(83 days)
The reticONE™ SYSTEM for EPICS® XL™ Flow Cytometry Systems combines a reagent kit consisting of a Coriphosphine-O dye and a Biological Calibrator, and software for automated analysis of reticulocytes in whole blood using EPICS® XL™ Flow Cytometry Systems with SYSTEM II™ Software. The system is intended "For In Vitro Diagnostic Use" and allows identification and enumeration of reticulocyte percentage and absolute count.
The reticulocyte count is diagnostically useful in discriminating between normal erythropoiesis. It can be useful in the diagnosis or detection of anemal hemorthaging, hemoglobinopathies and certain nutritional or vitamin deficiencies. Decreased or defective red cell production may result in a lower reticulocyte count such as in aplastic anemias. Elevated reticulocyte counts may be observed in clinical conditions where red cell destruction is increased (for example, hemolytic anemias and hypersplenism) or where there is increased red cell production (for example, erythropoietin drug therapy and a response to treated anemia).
Since the kidneys are a primary source of erythropoietin (a hormone that regulates erythroid development), the reticulosyte count is also affected in individuals with renal disease. In cases of renal atrophy, the reticulocyte count will be decreased. In cases of malignancy or hypersplenism, the reticulocyte count will be elevated.
Reticulocyte counts are also used as an indicator of bone marrow recovery following intensive or a bone marrow transplantation. Increased reticulocyte counts in these patients are indicative of bone marrow regeneration.
The reticONE™ SYSTEM for EPICS® XL™ Flow Cytometry Systems combines a reagent kit consisting of a Coriphosphine-O dye and a Biological Calibrator, and software for automated analysis of reticulocytes in whole blood using EPICS® XL™ Flow Cytometry Systems with SYSTEM II™ Software. The system is intended "For In Vitro Diagnostic Use" and allows identification and enumeration of reticulocyte percentage and absolute count.
The reticONE™ SYSTEM for EPICS® XL™ Flow Cytometry Systems has demonstrated its performance through a series of studies. The acceptance criteria and device performance are outlined below, along with details regarding the study methodologies.
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Test/Metric | Acceptance Criteria | Reported Device Performance | Study Supporting Performance |
|---|---|---|---|---|
| Stability | Stored (Unstained) Whole Blood Specimens (72 Hours at 2-8 °C) | Reticulocyte percentage and standard deviation demonstrate stability over time. | Stability demonstrated, meeting claims for stored unstained whole blood. | Stability Studies (1.a) |
| Stored (Unstained) Whole Blood Specimens (6 Hours at 20-25 °C) | Reticulocyte percentage and standard deviation demonstrate stability over time. | Stability demonstrated, meeting claims for stored unstained whole blood. | Stability Studies (1.b) | |
| Stored Prepared (Stained) Samples (6 Hours at 20-25 °C) | Reticulocyte percentage and standard deviation demonstrate stability over time. | Stability demonstrated, meeting claims for prepared stained samples. | Stability Studies (1.c) | |
| Carryover | Carryover Percent | Minimal carryover compared to Flow Cytometer Specification. | Minimal carryover demonstrated. | Carryover Study (2) |
| Linearity | Range of 0.2% to 12.5% reticulocytes | Linearity demonstrated for recovered vs. expected reticulocyte percentage. | Linearity demonstrated over the defined (reportable) range. | Linearity Study (3) |
| Precision | Within Run (Intralaboratory) Precision | Reproducible measurements (mean reticulocyte percentage, SD, %CV). | Reproducibility demonstrated for all levels. | Precision Study (4.a) |
| Interlaboratory Precision | Reproducible measurements across different labs (mean reticulocyte percentage, SD, %CV). | Reproducibility demonstrated across laboratories. | Precision Study (4.b) | |
| Site Precision | Reproducible measurements (mean reticulocyte percentage, SD, %CV). | Reproducibility demonstrated. | Precision Study (4.c) | |
| Accuracy | Comparison to Retic-COUNT™ (Predicate Device) | Identifies and enumerates comparable numbers of reticulocytes. | Clearly demonstrated comparable identification and enumeration of reticulocytes to Retic-COUNT™. | Accuracy Study (5) |
2. Sample Sizes Used for the Test Set and Data Provenance
- Stability Studies (1.a): 3 normal whole blood specimens. These were likely prospective as they involved specific handling and analysis over defined time points. The country of origin for these specimens is not explicitly stated but can be inferred as the USA, given the company's location and FDA submission.
- Stability Studies (1.b): 10 normal whole blood specimens. Similar to above, likely prospective and from the USA.
- Stability Studies (1.c): 5 normal whole blood specimens. Similar to above, likely prospective and from the USA.
- Carryover Study (2): Not explicitly stated as "specimens" but "a single sample" was prepared for each of the High Level and Low Level Retic-Chex control products. These are commercial control products, not patient specimens.
- Linearity Study (3): 2 whole blood specimens, serially diluted to create 10 data points. Likely prospective and from the USA.
- Precision Study (4.a, 4.c): "Sample [normal or abnormal] whole blood specimens" for each of five levels of reticulocyte percentage. The exact number of specimens is not specified beyond "for each of five levels."
- Precision Study (4.b): Samples from a single normal whole blood specimen.
- Accuracy Study (5): "Normal and abnormal whole blood specimens were collected from geographically diverse populations of males and females unselected as to race and ranging in age from 18 to 85 years." The exact number of specimens is not specified. The provenance is described as "geographically diverse populations," implying a broader reach, but still likely within the USA given the submission context. These were likely prospective as they involved parallel processing and assaying with two systems.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The ground truth in these studies is primarily established by a predicate device (Retic-COUNT™) and established laboratory methods and controls (e.g., NCCLS Document H44-A). No human experts are explicitly mentioned as establishing a "ground truth" for individual cases in the way that, for example, a radiologist would interpret an image. The performance of the reticONE™ SYSTEM is compared against the established performance of the predicate device and expected biological/analytical behavior.
4. Adjudication Method for the Test Set
Not applicable. As described above, the ground truth is primarily based on comparison to a predicate device or established analytical control materials/standards, not on human interpretation that would require adjudication.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, an MRMC comparative effectiveness study was not done. The studies focused on the analytical performance of the device itself (stability, linearity, precision, carryover) and its concordance with a predicate device, not on how human readers' performance might improve with or without AI assistance. This device is an automated reticulocyte analysis system, replacing manual microscopy, rather than an AI-assisted diagnostic tool for human interpretation.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies conducted demonstrate the standalone performance of the reticONE™ SYSTEM. The system is described as combining "a reagent kit...and software for automated analysis of reticulocytes." The performance metrics reported (stability, linearity, precision, accuracy) are inherent to the automated system and its reagents/software. There is no mention of a human-in-the-loop component for the analysis process itself as part of these performance studies.
7. The Type of Ground Truth Used
The primary type of "ground truth" used is:
- Predicate Device Performance: The Retic-COUNT™ system (K872166 and K880636) served as the reference for accuracy, with the reticONE™ SYSTEM demonstrating comparable results.
- Established Analytical Methods/Controls: The studies refer to NCCLS Document H44-A for procedures like carryover testing. Commercial control products (e.g., Streck Laboratories, Inc® multiple-level Reticulocyte Control product, Retic-Chex) were also used.
- Expected Physiological/Analytical Behavior: For linearity, serial dilutions were used to achieve a "defined range of expected reticulocytes." Stability was assessed against the expectation that measurements would not significantly change over time under specified conditions.
8. The Sample Size for the Training Set
No explicit training set is mentioned in the provided document. As a medical device that automates a laboratory assay rather than a machine learning model that needs to be "trained" on data, the concept of a training set as understood in AI/ML is not directly applicable here. The system's "training" would be more akin to software development and calibration during its design and manufacturing.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as no training set (in the AI/ML sense) is described. The system's underlying principles are based on established flow cytometry technology, fluorescent staining, and standard hematological analysis.
§ 864.5220 Automated differential cell counter.
(a)
Identification. An automated differential cell counter is a device used to identify one or more of the formed elements of the blood. The device may also have the capability to flag, count, or classify immature or abnormal hematopoietic cells of the blood, bone marrow, or other body fluids. These devices may combine an electronic particle counting method, optical method, or a flow cytometric method utilizing monoclonal CD (cluster designation) markers. The device includes accessory CD markers.(b)
Classification. Class II (special controls). The special control for this device is the FDA document entitled “Class II Special Controls Guidance Document: Premarket Notifications for Automated Differential Cell Counters for Immature or Abnormal Blood Cells; Final Guidance for Industry and FDA.”