(328 days)
The Synovasure Alpha Defensin Lateral Flow Test Kit is a qualitative visually read immunochromatographic assay for the detection of human host response proteins, Alpha Defensins 1-3, in the synovial fluid of adults with a total joint replacement who are being evaluated for revision surgery. The Synovasure Alpha Defensin Lateral Flow Test Kit results are intended to be used in conjunction with other clinical and diagnostic findings as an aid in the diagnosis of periprosthetic joint infection (PJI). The Synovasure Alpha Defensin Lateral Flow Test Kit is not intended to identify the etiology or severity of a PJI.
The Synovasure Alpha Defensin Control Kit is used in the Synovasure Alpha Defensin Lateral Flow Test Kit as assayed quality control samples to monitor performance and reliability of the Synovasure Alpha Defensin Lateral Flow Test Kit.
The Synovasure Alpha Defensin Lateral Flow Test Kit (Synovasure LFT) is an immunoassay for the detection of alpha defensin levels in the synovial fluid of patients with a potential PJI. Antibodies specific to alpha defensin bind host alpha defensin in the synovial fluid, become immobilized on the lateral flow test strip, and are detected as a colored line due to the use of a colloidal gold reporter.
Synovasure Alpha Defensin Lateral Flow Test Kit contains two sub components:
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- Synovasure Alpha Defensin Lateral Flow Test Device
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- Synovasure Lateral Flow Sample Prep Assembly
The Synovasure Lateral Flow Sample Prep Assembly further contains
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- One Synovasure Dilution Buffer Bottle
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- One Sample Cup
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- Two Microsafe Tubes
The Synovasure Alpha Defensin Lateral Flow Test Device is a cassette that includes a reagent strip. Each cassette contains a reagent strip with all the critical components for the assay.
The Synovasure Alpha Defensin Lateral Flow Test Kit is accompanied by the Synovasure Alpha Defensin Control Kit. The Synovasure Alpha Defensin Control Kit further contains
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- Synovasure Alpha Defensin Positive Control
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- Synovasure Alpha Defensin Negative Control
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- Synovasure Control Reconstitution Bottle
The positive control contains 0.25 mL of 16 µg/mL alpha defensin in synthetic synovial fluid and the negative control contains 0.25 mL of synthetic synovial fluid.
Additional materials required but not provided include
- Timer
Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The core clinical acceptance criteria for the Synovasure Alpha Defensin Lateral Flow Test Kit's performance in diagnosing periprosthetic joint infection (PJI) are related to its sensitivity and specificity.
| Acceptance Criteria (Clinical Performance) | Reported Device Performance (Prospective Data) |
|---|---|
| Sensitivity: | Sensitivity: 89.5% (95% CI: 78.5-96.0%) |
| >90% with lower confidence bound >85% | |
| Specificity: | Specificity: 94.8% (95% CI: 91.2-97.2%) |
| >90% with lower confidence bound >90% |
Notes on Acceptance Criteria Met: The device met the specificity criterion in the prospective study (94.8% with 91.2% LCB, exceeding the >90% and >90% LCB requirement). The device did not fully meet the sensitivity criterion in the prospective study (89.5% with 78.5% LCB), as the lower confidence bound of 78.5% is below the required >85%. However, the sponsor appears to have supplemented this with retrospective data to support overall performance for the De Novo classification.
2. Sample Sizes and Data Provenance
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Test Set Sample Size:
- Prospective Study: 305 synovial fluid samples.
- Retrospective Study: 65 fresh remnant synovial fluid samples.
- Total Clinical Test Set: 370 samples (305 prospective + 65 retrospective).
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Data Provenance:
- Country of Origin: United States (Prospective study conducted at 3 US medical centers).
- Retrospective/Prospective: Both.
- The main clinical study was a prospective study.
- A retrospective collection of fresh remnant samples was used to supplement the prospective data and reach a target of at least 100 positive specimens.
3. Number of Experts and their Qualifications for Ground Truth
- Number of Experts: A two-physician panel was used to adjudicate the final MSIS status for prospective data. A third physician was consulted to resolve discrepant opinions.
- Qualifications of Experts: The document states "two-physician panel" and "third physician," implying medical doctors, but does not specify their specialties (e.g., orthopedic surgeons, infectious disease specialists) or years of experience.
4. Adjudication Method for the Test Set
- Adjudication Method: 2+1 adjudication.
- The "final status determination was adjudicated by a two-physician panel, with discrepant opinions being resolved by consultation of a third physician."
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
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Was an MRMC study done?: No, an MRMC comparative effectiveness study was not mentioned or conducted as this is a qualitative visually-read lateral flow immunoassay device, not an AI or imaging-based diagnostic where human reader performance would be a primary variable. The output is a visual line or no line, reducing inter-reader variability compared to complex interpretations.
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Effect Size of Human Readers with AI vs. without AI assistance: Not applicable, as no AI assistance is involved in the interpretation of this device.
6. Standalone Performance Study (Algorithm Only)
- Was a standalone performance study done?: Not applicable in the context of an algorithm. This device is a manual, visually-read lateral flow immunoassay. Its "standalone performance" is essentially its analytical and clinical performance as a device read directly by an operator, which is what the provided sensitivity and specificity figures represent. There is no separate "algorithm" for this product that would operate without human interaction (as it is a visually-read test).
7. Type of Ground Truth Used
- Type of Ground Truth: Expert Consensus using established clinical criteria.
- The ground truth for Periprosthetic Joint Infection (PJI) was established using the Musculoskeletal Infection Society (MSIS) criteria.
- For the prospective study, the final MSIS status was adjudicated by a two-physician panel with a third physician for conflicts.
- For the retrospective samples, the ground truth was based on a "status determination based positive confirmation of three minor MSIS criteria (neutrophil %, positive culture, and WBC count)."
8. Sample Size for the Training Set
- Training Set Sample Size: The document does not explicitly mention a separate "training set" for an algorithm or model. This is consistent with the nature of a lateral flow immunoassay, which does not typically involve machine learning or AI models that require distinct training sets. The studies described are performance validation studies.
9. How the Ground Truth for the Training Set was Established
- Ground Truth Establishment for Training Set: Not applicable, as no distinct training set for an algorithm or machine learning model is described for this device.
§ 866.3230 Device to detect and measure non-microbial analytes to aid in the detection and identification of localized human infections.
(a)
Identification. A device to detect and measure non-microbial analytes to aid in the detection and identification of localized human infections is identified as an in vitro diagnostic device intended for the detection and qualitative measurement, quantitative measurement, or both of one or more non-microbial analytes in human clinical specimens to aid in the assessment, identification, or both of a localized microbial infection 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) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of human specimens; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) An intended use with a detailed description of what the device detects and measures, the type of results provided to the user, the sample type, whether the measure is qualitative and/or quantitative, the clinical indications for the test use, and the specific population(s) for which the device is intended.
(ii) A detailed description of the performance characteristics of the device for all intended specimen types from the analytical and clinical studies (as applicable) required under paragraphs (b)(3)(ii) and (iii) of this section.
(iii) A detailed explanation of the interpretation of results, including acceptance criteria for evaluating the validity of individual runs (
e.g., assessment of internal and/or external quality controls, as applicable).(iv) The following limiting statements:
(A) A statement that a negative test result does not preclude the possibility of infection;
(B) A statement that the test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) A statement that consistent device performance is dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and
(D) A statement that details any limitations associated with the samples, as appropriate (
e.g., collected on the day of admission to the intensive care unit).(3) Design verification and validation must include the following:
(i) A detailed device description, including as appropriate, all device parts; control elements incorporated into the test procedure; instrument requirements; reagents required but not provided; and the principle of device operation and test methodology, including all preanalytical methods for the processing of specimens and the methodology from obtaining a sample to the result; design of primer/probe sequences; rationale for target analyte selection; and computational path from collected raw data to reported result (
e.g., how collected raw signals are converted into a reported result).(ii) Detailed documentation of analytical studies including analytical sensitivity (Limit of Detection, Limit of Quantitation, and Limit of Blank), inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross-contamination, specimen stability, within-lab precision, reproducibility, and linearity, as applicable.
(iii) Detailed documentation and results either from a clinical study, that includes prospective (sequentially collected) samples for each intended specimen type that are representative of the intended use populations and, when determined to be acceptable by FDA, additional characterized clinical samples; or, when determined to be acceptable by FDA, an equivalent sample set. The clinical study must compare the device performance to results obtained from an FDA-accepted reference method and/or FDA-accepted comparator method, as appropriate. Documentation from the clinical studies must include the clinical study protocol (
e.g., the predefined statistical analysis plan), clinical study report, testing results, and results of all statistical analyses.(iv) An evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and sex distribution) similar to the intended use population of the device.(v) Documentation of an appropriate end user device training program that will be offered as part of efforts to mitigate the risks of false results, failure to operate the device correctly, and failure to interpret test results correctly.
(vi) An appropriate risk mitigation strategy to ensure that the device does not prevent any other device(s) with which it is indicated for use, including incorporated device(s), from achieving their intended use (
e.g., safety and effectiveness of the functions of the indicated device(s) remain unaffected).(vii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.