(245 days)
RAPIDEC® CARBA NP is a phenotypic (colorimetric) in vitro diagnostic test for the qualitative detection of carbapenemase enzymes in Enterobacteriaceae and Pseudomonas aeruginosa colonies that have elevated MIC values to any carbapenem. RAPIDEC® CARBA NP is performed on pure colonies grown on non-selective sheep blood agar culture media.
RAPIDEC® CARBA NP is intended as an aid in the prevention and control of infection caused by carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa.
RAPIDEC® CARBA NP is not intended to guide or monitor the treatment for these bacterial infections. A negative result does not preclude the presence of carbapenemase enzymes. The ability of RAPIDEC® CARBA NP to detect carbapenemase enzymes encoded by genetic markers other than KPC, NDM, OXA-48, VIM, and IMP has not been established. RAPIDEC® CARBA NP testing should be used in conjunction with other laboratory tests including antimicrobial susceptibility testing.
The RAPIDEC® CARBA NP strip is composed of 5 wells prepared with premeasured portions of the necessary substrates for the reactions. In addition, the kit contains the necessary accessories for performing the test.
In order to rehydrate the dry reagents and initiate the reactions, wells a, b and c are filled with 100 uL of API Suspension Medium (purified water). The strip is left at room temperature for 4-10 minutes to allow the dry reagents to reconstitute in the wells. The bacterial inoculum suspension is prepared in well c until the turbidity equals well b. Well c contains the lysis buffer. In order to achieve lysis of the inoculum suspension, which enables the extraction of the enzyme, the strip is left at room temperature for additionally 30 minutes.
As the next step, 25 uL of the lysed inoculum suspension is transferred to wells d and e and 25 µL from well a (phenol red solution) is also transferred to wells d and e. The strip is incubated for 30 minutes at 33-38°C to allow for the hydrolysis to occur and change in color of the phenol red solution in case of presence of a carbapenemase enzyme. The initial reading is performed after 30 minutes of incubation. In case of a negative or doubtful reaction, the strip is re-incubated for an additional 1 hour and 30 minutes before performing the final reading.
The hydrolysis acidifies the medium which results in the change in color of the pH indicator. Reading is performed by comparing the colors in wells d and e. The test is positive when a significant variation in color is observed between the two wells. For example, the control well is red and the test well has changed to yellow.
The document provided describes the RAPIDEC® CARBA NP device, an in vitro diagnostic test for the qualitative detection of carbapenemase enzymes. This is a 510(k) submission, meaning the manufacturer is demonstrating that their new device is substantially equivalent to a legally marketed predicate device, rather than proving its safety and effectiveness de novo. Therefore, the study focuses on establishing performance characteristics compared to a reference method and demonstrating substantial equivalence.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. A table of acceptance criteria and the reported device performance
The document implicitly defines acceptance criteria through the reported analytical and clinical performance. While explicit numerical acceptance criteria (e.g., "sensitivity must be >X%") are not laid out in a dedicated table, the "Results of QC testing...met the pre-defined acceptance criteria (≥95% agreement)" suggests this was a criterion for analytical performance. For clinical performance, the reported agreement percentages themselves serve as the outcome against which an implicit set of criteria would have been measured.
Here’s a summary of the performance characteristics:
Acceptance Criteria (Implied) and Reported Device Performance for RAPIDEC® CARBA NP
| Category | Performance Metric / Criterion (Implied/Explicit) | Reported Device Performance |
|---|---|---|
| Analytical Performance | ||
| Quality Control | ≥95% agreement with expected results for QC strains. | Met. "The results of QC testing with RAPIDEC® CARBA NP met the pre-defined acceptance criteria (≥95% agreement) when compared to the expected results as determined for the recommended QC strains." |
| Analytical Reactivity | Detection of carbapenemase producers (Sensitivity). No explicit numerical criterion, but 100% detection is the ideal. | 100% (43/43) for 43 known carbapenemase producers (KPC, NDM, OXA-48, VIM, IMP and Pseudomonas aeruginosa) at the final 2-hour read. |
| Cross-reactivity | Specificity for non-carbapenemase producing strains. No explicit numerical criterion. | Overall: |
- 97.9% (91/93) at 30 minutes (2 false positives).
- 93.6% (87/93) at 2 hours (6 false positives).
For Intended Organisms (Enterobacteriaceae & P. aeruginosa): - 100% (67/67) at 30 minutes.
- 98.5% (66/67) at 2 hours (1 false positive: AmpC producing Morganella morganii). |
| Agar Compatibility | No significant differences in performance when using different culture media (Trypticase Soy agar + 5% sheep blood (TSS) vs. Columbia agar + 5% sheep blood (COS)). | Positive rate for carbapenemase producers: 94.6% (87/92) for TSS and 92.4% (85/92) for COS at 30 min. Positive rate increased to 98.9% (91/92) for both media at 2 hours. Negative rate for non-carbapenemase producers: 100% for both media at both time points. "The results indicates no significant differences between TSS and COS." |
| Clinical Performance | | |
| Overall Agreement (Clinical) | High agreement with composite reference method. No explicit numerical criterion. | Overall (All samples): - Routine Subculture: 98.7% (451/457)
- Short Subculture: 98.0% (440/449)
Enterobacteriaceae: - Routine Subculture: 98.5% (388/394)
- Short Subculture: 97.7% (383/392)
Pseudomonas aeruginosa: - Routine Subculture: 100% (63/63)
- Short Subculture: 100% (57/57) |
| Sensitivity (Clinical) | High sensitivity (agreement for positive samples). No explicit numerical criterion. | Overall (Positive samples): - Routine Subculture: 99.6% (264/265) (1 false negative, KPC-producing Enterobacteriaceae)
- Short Subculture: 98.5% (257/261) (4 false negatives: 1 KPC, 1 NDM, 1 VIM, 1 OXA-48 from Enterobacteriaceae) |
| Specificity (Clinical) | High specificity (agreement for negative samples). No explicit numerical criterion. | Overall (Negative samples): - Routine Subculture: 97.4% (187/192) (5 false positives, all Enterobacteriaceae)
- Short Subculture: 97.3% (183/188) (5 false positives, all Enterobacteriaceae). |
| Reproducibility | High reproducibility across sites and operators. No explicit numerical criterion. | Routine Subculture: 98.2% (884/900)
Short Subculture: 99.1% (892/900) |
2. Sample size used for the test set and the data provenance
-
Test Set Sample Size:
- Analytical Reactivity (Challenge testing): 43 carbapenemase producers.
- Cross-reactivity: 93 non-carbapenemase producing strains (67 Enterobacteriaceae/P. aeruginosa, 26 other organisms).
- Agar Culture Media Compatibility Studies: 106 strains (92 carbapenemase producers, 14 non-carbapenemase producers).
- Clinical Studies: 457 strains (394 Enterobacteriaceae, 63 P. aeruginosa).
- Reproducibility: A panel of 10 organisms (9 Enterobacteriaceae + 1 P. aeruginosa), tested in triplicates for 5 days at 3 sites (total 900 measurements per subculture procedure).
-
Data Provenance: The document does not explicitly state the country of origin for the clinical or analytical data. It mentions "5 sites" for the clinical study and "each study site" for QC, implying a multi-site study, but locations are not specified. The study appears to be prospective as it involves the evaluation of the device on collected strains and controlled experiments (e.g., QC, challenge testing, clinical evaluation).
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The document does not mention the number or qualifications of experts used to establish the ground truth. The ground truth for the clinical study was established by a composite reference method consisting of three laboratory tests: carbapenem MIC, CLSI® Carba NP, and PCR for carbapenemase genetic markers. The "final composite reference result based on agreement of at least two of the three tests" does not explicitly involve human expert review for establishing "ground truth," but rather relies on the combined results of established laboratory methods.
For the reproducibility study, results were interpreted by "2 operators" but their qualifications are not specified beyond being "operators."
4. Adjudication method for the test set
For the clinical study, the adjudication method for the composite reference ground truth was: agreement of at least two of the three tests (carbapenem MIC, CLSI® Carba NP, and PCR).
For the reproducibility study, the results were interpreted by "2 operators" and their interpretations were then compared ("blinded to each other"), suggesting a form of comparative adjudication for reproducibility but not for establishing primary ground truth.
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
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done for this device. This is an in vitro diagnostic device (a laboratory test kit), not an AI-assisted imaging device or a device that directly supports human reader interpretation in a complex diagnostic task like radiology. Therefore, questions regarding "human readers improve with AI vs without AI assistance" are not applicable to this device type. The device provides a direct result (positive/negative for carbapenemase) which then informs downstream clinical decisions.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
This refers to an in vitro diagnostic device, not typically an "algorithm only" device in the context of imaging or clinical decision support AI. The device itself is a test kit where reactions occur and a visual color change is observed. The "performance" described is of the device as a whole. While human operators perform the test and interpret the "visual based on color change," the core "algorithm" is the biochemical reaction itself. The analytical and clinical studies assess the performance of this system (device + human interpretation). No separate "algorithm only" study is described because the "algorithm" here is the chemical reaction and visual readout, which inherently involves human observation.
7. The type of ground truth used
The ground truth used was a composite reference method comprised of:
- Carbapenem MIC (Imipenem, Meropenem, Ertapenem and/or Doripenem).
- CLSI® Carba NP (a standardized carbapenemase test).
- Carbapenemase genetic markers by Polymerase Chain Reaction (PCR).
This is a form of expert consensus based on the agreement of established laboratory tests, rather than, for example, pathology or outcomes data.
8. The sample size for the training set
The document does not explicitly describe a separate "training set". In the context of a 510(k) submission for an in vitro diagnostic device, often the manufacturer develops and refines the device, and then tests its performance on a "test set" (clinical and analytical studies) to demonstrate substantial equivalence. If any internal development/optimization data was used, it's not detailed or referred to as a "training set" in this regulatory submission. The reported studies are validation studies on a specific set of samples.
9. How the ground truth for the training set was established
Since a distinct "training set" is not described, the method for establishing its ground truth is also not detailed. Any internal development ground truth would likely have been established using similar reference methods to the ones described for the validation set.
§ 866.1640 Antimicrobial susceptibility test powder.
(a)
Identification. An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).