ginger, Lime, and Whey.

Clinical Performance:
The document presents an agreement rate with clinical data. The acceptance criteria for clinical performance are implicitly defined by the reported lower and upper confidence intervals, which fall within generally accepted ranges for such diagnostic assays.

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For in vitro diagnostic use with the IMMULITE® 2000 Analyzer - for the quantitative measurement of allergen-specific IgE in human serum, as an aid in the clinical diagnosis of IgE-mediated allergic disorders.

IMMULITE® 2000 3gAllergy™ Specific IgE is a solid-phase, two-step, chemiluminescent immunoassay that exploits liquid phase kinetics in a bead format. It represents a significant advance over conventional methods relying on allergens attached to a solid-phase support, such as a paper disk. The allergens are covalently bound to a soluble polymer matrix, which in turn is labeled with a ligand. The use of an amino acid co-polymer amplifies the amount of allergen that the matrix can support. Incubation Cycles: 2 × 30 minutes.

The Siemens Healthcare Diagnostics Inc. IMMULITE® 2000 3gAllergy™ Specific IgE Assay is an in vitro diagnostic device intended for the quantitative measurement of allergen-specific IgE in human serum, to aid in the clinical diagnosis of IgE-mediated allergic disorders. The provided document focuses on the clearance of 27 additional specific allergens for use with this existing assay.

Here's an analysis of the acceptance criteria and study data provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for precision, linearity, or specificity (inhibition). Instead, it presents the study results and concludes that they demonstrate "acceptable analytical performance." For clinical performance, it discusses general agreement with clinical data.

Therefore, the table below will summarize the reported performance metrics, implying that these results were deemed acceptable by the manufacturer and the FDA for substantial equivalence.

• Concentration-dependent inhibition.
• Target of 50% inhibition met at the highest inhibitor concentration tested (5 mg/mL, or the starting concentration for Haddock, Red Snapper, and Sole). |
  | Clinical Performance | Good agreement with clinical documentation of allergen sensitivity. | Sensitivity: 66.2% (Lower Conf 64%, Upper Conf 69%)
  Specificity: 98.9% (Lower Conf 99%, Upper Conf 99%)
  Overall Agreement: 89.1% (Lower Conf 88%, Upper Conf 90%) |

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

• Precision: Three positive samples and one negative sample were tested for each allergen. Each sample was assayed in two aliquots, two runs per day, on 20 different days, for three allergen lots. This setup aims to assess within-run and total precision across different batches and extended testing periods.
• Linearity: For each allergen, two samples were diluted in 2-fold serial dilutions to 5 levels. Each diluted and undiluted sample was tested.
• Specificity (Inhibition): A "single serum sample or pool of sera" was used for competitive inhibition testing for each allergen. A negative sample was used as a background control. Inhibition experiments involved 70uL of undiluted and minimally 4-5 levels of serially diluted inhibitor extract (5, 1, 0.2, 0.04, 0.008 mg/mL, and sometimes more dilute levels). Each sample mixture with inhibitor extract and controls was assayed with 1 lot of each allergen.
• Clinical Performance: 4,118 samples were tested: 1,238 from clinically positive individuals and 2,880 from clinically normal (non-atopic) individuals.
• Data Provenance: The document does not explicitly state the country of origin or whether the data is retrospective or prospective for any of these studies. It can be inferred that these are prospective studies conducted by the manufacturer, Siemens Healthcare Diagnostics Inc., for regulatory submission.

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

• Precision, Linearity, Specificity: For these analytical performance studies, the "ground truth" is based on the inherent properties of the measurements and controls, rather than expert interpretation of a diagnostic outcome. The accuracy of the assay itself is being evaluated.
• Clinical Performance: For the clinical performance study, the "ground truth" (clinical data for IgE-mediated allergic disorders) was established based on "clinically diagnosed atopic and non-atopic individuals." The document does not specify the number or qualifications of the experts (e.g., allergists, physicians) who performed these clinical diagnoses.

4. Adjudication Method for the Test Set

• Precision, Linearity, Specificity: Not applicable. These are analytical studies where results are quantitative measurements against known standards or controls.
• Clinical Performance: The document states that the ground truth for clinical performance was based on "clinical data" to define individuals as "clinically diagnosed atopic and non-atopic individuals." There is no mention of an adjudication method (like 2+1, 3+1 consensus) explicitly detailed for the clinical diagnoses themselves. It implies that these were established clinical classifications prior to testing with the IMMULITE® 2000.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic assay, not an imaging device or AI algorithm intended to assist human readers in interpretation. Therefore, the concept of "human readers improve with AI vs. without AI assistance" does not apply here.

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

Yes, the studies evaluating the IMMULITE® 2000 3gAllergy™ Specific IgE Assay are fundamentally standalone. The device performs quantitative measurements of IgE levels in serum, and its performance (precision, linearity, specificity, and comparison to clinical diagnoses) is assessed based on these measurements. There is no "human-in-the-loop" component in the analytical operation of the assay or the interpretation of its quantitative output for the purpose of these performance studies. Clinicians then use these quantitative results, alongside other clinical information, for diagnosis.

7. Type of Ground Truth Used

• Precision, Linearity: Ground truth is based on known concentrations or expected values derived from serial dilutions.
• Specificity (Inhibition): Ground truth is based on the known presence and concentration of the inhibitor extract and the expected inhibition of the specific allergen reaction.
• Clinical Performance: The ground truth was "clinical data," referring to the diagnosis of "clinically diagnosed atopic and non-atopic individuals." This would typically involve a combination of patient history, physical examination, and potentially other diagnostic tests (e.g., skin prick tests, other lab results, patient symptoms, and outcomes). It is not solely pathology or "outcomes data" in a broader sense but relies on a clinical determination of allergy status.

8. Sample Size for the Training Set

The document describes performance studies for the device itself, not the development of an algorithm that would require a distinct "training set" in the context of machine learning or AI. Therefore, the concept of a training set for an AI algorithm is not applicable to this submission. The studies detailed are for validation of the assay performance.

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

As explained in point 8, the concept of a "training set" for an AI algorithm is not applicable to these studies for this in vitro diagnostic device.

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