TETRAONE SYSTEM FOR EPICS XL FLOW CYTOMETRY SYSTEMS AND CYTO-STAT TERTRACHROME CD45-FITC/CD4-RDI/CD8-ECD/CD3-PC5
Applicant
Coulter Corp.
Product Code
GKZ · Hematology
Decision Date
Jan 22, 1997
Decision
SESE
Submission Type
Traditional
Regulation
21 CFR 864.5220
Device Class
Class 2
Indications for Use
The tetraONE™ SYSTEM for EPICS® XL Flow Cytometry Systems and CYTO-STAT® tetraCHROME™ CD45-FITC/CD4-RD1/CD8-ECD/CD3-PC5 Monoclonal Antibody Reagent combines a four-color fluorescent monoclonal antibody reagent, four quality control reagents, an optional absolute count reagent, and software for automated analysis of lymphocyte populations in whole blood using EPICS® XL Flow Cytometry Systems with SYSTEM II™ Software. The system is intended “For In Vitro Diagnostic Use” and allows simultaneous identification and enumeration of total CD4+, total CD8+, total CD3+, dual-positive CD3+/CD4+ and dual-positive CD3+/CD8+ T lymphocytes percentages and absolute counts. The system also provides the T4/T8 ratio.
Device Story
System uses four-color fluorescent monoclonal antibody reagents (CD45/CD4/CD8/CD3) to label whole blood samples; analyzed via EPICS® XL Flow Cytometry System. Software performs automated lymphocyte gating and population enumeration; eliminates need for isotypic controls by automatically adjusting cursors based on peak separation. Output includes percentages and absolute counts of T-cell subsets and T4/T8 ratio. Used in clinical laboratory settings by trained technicians/pathologists. Provides rapid, automated immunophenotyping to assist clinicians in assessing immune status in patients with HIV, autoimmune disorders, or transplant recipients.
Clinical Evidence
Bench testing only. Accuracy evaluated using normal and abnormal (HIV, transplant, autoimmune) whole blood specimens (n unspecified, age 18-85). Compared against predicate reagents (CD3/T4, CD3/T8). Results showed equivalent identification/enumeration of T-cell subsets. Linearity confirmed via serial dilution of control cells. Precision (within-run and interlaboratory) demonstrated via CV and SD metrics. No clinical diagnostic outcomes reported.
Technological Characteristics
Four-color fluorescent monoclonal antibody reagent (CD45-FITC, CD4-RD1, CD8-ECD, CD3-PC5). Flow cytometry sensing principle using immunofluorescence. System includes automated software for gating and analysis. Operates on EPICS® XL Flow Cytometry Systems. Reagents are liquid-based.
Indications for Use
Indicated for in vitro diagnostic identification and enumeration of T lymphocyte subsets (CD3+, CD4+, CD8+, CD3+/CD4+, CD3+/CD8+) and T4/T8 ratio in whole blood. Applicable to adult populations (18-85 years) including normal individuals and those with conditions such as HIV, organ transplant, autoimmune disease, or abnormal white blood cell counts.
Regulatory Classification
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.
Special Controls
*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.”
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JAN 22 1997
K963263
COULTER
COULTER CORPORATION
P.O. BOX 169015
Miami, Florida 33116-9015 USA
Customer Service: (800) 526-7694
Product Information: (800) 526-6932
(305) 380-3800
(800) 327-6531
Coulter Corporation
Miami, Florida USA
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Coulter Electronics, Pty. Ltd.
Sydney, Australia
Coulter Electronics Ind. & Com., Ltda.
Rio de Janeiro, Brazil
Coulter Electronics of Canada, Ltd.
Burlington, Ontario, Canada
Coulter Electronics, Ltd.
Luton Bedfordshire, England
Coultronics France, S.A.
Margence, France
Coulter Electronics GmbH
Krefeld, Germany
Coulter Electronics (HK), Ltd.
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Coulter K.K.
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Auckland, New Zealand
Coulter Electronics Salsa of 2011, Inc.
San Juan, Puerto Rico
Coulter Electronics, Ltd.
Imanac, Turkey
Coulter Electronics, Ltd.
Imanac, Turkey
Coulter Electronics, Ltd.
Imanac, Turkey
Date: August 16, 1996
Title: Summary of Safety and Effectiveness Information For 510(k) Premarket Notification
Product: tetraONE™ SYSTEM for EPICS® XL Flow Cytometry Systems and CYTO-STAT® tetraCHROME™ CD45-FITC/CD4-RD1/CD8-ECD/CD3-PC5 Monoclonal Antibody Reagent
Company: Coulter Corporation
11800 SW 147 Avenue
Miami, FL 33196-2500
Contact: Dr. Marion S. Gaide (M/C: 31-B06)
Senior Regulatory Affairs Specialist
Corporate Regulatory Affairs
Telephone: 305-380-2594
Common or Usual or Classification Name: Lymphocyte Immunophenotyping System with Reagents and Software for Flow Cytometry
Product Classification: Product Code: GKZ; C.F.R. Section: 864.5220; Classification Panel: Hematology and Pathology Devices; Device Class: II
Intended Use: The tetraONE™ SYSTEM for EPICS® XL Flow Cytometry Systems and CYTO-STAT® tetraCHROME™ CD45-FITC/CD4-RD1/CD8-ECD/CD3-PC5 Monoclonal Antibody Reagent combines a four-color fluorescent monoclonal antibody reagent, four quality control reagents, an optional absolute count reagent, and software for automated analysis of lymphocyte populations in whole blood using EPICS® XL Flow Cytometry Systems with SYSTEM II™ Software. The system is intended “For In Vitro Diagnostic Use” and allows simultaneous identification and enumeration of total CD4+, total CD8+, total CD3+, dual-positive CD3+/CD4+ and dual-positive CD3+/CD8+ T lymphocytes percentages and absolute counts. The system also provides the T4/T8 ratio.
Substantial Equivalence: 510(k) Premarket Notification: K922745
CYTO-STAT®/COULTER CLONE® CD3(IgG1)-FITC/T4-RD1
Monoclonal Antibody Reagent
510(k) Premarket Notification: K922744
CYTO-STAT®/COULTER CLONE® CD3(IgG1)-FITC/T8-RD1
Monoclonal Antibody Reagent
Product Differences: CD45/CD4/CD8/CD3, CD3/T4 and CD3/T8 are essentially identical with respect to features and principles of operation. The new and comparator systems use the same, well-established, state-of-the-art technologies of immunophenotyping with monoclonal antibodies and flow cytometry to measure cellular components in whole blood via immunofluorescence analysis. Further, the intended use of the new and comparator systems is the same. Also, each liquid reagent allows simultaneous identification and enumeration of more than one lymphocyte population in a single specimen using a single reagent.
Science Serving Humanity
4232216-E R 11-94
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The new and comparator systems differ in only a few respects. One difference results from the more advanced software for the new tetraONE™ SYSTEM. The tetraONE™ SYSTEM software is designed to further simplify flow cytometric analysis by increasing automated modes of operation and the accuracy, precision and reliability of results. The new and comparator systems also differ in that the new tetraONE™ SYSTEM does not require an isotypic control for monitoring and adjusting for non-specific and non-targeted monoclonal antibody binding to irrelevant cellular populations. The tetraONE™ SYSTEM software monitors and adjusts for such binding by automatically placing cursors based on the separation of positive and negative peaks.
There are two differences between the reagents.
a. Lymphocyte Gating: The CD45/CD4/CD8/CD3 reagent contains a monoclonal antibody, CD45, to identify a lymphocyte gate to allow CD3+, CD4+, CD8+, dual-positive CD3+/CD4+ and dual-positive CD3+/CD8+ measurements. In contrast, CD3/T4 and CD3/T8 require a separate reagent, Mo2-RD1/KC56 (T-200)-FITC, for this purpose.
b. Fluorescent Labeling:
CD45/CD4-RD1/CD8-ECD/CD3-PC5:
CD45: FITC (Fluorescein Isothiocyanate); CD4: RD1 (Phycoerythrin); CD8: ECD (Phycoerythrin-Texas Red); CD3: PC5 (Phycoerythrin-Cy5).
CD3/T4 and CD3/T8:
CD3: FITC (Fluorescein Isothiocyanate); T4: RD1; T8: RD1 (Phycoerythrin).
Product Testing: Product testing to assess the performance of CD45/CD4/CD8/CD3 is described below. Studies were designed in line with instructions for use given in the tetraONE™ SYSTEM Guide, Package Inserts, Product Manuals, and performance specifications. Specimens were assayed with CD3/T4 and CD3/CD8 for comparison purposes. The results of product testing demonstrated that CD45/CD4/CD8/CD3 met all performance specifications and provided mature T (CD3+), inducer T (CD4+; CD3+/CD4+) and suppressor/cytotoxic T (CD8+; CD3+/CD8+) lymphocyte values comparable to those of CD3/T4 and CD3/T8.
1. Accuracy:
Normal and abnormal (e.g., Human Immunodeficiency Virus, organ transplant, autoimmune disease, low white blood cell count) 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. Specimens were divided, processed as lysed preparations and assayed in parallel with CD45/CD4/CD8/CD3, CD3/T4 and CD3/T8. The CD3+, CD4+, CD8+, CD3+/CD4+ and CD3+/CD8+ percentages expressed in terms of the total lymphocyte count and absolute counts (cells/μL) were determined with EPICS® XL-MCL flow cytometers gated on lymphocytes. White blood cell counts and 5-part differentials were obtained for all specimens. CD3/T4 and CD3/T8 values were corrected for lymphocyte purity (Lymphocyte Gate Limits: lymphocyte recovery ≥ 90%; lymphocyte purity ≥ 85%).
Results analyzed in terms of minimums, maximums, means ± 1 SD, confidence intervals with 95% limits, regression and correlation analyses, and analyses of variance demonstrated that CD45/CD4/CD8/CD3, CD3/T4 and CD3/T8 identify and enumerate essentially identical numbers of the targeted lymphocytes in whole blood specimens.
2. Linearity:
Three replicate measurements were made on a concentrated COULTER™ Cyto-TROL™ Control Cells sample serially diluted to achieve a range of CD3+, CD4+ (CD3+/CD4+) and CD8+ (CD3+/CD8+) lymphocyte concentrations. Samples were assayed with CD45/CD4/CD8/CD3 and analyzed on an EPICS® XL-MCL flow cytometer gated on lymphocytes. Values were expressed in terms of absolute counts (cells/μL).
Results analyzed in terms of regression and correlation analyses for recovered versus expected absolute counts demonstrated linearity of the assay.
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3. Within Run (Intralaboratory) Precision:
Ten replicate measurements were made for each of three levels of CD3+, CD4+ (CD3+/CD4+) and CD8+ (CD3+/CD8+) lymphocyte concentrations using a COULTER EPICS® XL-MCL flow cytometer gated on lymphocytes. Levels were obtained by selective depletions of a normal whole blood specimen and assayed with CD45/CD4/CD8/CD3. Values were expressed in terms of % of the total lymphocyte count.
Results analyzed in terms of mean ± 1 SD and CV demonstrated Within Run (Intralaboratory) Precision of the assay.
4. Interlaboratory Precision:
Ten replicate measurements were made on the same day using different laboratories and EPICS® XL-MCL flow cytometers. All measurements were made on a single normal whole blood specimen divided and assayed with CD45/CD4/CD8/CD3. Values were expressed in terms of % of the total lymphocyte count.
Results analyzed in terms of mean ± 1 SD and CV demonstrated Interlaboratory Precision of the assay.
Marion S. Gaide, Ph.D.
Senior Regulatory Affairs Specialist
Corporate Regulatory Affairs
August 16, 1996
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Part 1 — Search, results, and everyday workflows 16 min
Part 2 — Embeddings: the galaxy map 3 min
1. Search: exact and fuzzy
Type a phrase like "coronary artery calcification" into the search box. You get two kinds of results. Exact results match the literal phrase — prefix searches work ("coronary artery calcificati") but suffix searches do not. Fuzzy results match on the meaning and intent of your phrase rather than the exact words, and are sorted by relevance score. Hover over the Exact or Fuzzy badge on any row to see exactly why it matched.
Use the checkboxes above the results to narrow: SaMD keeps only software-only devices, AI / ML keeps only devices with AI.
Exact vs. fuzzy search: what's the difference?
Exact matches on the literal phrase (prefix search works, suffix does not). Fuzzy matches on the meaning and intent of the phrase rather than the exact words. Hover over the badge on any row to see why it matched.
You search "coronary artery calcification" and want only software devices with AI. What two filters do you apply?
Narrow by SaMD (software-only devices), then narrow by AI/ML (devices with AI).
2. The results table
Scroll right in the results table. The intended use is extracted for you — no need to open the PDF. The device story gives a high-level snapshot of what the device does and how it's used. The AI Performance sub-table shows each output name, acceptance criteria, observed values, and development/test dataset descriptions — the same format Innolitics uses for regulatory strategy outputs, and the fastest high-level fingerprint of an AI device. It is AI-generated but has been very reliable in practice.
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Scroll right in the search results table. The intended use column is extracted for you; no need to dig into the 510(k) summary PDF.
What does the AI Performance sub-table show, and why is it useful?
Output name, acceptance criteria, observed values, development dataset description, and test dataset description. It's the same format we use for regulatory strategy output and Fast 510(k) input, and the fastest high-level fingerprint of an AI device. AI-generated but reliable in practice.
3. Judging fuzzy relevance
Fuzzy results trail off in relevance as you scroll. Use three signals to decide how far down to go: the fuzzy badge explanations, the intended use column, and whether your target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, you're past the relevant zone. A top hit with a low score (~0.4) and a stretched explanation is a hint the closest predicates are far away — the project may be headed for De Novo. Note the fuzzy search is a pattern match: it doesn't handle negation ("not") well, and hardware devices can appear — filter by SaMD/AI ML to cut them.
How do you judge how far down fuzzy search results to go?
Use the relevancy signals: the fuzzy badge explanations, the intended use column, and whether the target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, results are trailing off in relevancy.
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Reading rule for every project: how many summaries do you read in full?
At least the three most relevant 510(k) or De Novo summaries, in full. After that, use targeted chat questions to confirm your memory quickly. The tool supports this professional habit — it doesn't replace it.
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Select multiple rows in the results table (aim for under ~10), then open the PDF Viewer tab. Ask one question — it goes to all selected devices in parallel, each with citations. This is the fastest way to compare and contrast devices: training data, PCCP scope, how they handled adding new scanners, and so on.
What does the side-by-side PDF viewer mode do?
Select multiple devices, open the PDF viewer tab, and ask one question (e.g., "Describe the training data"). It queries all selected devices simultaneously with citations, so you can compare and contrast quickly.
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With rows selected, go to the Collections tab and create a labeled collection (e.g., "Cobb Angle Project"). Reload that selection any time — before a client call, pull up the collection and ask questions across all of its devices at once.
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What can you do from the regulations tree view?
Browse product codes and regulation numbers, read the identification text and special controls, browse sibling product codes, open device PDFs on the right, and search by product code or regulation number at the top of the tree.
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Click Show Chart and segment by regulation number (or product code) to see which regulations dominate your result set. Clicking a regulation takes you into the regulations tree. Great for spotting that most matches are, say, hardware laparoscopic devices — a cue to go back and filter.
How do you see which regulations dominate a search result set?
Click "Show Chart" and segment by Regulation Number. Clicking a regulation takes you to the regulations tree.
9. The predicate graph
Open the Predicates tab for a family-tree view of predicate relationships. Click a node to trace its parents and children; selections from search carry over pre-selected. Commonly predicated devices are worth reading — a lot of people predicated them for a reason. The visual lineage is also handy on client calls, e.g. to show how a predicate family evolved and justify why your predicate still holds.
In the predicate graph, why are commonly predicated devices worth reading?
A lot of people predicated them for a reason. Clicking a node traces parents and children, and selections from search carry over pre-selected.
10. Embeddings: the galaxy map
The Embeddings tab plots every matching document in a 2-D "galaxy map" where semantically similar devices cluster together. Hover or click clusters to explore, and let AI label the clusters for you. Embeddings beat product codes for grouping: two devices can carry different product codes (LLZ vs. QIH) yet do the same thing — the embedding captures the meaning of the intended use and device story. This is also exactly how retrieval-augmented generation (RAG) works under the hood, and it makes a great visual on client calls.
Try it yourself
Head to the search page and work through a few of these AI/ML fuzzy searches to build intuition: perivascular fat on CT · aortic valve calcification opportunistic screening on noncontrast CT · breast cancer prediction on digital pathology slides · autism detection · gestational age prediction · a hearing aid that can also detect a pulse · foundation model based analysis of ECG · large language models · penetration test. Watch how the relevance scores, intended use, and AI Performance tables tell you when results stop being meaningful.
