(266 days)
T2Candida® 1.1 Panel and T2Dx® Instrument is a qualitative T2 Magnetic Resonance (T2MR®) assy for the direct detection of Candida species in K₂EDTA human whole blood specimens from patients with symptoms of, or medical conditions predisposing the patient to, invasive fungal infections. The T2Candida 1.1 Panel identifies five species of Candida and categorizes them into the following three species groups:
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- Candida albicans and/or Candida tropicalis
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- Candida parapsilosis
- Candida glabrata and/or Candida krusei 3.
The T2Candida 1.1 Panel does not distinguish between C. albicans and C. tropicalis. The T2Candida 1.1 Panel does not distinguish between C. glabrata and C. krusei.
The T2Candida 1.1 Panel is indicated for the presumptive diagnosis of candidemia. The T2Candida 1.1 Panel is performed independent of blood culture. Concomitant blood cultures are necessary to recover organisms for susceptibility testing or further identification.
The T2Candida positive and negative External Controls (T2Candida QCheck Positive Kit and the T2Dx QCheck Negative Kit) are intended to be used as quality control samples with the T2Candida 1.1 Panel when run on the T2Dx Instrument. These controls are not intended for use with other assays or systems.
The T2Candida 1.1 Panel and T2Dx Instrument is comprised of the T2Candida 1.1 Panel performed on the T2Dx Instrument. The T2Candida 1.1 Panel is a qualitative molecular diagnostic assay that employs a whole blood compatible PCR amplification followed by T2 magnetic resonance (T2MR) detection. The T2Candida 1.1 Panel is performed on the T2Dx Instrument which executes all steps after specimen loading. A K₂EDTA whole blood specimen is loaded onto the T2Candida 1.1 Sample Inlet, which is then placed on the T2Candida 1.1 Cartridge along with the T2Candida 1.1 Reagent Tray. The Reagent Tray contains the internal control, amplification reagent, enzyme and the probe-coupled superparamagnetic particles for each Candida target. Two milliliters of the blood specimen is transferred to the T2Dx Instrument where lysis of the red blood cells, concentration and lysis of the Candida cells and amplification of the Candida DNA takes place. Amplification products are detected by T2MR detection using species-specific probes which are attached to the superparamagnetic particles. The assay identifies Candida albicans and/or Candida tropicalis, Candida parapsilosis, and Candida glabrata and/or Candida krusei. The test does not distinguish between C. albicans and C. tropicalis. The test does not distinguish between C. glabrata and C. krusei
The provided text describes a 510(k) premarket notification for the T2Candida 1.1 Panel, aimed at amending labeling to include pediatric patients. The information focuses on analytical and clinical performance to demonstrate substantial equivalence to a previously cleared device.
Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:
1. A table of acceptance criteria and the reported device performance:
The document primarily focuses on demonstrating substantial equivalence by relying on previously obtained performance data and additional tests for pediatric populations and cross-reactivity. Explicit acceptance criteria for clinical performance are not directly stated in percentages (e.g., minimum sensitivity/specificity), but the summary indicates "acceptable performance" was demonstrated. The analytical acceptance criteria for cross-reactivity are defined for the new tests.
Table of Acceptance Criteria and Reported Device Performance
| Category | Acceptance Criteria (Implied/Stated) | Reported Device Performance |
|---|---|---|
| Clinical Performance (Pediatric) | Acceptable performance for detecting Candida albicans, Candida parapsilosis, Candida glabrata, and Candida krusei infection in pediatric patients. (Implied: performance comparable to adult studies and sufficient for clinical utility). | Sensitivity (PPA): Ranged from 50-100% in pediatric studies. |
| Specificity (NPA): Ranged from 97-99% in pediatric studies. | ||
| (Note: These ranges are from external peer-reviewed publications used to support the submission, and low prevalence of positive blood cultures (1.2%) was observed in these studies, which can impact PPA/NPA interpretations). | ||
| Analytical Cross-Reactivity | Cross-reactivity defined as an increase in T2 signal above the established cutoff for the Candida detection channel when tested at clinically relevant concentrations, requiring both amplification with Candida primers and detection with capture probes. (Acceptance: No cross-reactivity at clinically relevant concentrations). | Of 5 organisms tested at 10^6 CFU/mL, 2 (S. agalactiae, H. influenzae) showed some cross-reactivity initially. |
| Retesting at "clinically relevant concentrations" (100-1000 CFU/mL): | ||
| S. agalactiae: No cross-reactivity observed at 1000 CFU/mL, 100 CFU/mL, or 33 CFU/mL. | ||
| H. influenzae: No cross-reactivity observed at 1000 CFU/mL or 100 CFU/mL. (One instance of 1/3 positive at 100 CFU/mL was observed but not deemed cross-reactive after additional replicates). | ||
| N. meningitidis, S. mitis, L. monocytogenes: No cross-reactivity at 10^6 CFU/mL. | ||
| Internal Control | Internal Control (IC) must be valid for the test to be considered acceptable. (Implicit: Pass rate for IC under various conditions). | Valid for all cross-reactivity tests (3/3 or 6/6 depending on replicates). |
2. Sample sizes used for the test set and the data provenance:
- Clinical Performance (Pediatric):
- Sample Size: A total of 246 pediatric samples were evaluated across two peer-reviewed publications.
- Data Provenance: The data came from existing studies (peer-reviewed publications) where the T2Candida 1.1 Panel was utilized. The document does not specify the country of origin, but generally, such studies supporting FDA submissions would often include data from the US or other regions with comparable clinical practices. The studies were retrospective in the sense that they were "existing studies" identified and utilized for this submission, although the original data collection within those studies might have been prospective.
- Analytical Cross-Reactivity:
- Sample Size:
- Initial testing: 3 replicates per organism at 10^6 CFU/mL.
- For organisms showing initial cross-reactivity: Additional 6 replicates (from two additional sample preparations) at 10^6 CFU/mL, and 3 replicates at lower concentrations (1000 CFU/mL, 100 CFU/mL, 33 CFU/mL).
- Data Provenance: This appears to be prospective laboratory testing conducted specifically for this submission, as it's described as "Additional cross-reactivity testing was performed in this submission."
- Sample Size:
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Clinical Performance (Pediatric): The ground truth for this segment of the study was primarily established by blood culture results. The document does not mention the use of experts (e.g., radiologists) for establishing this ground truth, as it's a molecular diagnostic device measuring specific microbial presence. Blood culture is a laboratory-based gold standard for candidemia diagnosis.
- Analytical Cross-Reactivity: Ground truth for this was based on known spiked concentrations of the organisms and the inherent characteristics of the T2Candida 1.1 Panel's detection mechanism (T2 signal cutoff). No external human experts are mentioned for ground truth establishment here.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Clinical Performance (Pediatric): Not applicable. The ground truth was based on blood cultures.
- Analytical Cross-Reactivity: A form of adjudication was applied for cross-reactivity. If an organism demonstrated cross-reactivity at 10^6 CFU/mL, it was "further evaluated with additional replicates from two additional sample preparations." Furthermore, the rule for confirming cross-reactivity was: "Results were not considered cross-reactive if only one replicate demonstrated cross-reactivity." This implies a majority rule or consistency requirement rather than a specific expert consensus 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 device is a molecular diagnostic test for detecting Candida species directly from blood, not an imaging-based AI diagnostic. Therefore, a multi-reader multi-case study involving human readers and AI assistance is not relevant to this type of device.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, this is effectively a standalone device. The T2Candida 1.1 Panel (and T2Dx Instrument) runs the assay and provides results (positive/negative for specific Candida groups, or invalid). Its performance is evaluated intrinsically through its ability to detect the target organisms (clinical sensitivity/specificity) and avoid false positives/negatives (analytical cross-reactivity). While a clinician interprets the results, the device's diagnostic output itself (e.g., "Candida albicans/tropicalis detected") is generated by the algorithm/system without human intervention in the diagnostic process of reading the T2MR signals.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Clinical Performance (Pediatric): Primarily blood culture results.
- Analytical Cross-Reactivity: Known concentrations of spiked organisms in blood, with the "ground truth" for cross-reactivity being the absence or presence of specific amplification and detection events as defined by the assay's cutoffs.
8. The sample size for the training set:
- The document does not explicitly mention a "training set" in the context of machine learning, as this is a molecular diagnostic device with a defined mechanism (T2MR technology, PCR amplification) rather than a machine learning algorithm that learns from data. Its "training" is inherent in its design and optimization during development, validated by analytical and clinical studies. No specific sample size for "training" is provided in the submission summary.
9. How the ground truth for the training set was established:
- As above, "training set" and its associated ground truth establishment methods (e.g., expert labels for images) are not applicable in the typical AI/ML sense for this device. The development process for such molecular diagnostics involves extensive analytical characterization (e.g., limit of detection, inclusivity, exclusivity, precision studies) to define performance parameters and establish expected results, which serves a similar function to providing "ground truth" for the device's operational parameters.
§ 866.3960 Nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens.
(a)
Identification. A nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens is a qualitative in vitro device intended for the amplification, detection, and identification of microbial-associated nucleic acid sequences from patients with suspected bloodstream infections. This device is intended to aid in the diagnosis of bloodstream infection when used in conjunction with clinical signs and symptoms and other laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (limit of detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carryover, and cross contamination.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate.
(6) 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.
(7) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate.
(8) As part of the risk management activities performed as part of your 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.