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Ortho-mune OKT4A (CD4) Monoclonal Antibody (Murine) FITC Conjugate is used to identify and enumerate the percentage of CD4+ human T lymphocytes in whole blood by flow cytometry.

Identification and enumeration of abnormal levels of CD4lymphocytes may be clinically significant in the prognosis of secondary immunodeficiency diseases (acquired immunodeficiency syndrome [AIDS]).

AIDS is characterized by a severe reduction in T helper CD3+CD4+) lymphocytes and a decrease in the CD4:CD8 ratio. The CD4:CD8 ratio has been used as a predictor of time to the development of AIDS. CD4 counts should also be determined using a CD3/CD4 combination reagent to eliminate monocyte contamination (CD3-CD4+dim). CD4+lymphocytes (expressed as an absolute number, a percentage of lymphocytes or as a ratio of CD4+ to CD8+ T lymphocytes) represents the best single predictor of the progression of AIDS. CD4+ lymphocyte numbers usually start to decline relatively soon after human immunodeficiency virus (HIV) infection.

Ortho-mune OKT4A Monoclonal Antibody (Murine) FITC Conjugate contains the purified monoclonal antibody OKT4A conjugated to the fluorochrome fluorescein isothiocyanate.

Acceptance Criteria and Device Performance for Ortho-mune™OKT™4A (CD4) FITC Conjugate

This document outlines the acceptance criteria and performance data for the Ortho-mune™OKT™4A (CD4) Monoclonal Antibody (Murine) FITC Conjugate, as submitted in K951459. The study aimed to demonstrate substantial equivalence to the predicate device, CD4 (Leu™-3a) FITC.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for substantial equivalence are inferred from the performance characteristics presented, specifically demonstrating comparable results to the predicate device and acceptable reproducibility and linearity. Given the nature of a 510(k) submission for substantial equivalence, the "acceptance criteria" are implicitly met by showing that the new device performs "as well as" or "equivalently to" the predicate device on key performance metrics.

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

• Sample Size for Equivalence Study:
  • 206 normal donors
  • 88 AIDS/ARC patients
  • Total: 294 whole blood specimens.
• Sample Size for Reproducibility Studies:
  • 10 normal donors for within-laboratory study (processed to create low, normal, high CD4 populations).
  • 10 normal donors for between-laboratory study (processed to create low, normal, high CD4 populations).
• Sample Size for Linearity Study:
  • Specimens from 4 normal donors (processed to produce low, normal, high numbers of lymphocyte subsets via concentration/dilution).
• Data Provenance: The studies were conducted at three external, geographically distinct sites. The data is prospective for the purpose of this submission, though the underlying specimens are from existing populations (normal donors and AIDS/ARC patients). The country of origin of the data is not explicitly stated but is implied to be the United States given the submission to the FDA.

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

No external experts were explicitly used to establish ground truth in the traditional sense of consensus reading. The "ground truth" for the comparative effectiveness study was the measurement obtained by the predicate device, CD4 (Leu-3a) FITC, using flow cytometry. For the reproducibility and linearity studies, the ground truth was derived from the measurements of the device itself (Ortho-mune OKT4A) against established laboratory methods (e.g., automated hematology analyzer for total lymphocyte count).

4. Adjudication Method for the Test Set

No adjudication method was used for the test set. The study directly compared the measurements obtained by the new device to those obtained by the predicate device for equivalence, and relied on statistical analysis of direct measurements for reproducibility and linearity.

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

No MRMC study was done, as this device is an immunophenotyping reagent for flow cytometry, not an imaging device requiring human reader interpretation in the same manner. The "human readers" (flow cytometry operators) would be operating the instruments rather than interpreting complex images. The focus was on the performance of the reagent itself. Therefore, comparing human reader improvement with and without AI assistance is not applicable here.

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

Yes, the studies evaluating the performance of the Ortho-mune OKT4A (CD4) FITC Conjugate can be considered "standalone" in the sense that they assess the direct analytical performance of the reagent itself, as measured by a flow cytometer. The flow cytometry process is automated in terms of cell counting and fluorescent signal detection, and the reagent's performance is objectively measured. While human operators are involved in sample preparation and instrument setup, the core performance metrics (staining, enumeration, reproducibility, linearity) characterize the reagent's analytical capability independently of direct "human interpretation" of results in the way an imaging AI might be evaluated.

7. The Type of Ground Truth Used

• For Equivalence Study: The predicate device, CD4 (Leu-3a) FITC, was used as the reference standard. The goal was to establish substantial equivalence, meaning the new device performs comparably to a legally marketed device. This is a form of comparative ground truth.
• For Reproducibility Studies: The measurements from the Ortho-mune OKT4A reagent itself, over multiple replicates and sites, were used to assess the consistency of its own performance. This relies on the inherent precision of the laboratory measurements.
• For Linearity Study: A combination of an automated hematology analyzer (for total lymphocyte count) and the CYTORONABSOLUTE flow cytometer (with the Ortho-mune reagent for percent positive CDx cells) was used. The "expected" values were calculated based on serial dilutions and established counts, which serves as a form of derived or calculated ground truth.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI development. This device is a monoclonal antibody reagent, and its development typically involves laboratory-based optimization (e.g., antibody titration, conjugation efficiency) rather than algorithm training with large datasets. The studies described here are for validation of the final product.

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

As noted above, the concept of a "training set" and associated ground truth establishment for AI/machine learning is not applicable to this type of medical device (an immunophenotyping reagent). The development process would have involved standard biological and chemical methods to characterize the antibody and its conjugate, ensuring specificity and reactivity, but not a "training set" with ground truth in the AI context.

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Ortho-mune OK-COMBO Control is intended for use as negative control for immunophenotying of human lymphocytes in whole blood by flow cytometry using Orthomune OK-COMBO immunophenotyping reagents. Ortho-mune OK-COMBO immunophenotyping reagents are blends of two purified monoclonal antibodies conjugated to fluorescein isothiocyanate and phycoerythrin, respectively. The negative control is used to check for nonspecific background staining and to set the negative/positive rergions of the fluorescent cytograms.

Ortho-mune OK-COMBO Control IgG2-FITC/IgG2-PE Monoclonal Antibody (Murine) is a blend of murine monoclonal antibodies, not specific for human cellular antigens, conjugated to the fluorochromes, fluorescein isothiocyanate (FITC) and phycoerythrin (PE), respectively.

Here's an analysis of the provided text, outlining the acceptance criteria and study details for the Ortho-mune™ OK-COMBO Control IgG2-FITC/IgG2-PE Monoclonal Antibody (Murine):

Device: Ortho-mune™ OK-COMBO Control IgG2-FITC/IgG2-PE Monoclonal Antibody (Murine)
Intended Use: Negative control for immunophenotyping of human lymphocytes in whole blood by flow cytometry using Ortho-mune OK-COMBO immunophenotyping reagents. Used to check for non-specific background staining and to set negative/positive regions of fluorescent cytograms.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" with numerical thresholds for performance. Instead, the study aims to demonstrate substantial equivalence to a predicate device (Simultest™ IMK Plus Reagent B-Control) and acceptable reproducibility and linearity. Therefore, the "acceptance criteria" are implied by the comparative performance and good internal consistency.

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

• Equivalence to Predicate Device (Percent of Events in Positive Region):
  • Normal Donors: N = 203 whole blood specimens.
  • AIDS/ARC Patients: N = 84 whole blood specimens.
  • Provenance: "three external, geographically distinct sites." Implies prospective collection, but not explicitly stated. Country of origin not specified.
• Reproducibility Studies:
  • N = 11 donors (processed to produce CD4 depleted, CD8 depleted, CD19 depleted, and normal sample types).
  • Number of Replicates: 10 replicates per sample type per site for within-laboratory, aggregated results for between-laboratory.
  • Provenance: "three independent laboratories." Implies prospective collection. Country of origin not specified.
• Linearity Study:
  • N = 4 normal donor samples (whole blood, EDTA) processed to generate low, normal, and high numbers of lymphocyte subsets.
  • Number of Replicates: Triplicate staining for each sample.
  • Provenance: Normal donor samples; not explicitly stated if from external sites or internal. Country of origin not specified.
• Comparison of Ortho-Mune Reagents + Control vs. Predicate Reagents + Control:
  • Normal Donors (Tables G, H): N = 191 (CD3/CD19), N = 190 (CD4/CD8) whole blood specimens.
  • AIDS/ARC Patients (Tables I, J): N = 85 (CD3/CD19), N = 83 (CD4/CD8) whole blood specimens.
  • FACScan Comparison (Tables K, L, M, N): N = 29 (OKT3/OKB19A), N = 49 (OKT4A/OKT8) normal donor whole blood samples.
  • Provenance: Not explicitly stated for all these specific comparisons, but generally "Whole blood specimens from normal donors and AIDS/ARC patients" were used.

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

This study does not involve "experts" establishing a disease diagnosis or image ground truth for the test set. Instead, it involves laboratory measurements using flow cytometry. The accuracy of the measurements relies on the instrument (ORTHO CYTORONABSOLUTE laser flow cytometer) and established laboratory protocols for staining and analysis. The "ground truth" for the test samples in the linearity study, for example, was derived from automated hematology analyzers and further calculations based on dilutions and flow cytometry results (expected X-axis values).

4. Adjudication Method for the Test Set

Not applicable. This is a technical performance study of a control reagent in a laboratory setting, not a clinical study requiring expert adjudication of diagnoses.

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

No, this is not an MRMC study. It is a technical performance study of a laboratory reagent demonstrating equivalence to a predicate and acceptable performance characteristics. It does not involve human readers interpreting results with or without AI assistance.

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

Yes, the study primarily evaluates the standalone performance of the Ortho-mune OK-COMBO Control reagent in conjunction with flow cytometers. The primary data presented (mean percentages, ranges, reproducibility CVs, linearity slopes/intercepts/R-values) are objective measurements generated by the instruments and the reagents, not subject to human interpretation in the sense of a diagnostic decision. The device itself is a "negative control" reagent, used for instrument calibration and assessment of non-specific staining, rather than a diagnostic algorithm that produces an output for human interpretation.

7. The Type of Ground Truth Used

The ground truth is based on:

• Comparative Performance: The established performance data of the legally marketed predicate device, Simultest™ IMK Plus Reagent B-Control. The goal is to show the new device produces equivalent results.
• Internal Consistency: For reproducibility and linearity, the "ground truth" is derived from consistency across replicates, laboratories, and expected values based on known dilutions or physiological ranges (e.g., in normal vs. AIDS/ARC patient samples).
• Instrument Measurements: The quantitative outputs from the ORTHO CYTORONABSOLUTE laser flow cytometer and automated hematology analyzers.

8. The Sample Size for the Training Set

Not applicable. This is a performance study for a laboratory reagent. There is no "training set" in the context of machine learning or AI algorithms; the reagents are chemical/biological products whose performance characteristics are intrinsically determined by their composition and manufacturing process.

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

Not applicable, as there is no training set for this type of device.

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Ortho-mune OKB19A PE Conjugate is intended for use in identification and enumeration of CD19+ human B lymphocytes in whole blood by flow cytometry.

Ortho-mune OKB19A Monoclonal Antibody (Murine) Phycoerythrin (PE) Conjugate contains the purified monoclonal antibody OKB19A conjugated to the fluorochrome phycoerythrin.

The provided document describes the performance characteristics of the Ortho-mune™ OKB™19A (CD19) Monoclonal Antibody (Murine) Phycoerythrin Conjugate, a diagnostic device for identifying and enumerating CD19+ human B lymphocytes.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state numerical acceptance criteria in a formal table. Instead, the acceptance is based on demonstrating "substantial equivalence" to a predicate device (Monoclonal Antibody Test for B Cells [Anti-Leu-12 (CD19) PE (Phycoerythrin)]). The performance is assessed through various studies. Below is a table summarizing the reported device performance and implicitly derived acceptance criteria based on equivalence:

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

• Comparative Performance Study (against predicate):
  • Sample Size: 205 normal donors and 87 AIDS/ARC patients.
  • Data Provenance: The study was conducted at "three external, geographically distinct sites." The specific countries are not mentioned, but the distributed nature suggests a multi-center study. The data is prospective as specimens were stained and analyzed during the study.
• Reproducibility Studies:
  • Sample Size: 10 normal donors for each of the three independent laboratories.
  • Data Provenance: Three independent laboratories (suggesting different locations, likely within the same country as the submitter, USA, but not explicitly stated). The data is prospective as samples were processed and stained for the study.
• Linearity Study:
  • Sample Size: Four normal donors.
  • Data Provenance: Not explicitly stated where the donors or testing took place, but implied as part of the overall development and testing by the submitter. The data is prospective.

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 to this device. The device is a diagnostic reagent for flow cytometry, which measures cell populations based on antibody binding. The "ground truth" for the comparative study is the measurement obtained by the predicate device and the clinical classification of the patients (normal donor vs. AIDS/ARC). For reproducibility and linearity, the ground truth is statistical consistency and expected values determined by dilutions and other analytical methods, not expert consensus on an image or clinical case.

4. Adjudication Method for the Test Set:

This information is not applicable. Adjudication methods (like 2+1, 3+1) are typically used in studies where human readers are making subjective diagnoses or classifications from images/data, and discrepancies need to be resolved. This study involves objective measurements from a flow cytometer.

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

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. MRMC studies are associated with evaluating the effectiveness of diagnostic tools where multiple human readers interpret cases. This study is comparing a new reagent's performance to an existing reagent using instrumental measurements.

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

Yes, the studies described are essentially a standalone performance evaluation of the Ortho-mune OKB19A reagent. The flow cytometer analyzes the stained cells, and the resulting data (percentage of CD19+ cells) is the output of the "algorithm" (the staining and detection process). Human involvement is in sample preparation, running the instrument, and data analysis, but the core measurement itself is automated and doesn't involve human interpretation of complex patterns in the way an AI algorithm for image analysis would. The performance is assessed purely on the device's ability to accurately identify and enumerate the target cells, comparing its output to a predicate device's output.

7. Type of Ground Truth Used:

• Comparative Performance: The ground truth was effectively the measurement obtained by the predicate device (Monoclonal Antibody Test for B Cells [Anti-Leu-12 (CD19) PE (Phycoerythrin)]) on the same samples. The clinical categorisation of "normal donor" and "AIDS/ARC patient" also serves as a clinical context for evaluating performance.
• Reproducibility Studies: The ground truth was based on the statistical expectation of consistent measurements when the same samples are tested multiple times (within-laboratory) and across different laboratories (between-laboratory). The "true" value for the percentage of CD19+ cells in the prepared samples was the reference point.
• Linearity Study: The ground truth was the expected values calculated by multiplying serial dilutions by the hematology analyzer-derived buffy coat lymphocyte count and the CYTORONABSOLUTE-derived lymphocyte subset percent positive.

8. Sample Size for the Training Set:

This information is not applicable as this is not an AI/Machine Learning device that requires a training set. The device is a monoclonal antibody conjugate; its performance is based on its biochemical properties and interaction with target cells.

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

This information is not applicable for the reason stated above.

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Ortho-mune OK-COMBO CD4-FITC/CD8-PE is intended for use in identification and enumeration of CD4+ and CD8+ human T lymphocytes in whole blood by flow cvtometry. The intended use is the same as the intended use of the predicate device. Simultest CD4/CD8 (Leu-3a/2a) commercially distributed by Becton Dickinson Immunocytometry Systems.

Ortho-mune OK-COMBO CD4-FITC/CD8-PE (OKT4A/OKT8) Monoclonal Antibody (Murine) is a blend of the individual purified monoclonal antibodies OKT4A and OKT8 conjugated to the fluorochromes fluorescein isothiocyanate and phycoerythrin respectively.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Test Set for Equivalence (Comparison with Predicate Device):

  • Sample Size: 190 normal donors and 83 AIDS/ARC patients (total 273 specimens).
  • Data Provenance: The study was conducted at "three external, geographically distinct sites." The countries of origin are not specified, but the use of "normal donors" and "AIDS/ARC patients" suggests clinical samples. The data is prospective, collected specifically for this study.

• Test Set for Reproducibility:

  • Sample Size: 11 normal donors. Samples from these donors were processed to create low, normal, and high relative percent CD4+ and CD8+ cells. Each sample was stained in replicates of 10.
  • Data Provenance: Not explicitly stated, but samples were processed and analyzed at "three independent laboratories." This implies the samples were real human whole blood specimens. The data is prospective.

• Test Set for Linearity:

  • Sample Size: 4 normal donors. Specimens were processed to produce samples with low, normal, and high numbers of lymphocyte subsets. Each sample was stained in triplicate.
  • Data Provenance: Not explicitly stated, but implies real human whole blood specimens. The data is prospective.

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

Not applicable. This device is an in vitro diagnostic reagent for flow cytometry, which measures cell populations. The "ground truth" for this type of device is the measurement obtained from the predicate device and the internal consistency/characteristics (reproducibility, linearity) of the new device itself. There are no human expert adjudicators for establishing a "ground truth" in the way one would for diagnostic imaging. The comparison is against an established method and assessed by statistical measures.

4. Adjudication Method for the Test Set

Not applicable. As described above, this is a quantitative measurement device, not an imaging or qualitative diagnostic device requiring expert adjudication. The comparison with the predicate device was based on statistical regression analysis and direct comparison of mean percentages and ranges.

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 is not an AI/imaging device that involves human readers or interpretation of complex cases. It is an in vitro diagnostic reagent that identifies and enumerates specific cell populations using flow cytometry.

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

Yes, in a sense. The "device" (reagent) is evaluated in a standalone manner by comparing its output (percentage of positive stained cells) directly against that of a predicate device and by assessing its intrinsic performance characteristics (reproducibility, linearity). The analysis is performed by a flow cytometer, and the interpretation of the results from the flow cytometer (i.e., the percentages) is then compared between the new reagent and the predicate reagent. There is no "human-in-the-loop performance" that would alter the quantitative output of the reagent and cytometer system itself.

7. The Type of Ground Truth Used

• For Equivalence Study: The "ground truth" was established by the predicate device's measurements (Simultest CD4/CD8). The study aimed to show that the new device's measurements were statistically equivalent to the predicate device's measurements.
• For Reproducibility and Linearity Studies: The "ground truth" was established based on internal consistency and expected biological behavior. For reproducibility, the ground truth is that repeated measurements of the same sample should yield similar results (low variance). For linearity, the ground truth is that the measured cell counts should scale proportionally with dilution.

8. The Sample Size for the Training Set

Not applicable. This device is a monoclonal antibody reagent used in flow cytometry, not a machine learning or AI model. Therefore, there is no "training set" in the context of algorithm development. Its performance is based on the inherent specificity and binding characteristics of the antibodies.

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

Not applicable, as there is no training set for this type of device.

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Ortho-mune OK-COMBO CD3-FITC/CD4-PE is intended for use in identification and enumeration of CD3+ and CD4+ human T lymphocytes in whole blood by flow cytometry. The intended use is the same as the intended use of the predicate device, Simultest CD3/CD4 (Leu-4/3a) commercially distributed by Becton Dickinson Immunocytometry Systems.

Ortho-mune OK-COMBO CD3-FITC/CD4-PE (OKT3/OKT4A) Monoclonal Antibody (Murine) is a blend of the individual purified monoclonal antibodies OKT3 and OKT4A conjugated to the fluorochromes fluorescein isothiocyanate and phycoerythrin respectively.

The provided text describes a 510(k) summary for the Ortho-mune OK-COMBO CD3-FITC/CD4-PE (OKT3/OKT4A) Monoclonal Antibody (Murine) device, which is intended for the identification and enumeration of CD3+ and CD4+ human T lymphocytes in whole blood by flow cytometry. The study aims to demonstrate substantial equivalence to a predicate device, Simultest™ CD3/CD4 Ortho-mune™ OK-COMBO (Leu™-4 / 3a) CD3-FITC/CD4-PE (OKT™3 /OKT4A) Monoclonal Antibody (Murine).

Here's a breakdown of the requested information based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by achieving a statistically significant correlation between the performance of the new device (Ortho-mune OK-COMBO CD3-FITC/CD4-PE) and the predicate device (Simultest CD3/CD4), as well as between different flow cytometers used with the new device. The benchmark for significance is a p-value (SL) of 0.0001, indicating a very high probability of correlation. The Pearson Product Moment Correlation Coefficient is the metric used to assess this.

Table 1: Acceptance Criteria and Reported Device Performance

Additional Information:

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

   • Primary Test Set: 202 normal donors and 86 AIDS/ARC patients.
   • Secondary Test Set (Cytometer Comparison): 17 normal donors.
   • Data Provenance: The text does not explicitly state the country of origin. It indicates "Whole blood specimens" were collected, implying prospective collection for the purpose of the study. It does not mention retrospective data.

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

   • This device is a diagnostic reagent for flow cytometry, which measures cell populations directly. The "ground truth" is established by the flow cytometer itself detecting the stained cells. There is no mention of human experts interpreting images or signals to establish a ground truth; rather, the "truth" is the quantitative measurement of stained cells.

3. Adjudication method for the test set:

   • Not applicable. The study compares the performance of two different monoclonal antibody reagents and two different flow cytometers by measuring the percentage of positive stained cells. This is a direct quantitative comparison, not one that requires adjudication by human readers.

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. This is a direct comparison of diagnostic reagents and flow cytometers, not an AI-based system involving human readers interpreting outputs.

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

   • Yes, in essence. The comparison is between the performance of two different reagents in identifying and enumerating cell populations using flow cytometry, which is an automated process of cell counting and characterization. The performance is measured directly by the instrument, without human interpretation of subjective data.

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

   • The ground truth is established by the quantitative measurement of cells positively stained by the predicate device's reagents (Simultest CD3/CD4). The study then evaluates if the new device's reagents produce statistically equivalent measurements. In the cytometer comparison, the ground truth for comparing the CytoronAbsolute to the FACScan is also the measurement performed by the predicate device on the FACScan. The underlying biological "ground truth" is the actual percentage of CD3+ and CD4+ T lymphocytes present in the whole blood samples, as identified by specific antibody binding.

7. The sample size for the training set:

   • Training sets are not mentioned. This type of study validates a specific reagent's performance against a legally marketed predicate device rather than training a machine learning model. The study evaluates the performance of the reagent on a test set (normal donors and AIDS/ARC patients).

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

   • Not applicable, as there is no mention of a training set in the context of machine learning. The study focuses on comparing the new device's performance to a predicate device.

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Ortho-mune OK-COMBO CD3-FITC/CD8-PE is intended for use in identification and enumeration of CD3+ and CD8+ human T lymphocytes in whole blood by flow cvtometry. The intended use is the same as the intended use of the predicate device(s), Ortho-mune OKT3 Monoclonal Antibody (Murine) FITC Conjugate, and Ortho-mune OKT8 Monoclonal Antibody (Murine) Phycoerythrin conjugate.

Ortho-mune OK-COMBO CD3-FITC/CD8-PE (OKT3/OKT8) Monoclonal Antibody (Murine) is a blend of the individual purified monoclonal antibodies OKT3 and OKT8 conjugated to the fluorochromes fluorescein isothiccyanate and phycoerythrin respectively.

This document describes the performance characteristics of the Ortho-mune™ OK-COMBO CD3-FITC/CD8-PE (OKT3/OKT8) Monoclonal Antibody (Murine) and its equivalence to predicate single-color reagents. Note: This document is from 1996 and uses terminology and study designs common for that era. There are no explicitly stated "acceptance criteria" in the format of pass/fail thresholds in this summary. Instead, the study aims to demonstrate "equivalence" through statistical comparisons and reproducibility. The document also does not describe an AI/algorithm-based device but rather a new diagnostic reagent. Therefore, sections related to AI-specific criteria (e.g., human-in-the-loop, AI vs. without AI assistance, training data) are not applicable.

Here's an analysis of the provided information:

1. Table of Acceptance Criteria and Reported Device Performance

As mentioned, explicit, quantitative acceptance criteria with pass/fail thresholds are not stated. Instead, the studies aimed to demonstrate equivalence to predicate devices and acceptable reproducibility and linearity. The reported device performance is presented as statistical comparisons and descriptive statistics.

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

Equivalence to Predicate Reagents Study:

• Sample Size: 199 normal donors and 77 AIDS/ARC patients. Total N=276.
• Data Provenance: Not explicitly stated, but likely from a US-based clinical setting as it's a 510(k) submission to the FDA. The data is prospective, collected for the purpose of this study.

Equivalence to Other Flow Cytometers Study:

• Sample Size: Ten normal donors (whole blood, EDTA).
• Data Provenance: Not explicitly stated, but likely from a US-based clinical setting, prospective.

Reproducibility Studies:

• Sample Size: Eleven normal donors (whole blood, EDTA).
• Data Provenance: Not explicitly stated, but likely from a US-based clinical setting, prospective. Conducted at three independent laboratories.

Linearity Study:

• Sample Size: Four normal donors (whole blood, EDTA).
• Data Provenance: Not explicitly stated, but likely from a US-based clinical setting, prospective.

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

This device is a reagent for flow cytometry, which directly identifies and enumerates cell populations. The "ground truth" for the test set is established by the measurements from the predicate devices (single-color reagents) which are considered the established method. There are no human experts "establishing ground truth" in the sense of image interpretation or diagnostic classification. The measurements are quantitative outputs from flow cytometers.

4. Adjudication method for the test set

Not applicable. This device provides quantitative measurements from a flow cytometer. The "ground truth" is derived from a comparative measurement against established methods (predicate reagents) or from internal consistency (reproducibility, linearity). There is no subjective human assessment requiring adjudication.

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 is not an AI/algorithm-based diagnostic device where human readers interact with AI. It is a laboratory reagent.

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

Not applicable. This is not an AI algorithm. Its performance is evaluated in a standalone manner against predicate reagents and for its intrinsic measurement characteristics (reproducibility, linearity) when used with a flow cytometer.

7. The type of ground truth used

The ground truth used for assessing the new dual-color reagent (Ortho-mune OK-COMBO CD3-FITC/CD8-PE) was primarily:

• Comparative Measurements: Measurements obtained from the predicate single-color reagents (Ortho-mune OKT3 Monoclonal Antibody FITC Conjugate and Ortho-mune OKT8 Monoclonal Antibody Phycoerythrin conjugate) for CD3+ and CD8+ cell percentages.
• Internal Consistency: For reproducibility and linearity studies, the ground truth is the expected statistical behavior (e.g., low coefficient of variation for reproducibility, R-value near 1 and slope near 1 for linearity with serially diluted samples or known concentrations).
• Comparison to other established flow cytometers: For the instrument comparison part of the study, the measurements from the Becton Dickinson FACScan and COULTER EPICS flow cytometers were used as a comparative benchmark for the ORTHO CYTORONABSOLUTE.

There is no pathology, expert consensus on subjective findings, or outcomes data used as ground truth in this submission for this specific device.

8. The sample size for the training set

Not applicable. This is not an AI/machine learning algorithm. There is no concept of a "training set" for this type of diagnostic reagent.

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

Not applicable. As this is not an AI/machine learning algorithm, there is no training set or ground truth established for it in that context.

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Ortho-Count Calibration Kit for ORTHO CYTORONABSOLUTE Laser Flow Cytometry System is intended to be used to calibrate and verify calibration of the absolute lymphocyte counting function of the ORTHO CYTORONABSOLUTE.

Ortho-Count Calibration Kit for ORTHO CYTORONABSOLUTE Laser Flow Cytometry System, contains a Calibrator Bead Suspension for absolute lymphocyte count calibration and Verifier Bead Suspensions (I, II and III) to verify accuracy of absolute count calibration. The Calibrator Bead Suspension is manufactured as known "events"/unit volume (i.e. the Calibration Number) in the form of microparticle beads suspended in a proprietary buffer. The size of the microparticles has been selected to emulate the range of size of leukocytes detected by the ORTHO CYTORONABSOLUTE under specified gating conditions. The Verifier Bead Suspensions (I, II and III), are composed of materials identical to the Calibrator Bead Suspension and collectively provide a range of particle bead concentrations. The target values chosen approximate values expected from patients with low (Verifier I), normal (Verifier II) and high (Verifier III) white blood cell counts, The Verifiers are used to verify accuracy of the absolute respectively. lymphocyte count calibration immediately following calibration and are also used as daily quality control verification that the ORTHO CYTORONABSOLUTE is in calibration. A properly calibrated instrument will provide absolute counts within + 10% of the labeled events/uL for each Verifier supsension. In the context of immune status monitoring, absolute cell count is defined as the number of cells per unit volume. The ORTHO CYTORONABSOLUTE uses precision stepper motors to deliver diluted sample to the instrument's flow cell at a constant rate. Since constant flow rate means movement of a fixed volume per unit time, analysis time determines the volume of sample analyzed. Calibration of the ORTHO CYTORONABSOLUTE consists of setting analysis time such that a volume corresponding to 1 uL of undiluted sample is examined. Ortho-Count Calibrator Bead Suspension, representing a known number of particles per unit volume (i.e. events/uL) at the same dilution as used for testing samples, is counted until its "Calibration Number" is reached; the instrument is set to this analysis time. In subsequent analyses events are to passage of the equivalent of 1 uL of undiluted sample the instrument flowcell. As a result of this calibration, sample results can be read in absolute count, i.e. "events"/uL.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

The core acceptance criterion for the Ortho-Count Calibration Kit is that a properly calibrated ORTHO CYTORONABSOLUTE instrument will provide absolute counts within ±10% of the labeled events/uL for each Verifier suspension.

Study Details

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

   • Table 1 (Comparison to Predicate Device): 10 donors. Data provenance not explicitly stated (e.g., country of origin), and it's not clear if it was retrospective or prospective.
   • Table 2 (Inter-laboratory Reproducibility): Verifier Bead Suspensions (I, II, and III) were used across four different ORTHO CYTORONABSOLUTE instruments located in different regions of the United States. The frequency or total number of measurements for establishing "Mean" values for each verifier is not specified, but it's likely prospective for this component.
   • Figure 1 (Consistency of Calibration/Cross-Calibration): 41 samples (whole blood panel). Provenance not explicitly stated beyond "different regions of the United States" for the instruments. The samples were handled "overnight at room temperature or shipped for next day delivery to each site," suggesting prospective collection for this study, though the source of the donors/patients is not specified.
   • Figure 2 (Direct vs. Calculated Absolute Counts): Data points for CD19, CD3+CD8+, CD3+CD4+, and Total CD3+. The total number of individual samples is not specified, but the regression analysis implies a substantial number of data points for these subsets. Provenance not explicitly stated.
   • Figure 3 (Quality Control Indicators): Counts/volume were measured on the three verifier suspensions twice per week over a period of 60 days for four ORTHO CYTORONABSOLUTE instruments.

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

   • The document does not explicitly state the number or qualifications of experts used to establish ground truth for the test sets. Instead, the ground truth is established through:
     • Comparison to a predicate device (Coulter JT2 calibrated with S-CAL Kit) (for Table 1).
     • Labeled 'events'/uL for the Verifier Bead Suspensions themselves, which are manufactured values (for Table 2 and Figure 3).
     • "Calculated from combined hematology and other flow cytometer/reagent results" (for Figure 2's comparative ground truth).

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

   • No adjudication method involving experts is described. The comparisons are quantitative measurements against established methods or known values.

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 MRMC comparative effectiveness study involving human readers (as in interpretation of images or complex data) was conducted. This device is a calibration kit for an automated instrument, not an AI diagnostic tool requiring human interpretation. Therefore, the concept of "human readers improve with AI" is not applicable here.

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

   • The study primarily focuses on the standalone performance of the calibration kit in ensuring the accuracy and reproducibility of the ORTHO CYTORONABSOLUTE instrument's absolute counting function. The ORTHO CYTORONABSOLUTE itself is an automated device, so its performance (when calibrated) is inherently "algorithm only" in terms of cell counting. The "human-in-the-loop" would be the technician operating the flow cytometer and applying the calibration kit.

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

   • Known Reference Values: For the Verifier Bead Suspensions, the ground truth is the "labeled events/uL," which are manufactured and accurately determined "events"/unit volume.
   • Predicate Device/Method: For the comparison of absolute lymphocyte counts (Table 1), the ground truth is established by a "Coulter JT2 calibrated using S-CAL Kit" which is the predicate device/method.
   • Combined Method: For Figure 2, the ground truth is established by "values calculated from separate flow cytometers and automated hematology analyzers."

7. The sample size for the training set:

   • The document does not describe a "training set" in the context of machine learning or AI. This is a calibration kit, and its performance is evaluated against established methods and internal consistency, not through an iterative training process for an algorithm.

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

   • As there is no described training set for an algorithm, this question is not applicable. The kit itself is manufactured with known characteristics (e.g., "known 'events'/unit volume" for the Calibrator Bead Suspension).

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ORTHO™ ImmunoCount Flow Cytometry System is intended to be used for lymphocyte immunophenotyping. Results may be reported as either percent positive cells, or as absolute counts of lymphocytes and lymphocyte subsets.

ORTHO ImmunoCount Flow Cytometry System consists of ORTHO CytoronAbsolute Laser Flow Cytometer, ImmunoCount II Software, ORTHO TRIO Monoclonal Antibodies for lymphocyte immunophenotyping, and Ortho-Count Calibration Kit for calibration and verification of system calibration.

Here's an analysis of the provided text, focusing on the acceptance criteria and study details for the ORTHO ImmunoCount Flow Cytometry System:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to a "predicate method" and the demonstration of linearity and reproducibility. The tables provided (TABLE A, B, C, D, E, F, G, H) present the performance data, which implicitly serves as the "reported device performance." Since explicit numerical acceptance criteria (e.g., "R-value > 0.95") are not stated, I will infer them from the data presented, particularly the R-values, slopes, and intercepts for comparability, and CVs for reproducibility. For comparability, "equivalent" means the values are close to the predicate. For reproducibility, "low CV" is the criterion. For linearity, an R-value close to 1.00 is the criterion.

The study demonstrates that the ORTHO ImmunoCount Flow Cytometry System meets its acceptance criteria by showing substantial equivalence to the predicate method for both normal and HIV-positive donors in percent positive cells and absolute counts. Furthermore, it exhibits excellent within- and between-laboratory reproducibility, stability over a 72-hour period post-collection, and strong linearity across a broad range of cell counts.

2. Sample Size and Data Provenance

• Comparability Study (Normal Donors):

  • Test Set Size (Percent Positive): 200 normal whole blood specimens.
  • Test Set Size (Absolute Counts): 151 normal whole blood specimens.
  • Data Provenance: Retrospective, collected from apparently healthy donors (44.5% male, 55.5% female, age 21-62 years) in the United States. Three geographically distinct clinical sites were used for absolute counts, and four for percent positive cells.

• Comparability Study (HIV-Antibody Positive Donors):

  • Test Set Size (Percent Positive): 119 HIV-antibody positive whole blood specimens.
  • Test Set Size (Absolute Counts): 89 HIV-antibody positive whole blood specimens.
  • Data Provenance: Retrospective, collected from HIV-antibody positive donors (88.1% male, 11.9% female, age 3- years; likely meaning 3 years and above, or the data has a typo for the lower bound) in the United States. Three geographically distinct clinical sites were used for absolute counts, and four for percent positive cells.

• Within-Laboratory Reproducibility: 5 normal whole blood specimens, tested in replicates of 10 at three independent laboratories.

• Between-Laboratory Reproducibility: 5 normal whole blood specimens, compared between three independent laboratories, tested in replicates of 10.

• Specimen Age Criteria: 64 whole blood specimens (34 normal, 30 HIV-antibody positive), tested at three external clinical sites.

• Linearity: 4 normal whole blood specimens, tested at Ortho Diagnostic Systems.

3. Number of Experts and Qualifications (for Ground Truth)

The documentation does not explicitly state the number or qualifications of "experts" used to establish the ground truth for the test set. Instead, the ground truth is established by the "predicate method," which consists of:

• FACScan™ Flow Cytometer with Simulset Software (Becton Dickinson)
• Simultest™ Monoclonal Antibody Immunophenotyping Reagents (Becton Dickinson)
• Coulter® JT2 Automated Hematology Analyzer (Coulter Electronics)
• Coulter T Series Automated Hematology Analyzer (Coulter Electronics)
• Argos Hematology Analyzer (ABX France)

These are established, FDA-cleared (or equivalent at the time) medical devices used in clinical laboratories. The "experts" in this context would be the trained laboratory personnel operating these predicate devices according to their standard operating procedures, rather than individual "expert adjudicators" in the sense of image interpretation.

4. Adjudication Method for the Test Set

No explicit adjudication method (like 2+1 or 3+1 consensus) is described. The "ground truth" is derived directly from the measurements of the predicate devices. The implicit "adjudication" is inherent in the established and validated performance of these predicate devices and the standard laboratory protocols used for their operation. Differences between the ImmunoCount system and the predicate are then analyzed statistically (e.g., linear regression, mean differences).

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

No MRMC comparative effectiveness study was done. This device is a flow cytometer system for quantitative measurements, not an AI-assisted diagnostic imaging device requiring human-in-the-loop performance evaluation. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" is not applicable here.

6. Standalone Performance

Yes, a standalone performance evaluation was done in the sense that the ORTHO ImmunoCount Flow Cytometry System's measurements were directly compared against the established predicate methods, as well as evaluated for its own reproducibility, specimen age stability, and linearity. It provides a direct measurement, and its results are compared to the predicate device's direct measurements. There isn't a "human-in-the-loop" component for its primary intended use, making its performance inherently standalone in its measurement function.

7. Type of Ground Truth Used

The ground truth used is based on measurements from established, predicate medical devices and reagents (flow cytometers, immunophenotyping reagents, and hematology analyzers) which represent the "traditional method" for lymphocyte immunophenotyping and absolute count determination. This can be considered a form of reference standard measurement from existing, accepted clinical methodology.

8. Sample Size for the Training Set

The document does not specify a separate "training set" or its size. This type of submission (a 510(k) for an instrument and reagent system) typically focuses on verification and validation studies using clinical samples, rather than machine learning model training. The development (calibration, optimization) of the ImmunoCount system itself would have involved internal testing and calibration, but a distinct "training set" as understood in AI/ML is not mentioned or implied.

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

As no explicit training set is mentioned in the context of AI/ML, this question is not directly applicable. If there were internal development/calibration data used, the ground truth would likely have been established similar to the predicate method for the validation studies, by running samples on established instruments to set targets for the new system's development.

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