(28 days)
The Cytovale IntelliSep test is a semi-quantitative test that assesses cellular host response via deformability cytometry of leukocyte biophysical properties and is intended for use in conjunction with clinical assessments and laboratory findings to aid in the early detection of sepsis with organ dysfunction manifesting within the first 3 days after testing. It is indicated for use in adult patients with signs and symptoms of infection who present to the Emergency Department. The test is performed on an EDTA anticoagulated whole blood sample.
The IntelliSep test generates an IntelliSep Index value that falls within one of three discrete interpretation bands based on the probability of sepsis with organ dysfunction manifesting within the first three days after testing. The IntelliSep test represents the probability of the clinical syndrome of sepsis and is intended to be used alongside other clinical information and clinical judgement. It does not identify the causative agent of infection and should not be used as the sole basis to determine the presence of sepsis. The IntelliSep test is intended for in vitro diagnostic use.
The Cytovale IntelliSep test is a short turn-around time (STAT) test, producing results in 10 minutes or less, to aid in the early detection of sepsis with organ dysfunction manifesting within the first 3 days after testing. It assesses the state of immune activation in patients with signs and symptoms of infection who present in the Emergency Department (ED).
The IntelliSep test is run on the Cytovale System, a laboratory benchtop analyzer depicted in Figure 1 and Figure 2.
To run a test, the laboratory operator transfers 100 uL of whole blood into the sample preparation tube which is then placed into the Cytovale System. The system automatically lyses red blood cells, and washes the purified leukocytes in a diluent, producing a total volume of approximately 1mL of prepared sample, which the operator then transfers to the IntelliSep cartridge for analysis on the Cytovale System. A microfluidic deformability cytometry technique is used to measure the biophysical properties of thousands of individual leukocytes in rapid succession. These properties have been shown to differ in quiescent white blood cell populations when compared to those in septic patients, enabling rapid assessment of the host response and the likelihood of having sepsis with organ dysfunction manifesting within the first 3 days after testing.
Based on these measurements, the test provides a single score, the IntelliSep Index (ISI), ranging from 0.1-10.0, stratified into three discrete interpretation bands (Band 2, Band 3) of increasing sepsis likelihood.
The provided document, K250513, focuses on a Special 510(k) submission for modifications to an already cleared device, the Cytovale IntelliSep test (K220991). As such, it does not detail a full clinical study with specific acceptance criteria and performance metrics for initial device clearance. Instead, it aims to demonstrate that the modifications made do not negatively impact the previously established performance of the device.
Therefore, the response below will describe the approach taken to prove the modifications meet the underlying performance requirements, rather than a new standalone clinical study with fresh acceptance criteria.
Key takeaway: The study proves that the modified device maintains identical analytical and clinical performance to the previously cleared device (K220991). The acceptance criteria, in this context, are implicitly tied to the performance claims and limitations established in the original K220991 clearance.
Acceptance Criteria and Study Proving Device Meets Criteria (for Modified Device)
Given that K250513 is a Special 510(k) for device modifications, the "acceptance criteria" here refer to demonstrating that the modified device performs identically to the original cleared device (K220991). The study's goal was to show non-inferiority and preservation of performance.
1. Table of Acceptance Criteria (Implicit) and Reported Device Performance
| Acceptance Criteria (based on K220991 performance) | Reported Device Performance (K250513) |
|---|---|
| Maintain identical analytical performance. | No performance differences observed compared to K220991 for Within Laboratory Precision, Reproducibility, and Healthy Reference Range. |
| Maintain identical clinical performance. | No performance differences observed compared to K220991 when re-processing data from the IntelliSep Clinical Validation Study (CV-CLN-007). |
| No new risks identified. | No new risks identified following risk assessment of modifications; successful software V&V, cybersecurity testing, and electrical safety/EMI/EMC testing. |
| No changes to labeled performance claims or limitations. | Confirmed. All performance claims and limitations remain as per K220991. |
| Accurate and valid internal quality control metrics. | Modifications to internal QC metrics refine clog detection and discern assay failures, without changing the core result calculation. Demonstrated to not impact performance. |
| Data integrity for remote log export function. | Confirmed data integrity between Cytovale System and external network location. |
| Robust cybersecurity for network connection. | Independent penetration testing demonstrated controls against physical and digital cyberattacks. |
| Electrical safety, EMC, EMI compliance. | Successfully demonstrated per IEC 60601-1-2:2014/AMD1:2020 and applicable IEC 61010-1:2010, AMD1:2016. |
2. Sample Sizes Used for the Test Set and Data Provenance
The document explicitly states that "raw assay videos from the following performance studies were processed on both the modified device (K250513) and the baseline device (K220991)." This indicates that existing previously collected data from these studies served as the test set.
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Test Set Data Provenance:
- IntelliSep Clinical Validation Study (CV-CLN-007): The original source of clinical data from K220991 clearance. The document does not specify the country of origin, but generally, clinical validation studies for FDA clearance are conducted in the United States or include diverse sites if international. It was a prospective study for the original clearance.
- Within Laboratory Precision (CLSI EP05-A3): Data from analytical precision studies.
- Reproducibility (CLSI EP05-A3): Data from analytical reproducibility studies.
- Healthy Reference Range (CLSI EP28-A3C): Data for establishing a healthy population reference.
- Sequestered Data Set: Processed on both devices for comparison. This implies a previously collected, retrospective dataset or a subset of data held separate from training/development.
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Sample Size for Test Set: The document does not specify the sample sizes for these re-analyzed datasets. It refers to the Decision Summary for K220991 for detailed performance claims and limitations, implying sample sizes for these studies would be found there. For a Special 510(k), the key is comparative performance on existing data, not necessarily new, large-scale clinical trials.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
The document does not explicitly state the number or qualifications of experts used to establish ground truth for the test set in the context of this Special 510(k) re-analysis.
However, for the original K220991 clinical validation study (CV-CLN-007), the ground truth for sepsis with organ dysfunction would have been established by clinical experts based on:
- Standard clinical definitions (e.g., Sepsis-3 criteria).
- Review of electronic health records, lab findings, clinical assessments, and patient outcomes by qualified physicians (likely intensivists, emergency medicine physicians, or infectious disease specialists).
- This process would have involved their clinical judgment and interpretation of a comprehensive patient profile.
4. Adjudication Method for the Test Set
The document does not describe an adjudication method for the test set used in this Special 510(k). This is because the study re-ran previously established data (raw assay videos) through the modified and unmodified systems and compared the device's output directly. The focus was on whether the device's results changed, not on re-evaluating the ground truth diagnoses.
For the original clinical validation study that established the ground truth (CV-CLN-007), it is highly likely that an adjudication process (e.g., by expert clinicians, 2+1 or 3+1 consensus on patient outcomes/diagnosis) was used to establish the gold standard for sepsis with organ dysfunction. However, this is not detailed in the K250513 document.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
No MRMC study was done or is described in this document. The IntelliSep test is an in vitro diagnostic (IVD) device that provides a quantitative index (IntelliSep Index) and an interpretation band. It is not an imaging AI system that aids human readers in interpretations. Its output is a score, not an image for human reading or analysis. Therefore, an MRMC study is not applicable to this type of device.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the primary evaluation for this device is standalone performance. The IntelliSep test is designed to generate an IntelliSep Index value and associated interpretation bands based on the biophysical properties of leukocytes. It's an automated measurement. For K250513, the core comparison was whether the modified algorithm/hardware produced the same ISI values and interpretation bands as the original algorithm/hardware when given the same raw data. The document explicitly states: "Raw assay videos from the following performance studies were processed on both the modified device (K250513) and the baseline device (K220991). The results were then directly compared to each other..." This confirms a standalone-like comparison of the device's output.
7. The Type of Ground Truth Used
For the foundational clinical performance validation (referenced from CV-CLN-007, originally for K220991), the ground truth for "sepsis with organ dysfunction manifesting within the first 3 days after testing" would have been established using expert consensus based on clinical assessments, laboratory findings, and patient outcomes data. This would align with standard clinical definitions of sepsis (e.g., Sepsis-3 criteria) and involved careful retrospective review of patient charts/records by clinicians and/or adjudication committees to determine the presence or absence of sepsis with organ dysfunction.
For the purpose of this Special 510(k), the "ground truth" was effectively the performance of the predicate device (K220991) on the re-analyzed data. The goal was to show that the modified device produced inputs/outputs identical to that ground truth.
8. The Sample Size for the Training Set
The document does not specify the sample size for the training set.
- The IntelliSep test's underlying algorithm (ISI calculation) and the deformability cytometry technique "remain unchanged from K220991." This suggests the core model was trained for the original K220991 submission.
- The modifications described in K250513 relate to software refinements (internal QC metrics, remote log export) and hardware changes (new IAM variant). These modifications would likely involve internal testing and verification/validation using previously established data or internal engineering samples, rather than a new "training set" in the machine learning sense, as the core algorithm itself was not re-trained.
- The comparison against a "sequestered data set" for internal quality control metrics indicates good machine learning practice, suggesting that if any internal model within the QC process was re-trained (which is not explicitly stated), this set would have been held out from that specific training.
9. How the Ground Truth for the Training Set was Established
Since the K250513 document does not describe new training, it relies on the previous K220991 submission. For the original development of the IntelliSep test (prior to K220991), the ground truth for training the algorithm would have been established through a similar process as the clinical test set: expert consensus based on clinical assessments, laboratory findings, and patient outcomes data according to established sepsis criteria. This clinical information would have been associated with the biophysical property measurements from the Cytovale system to enable the algorithm to learn the correlation between leukocyte deformability and sepsis severity/likelihood.
§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.
(a)
Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.
(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.
(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.
(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.
(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.
(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.
(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (
e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.