(775 days)
The DiaSorin Molecular Simplexa™ Congenital CMV Direct is a real-time PCR assay intended for use on the LIAISON® MDX instrument for the in vitro qualitative detection of cytomegalovirus (CMV) from saliva swabs and urine from infants less than 21 days of age. Positive results from saliva are presumptive and should be confirmed with urine. The results of the Simplexa™ Congenital CMV Direct assay should be used in conjunction with the results of other clinical findings as an aid in the diagnosis of congenital CMV infection.
This test has not been cleared for screening of blood products for the presence of CMV or for use with samples other than urine and saliva swabs.
DiaSorin Molecular's Simplexa™ Congenital CMV Positive Control Pack is intended to be used as a control with the Simplexa Congenital CMV Direct kit for use on the LIAISON MDX instrument. This control is not intended for use with other assays or systems.
The Simplexa™ Congenital CMV Direct assay is a real-time PCR system that enables the direct amplification and detection of CMV DNA from either saliva swab or urine specimens without nucleic acid extraction. The system consists of the Simplexa™ Congenital CMV Direct Reaction Mix, the LIAISON® MDX (with LIAISON® MDX Studio Software), the Direct Amplification Disc (DAD) and associated accessories.
In the Simplexa™ Congenital CMV Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify CMV DNA. A well-conserved region of the CMV UL83 gene is targeted to identify CMV DNA. An internal control is used to detect PCR failure and/or inhibition.
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 document doesn't explicitly state quantitative acceptance criteria in a dedicated table format. However, the reported performance metrics imply the criteria for acceptance. For the purpose of this response, I'll infer the implicit acceptance criteria based on the demonstrated performance, generally implying "high agreement" for positive and negative cases.
| Metric (Implicit Acceptance Criteria) | Saliva Swab Performance (Retrospective) | Urine Performance (Retrospective) | Saliva Swab Performance (Prospective) | Urine Performance (Prospective) |
|---|---|---|---|---|
| Positive Percent Agreement (PPA) | 100.0% (95% CI: 93% - 100%) | 100.0% (95% CI: 93% - 100%) | 94.1% (95% CI: 73% - 99%) | 95.3% (95% CI: 85% - 99%) |
| Negative Percent Agreement (NPA) | 100.0% (95% CI: 97% - 100%) | 98.4% (95% CI: 94% - 100%) | 99.9% (95% CI: 100% - 100%) | 100.0% (95% CI: 100% - 100%) |
| Reproducibility (%CV) | Between 0.5% and 1.6% | Between 0.7% and 1.5% | N/A (not directly from this study) | N/A (not directly from this study) |
| Analytical Sensitivity (LoD) | 500 Copies/mL (AD-169, Towne, Merlin) in UTM | 400 Copies/mL (AD-169), 800 Copies/mL (Towne), 6400 IU/mL (Merlin) | N/A | N/A |
| Cross-Reactivity | 100% agreement (no cross-reactivity) | 100% agreement (no cross-reactivity) | N/A | N/A |
| Interference | 100% agreement (no interference) | 100% agreement (no interference) | N/A | N/A |
| Microbial Inhibition | 100% agreement (no inhibition) | 100% agreement (no inhibition) | N/A | N/A |
2. Sample Size and Data Provenance
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Retrospective Study:
- Saliva Swab: 173 total specimens (3 removed due to indeterminate CRM result, 170 analyzed)
- Urine: 173 total specimens
- Provenance: "collected during the clinical study", "stored at a central site", then distributed to three (3) laboratories. The document doesn't explicitly state the country of origin for these retrospective samples, though the testing sites were in the USA. These were pre-selected positive and negative samples based on routine laboratory results.
-
Prospective Study:
- Saliva Swab: 1,859 initially collected, 6 deemed ineligible, resulting in 1,853 analyzed specimens.
- Urine: 1,656 initially collected, 32 deemed ineligible, resulting in 1,624 analyzed specimens.
- Provenance: Prospectively collected (frozen and/or fresh) from ten (10) collection sites across the USA and two (2) collection sites outside the USA. Testing was performed at six (6) testing sites located in the USA.
3. Number of Experts and Qualifications
The document states that a "Composite Reference Method (CRM)" was used, which involved "two (2) validated PCR followed by bi-directional sequencing assays." One (1) central laboratory performed these comparator assays.
- The document does not specify the number of experts used to establish the ground truth or their specific qualifications (e.g., radiologist with 10 years of experience). It relies on the validation of the PCR and bi-directional sequencing assays as the basis for ground truth, implying that these are established and reliable laboratory methods.
4. Adjudication Method
The ground truth for the clinical agreement studies (both retrospective and prospective) was established via a "Composite Reference Method (CRM)".
This CRM "utilized two (2) validated PCR followed by bi-directional sequencing assays. A sample had a final sequencing result of 'Detected' if one or both sequencing results were 'Detected'. Conversely a sample had a final sequencing result of 'Not Detected' if both results were 'Not Detected'." This implies a form of 2+0 or 1+1 adjudication model where if either reference method detects CMV, the sample is considered positive, and both must be negative for the sample to be considered negative.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, an MRMC comparative effectiveness study was not done. This study focuses on the diagnostic performance of the device itself against a laboratory-based reference method, not on how human readers/clinicians improve with AI assistance.
6. Standalone (Algorithm Only) Performance
Yes, a standalone performance evaluation was done. The Simplexa™ Congenital CMV Direct assay is a real-time PCR assay and its performance was evaluated directly against the Composite Reference Method (CRM) without human-in-the-loop assistance. The reported PPA and NPA values represent the algorithm's standalone performance.
7. Type of Ground Truth Used
The ground truth used was expert consensus on laboratory results, specifically based on a "Composite Reference Method (CRM) utilized two (2) validated PCR followed by bi-directional sequencing assays." This is a highly robust and objective form of ground truth for nucleic acid detection devices, often considered a gold standard in molecular diagnostics.
8. Sample Size for the Training Set
The document does not provide information on the sample size used for the training set. This is typical for submissions of this nature, where the focus is on the validation of the final device/algorithm using a separate, independent test set, rather than details of the developmental (training) phase.
9. How the Ground Truth for the Training Set Was Established
The document does not provide information on how the ground truth for the training set was established, as details about the training phase are not included in this summary.
§ 866.3181 Cytomegalovirus nucleic acid detection device for congenital cytomegalovirus infection.
(a)
Identification. A cytomegalovirus nucleic acid detection device for congenital cytomegalovirus infection is an in vitro diagnostic device intended for the qualitative detection of cytomegalovirus DNA in clinical samples from newborn babies to aid in the diagnosis of congenital cytomegalovirus infection. Negative results do not preclude infection and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results should be interpreted with consideration of other clinical information and laboratory findings and should not be used as the sole basis for treatment or other patient management decisions.(b)
Classification. Class II (special controls). The special controls for this device are:(1) 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, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) to be tested.
(ii) A detailed device description, including all device components, instrument requirements, ancillary reagents required but not provided, and an explanation of the methodology, including all pre-analytical methods for specimen processing.
(iii) Performance characteristics from analytical and clinical studies required under paragraphs (b)(2)(ii) and (iii) of this section.
(iv) A detailed explanation of the interpretation of results and criteria for validity of results.
(v) A limiting statement that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(vi) As applicable, a limiting statement and specific sample collection recommendations to indicate that breast milk can result in false positive results for saliva samples if samples are collected less than 1 hour after breastfeeding. Sample collection a minimum of 1 hour from breastfeeding must be recommended.
(vii) Detailed instructions for use that minimize the risk of generating a false result.
(2) Design verification and validation must include:
(i) Detailed device description documentation, including methodology from obtaining sample to result, design of primer/probe sequences, rationale for sequence 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 characterization of the cutoff, analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, instrument and method carryover/cross contamination, and sample stability and handling.
(iii) Detailed documentation from a clinical study documenting sensitivity and specificity of the device; if the number of positive samples in the clinical study is insufficient to properly estimate device sensitivity, additional pre-selected positive samples must be evaluated to supplement the study. Clinical study subjects must be consistent with the intended use population (
i.e., infants younger than 21 days of age), and device results must be compared to FDA-accepted comparator methods. Documentation from the clinical study must include the clinical study protocol, the clinical study report, testing results, and results of all statistical analyses.(iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software.