(33 days)
The Prodesse® ProAdeno®+ Assay is a multiplex Real Time PCR in vitro diagnostic test for the qualitative detection of human Adenovirus (HAdV) DNA isolated and purified from nasopharyngeal (NP) swab specimens obtained from individuals exhibiting signs and symptoms of acute respiratory infection. This test is intended for use to aid in the diagnosis of HAdV infections in humans in conjunction with other clinical and laboratory findings. The test detects, but does not differentiate, serotypes 1-51.
Negative results do not preclude HAdV infection and should not be used as the sole basis for treatment or other patient management decisions.
The ProAdeno+ Assay enables detection of human adenovirus and internal control nucleic acid. Nasopharyngeal swab specimens are collected from patients with signs and symptoms of a respiratory infection using a polyester, rayon or nylon tipped swab and placed into viral transport medium.
A Universal Internal Control (UIC) is added to each sample prior to nucleic acid isolation to monitor for inhibitors present in the specimens. The isolation and purification of the nucleic acids is performed using either a MagNA Pure LC Instrument (Roche) and the MagNA Pure Total Nucleic Acid Isolation Kit (Roche) or a NucliSENS® easyMAG™ System (bioMérieux) and the Automated Magnetic Extraction Reagents (bioMérieux).
The purified nucleic acids are added to ProAdeno+ Supermix included in the ProAdeno+ Assay Kit. The ProAdeno+ Supermix contains oligonucleotide primers, target-specific oligonucleotide probes and a Taq DNA polymerase. The primers are complementary to highly conserved regions of the HAdV hexon gene. The probes are dual-labeled with a reporter dye attached to the 5-end and a quencher dye attached to the 3'-end.
Amplification of DNA is performed in a Cepheid SmartCycler® II instrument. In this process, the probe anneals specifically to the template followed by primer extension and amplification. The ProAdeno+ Assay is based on Tagman chemistry, which utilizes the 5' - 3' exonuclease activity of the Taq polymerase to cleave the probe thus separating the reporter dye from the quencher. This generates an increase in fluorescent signal upon excitation from a light source. With each cycle, additional reporter dye molecules are cleaved from their respective probes, further increasing fluorescent signal. The amount of fluorescence at any given cycle is dependent on the amount of amplification products present at that time. Fluorescent intensity is monitored during each PCR cycle by the SmartCycler II instrument.
Here's a breakdown of the acceptance criteria and study information for the Prodesse® ProAdeno®+ Assay, based on the provided document:
Acceptance Criteria and Device Performance
The provided document describes a Special 510(k) Submission, which means the device (Prodesse® ProAdeno®+ Assay) is a modification of an already cleared device (K102952, ProAdeno™+ Assay). Therefore, the primary acceptance criteria revolve around demonstrating that the modifications did not negatively impact the performance established for the predicate device and that the device continues to meet the performance claims.
The acceptance criteria are implied by the "Potential Impact of Modification" and the "Verification/Validation Result" sections. The "Verification/Validation Result" column details how the device performance was shown to meet these implicit criteria.
| Acceptance Criteria (Implied) | Reported Device Performance (Verification/Validation Result) |
|---|---|
| For Outsourcing of Internal Control Stock Manufacturing (leading to minor changes in sequence): | |
| Ability of the device to detect target organisms at the limit of detection should not be affected. | The modified UIC did not affect the ability of the ProAdeno+ Assay to detect target organisms at the limit of detection as evinced by the results of Analytical Sensitivity, IC Interference, Extractor Equivalency, and Sample Stability studies. |
| Clinical performance of the ProAdeno+ Assay should not be affected. | Additionally, the results of a retrospective clinical comparison study demonstrated the modified ProAdeno+ Assay with UIC continues to meet the performance claims for the current ProAdeno+ Assay. |
| For Modified Positive Controls (provided "at use" concentration, no dilution necessary): | |
| The positive control's continued ability to monitor for global assay failures should not be affected at the increased testing concentration. | A Positive Control Effectiveness Study demonstrated the positive control's continued ability to monitor for global assay failures at the increased testing concentration. |
Study Details
The submission focuses on proving substantial equivalence after minor modifications to an already cleared device. Therefore, the studies conducted are primarily verification and validation studies to confirm that the modifications did not alter the fundamental scientific technology or performance.
2. Sample Sizes and Data Provenance
- Test Set Sample Size:
- Analytical Sensitivity, IC Interference, Extractor Equivalency, and Sample Stability studies: No specific sample sizes are provided in the document for these analytical studies.
- Retrospective Clinical Comparison Study: No specific sample size for the clinical comparison study is provided.
- Positive Control Effectiveness Study: No specific sample size is provided.
- Data Provenance:
- The "retrospective clinical comparison study" indicates retrospective data.
- The document does not specify the country of origin of the data for any of the studies.
3. Number of Experts and Qualifications for Ground Truth
- The document describes an in vitro diagnostic test (nucleic acid amplification assay). For such tests, "ground truth" is typically established through reference methods, gold standard assays (like sequencing or culture in some contexts), or clinical diagnosis. It does not typically involve human expert readers in the same way as imaging or pathology devices.
- Therefore, the concepts of "number of experts" and "qualifications of those experts" for establishing ground truth are not applicable in this context.
4. Adjudication Method
- Adjudication methods (e.g., 2+1, 3+1) are primarily relevant for studies involving human interpretation (e.g., radiology reads).
- Given this is an in vitro diagnostic (IVD) assay, and the ground truth is established analytically or through reference methods, an adjudication method in the human-reader sense is not applicable.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done.
- MRMC studies are typically for devices that assist human interpretation (e.g., CAD systems for radiologists). The Prodesse® ProAdeno®+ Assay is a standalone diagnostic test for detecting viral DNA, not an assistive tool for human readers.
6. Standalone Performance Study
- Yes, a standalone performance was done for the device. The entire submission is about the performance of the algorithm/assay itself in detecting Human Adenovirus (HAdV) DNA.
- The "Analytical Sensitivity, IC Interference, Extractor Equivalency, and Sample Stability studies" and the "retrospective clinical comparison study" all pertain to the standalone performance of the Prodesse® ProAdeno®+ Assay.
7. Type of Ground Truth Used
- For the analytical studies (Analytical Sensitivity, IC Interference, etc.), the ground truth would typically be established by known concentrations of target nucleic acid or reference methods for determining presence/absence of inhibitors or specific analytes.
- For the "retrospective clinical comparison study," the ground truth for HAdV infection in patient samples would likely have been established by a predicate device (ProAdeno™+ Assay) or another validated reference method for HAdV detection, but the document specifically states the comparison was to show the modified assay "continues to meet the performance claims for the current ProAdeno+ Assay," implying the predicate device's expected results served as a comparator for clinical performance. The details of the "gold standard" for the initial predicate device are not in this document.
8. Sample Size for the Training Set
- The document describes an assay (Real Time PCR in vitro diagnostic test), not a machine learning or AI-based device that requires a "training set" in the conventional sense.
- Therefore, the concept of a "training set sample size" is not applicable. The assay's performance is based on its chemical and biological reactions, not on data-driven learning.
9. How Ground Truth for the Training Set Was Established
- As explained above, there is no "training set" for this type of device.
§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.
(a)
Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.