(341 days)
The SeptiCyte ® RAPID test is a gene expression assay using reverse transcription polymerase chain reaction to quantify the relative expression levels of host response genes isolated from whole blood collected in the PAXgene ® Blood RNA Tube. The SeptiCyte ® RAPID test is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infectionnegative systemic inflammation in patients suspected of sepsis on their first day of ICU admission. The SeptiCyte ® RAPID test generates a score (SeptiScore®) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infectionpositive systemic inflammation. SeptiCyte ® RAPID is intended for in-vitro diagnostic use on the Biocartis IdyllaTM System.
SeptiCyte RAPID is an in vitro diagnostic test for simultaneous amplification and detection of two RNA transcripts (PLA2G7 and PLAC8) using total RNA extracted from human blood. The test has been designed, manufactured, and validated for use on the Biocartis Idylla real-time PCR system. The SeptiCyte RAPID test is performed with an Idylla Cartridge, a single-use, disposable, multi-chambered fluidic cartridge that runs on the Biocartis Idylla System. In an automated fashion, all reaction steps take place within the cartridge, including sample extraction/purification, RT-qPCR for the detection and relative quantification of the two human mRNA targets PLAC8. PLA2G7. Test results (measured Cg values and calculated SeptiScore) are available in about 65 minutes.
The specimen used for the SeptiCyte RAPID is a sample of whole blood collected in a PAXgene blood RNA tube (FDA 510k number K042613). The cartridge contains all of the necessary reagents to perform RNA isolation from the sample.
SeptiCyte RAPID uses quantitative, real-time determination of the amount of each transcript in the sample based on the detection of fluorescence by the Biocartis Idylla qPCR instrument function. The cartridge includes the reagents for reverse transcription and PCR. Transcripts PLAC8 and PLA2G7 are amplified and quantified. These values are combined to produce the SeptiScore, which is interpreted and categorized into four discrete bands, which are associated with a sequentially higher likelihood of sepsis.
Here's a breakdown of the acceptance criteria and the study details for the Immunexpress, Inc. SeptiCyte RAPID device, based on the provided FDA 510(k) summary:
1. Acceptance Criteria and Reported Device Performance
The clinical studies for SeptiCyte RAPID had the following acceptance criteria for the primary endpoint:
- A monotonic increase in the probability of sepsis across the four SeptiScore interpretation bands.
- Non-overlapping 80% confidence intervals for the probability of sepsis between non-adjacent SeptiScore interpretation bands (i.e., between bands 1 and 3; and between bands 2 and 4).
Here's the performance reported using the Forced RPD Method (as it covers the full dataset and shows the trend across all bands):
| SeptiScore Interpretation Band | Acceptance Criteria 1: Monotonic Increase (Observed Probability of Sepsis) | Acceptance Criteria 2: Non-overlapping 80% Confidence Intervals (Observed Probability) |
|---|---|---|
| Band 1 (0 - 4.9) | 0.12 | (0.08 - 0.18) |
| Band 2 (5.0 - 6.1) | 0.24 | (0.18 - 0.3) |
| Band 3 (6.2 - 7.3) | 0.48 | (0.4 - 0.56) |
| Band 4 (7.4 - 15.0) | 0.80 | (0.74 - 0.84) |
Proof of Acceptance:
The reported device performance demonstrates:
- Monotonic Increase: The observed probabilities of sepsis (0.12, 0.24, 0.48, 0.80) clearly increase monotonically across the four bands, meeting the first criterion.
- Non-overlapping 80% Confidence Intervals:
- Band 1 (0.08 - 0.18) vs. Band 3 (0.4 - 0.56): The intervals do not overlap.
- Band 2 (0.18 - 0.3) vs. Band 4 (0.74 - 0.84): The intervals do not overlap.
This meets the second criterion.
The analysis using Consensus and Unanimous RPD methods also showed similar results, fulfilling the acceptance criteria.
2. Sample Size and Data Provenance for the Test Set
- Sample Size: N = 386
- N = 356 from retrospective studies
- N = 30 from a prospective study
- Data Provenance:
- Retrospective Study: Netherlands-based Molecular diagnosis And Risk Stratification of sepsis (MARS) clinical trial (NCT01905033)
- Retrospective Study: USA-based Validation of septic gene Expression Using SeptiCyte (VENUS) clinical trial (NCT02127502)
- Prospective Study: USA-based NEar PatienT MolecUlar TestiNg in Sepsis (NEPTUNE) clinical trial
3. Number of Experts and Qualifications for Ground Truth Establishment
- Number of Experts: Three-member expert panel.
- Qualifications of Experts: Not explicitly stated beyond "external three-member expert panel not involved in the care of the patients." It does not specify their medical specialty (e.g., critical care physicians, infectious disease specialists) or years of experience.
4. Adjudication Method for the Test Set
Three different methods of Retrospective Physician Diagnosis (RPD) were used:
- Consensus: Two or three RPD panelists agree that the patient is either sepsis or SIRS. Indeterminates are excluded.
- Unanimous: All three RPD panelists, as well as the consensus discharge evaluation of the site investigators, agree that the patient is either sepsis or SIRS.
- Forced: Applied to patients initially called "indeterminate" by RPD panelists. The panelists are then forced to make a consensus or unanimous call of sepsis or SIRS.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed. The device is an in vitro diagnostic (IVD) assay that provides a score to aid in diagnosis, not an imaging AI or a system designed to assist human readers in interpretation. Therefore, the question of human readers improving with AI vs. without AI assistance is not applicable in this context.
6. Standalone Performance Study
Yes, a standalone performance study was done. The entire clinical evaluation is based on the SeptiCyte RAPID test (algorithm only) generating a SeptiScore and its associated interpretation bands. The clinical studies aim to validate the device's ability to differentiate infection-positive (sepsis) from infection-negative systemic inflammation based solely on its output.
7. Type of Ground Truth Used
The ground truth used was expert consensus or retrospective physician diagnosis (RPD). This involved an external three-member expert panel reviewing clinical cases to determine whether a subject's clinical status was SIRS, sepsis, or indeterminate.
8. Sample Size for the Training Set
The document does not explicitly state a separate sample size for a training set. The clinical studies described (MARS, VENUS, NEPTUNE) were primarily for validation and 510(k) clearance of the already developed SeptiCyte RAPID test. It's common for gene expression assays to be developed using earlier research cohorts, but this document focuses on the validation of the specific device. The clinical studies might have been used for final validation and refinement of the SeptiScore cut-offs, but a distinct "training set" for the algorithm itself is not mentioned here.
9. How the Ground Truth for the Training Set Was Established
As a distinct training set is not explicitly detailed, the method for establishing its ground truth is also not described. However, given that the clinical validation ground truth was established by expert consensus/RPD, it is highly probable that any development or training earlier in the product lifecycle would have used similar methodologies.
§ 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.